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Pharmaceutical Approvals Monthly

From the editors of

“ The Pink Sheet”

R E G U L AT O R Y A F FA I R S & C L I N I C A L D E V E L O P M E N T Vol. 16, No. 3

MARCH 2011

TOP STORIES

PIPELINE UPDATES

Drug Review Profile Jevtana Review Shows Power Of A Survival Advantage Sanofi-Aventis’ hormone-refractory prostate cancer therapy Jevtana sprinted through FDA approval despite toxicity issues. But Jevtana also offered the first survival advantage shown in docetaxel-experienced HRPC. Survival data, unmet medical need, and FDA’s ability to require studies of a lower dose that could reduce toxicity enabled the expedited review . . . . . . . . . . . . . . . . . . 33

R&D News How A Biomarker Revived Synta’s Cancer Drug Elesclomol Two years ago, Synta’s elesclomol flamed out in Phase III and GSK walked out on its partnership. Today the drug is back in Phase II – thanks to Synta’s relentless investigation into why the trial failed. The firm found patients with high levels of the enzyme LDH died earlier; high LDH is linked to hypoxia, and elesclomol has less activity in low oxygen conditions. A cheap LDH test is already widely available, allowing more targetted trial enrollment . . . . . . . . . . 22

FDA Policy Changes To REMS Policy? The number of products approved with REMS could plunge if FDA adopts a draft guidance proposing to make Medication Guides “in most cases” a part of REMS only when elements to ensure safe use are also required . . . . . . . . . . . . . . . . . . 15

Table of Contents > 3

Efficacy Supplement Numbers On The Rise As Industry Braces For Patent Cliff SHIRLEY HALEY s.haley@elsevier.com

rug makers are squeezing more new and expanded indications out of approved drugs to compensate for patent expiries and the lagging pace of new drug approvals, according to an analysis from the Tufts Center for the Study of Drug Development. The findings provide quantification of the general perception that as innovation disappoints and the patent cliff approaches, pharmaceutical companies have been focusing on lifecycle management for existing brands. The total number of efficacy supplement approvals was up 17% in the period of 2004-2009 over the 1998-2003 period, CSDD reports. More than half of the new drugs approved between 1998 and 2009 had more than one supplemental approval, and one in eight of those had six, including a small number (9%) gained through a new NDA (which would be needed for applications with a major new use with extensive clinical data or formulation work). The report is derived from an examination of 889 efficacy supplements using information from the center’s own database along with data from FDA. Continued > Page 4

FDA PERFORMANCE TRACKER User Fee Goals For Recently Announced NDA/BLA Submissions .........................................27 NDAs/BLAs With User Fee Goals In February, March, April ..................28 Recently Announced “Complete Response” Letters...............................18 New Molecular Entities Approved In 2011 .................................14 Biologics Approved In 2011 ..............14

Recent Risk Evaluation & Mitigation Strategies ..........................16 2011 FDA Advisory Committee Recommendations ..............................18 February Full Approvals.....................10 February Supplemental Approvals ................................................ 6 February Abbreviated Approvals ................................................ 11

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The Parenteral Drug Association presents the...

2011 PDA Pharmaceutical Ingredient Supply Chain Workshop End-to-End Supply Chain Security Co-sponsored by

and Member

June 6-7, 2011 Bethesda North Marriott | Bethesda, Maryland The 2011 PDA Pharmaceutical Ingredient Supply Chain Workshop co-sponsored by IPEC-Americas and RX-360 will expound upon how high quality, safe and effective drug products and drug ingredients depend upon a consistent supply of high quality ingredients and starting materials. The recent surge in global cooperation and efforts toward harmonization of Good Manufacturing and Distribution Practices (GMPs and GDPs) and controls pertaining to the Supply Chain stresses the need to secure the entire ingredient manufacturing and distribution chain to ensure quality and safety of medicines for our patients. Through a series of plenary sessions and breakout sessions, the program will provide participants the opportunity to: • Hear directly from senior FDA personnel on current regulatory situations • Share improvements in programs and technology • Identify any barriers and associated actions to enable implementation of good solutions The PDA Training and Research Institute (PDA TRI) will host a training course immediately following the workshop on June 8th on Developing a Robust Supplier Management Process.

www.pda.org/supplychain2011 CONFERENCE June 6-7

EXHIBITION June 6-7

COURSE June 8

Pharmaceutical Approvals Monthly ‘‘Pharmaceutical Approvals

FOUNDED 1996

THE NEWS THIS MONTH PharmaceuticalAppovals.ElsevierBI.com

PIPELINE UPDATES Editorial oﬃce: 5635 Fishers Lane Suite 6000 Rockville, MD 20852 PHONE 240-221-4500 FAX 240-221-4400

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EDITOR IN CHIEF Chris Morrison c.morrison@elsevier.com

MANAGING EDITOR Mary Jo Laﬄer 240-221-4445 m.laﬄer@elsevier.com

• How A Biomarker Revived Synta’s Cancer Drug Elesclomol . . . . . . . . .22 • Vertex Offers Cystic Fibrosis Patients A Chance To Breathe Easier . . 19 • Ventrus Could Start Pivotal Trial For Rx Hemorrhoid Therapy Mid-Year . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

NEW DRUG REVIEWS • Efficacy Supplement Numbers On The Rise As Industry Braces For Patent Cliff . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . cover

SENIOR EDITOR Bridget Silverman 240-221-4447 b.silverman@elsevier.com

VICE PRESIDENT OF CONTENT David Cassak

COMPOSITION Ting Yang

VICE PRESIDENT OF CORPORATE SERVICES Scott Breed

• Uncertain Future For Otelixizumab In Type 1 Diabetes After Phase III Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

VICE PRESIDENT OF COMMERCIAL Deanna Flanick

• Merck KGaA Pins Cladribine Hopes On Ongoing Studies After “Complete Response” Letter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

BUSINESS DEVELOPMENT Joshua Berlin

• Regeneron Files BLA For VEGF Trap-Eye In Wet AMD; Second Filing Anticipated This Year . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26

MARKETING Mike Fergus, Director Allison Isett CORPORATE SALES Tom DePaul John Lucas COMMERCIAL SALES Ken May, Director

PRESIDENT Gerard J. Stoia

R&D NEWS

FDA POLICY • MedGuide-Only REMS Will Be The Exception, Not The Norm, As FDA Relaxes Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

DRUG REVIEW PROFILE © 2011 F-D-C Reports, Inc., an Elsevier company. All rights reserved. Reproduction, photocopying, storage or transmission by magnetic or electronic means is strictly prohibited by law. For bulk reprints of Elsevier Business Intelligence articles contact: Ken May, Elsevier, at 914-332-1419. Authorization to photocopy items for internal use is granted by Elsevier Business Intelligence, when the fee of $25.00 per copy of each page is paid directly to Copyright Clearance Center, 222 Rosewood Dr., Danvers, MA 01923, 978-750-8400. The Transaction Reporting Service fee code is: 1530-6232/11 $0.00 + $25.00. Violation of copyright will result in legal action, including civil and/or criminal penalties, and suspension of service.

• The Lesson Of Jevtana: With A Survival Advantage, All Things Are Possible . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33 • Why Survival Is The Fittest Endpoint For HRPC: The Problem With Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36 • Jevtana Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35 • Jevtana Clinical Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Pharmaceutical Approvals Monthly (ISSN 1530-6232) is published monthly by Elsevier Business Intelligence, 685 Route 202/206, Bridgewater, NJ 08807. The annual subscription rate is (1) $975 or (2) $540 for additional copies mailed in the same envelope with $975 subscription. Periodicals Postage paid at Rockville, MD and at additional mailing offices. POSTMASTER: Send address changes to Elsevier Business Intelligence, Attn: Pharmaceutical Approvals Monthly, 685 Route 202/206, Bridgewater, NJ 08807. In Japan, Elsevier Science KK is the exclusive subscription representative for Pharmaceutical Approvals Monthly. E-mail: jp.bkinfo@elsevier. com. URL: www.elsevierjapan.com. Telephone: 03-3589-6370. Fax: 03-3589-6371.

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March 2010 | 3

Pharmaceutical Approvals Monthly

Efficacy Supplement Numbers Up... CONTINUED FROM COVER

The results are consistent with the perceived emphasis on adding new and expanded indications to workhorse drugs to keep up the revenue stream, and some observers fear that the resulting R&D could be coming at the expense of badly needed investments in new discoveries. Drug makers are working to find the right balance between new indications and novel compounds, CSDD asserts in the report. It makes good business sense to develop new drugs with lifecycle management in mind. Moreover, in some therapeutic areas, drug makers tend to seek approvals in a stepwise fashion, testing the waters first in an indication that might not provide the biggest potential marketing opportunity but because it offers another advantage, perhaps orphan protection or an easier regulatory path because of unmet need. All new and expanded indications are not incremental, though CSDD didn’t assign value to the supplemental applications in its analysis.

Pediatric Indications Drove Approvals Not surprisingly, given the emphasis placed on studying drugs in pediatric populations by Congress and the federal government during the years examined in the CSDD study, pediatric indications drove approvals.

The emphasis and incentives given to pediatric research accounts for the large increase in those approvals. Comparing the 1998-2003 period to the 2004-2009 period, the number of pediatric indication approvals grew by 107%. They represented 26% of approvals for new or modified indications when the overall period of 1998–2009 is considered. The number of pediatric supplements likely will grow even larger if FDA begins to use its pediatric studies authority to require research on approved drugs that are being used offlabel in children (“Pediatric Studies In Off-label Indications Needed, Advisory Committee Tells FDA,” “The Pink Sheet,” Feb. 7, 2011).

Two Therapeutic Categories Grabbed 41% Two therapeutic categories dominated the supplemental indications, with anti-infectives and central nervous system drugs amounting to 21.3% and 20%, respectively, of all new or modified indication approvals from 1998 to 2009.

4 | March 2011

Elsevier Business Intelligence

Supplement Trends Most new drugs approved from 1998-2009 have had more than one supplemental approval, and one in eight of those had six. • The number of efficacy supplements was up 17% in the period of 2004-2009 over 1998-2003. • Pediatric supplements were the largest source for the rise. • Central nervous system drugs and anti-infectives had the most supplemental indications. • The average approval time for a supplement improved 21% from 1998-2003 to 2004-2009.

Immunologic, gastrointestinal, pain, endocrine and respiratory drugs had shares in the single digits. Exploring the CNS category further, CSDD found that while they constituted only 12% of the original approvals among drugs originally approved between 1963 and 2009, they evergreened nicely, accounting for 20% of add-on indications overall. In fact, CNS drugs dominated the period 2004-2009 with 107 new or modified indications, or 23.8% of the total of 449 granted during those years. Anti-infectives had 19.2% of those approvals and antineoplastics had 15.1%. It was anti-infectives, however, that dominated the earlier period, 1998-2003, with 89 of 374 approvals, or 23.8%. CNS drugs accounted for 15.5% and cancer drugs had 11.2% of the total. Cardiovascular drugs also had a good run, accounting for 15.3% of approvals overall: 18.2% in the 1998-2003 timeframe and 12.9% in the 2004-2009 period.

Approval Times Vary By Type And Class Average approval times through the span of years studied varied from 8.7 months for cancer drugs to 13.6 months for CNS drugs, a difference of 56%, CSDD points out. Between the two timeframes, approval times increased for cardiovascular, endocrine, immunologic and respiratory drugs while they went down for pain, anti-infective, cancer, CNS and gastrointestinal drugs. In almost every therapeutic class, the average time is longer than the median, the middle number, hinting that the average might have been made longer by outliers that had an extended review. Within therapeutic areas, the largest increase in average approval time was for immunologics (up 22%), while the largest decrease was for the anti-infective class (down 33%).

Pharmaceutical Approvals Monthly

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Taking all applications for a new or modified indication together, however, the average approval time improved by 21% when comparing the two timeframes: from 13.6 months to 10.8 months.

Average approval times for supplements improved by 21% between the study periods. The difference is particularly noticeable in pediatric indications, where approval time dropped from 13 months to 9.3 months. It takes almost 10 years after a new drug approval for the first new or modified indication to appear via any supplemental pathway, and that time span hasnâ&#x20AC;&#x2122;t changed over the years. The average time between new drug approval and first new or modified indication is 9.2 years; the mean is 7.6, another sign that sometimes an extended review skews the average. Comparing supplements, new NDAs and pediatric indications, the average time from original approval to a new pediatric indication was 2.9 years longer than for other supplemental approvals and 4.2 years longer than for NDA new indication approvals. Overall, the NDA approach took an average of 7.3 years, an sNDA for a new indication took 8.6 years and a pediatric indication took 11.5 years from original approval to approval of a new or expanded indication.

Managing The Novartis CV Franchise A classic example of a drug maker attempting to balance innovation with lifecycle management is the Novartis AG cardiovascular portfolio. During a November 2008 R&D day, the company put its company-wide ratio of NME development to lifecycle management projects at 39%/61%. For years, the Swiss firm has been preparing for the loss of its mature CV brands. Lotrel went generic in 2007, and Diovan (valsartan) starts losing European protections this year and U.S. protections in mid-2012 (â&#x20AC;&#x153;The Heart Of A Pipeline: Can Novartis Keep The Cardio Portfolio Beating?â&#x20AC;? Pharmaceutical Approvals Monthly, December 2008). To compensate, Novartis launched Tekturna (aliskiren), marketed as Rasilez in the EU, a first-in-class rennin inhibitor, in 2007. Growth was slow at first, but the ship appears to have righted, and the company is confident the blood pressure drug will follow in Diovanâ&#x20AC;&#x2122;s blockbuster footsteps. After all, it took Diovan five years to ring the bell (â&#x20AC;&#x153;Tekturna Will Track Diovanâ&#x20AC;&#x2122;s Steady Growth To Blockbuster Status â&#x20AC;&#x201C; Novartis,â&#x20AC;? â&#x20AC;&#x153;The Pink Sheet,â&#x20AC;? Feb. 2, 2009). Meanwhile, the company has a portfolio of rational combinations based on Tekturna either approved or in the

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works, with the aim of extending its use in the same way it has extended and amplified sales of Diovan. Even with flattening sales, the Diovan franchise brought in almost $18 billion over 2008-2010. Exforge, a fixed-dose combination of valsartan and Pfizer Inc.â&#x20AC;&#x2122;s amlodipine approved in July 2008 added another $900 billion in 2010. And though aliskiren isnâ&#x20AC;&#x2122;t expected to be able to plug the Diovan hole, that franchise is on track to hit $1 billion in sales faster than Diovanâ&#x20AC;&#x2122;s pace after all, with $912 million booked so far, including the lackluster $40 million in 2007. At the end of fiscal 2010, the Novartis hypertension portfolio had $7.395 billion in sales, up 6% over $6.974 billion in fiscal 2009.

Novartisâ&#x20AC;&#x2122; cardiovascular portfolio is a classic example of lifecycle management. Part of that overall growth came from fixed-dose combinations of aliskiren with its older brands; Valturna (valsartan/aliskiren) won U.S approval in September 2009, and Tekamlo (aliskiren/ amlodipine) was approved in the U.S. in August 2010, while European advisors voted in favor of approving it as Rasilamlo in Europe Feb. 18 (â&#x20AC;&#x153;EU Recommends Novartisâ&#x20AC;&#x2122; CV Combo Rasilamlo,â&#x20AC;? â&#x20AC;&#x153;The Pink Sheetâ&#x20AC;? DAILY, Feb. 18, 2011). The aliskiren franchise includes a fixed-dose combination with hydrochlorothiazide (Tekturna HCT/Rasilez HCT), as well. Amturnide, a triple combination of aliskiren, amlodipine and hydrochlorothiazide, was approved by FDA in December 2009 and has been submitted for approval in the EU, with authorization anticipated this year. In addition to gaining approval for combinations, Novartis has also used supplemental approvals to expand the uses of the drugs. The most success has been with Diovan, which has had four efficacy supplements since its initial 2001 approval, including approval for use post-myocardial infarction, for heart failure in ACE-intolerant patients and pediatric use for hypertension. SAVE THE DATE! Windhoverâ&#x20AC;&#x2122;s 21st Annual

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March 2011 | 5

Pharmaceutical Approvals Monthly

Elsevier Business Intelligence

February Supplemental Approvals Chart lists efficacy supplements and labeling supplements selected by the editors of “Pharmaceutical Approvals Monthly.” This is not a comprehensive list of all supplemental approvals.

Product and Sponsor

Date Approved (Application No.)

Change

Drug Abilify Aripiprazole Otsuka

Expands indication to include maintenance treatment of bipolar I disorder as an 2/16/2011 adjunct to lithium or valproate (21-436/029) (21-713/021) (21-729/014) (21-866/016)

Actos Pioglitazone Takeda

Updates safety information in labeling to make warnings about possible hepatic 2/3/2011 effects more prominent and present precaution against use to treat type 1 (21-073/035) diabetics to a more prominent place at the top of labeling as an “Important Limitation of Use”

Adcirca Tadalafil Eli Lilly

Revises indication to note that the studies establishing effectiveness included predominantly patients with NYHA Functional Class II-III symptoms and etiologies of idiopathic or heritable pulmonary arterial hypertension (61%) or PAH associated with connective tissue diseases (23%)

Avandamet Metformin/rosiglitazone GlaxoSmithKline

Amends boxed warning and MedGuide with new safety information pertaining to 2/3/2011 the potential for an increased risk of ischemic cardiovascular events associated (21-410/026) with the use of rosiglitazone; revises indication to limit use to patients who either are already taking rosiglitazone or are unable to achieve adequate glycemic control on other diabetes medications and, in consultation with their health care provider, have decided not to take pioglitazone-containing medicines for medical reasons

Avandaryl Glimepiride/ rosiglitazone GlaxoSmithKline

Amends boxed warning and MedGuide with new safety information pertaining to 2/3/2011 the potential for an increased risk of ischemic cardiovascular events associated (21-700/010) with the use of rosiglitazone; revises indication to limit use to patients who either are already taking rosiglitazone or are unable to achieve adequate glycemic control on other diabetes medications and, in consultation with their health care provider, have decided not to take pioglitazone-containing medicines for medical reasons

Avandia Rosiglitazone GlaxoSmithKline

Amends boxed warning and MedGuide with new safety information pertaining to 2/3/2011 the potential for an increased risk of ischemic cardiovascular events associated (21-071/038) with the use of rosiglitazone; revises indication to limit use to patients who either are already taking rosiglitazone or are unable to achieve adequate glycemic control on other diabetes medications and, in consultation with their health care provider, have decided not to take pioglitazone-containing medicines for medical reasons

Avelox Moxifloxacin Bayer HealthCare

Adds new safety information for all fluoroquinolone products pertaining to the risk of fluoroquinolone-associated myasthenia gravis exacerbation, which is a potentially life-threatening event and may require ventilatory support

2/25/2011 (21-085/047) (21-277/041)

Brovana Arformoterol Sunovion

Provides for REMS required for the long-acting beta agonist class to ensure the benefits outweigh the risk of serious asthma outcomes, including asthmarelated death, intubations and hospitalizations

2/1/2011 (21-912/012)

6 | March 2011

2/8/2011 (22-332/003)

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Pharmaceutical Approvals Monthly

Date Approved (Application No.)

Product and Sponsor

Change

Celebrex Celecoxib Pfizer

Removes indication for reducing the number of adenomatous colorectal polyps in familial adenomatous polyposis

2/4/2011 (20-998/033) (21-156/003)

Cipro Ciprofloxacin Bayer HealthCare

2/25/2011 (19-537/075) (19-847/047) (19-857/054) (20-780/033) (21-473/028)

Diabinese Chlorpropamide Pfizer

Adds language regarding hepatic injury to adverse reactions, noting that hepatic porphyria and disulfiram-like reactions have been reported

2/1/2011 (11-641/066)

Factive Gemifloxacin Cornerstone

2/25/2011 (21-158/018)

Floxin Ofloxacin Ortho McNeil Janssen

2/25/2011 (19-735/061)

Glucotrol Glipizide Pfizer

Adds language regarding hepatic injury to adverse reactions, noting that hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas

2/7/2011 (17-783/021) (20-329/025)

Glynase Glyburide Pfizer

Adds language regarding hepatic failure to adverse reactions, noting that 2/7/2011 hepatic porphyria and disulfiram-like reactions have been reported with (20-051/017) sulfonylureas; however, hepatic porphyria has not been reported with glyburide and disulfiram-like reactions have been reported very rarely

Heparin Sodium Injection Baxter

Adds safety information regarding heparin-induced thrombocytopenia (with or without thrombosis)

2/23/2011 (17-037/168)

Humatrope Somatropin recombinant Lilly

Revises warnings and precautions to add that new onset type 2 diabetes mellitus has been reported in patients

2/23/2011 (19-640/084)

Intuniv Guanfacine Shire

Broadens indication to provide for use as adjunctive treatment with long-acting 2/25/2011 oral psychostimulants for the treatment of attention deficit hyperactivity (22-037/002) disorder

Metaglip Glipizide/metformin Bristol-Myers Squibb

Adds language regarding hepatic injury to adverse reactions, noting cholestatic 2/1/2011 and hipatocellular forms of liver injury accompanied by jaundice have been (21-460/009) reported rarely in association with Glipizide, a sulfonylurea

Micronase Glyburide Pfizer

Adds language regarding hepatic injury to adverse reactions, noting cholestatic 2/1/2011 jaundice and hepatitis may occur rarely, which may progress to liver failure (17-498/030)

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March 2011 | 7

Pharmaceutical Approvals Monthly

Elsevier Business Intelligence

Product and Sponsor

Change

Date Approved (Application No.)

Multihance Multipack Gadobenate dimeglumine Bracco

Adds new safety information to labeling pertaining to the risk of nephrogenic systemic fibrosis associated with the use of gadolinium-based contrast agents

2/16/2011 (21-358/008)

Levaquin Levofloxacin Ortho McNeil Janssen

2/25/2011 (21-721/025) (20-635/064) (20-634/058)

Noroxin Norfloxacin Merck

2/25/2011 (19-384/056)

Onglyza Saxagliptin Bristol-Myers Squibb

Expands labeling to include study data demonstrating safety and efficacy in patients with moderate to severe renal impairment or end-stage renal disease and showing saxagliptin plus metformin to be similar to glipizide plus metformin in A1c reduction among patients with inadequate glycemic control on metformin alone, with weight loss compared to weight gain versus the active control and fewer hypoglycemic events

2/18/2011 (22-350/001 & 002)

Perforomist Formoterol Dey

Provides REMS required for the long-acting beta agonist class to ensure the benefits outweigh the risk of serious asthma outcomes, including asthmarelated death, intubations and hospitalizations

2/1/2011 (22-007/005)

Plavix Clopidogrel Sanofi-Aventis

Provides a new Medication Guide and REMS

2/1/2011 (20-839/052)

Promacta Eltrombopag GlaxoSmithKline

Converts accelerated approval to full approval; incorporates efficacy and safety 2/25/2011 data from clinical studies; adds to thrombotic warnings that in a controlled (22-291/001 study in non-idiopathic thrombocytopenic purpura thrombocytopenic patients with chronic liver disease undergoing elective invasive procedures, the risk of thrombotic events was increased in patients receiving eltrombopag; modifies REMS

Proquin XR Ciprofloxacin Depomed

2/25/2011 (21-744/016)

Remodulin Treprostinil United Therapeutics

Revises indication and usage section of labeling to note that the studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable pulmonary arterial hypertension (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%) or PAH associated with connective tissue diseases (19%)

2/8/2011 (21-272/015)

Reyataz Atazanavir Bristol-Myers Squibb

Expands patient population to include treatment of HIV-1 infection during pregnancy based on data from A1424-182, a study of atazanavir/ritonavir in combination with zidovudine/lamivudine in HIV-infected pregnant women

2/4/2011 (21-567/025)

Sensipar Cinacalcet Amgen

New indication for treatment of severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy; adds data from an additional 19 subjects with hypercalcemia from parathyroid carcinoma

2/25/2011 (21-688/015)

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Pharmaceutical Approvals Monthly

Date Approved (Application No.)

Product and Sponsor

Change

Tamiflu Oseltamivir Roche

Adds new safety information regarding the emergence of resistance among influenza A viruses in children

2/7/2011 (21-087/057) (21-246/040)

Toviaz Fesoterodine Pfizer

Adds reports of angioedema of the face, lips, tongue and/or larynx to warnings and precautions

2/10/2011 (22-030/007)

Tracleer Bosentan Actelion

Revises indication and usage section of labeling to note that studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable pulmonary arterial hypertension (60%), PAH associated with connective tissue diseases (21%) and PAH associated with congenital systemic-to-pulmonary shunts (18%)

2/8/2011 (21-290/019)

Tyvaso Treprostinil United Therapeutics

Revises indication and usage section of labeling to note that studies establishing effectiveness included predominantly patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable pulmonary arterial hypertension (56%) or PAH associated with connective tissue diseases (33%)

2/8/2011 (22-387/004)

Ventavis Iloprost Actelion

Revises indication and usage section of labeling to note that studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable pulmonary arterial hypertension (65%) or PAH associated with connective tissue diseases (23%)

2/8/2011 (21-779/012)

Biologic Avastin Bevacizumab Genentech

Expands clinical trial results section of labeling for locally advanced, metastatic 2/8/2011 or recurrent unresectable non-squamous non-small cell lung cancer to (125-085/208) include results of a study testing two strengths of Avastin plus cisplatin and gemcitabine in patients who had received no previous chemotherapy, in which both arms showed significantly higher progression-free survival but failed to demonstrate an improvement in overall survival when Avastin was added to chemo compared to placebo

PegIntron Peginterferon alfa-2b Schering-Plough (Merck)

Updates warnings and precautions to caution against use in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g. chronic obstructive pulmonary disease)

2/1/2011 (103-949/5201)

Remicade Infliximab Centocor Ortho Biotech

Updates warnings and precautions regarding safety issues with TNFblockers, specifically, serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and etanercept with no added clinical benefit, so combination use with anakinra is not recommended; concurrent administration of TNF inhibitors and abatacept has been associated with an increased risk of infections, including serious infections, compared with TNF inhibitors alone without clinical benefit, so combination use with abatacept is not advised; also urges cautionwhen switching from one biologic to another, since overlapping biological activity may further increase the risk of infection

2/23/2011 (103772/5281)

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March 2011 | 9

Pharmaceutical Approvals Monthly

Elsevier Business Intelligence

February Full Approvals Full approvals of NDAs and BLAs

Product and Sponsor

Date Approved (Application No.)

Indication

New Drug Argatroban Sandoz 5S

Direct thrombin inhibitor tentatively approved under the 505(b)(2) NDA pathway for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia and as an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention

2/10/2011 (201-743)

Edarbi Azilsartan Takeda 1S

Angiotensin II receptor blocker for treatment of hypertension, either alone or in combination with other antihypertensive agents

2/25/2011 (200-796)

Hydromorphone hydrochloride Opioid analgesic tentatively approved via the 505(b)(2) NDA pathway for management of pain in patients where an opioid analgesic is Hospira appropriate

2/25/2011 (200-403)

Makena Hydroxyprogesterone Hologic 5P

Synthetic progestin injection approved under the 505(b)(2) NDA pathway to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth

2/3/2011 (21-945)

Omeprazole, clarithromycin and amoxicillin Dava 3S

Co-packaged omeprazole delayed-release capsules, clarithromycin tablets and amoxicillin capsules approved under the 505(b)(2) NDA pathway for treatment of patients with helicobacter pylori infection and duodenal ulcer disease (active or up to one-year history) to eradicate H. pylori

2/8/2011 (50-824)

Topotecan Hospira 5S

Topoisomerase inhibitor injection approved via the 505(b)(2) NDA pathway for treatment of adults with small cell lung cancer sensitive disease after failure of first-line chemotherapy

2/2/2011 (200-582)

Topotecan Sandoz

Topoisomerase inhibitor injection approved via the 505(b)(2) NDA pathway for treatment of adults with small cell lung cancer sensitive disease after failure of first-line chemotherapy and as combination therapy with cisplatin for stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy

2/25/2011 (200-199)

Zidovudine Matrix 5S

Nucleoside analog reverse transcriptase inhibitor, approved under the 505(b)(2) NDA pathway and PEPFAR, for use in combination with other antiretrovirals for the treatment of HIV-1 infection

2/23/2011 (200-732)

P: Priority Review (drug represents therapeutic gain over existing therapies) S: Standard review V: Orphan Drug 1: New molecular entity 2: New Salt 3: New formulation 4: New combination 5: Already marketed in U.S. by another firm 6: Already marketed by same firm, usually a new indication 7: First NDA for already marketed drug 10 | March 2011

Pharmaceutical Approvals Monthly

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February Abbreviated Approvals Product

Sponsor

Cyclobenzaprine HCl, 5 mg and 10 mg tabs.

KVK

Date Approved (Application No.) 2/28/2011 (78-048)

Desogestrel/ethinyl estradiol, 0.15 mg/0.03 mg oral-28 tabs.

Vintage

2/25/2011 (76-675)

Dextromethorphan hydrobromide/promethazine HCl, 15 mg/5 mL and 6.25 mg/5 mL syrup

Amneal

2/8/2011 (90-575)

Divalproex sodium, EQ 500 mg base valproic acid delayed-release tabs.

Watson

2/25/2011 (79-080)

Doxycycline, 150 mg caps.

Impax

2/17/2011 (200-065)

Fentanyl, 25 mcg, 50 mcg, 75 mcg and 100 mcg transdermal system

Mallinckrodt

2/9/2011 (77-154)

Fludeoxyglucose F-18, 20-200 mCi/mL intravenous inj.

Petnet

2/25/2011 (79-086)

Gabapentin, 100 mg, 300 mg and 400 mg caps.

Matrix

2/14/2011 (90-158)

Gabapentin, 250 mg/5 mL oral solution

Hi Tech

2/18/2011 (78-974)

Gabapentin, 600 mg and 800 mg tabs.

Zydus

2/11/2011 (78-926)

Galantamine hydrobromide, EQ 8 mg base, EQ 16 mg base and EQ 24 mg base extendedreleaase caps.

Sun

2/2/2011 (90-178)

Galantamine, 4 mg, 8 mg and 12 mg tabs.

Zydus

2/17/2011 (78-898)

Glyburide, 1.25 mg, 2.5 mg and 5 mg tabs.

Indicus

2/28/2011 (90-937)

Imiquimod, 5% topical cream

Tolmar

2/28/2011 (91-044)

Lamotrigine, 5 mg and 25 mg chewable tabs.

Jubilant Life

2/28/2011 (200-220)

Levetiracetam, 250 mg, 500 mg 750 mg and 1 gm tabs.

Accord

2/14/2011 (90-843)

Levocetirizine dihydrochloride, 5 mg tabs.

Glenmark

2/24/2011 (90-385)

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Pharmaceutical Approvals Monthly

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Date Approved (Application No.)

Product

Sponsor

Levocetirizine dihydrochloride, 5 mg tabs.

Dr. Reddyâ&#x20AC;&#x2122;s

2/24/2011 (90-392)

Levofloxacin, 0.5% ophthalmic solution

Hi Tech

2/10/2011 (76-826)

Lithium carbonate, 450 mg extended-release tabs.

Glenmark

2/14/2011 (91-616)

Meclizine HCl, 12.5 mg, 25 mg and 50 mg tabs.

Amneal

2/23/2011 (201-451)

Mirtazapine, 15 mg, 30 mg and 45 mg orally-disintegrating tabs.

Actavis Elizabeth

2/14/2011 (77-959)

Naproxen, 250 mg, 375 mg and 500 mg tabs.

Marksans

2/14/2011 (91-416)

Naratriptan HCl, EQ 1 mg base and EQ 2.5 mg base tabs.

Indicus

2/28/2011 (200-502)

Naratriptan, EQ 2.5 mg base tabs.

Sun

2/14/2011 (91-552)

Octreotide acetate, EQ 0.05 mg base/mL, EQ 0.1 mg base/mL and EQ 0.5 mg base/mL inj.

Bioniche

2/10/2011 (79-198)

Ondansetron, 4 mg and 8 mg

Ranbaxy

2/24/2011 (78-602)

Oxycodone HCl, 5 mg, 15 mg and 30 mg tabs.

Coastal

2/18/2011 (91-313)

Oxymorphone HCl, 5 mg and 10 mg tabs.

Teva

2/15/2011 (91-443)

Pantoprazole sodium, EQ 20 mg base and EQ 40 mg base delayed-release tabs.

Actavis

2/7/2011 (90-797)

Risperidone, 1 mg/mL oral solution

Taro

2/7/2011 (90-347)

Abacavir Sulfate, 20 mg oral solution

Cipla

2/16/2011 (78-348)

Abacavir sulfate, 300 mg tabs.

Mylan

2/15/2011 (91-294)

Argatroban, 125 mg inj.

Sandoz

2/10/2011 (201-743)

Donepezil HCl, 5 mg and 10 mg orally disintegrating tabs.

Sandoz

2/8/2011 (91-198)

Tentative Abbreviated

12 | March 2011

Pharmaceutical Approvals Monthly

http://PharmaceuticalApprovals.ElsevierBI.com

Date Approved (Application No.)

Product

Sponsor

Doxercalciferol, 2 mcg/mL inj.

Mylan

2/3/2011 (91-101)

Duloxetine HCl, 20 mg, 30 mg and 60 mg delayed-release caps.

Sandoz

2/2/2011 (90-775)

Irbesartan/hydrochlorothiazide, 150 mg/12.5 mg, 300 mg/12.5 mg and 300 mg/25 mg tabs.

Zydus

2/16/2011 (90-815)

Latanoprost, 0.005% ophthalmic solution

Pharmaforce

2/1/2011 (200-925)

Levofloxacin, 250 mg, 500 mg and 750 mg tabs.

Hikma

2/10/2011 (78-767)

Norgestimate/ethinyl estradiol, 0.18 mg/0.025 mg, 0.215 mg/0.025 mg and 0.25 mg/0.025 mg tabs.

Watson

2/17/2011

Tolterodine tartrate, 1 mg and 2 mg tabs.

Sandoz

2/9/2011 (78-419)

Venlafaxine HCl, 37.5 mg, 75 mg and 150 mg extended-release caps.

Aurobindo

2/17/2011 (200-834)

(90-479)

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New Molecular Entities Approved In 2011 Date Approved (Application Number)

Product & Sponsor

Indication

DaTscan Ioflupane I 123 GE Healthcare

Imaging agent for striatal dopamine transporter visualization using single photon emission computed tomography brain imaging to assist in the evaluation of adults with suspected Parkinsonian Syndromes

1/14/2011 (22-454) (P)

Natroba Spinosad ParaPRO

Topical suspension that causes neuronal excitation in insects, for the treatment of head lice infestation in patients 4 years of age and older

1/18/2011 (22-408) (S)

Viibryd Vilazodone Trovis Pharmaceuticals

Dual-acting selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist for treatment of major depressive disorder

1/21/2011 (22-567) (S)

Edarbi Angiotensin II receptor blocker for the treatment of Azilsartan hypertension, either alone or in combination with other Takeda Pharmaceuticals North America antihypertensive agents

2/25/2011 (200-796) (S)

Daliresp Roflumilast Forest Research Institute

Phosphodiesterase-4 inhibitor to reduce the risk of chronic obstructive pulmonary disease exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations

2/28/2011 (22-522) (S)

Gadavist Gadobutrol Bayer HealthCare Pharmaceuticals

Gadolinium-based contrast agent for use in diagnostic magnetic resonance imaging in adults and children (2 years of age and older) to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system

3/14/2011 (201-277) (S)

S: Standard review P: Priority review V: Orphan drug

Biologics Approved In 2011 FDA transferred review of most therapeutic biologics to the Center for Drug Evaluation & Research on Oct. 1, 2003. The Center for Biologics Evaluation & Research continues to review other biologics, including vaccines, cellular products, antitoxins and immunoglobulins. Products approved by CBER are designated with an asterisk (*).

Product & Sponsor

Date Approved (Application Number)

Indication

Corifact* Factor XIII concentrate made from the pooled plasma of healthy donors Factor XIII concentrate (human) for routine prophylaxis of bleeding in people with congenital Factor XIII deficiency CSL Behring

2/15/2011 (125385) (V, H)

Benlysta Belimumab Human Genome Sciences/ GlaxoSmithKline

B-lymphocyte stimulator (BLyS)-specific inhibitor for the treatment of adult patients with active, autoantibody-positive, systemic lupus erythematosus who are receiving standard therapy

3/9/2011 (125370)

Adenovirus Type 4 and Type 7 vaccine, live, oral* Teva Womenâ&#x20AC;&#x2122;s Health/Barr Labs

Live oral vaccine for use in military populations 17 through 50 years of age for active immunization for prevention of febrile acute respiratory disease caused by Adenovirus Type 4 and Type 7

3/16/2011 (125296)

S: Standard review P: Priority review V: Orphan drug H: Accelerated approval

14 | March 2011

http://PharmaceuticalApprovals.ElsevierBI.com

MedGuide-Only REMS Will Be The Exception, Not The Norm, As FDA Relaxes Policy SUE SUTTER s.sutter@elsevier.com

DA’s proposed new benchmark for incorporating a Medication Guide in a Risk Evaluation and Mitigation Strategy would reduce the regulatory burden on sponsors whose products do not warrant restricted distribution measures. In a draft guidance released Feb. 25, the agency says that “in most cases” a MedGuide will be included as part of a REMS only when elements to assure safe use are needed. However, a MedGuide could be part of a REMS that lacks elements to assure safe use if the agency determines that having a MedGuide without a REMS will be insufficient to ensure a drug’s benefits outweigh its risks.

”In most cases” a MedGuide will be part of a REMS only when elements to assure safe use are required. Elements to assure safe use (ETASU) are generally reserved for those drugs posing the most significant risks. ETASU include health care provider training or certification, restricted dispensing, documenting safe use conditions, and mandatory patient monitoring or registry enrollment. If FDA adopts this policy in a final guidance, sponsors and the agency could see a vast reduction in the number of products approved with REMS. This would result in less regulatory burden for sponsors, who must conduct REMS assessments at given intervals, and on FDA, which must evaluate the assessments. The guidance also explains how sponsors can seek removal of those REMS that contain only a MedGuide and a timetable for assessment.

MedGuide-Only REMS Predominate The FDA Amendments Act of 2007 gave FDA authority to require a MedGuide as part of a REMS. Since the law’s drug safety provisions took effect in March 2008, the agency has considered any new MedGuide, or safety-related changes to an existing MedGuide, to be part of a REMS, the draft guidance says. As a result, two-thirds of the REMS approved to date have been of the MedGuide-only variety. Counting various dosage forms separately, FDA approved 175 REMS, according to figures on the agency’s website updated Unauthorized photocopying is prohibited by law.

Pharmaceutical Approvals Monthly

as of Feb. 25. Of these, 116 were MedGuide-only REMS, 37 carried only MedGuides and communication plans, and 22 had ETASU. Only one sponsor has been released from its REMS requirements, according to the website. FDA approved a REMS for QOL Medical’s enzyme replacement therapy Sucraid (sacrosidase) in November 2008. The REMS, which included a communication plan, ETASU and an implementation system, was aimed at communicating information about a manufacturing change and to ascertain whether the change resulted in an increase in allergy-related adverse events. In December 2010 FDA said the company’s REMS assessment showed there were no reports of adverse events and it concluded the REMS was no longer required.

Looking For A Way Around REMS To reduce the burden on sponsors, FDA and the health care system, the agency has been searching for a way to allow development of MedGuides outside of the REMS framework. At the Drug Information Association’s annual meeting in June, Office of New Drugs Director John Jenkins said the agency was looking for a “creative way” around the FDAAA provision on MedGuides in REMS. At that time, however, Jenkins said MedGuides were still considered to be a component of REMS (“FDA Seeks To Write MedGuides Outside REMS Process,” “The Pink Sheet,” June 21, 2010). However, FDA now appears to have subscribed to the views of the Pharmaceutical Research and Manufacturers of America, which last year called for the agency to revert to its original, pre-FDAAA authority to implement MedGuides (“PhRMA Wants MedGuides Developed The Pre-FDAAA Way, Not REMS,” “The Pink Sheet” DAILY, July 26, 2010). The original authority stems from a 1998 final rule on patient-directed labeling (“MedGuides Required Only In Classes Where Patient Info Already Requested,” “The Pink Sheet,” Dec. 7, 1998). The rule is known as Section 208. FDA has the authority to determine, based on a drug’s risks and public health concerns, whether a MedGuide should be required as part of a REMS when the 1998 rule’s standards are met, the draft guidance states. The agency may decide the MedGuide should be required as labeling but not part of a REMS if the latter is not necessary to ensure the benefits of the drug outweigh its risk. “While all Medication Guides must meet the standard and requirements in part 208, not every newly required Medication Guide will be an element of a REMS,” the guidance states. “Depending on the risks involved, FDA may approve a Medication Guide under part 208 without requiring a REMS when that is adequate to address the March 2011 | 15

Pharmaceutical Approvals Monthly

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serious and significant public health concern and meets the standard in 208.1.”

of any post-approval studies undertaken to investigate a safety issue.

Getting Out Of REMS

Exercising Enforcement Discretion

The guidance provides a pathway for sponsors to escape the burden of an existing MedGuide-only REMS.

The guidance also explains when FDA will use its enforcement discretion on MedGuide distribution requirements in certain settings.

Applicants may submit a prior approval supplement for a REMS modification that proposes to eliminate the program. Applicants with a REMS that includes both a MedGuide and a communication plan may submit a prior approval supplement that seeks removal of the MedGuide component. All REMS programs include a timetable for assessment, and any proposed REMS modification must be accompanied by an assessment. If the REMS was assessed in the past 18 months, the assessment may consist of a statement to that effect. If the REMS was not assessed during that time period, the assessment may include an update on the status

A MedGuide need not be distributed when a drug is dispensed to a health care professional for administration to a patient in an inpatient setting or an outpatient setting, such as a dialysis or infusion center, the guidance says. However, there are four exceptions to this rule. A MedGuide must be distributed: when the patient requests it; when the drug is dispensed in an outpatient setting and used by the patient without a professional’s direct supervision; the first time the drug is dispensed for a patient in an outpatient setting; and the first time a drug is dispensed after a MedGuide is materially changed.

Recent Risk Evaluation & Mitigation Strategies Here is an update of the FDA’s most recent REMS requirements, as well as a listing of drugs where it has been announced that REMS are being developed. For a full list of all approved REMS, see our website, www.PharmaceuticalApprovals.com. REASON FOR REMS

Gralise (gabapentin) Abbott/Depomed

Anti-epileptic drug associated with Medication Guide risk of suicidality

1st: 7/28/2012 2nd: 1/28/2014 3rd: 1/28/2018

Perforomist (formoterol inhalation solution) Dey Pharma

To inform health care providers and patients of the increased risk of asthma-related death and serious outcomes with the longacting beta2-adrenergic agonists (LABA) class, as well as other serious risks, and inform them about appropriate use

Medication guide and communication plan consisting of “Dear Health Care Provider” and “Dear Medical Society” letters and website

2/1/2012 and annually thereafter

Medication Guide

1st: 6/1/2012 2nd: 2/1/2014 3rd: 2/1/2018

Plavix (clopidogrel) Co-administration with a drug Sanofi-Aventis/ Bristol- that inhibits CYP450 2C19 results in a reduction in blood levels of Myers Squibb clopidogrel’s active metabolite and a loss of the desired antiplatelet effect

16 | March 2011

ELEMENTS OF REMS

TIMETABLE FOR ASSESSMENTS

DRUG & SPONSOR

POST-MARKETING REQUIREMENTS

http://PharmaceuticalApprovals.ElsevierBI.com

Merck KGaA Pins Cladribine Hopes On Ongoing Studies After “Complete Response” Letter

Pharmaceutical Approvals Monthly

won U.S. approval in September and already is challenging the market share held by key Merck KGaA MS asset Rebif (interferon beta-1a), an injectable product that accounted for 29% of Merck’s 2010 pharma revenues.

SHIRLEY HALEY s.haley@elsevier.com

erck KGaA is hoping data from already completed and ongoing studies will satisfy FDA’s need to better understand the risk-benefit profile for its oral multiple sclerosis therapy cladribine, after the agency issued a “complete response” March 2. While the agency agreed the results of the pivotal Phase III CLARITY study, which formed the basis for the submission, provides “substantial evidence” of cladribine’s effectiveness, regulators are looking for an “improved understanding” of the safety risks and the overall benefit-risk profile, either through further analyses or by additional studies, U.S. affiliate EMD Serono said. Serono, in Rockland, Mass., said it would meet with the agency as soon as possible to determine next steps and discuss whether forthcoming study data, or even a re-evaluation of data already in hand, will be adequate to resolve the agency’s concerns.

U.S. affiliate EMD Serono will meet with FDA to discuss whether forthcoming study data or a reevaluation of existing data will resolve the agency’s concerns. Three ongoing trials are fully enrolled, and top-line data from two are expected by the end of this year. The first is a two-year extension of the CLARITY study designed to provide long-term safety and efficacy data from patients on the drug for up to four years. The second, ORACLE, is a twoyear Phase II study evaluating cladribine as monotherapy in patients who have experienced a first clinical event suggestive of MS. The other study, ONWARD, is a Phase II placebo-controlled study in patients with relapsing MS who have experienced breakthrough while on established interferon-beta therapy. The trial has completed recruitment and top-line results are expected in the first half of 2012.

Regulatory And Commercial Headwinds In Europe And The U.S. Darmstadt, Germany-based Merck KGaA is in the midst of reassessing its pharma priorities and may well be rethinking its MS strategy. Novartis AG’s oral drug Gilenya (fingolimod) Unauthorized photocopying is prohibited by law.

Merck KGaA issued financial guidance for 2011 with and without cladribine approval. During its 2010 earnings report, Merck KGaA released two sets of financial guidance for 2011: with and without U.S. cladribine approval (“Merck KGaA 2010 Results Marred By Cladribine And Poor OTC Growth,” “The Pink Sheet” DAILY, Feb. 22, 2011). The guidance will now be the lower of the two projections, with biopharma revenues predicted to grow by only 1% to 6%, as opposed to 5% to 10%, and the Merck Group’s revenues lowered from 13% to 18% to 10% to 15%.

FDA’s rejection follows the European Medicines Agency’s denial of Merck KGaA’s appeal of its earlier negative opinion on cladribine. To make matters worse, after a positive opinion from the European Medicines Agency’s Committee for Human Medicinal Products in January, Novartis’ Gilenya could be available in Europe in a few months, while at the same meeting CHMP denied Merck’s appeal of an earlier negative opinion on cladribine (“Novartis’ Gilenya Shines Amid Bleak Day For MS Drugs In Europe,” “The Pink Sheet” DAILY, Jan. 21, 2011). Still, Merck hasn’t given up on cladribine in Europe either. It is counting on the same forthcoming trial data it wants to give FDA to also dispel CHMP’s safety concerns. Those worries derive from an increased risk of lymphopenia (abnormally low lymphocyte count) and about four cases of cancer in patients who received the drug during the 1,300-patient CLARITY study. Proponents argue that lymphopenia is a manageable side effect of the drug, which works by killing lymphocytes that, triggered by the autoimmune disease, attack the myelin sheathing that protects nerve tissue and that the cancers were random (“EU Regulators Reject Merck KGaA’s Oral MS Drug Cladribine,” “The Pink Sheet” DAILY, Sept. 24, 2010). Despite the regulatory angst in the U.S. and EU, cladribine won approval in Australia and Russia in 2010, where it is marketed as Movectro. March 2011 | 17

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Recently Announced “Complete Response” Letters FDA stopped issuing “approvable” and “not approvable” letters in favor of “complete response” letters on Aug. 11, 2008. The following chart lists “complete response” actions that were recently announced.

Product/Sponsor

Indication

Effective Date

Amyvid Florbetapir F 18 b

Diagnostic agent that binds to amyloid plaque for use with positron emission tomography to detect beta-amyloid plaques in the brains of living patients as part of the diagnosis of Alzheimer’s disease

Announced 3/18/2011 (FDA focused on “the need to establish a reader training program for market implementation that helps to ensure reader accuracy and consistency of interpretations of existing Amyvid scans,” Lilly reported)

Cladribine Merck Serono (Merck KGaA)

Oral tablet formulation of the drug, which may interfere with lymphocyte proliferation, to reduce relapses in people with relapsing forms of multiple sclerosis

Announced 3/2/2011 (FDA requested an improved understanding of safety risks and overall riskbenefit profile through additional analyses or additional studies)

Uplyso Taliglucerase alfa b

Plant-cell expressed recombinant form of human glucocerebrosidase for the treatment of the lysosomal storage disorder Gaucher disease

2/25/2011 (FDA requested additional data from a switchover trial and a long-term extension trial, which were not available at the time of NDA submission; FDA also requested chemistry, manufacturing and controls information regarding testing specifications and assay validation)

New indication for the high-dose 550 mg tablet formulation of the gut-selective antibiotic for treatment of non-constipation irritable bowel syndrome and IBS-related bloating

3/7/2011 (FDA’s concerns relate primarily to what Salix calls a “newly expressed need” for retreatment information)

Lilly (formerly Avid Radiopharmaceuticals)

Pfizer/Protalix

Xifaxan a Rifaximin 550 mg tabs. Salix Pharmaceuticals a b

Submission is for a new use or new formulation of product that sponsor already markets New molecular entity or combination product with NME as component

2011 FDA Advisory Committee Recommendations Product

Sponsor

Indication

Meeting Date

Arcapta Neohaler Novartis Indacaterol

3/8/2011 Committee voted 13-4 and 5-12 that efficacy and safety data provide substantial evidence to support approval of indacaterol 75 and 150 mcg, respectively, for the long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease; 15-2 that 75 mcg demonstrated substantial evidence of efficacy; 11-6 that indacaterol 150 mcg has not demonstrated substantial evidence of efficacy over the 75 mcg dose; 12-5 and 11-6 that the safety profiles of the 75 and 150 mcg doses, respectively, are adequate for approval; 10-7 and 13-4 that a claim for improvement in health-related quality of life as measured by the St. George’s Respiratory Questionnaire is supported for the 75 and 150 mcg doses, respectively

Lamictal XR Lamotrigine extended-release

Committee voted 10-2, with one abstention and one member absent, finding substantial evidence of effectiveness as monotherapy treatment of partial seizures; voted 14-0 that a historical control approach can be acceptable for establishing efficacy as monotherapy when a drug is known to be effective as adjunctive treatment

18 | March 2011

GlaxoSmithKline

3/10/2011

Pharmaceutical Approvals Monthly

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Vertex Offers Cystic Fibrosis Patients A Chance To Breathe Easier

All of the patients in the trial had the G551D genetic mutation, which affects only about 4% of the U.S. cystic fibrosis population. But Vertex is also studying the drug in combination with VX-809 in patients who have the F508del mutation, a much broader population of cystic fibrosis patients.

LISA LAMOTTA l.lamotta@elsevier.com

hile most attention has been on Vertex Pharmaceuticals’ hepatitis C drug telaprevir, which is widely expected to gain FDA approval in May, the company has also been steadily progressing on its investigational cystic fibrosis agents, and it may have lined up another home run. Vertex has a pair of drugs in development for the orphan genetic disease that aim to address some of the genetic mutations at the heart of the disease, instead of treating symptoms and secondary infections that are the focus of current treatment. In cystic fibrosis, any one of a group of genetic defects in the CFTR protein cause the body to produce sticky, thick mucus in the lungs and digestive system, leading inevitably to an early death, often by age 40. The orphan disease affects about 70,000 patients worldwide and 30,000 in the U.S. Only a handful of drugs are currently available to treat CF, of which two are antibiotics made by Novartis and Gilead. These drugs can help thin mucus and fight off the lung infections to which CF patients are prone.

Vertex’s pipeline holds two diseasemodifying agents that target different genetic defects – and could have complementary effects. A combination study should report by year-end. Vertex’s lead candidate, VX-770, is a potentiator of the CFTR protein. In patients with the G551D mutation, the proteins do not function normally at the cell surface, the company explains. The drug aims to increase the function of defective CFTR proteins by increasing the gating activity of CFTR and improving transport across the cell membrane. A different genetic mutation is the focus of Vertex’s other CF candidate, VX-770. In patients with the F508del mutation, CFTR proteins do not reach the cell surface in normal amounts, Vertex reports, and VX-809 acts as a CFTR corrector to increase the proteins’ function by increasing its movement to the cell surface. Vertex announced Feb. 23 that the Phase III STRIVE study in 161 cystic fibrosis patients over age 12 showed that patients taking VX-770 had a statistically significant improvement in the ability to exhale compared with those given a placebo.

Unauthorized photocopying is prohibited by law.

Vertex plans to file an NDA for VX-770 in G551D patients in the second half of 2011 and to present data from the combination trial during that time frame as well, executives said.

A Collaborative Process VX-770 has been heavily funded by the Cystic Fibrosis Foundation, a patient advocacy group with a pioneering venture philanthropy arm (“Breath Of Fresh Air For Cystic Fibrosis Drug Pipeline,” Pharmaceutical Approvals Monthly, December 2007). CFF contributed more than $75 million to the discovery phase of Vertex’s CF program, hoping that a high-profile screening technique invented by a company Vertex bought years ago would produce a few molecules that could evolve into disease-modifying drugs. In exchange, it will now receive a single-digit royalty on sales if the drug is approved. The Foundation’s bet has paid off: VX-770 is the first drug that has been able to show a disease-modifying effect on cystic fibrosis, by correcting the G551D defect to improve the transport of chloride ions between cells. Because it is disease-modifying, the drug has better efficacy than existing therapies and its effects are sustainable over time, said CFF President and CEO Richard Beall. “The foundation had been instrumental in laying important groundwork including identifying the CFTR gene as a cause of CF as well as characterization of the biological and biochemical function of the protein and its link to the disease process,” Vertex Chief Scientific Officer Peter Mueller said on a conference call on the trial results. Even after funding ended, CFF has remained involved in the development program; by using its clinical trial network of 80 sites, Vertex was able to enroll patients in its trials rapidly. Clinical trial recruitment is one way disease advocacy groups are able to assist drug development (“Myeloma Foundation Uses Patient Connections To Help Speed Drug Trials,” Pharmaceutical Approvals Monthly, January 2011).

Results Exceed Analyst Expectations Results from the STRIVE study showed that patients who received VX-770 improved their lung function from baseline by 10.6 percentage points compared to placebo after 24 weeks, with sustained improvement over the next 24 weeks. Lung function, the primary endpoint of the trial, was determined by a standard test that measured how much breath a person could exhale in one second, or FEV1. The total FEV1 was about 17% higher in patients who received the drug.

March 2011 | 19

Pharmaceutical Approvals Monthly

Statistically significant improvements were also found in the trial’s secondary endpoints. STRIVE patients on VX-770 were 55% less likely to have a pulmonary exacerbation, and 67% of people treated with VX-770 were free of exacerbations through 48 weeks compared to 41% in the controlled group. Patients on VX-770 gained 6.8 pounds, on average, compared to 0.9 pounds for those on placebo. Weight gain is often a problem for CF patients, who have severe digestive problems. VX-770 also resulted in a reduction in the amount of salt in the sweat, which is a key marker of CFTR protein dysfunction, the underlying mechanism responsible for cystic fibrosis. While the reduced sweat chloride does not directly indicate improvement in the disease, it does represent a restoration of function to the CFTR protein. The results of STRIVE far exceeded clinician and Wall Street expectations. Analysts and investors were generally predicting a 6% improvement on the FEV1 test, but the better results will help the company with pricing and positioning with providers and patients. Although it addresses a relatively small patient population, the drug could reach peak sales of $800 million, based on pricing and chronic use, according to J.P. Morgan analyst Geoff Meacham, who described the trial results as a home run in a note to clients. Vertex also presented results from the DISCOVER trial, which tested VX-770 in 140 patients with a different gene mutation called F508del, a very common CFTR mutation. VX-770 doesn’t work well on its own in patients with F508del, but the study aims to demonstrate the drug’s safety. Patients taking VX770 experienced cough, nausea, rash and contact dermatitis. A third trial, nicknamed ENVISION, is studying ‘770 in G551D patients between the ages of six and 12. Results are expected later this year. Vertex is studying a combination of VX-770 and VX-809 in a trial evaluating patients aged 18 and older who have two copies of the F508del mutation. More than 90% of cystic fibrosis patients have at least one copy of the F508del mutation while about 50% have two copies. Because of VX-809’s CFTR corrector function, increasing movement of the CFTR protein to the cell surface, it could prime patients for treatment with VX-770 by bringing more CFTR to the cell surface, where VX-770 can assist with transport out of the cell. “We believe that enhancement of trafficking could be a viable approach for patients that have not enough or intrinsically low levels of CFTR channels on their lung surface and thus cannot clinically benefit from the sole application of a potentiator such as VX-770,” said Meuller. “Therefore we believe the best approach for people with this type of CF mutation may be the combination of a potentiator and a corrector.” 20 | March 2011

Elsevier Business Intelligence

Ventrus Could Start Pivotal Trial For Rx Hemorrhoid Therapy Mid-Year SHIRLEY HALEY s.haley@elsevier.com

entrus Biosciences Inc. is ready to take its lead candidate iferanserin, a novel compound aimed at arresting hemorrhoid symptoms rather than soothing them, into Phase III studies after the micro-cap biotech’s lateDecember initial public offering brought in $20 million to support the program. For such a small company, “there’s a certain noise level you’ve got to rise above, and we got lucky there because it’s an interesting story of a late-stage product in a market where nobody’s done anything for about 70 years,” CEO Russell Ellison said in an interview. “I think [the success of the IPO] had a lot to do with getting our story out to a broader audience.” A noteworthy aspect of the IPO is that the shareholders are largely retail as opposed to institutional investors, Ellison pointed out, adding that many who bought stock are physicians. “This is a tremendous retail story and a huge participation in the IPO was in fact retail, something we haven’t seen since the ‘90s,” Ellison said. On Dec. 23, Ventrus announced it had closed an offering of 2.9 million shares, and then on Jan. 7 came news that the underwriters of the IPO, Rodman & Renshaw LLC and National Securities Corp., had exercised in full their over-allotment option to purchase an additional 435,000 shares of stock at $6 per share. Including the over-allotment, a total of 3.335 million shares were sold, grossing about $20 million. New York-based Ventrus has plenty of cash to take both iferanserin and a second late-stage compound, diltiazem cream for anal fissures, to Phase III study endpoints “and have runway to do something about it,” Ellison said during a presentation Feb. 14 at the BIO CEO & Investor Conference in New York.

New SPA Endpoints Make For A Stronger Label Ventrus has been working with FDA on a trial design and endpoints to test prescription hemorrhoid products, since iferanserin (VEN 309) would be the first to market if approved. “It’s been really great working with the GI division. They’ve been incredibly transparent and thoughtful,” Ellison said. Contingent on a revised special protocol assessment, which Ventrus hopes to hear on by mid-May, the first Phase III trial is shaping up to be about 400 patients at 60 U.S. sites randomized to drug plus ointment versus ointment alone. The ointment is applied using a single-use applicator twice daily for two weeks. The company got feedback from the agency on the endpoint definitions in its proposed protocol in mid-March that could “provide a much stronger label” that would encourage faster

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Pharmaceutical Approvals Monthly

and broader adoption of the therapy, the firm said. Ventrus has amended the protocol and resubmitted it.

that in our filings because this is seen as a chronic use drug,” Ellison said.

The study is still on track to launch mid-year, with enrollment completed by the end of December and results from the double-blinded phase reporting in the first quarter of 2012.

Iferanserin works by blocking the 5HT2a receptor, which is involved in clotting and contraction of arteries and veins. Once the receptor is under control, blood flow out of the dilated hemorrhoidal area is improved, and itching and pain are relieved. The science underlying the drug’s mechanism was discovered in the 1990s but has never been published.

The endpoints are unambiguously tied to cessation of symptoms, Ellison said in the interview. “This is very important because both FDA and the company wanted endpoints that were very clinically meaningful and incontrovertible. No worries about scale validation, etc. You really have to stop having symptoms.” The primary endpoint now is proportion of patients with cessation of bleeding by the end of day seven that persists for the remainder of the treatment period (through day 14). A key secondary endpoint is proportion of patients with cessation of pain and/or itching by the end of day seven that persists for the remainder of the treatment period (through day 14). Having clear evidence of clinically meaningful benefit from the study endpoints will be important for the company. Instead of turning to over-the-counter products, “patients are going to have to pay a copay here, and they have to believe it’s worth it,” Ellison said. He didn’t expect that intraanal steroids, the only prescription alternative, could meet the same endpoints. “I would be very surprised if they could. Who knows? There’s no data.” Enrollment criteria are two days of consecutive bleeding at randomization with two days of either pain or itching, and hemorrhoids that “pretty much do not require surgery,” Ellison said. The treatment period is two weeks, with a two-week followup, and then patients who complete the 28 days have access to the drug open label for a year for treatment of recurrence. Recurrence is important to FDA, stressed Ellison. One thing Ventrus hopes to determine is what a recurrence rate might look like with an effective drug treatment for hemorrhoids, because one has never been approved. Because a patient could have as many as 12 retreatments in a lifetime, Ventrus has to do a full chronic use NDA with 1,500 patients exposed, as well as the accompanying animal carcinogenicity and toxicology studies.

Because the product will entail chronic use, Ventrus is planning a second Phase III trial in recurrent patients. A second Phase III, in recurrent patients, will be planned based on the results of the first study. “We’ll probably want Unauthorized photocopying is prohibited by law.

The compound is less than 10% bioavailable and very specific only to 5HT2a receptors, and it is administered at too low a dose to cross the blood-brain barrier, Ellison explained at the BIO CEO Conference in reference to serious adverse events seen with 5HT2 receptors and weight-loss drugs.

A Repurposed Compound To Treat Anal Fissures The other advanced candidate, diltiazem cream (VEN 307), is a topical treatment for the relief of pain associated with anal fissures, small tears or cuts in the skin that lines the anus. There also are no FDA-approved drugs for this indication, though Cellegy/ProStrakan have spent more than seven years trying to gain approval for nitroglycerin ointment Rectogesic (formerly Cellegesic). Currently, according to Ventrus, gastroenterologists order diltiazem from compounding pharmacists individually for each patient.

Ventrus will likely be able to use the 505(b)(2) pathway to seek approval of diltiazem for anal fissures. Diltiazem, used for decades for hypertension and angina, dilates the blood vessels supplying the region, reduces anal sphincter tone and thereby decreases pain. Much data is available on the molecule, and it is likely Ventrus will seek approval via the 505(b)(2) NDA pathway (“Ventrus Biosciences Inc.: Aiming For Innovative Anal Treatments,” Start-Up, January 2010). SLA Pharma AG, Ventrus’ partner for the compound outside of North America, began a European Phase III study of the anal fissure product in November, with data possible in the second quarter of 2012. The study is enrolling 465 patients at 30 sites, randomized to one of two strengths of the test drug or placebo. A third candidate may be progressed in 2012, phenylepherine gel (VEN 308) for fecal incontinence, depending on the readouts from the first two products, Ellison said. The gel has had clinical proof of concept studies, and there are quite a few investigator-initiated trials in the prospectus, but it still needs a Phase IIb to get the dose right and possibly some formulation work, he said. March 2011 | 21

Pharmaceutical Approvals Monthly

How A Biomarker Revived Synta’s Cancer Drug Elesclomol EMILY HAYES e.hayes@elsevier.com

sing a simple, cheap, available enzyme test, Synta Pharmaceuticals Corp. has been able to rescue the development program for its oncology candidate elesclomol after a high-profile Phase III failure in melanoma.

Research shows that the enzyme lactate dehydrogenase – which can be measured with a basic test – is a good marker for whether a drug will work in a patient, and elesclomol is now back on track as a result, Synta Director of Translational Biology Ron Blackman explained during a presentation at the Molecular Medicine Tri-Conference in San Francisco on Feb. 25. The drug is currently progressing in human testing for a number of cancers. Incorporating diagnostics to identify responders in clinical practice can sometimes be a challenge for a variety of reasons, but in the case of LDH, the test is readily available and cheap. One LabCorp branch quoted a total cash price of $27. Depending on the stage and type of cancer, the LDH test may already be part of the diagnostic work-up, according to Synta. For patients with Stage III/IV melanoma, for example, LDH tests are routine.

Turning To A Biomarker • Patients with high levels of the enzyme lactate deyhydrogenase (LDH) tend to have a poorer prognosis, dying earlier. • Under low oxygen conditions, or “hypoxia,” elesclomol has less activity.

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Leaves Synta In Need Of Plan B,” “The Pink Sheet” DAILY, Feb. 27, 2009). It wasn’t long before partner Glaxo walked out on the development deal signed in 2007 – returning elesclomol rights despite having paid $80 million upfront. Synta had also stood to earn up to $585 million in development and regulatory milestones in melanoma and other cancers as part of that deal.

Reviving drugs after trial failures is now common, Synta says, like Provenge for prostate cancer and Benlysta for lupus.

Elesclomol Will Survive In light of the SYMMETRY news, and mixed results in other trials, analysts at the time had predicted GSK would walk and that would be the end of the elesclomol story and the oxidative stress induction hypothesis. But elesclomol wound up surviving, thanks to a lot of hard work towards understanding why SYMMETRY failed, according to Blackman. It’s long been known that LDH at high levels is linked to tissue damage and a range of poor health conditions, including heart attack and liver disease. LDH has been associated with more advanced disease and a poorer prognosis in many cancers, and patients with high LDH are known to die earlier regardless of medical interventions. LDH levels were measured at baseline in the SYMMETRY trial, and a subpopulation analysis clearly showed that elesclomol worked in patients with normal or low LDH, but not in those with high LDH.

• High LDH is linked to hypoxia. • LDH tests are inexpensive and readily available. • Elesclomol is now back in the clinic for a number of cancers, but not yet melanoma.

Synta Loses Partner, But Regains Compound An investigational first-in-class compound, elesclomol (STA4783) was designed to increase already high levels of oxidative stress in cancer cells, triggering cell death. It was thought that the drug could work in multiple oncology indications and elesclomol initially attracted a generous partnership deal with GlaxoSmithKline PLC. The discovery of the role LDH plays came out of an analysis of data from the failed SYMMETRY Stage IV melanoma trial. That study was stopped early because there were higher death rates for the elesclomol/paclitaxel combination arm than for paclitaxel alone (“Elesclomol’s Phase III Fizzle 22 | March 2011

Elesclomol is in Phase II for a number of cancers – but not melanoma for now, in light of the high expense for a Phase III trial. Trials are now being designed and run accordingly, to exclude those unlikely to respond based on LDH tests. The Gynecology Oncology Group is starting a Phase II trial in ovarian cancer. And FDA and Health Canada have given the green light for a Phase II study in relapsed or refractory acute myeloid leukemia; Synta announced on Feb. 8 that the first patient had been dosed. Both trials will enroll only patients with low LDH. Elesclomol has also been studied in non-small cell lung cancer and a Phase II study in low LDH patients with this disease is set to kick off in the second quarter of this year.

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About 30% of the patient population with solid tumors have low LDH and prevalence in AML is unknown.

Back In Melanoma? Not For Now As for melanoma, the company commented that a Phase III trial would be a “very expensive undertaking” and, consequently, it probably won’t proceed without a partner. Synta is now devoting most of its resources to its candidate du jour – the heat shock protein 90 inhibitor ganetespib (formerly called STA-9090) – which showed positive results in a single agent, Phase II trial in Stage IIIb/IV non-small cell lung cancer reported at the end of February. Synta recently announced that a registration-enabling Phase IIb/Phase III trial of ganetespib with docetaxel in 800 NSCLC patients will get under way in the first quarter of 2011. The Phase IIb part will have 240 patients, twice as large as the Phase IIb trial it had conducted for elesclomol in melanoma. This will increase the power of the trial and also allow for earlier analysis of response in various patient subpopulations, the company said. Analysts at Edison Research and Morgan Joseph TriArtisan have noted that ganetespib’s excellent tolerability profile helps differentiate it from other drugs in the same class. The Hsp90 inhibitor is also in Phase II for 10 other kinds of cancers.

Most of Synta’s resources are now being devoted to the heat shock protein 90 inhibitor ganetespib. But elesclomol is also showing promise. Synta is also concentrating on NSCLC as it resurrects elesclomol. In an early Phase II study conducted several years ago, the company saw encouraging signals of activity for the drug in patients with a range of LDH levels. The Phase II NSCLC study set for the second quarter will include only low LDH patients. “NSCLC also has a very high need for new therapeutic options and a Phase II trial would serve as an important validation of the marker, which would then set the program up well for expanding into a number of indications, including potentially another melanoma trial,” said Rob Kloppenburg, Synta VPInvestor Relations and Corporate Communications, in an e-mail exchange after the Molecular Tri-Con meeting.

Dissecting Unexpected SYMMETRY Failure Elesclomol is aimed at increasing the high levels of reactive oxidation species (ROS) in cancer cells, triggering apoptosis. The drug had performed very well in a Phase II study that had an almost identical design as SYMMETRY. In that randomized, controlled trial of 81 patients, elesclomol met its progressionUnauthorized photocopying is prohibited by law.

Pharmaceutical Approvals Monthly

free survival endpoint (median PFS of 3.7 months versus 1.8 months). And at six months, 35% of elesclomol patients had PFS versus 18% of control patients. Elesclomol looked poised to become a breakthrough treatment. Company execs were waiting for the great results from Phase III to roll in and instead got a call from the safety monitoring committee notifying them that there was an imbalance in the number of deaths favoring the control arm (80 vs. 53). “We had had great hopes – the Phase III trial was identical to Phase II and we hadn’t seen this,” Blackman said at the Molecular Tri-Con meeting. The SYMMETRY study had tested the drug in combination with paclitaxel versus paclitaxel alone in 630 chemotherapynaïve patients Paclitaxel is known to have ROS-inducing properties, so the thinking was that there would be synergy with elesclomol. Progression-free survival results in the trial actually favored the treatment arm. Synta went on to spend a full year performing lab tests and analyzing the data in order to solve the mystery of why patients in the treatment arm were dying earlier. As time went on after the SYMMETRY was suspended, and data continued to be collected, it became clear that the overall survival results were improving. The company was able to show that if patients with high LDH were excluded, there was a significant benefit in the elesclomol arm. The data safety monitoring board had looked at the results early and were picking up on the earlier deaths of patients with high LDH. As the survival rates for those with low or normal LDH were included, the study curves were looking up, Blackman said. In terms of median PFS, benefits were seen in low and normal LDH patients, but not high LDH. As it turns out, LDH levels appear to be not only a biomarker for poor prognosis, but also a predictive biomarker for elesclomol’s efficacy, the exec said.

High LDH = Tumor Hypoxia = Low Activity The company could have tried to get permission to restart research based on the subpopulation analyses, but it also wanted to understand how LDH was impacting results in terms of mechanism of action. Through this investigation, Synta refined its understanding about the way the drug works. With some digging, the company learned that the drug needs a functional mitochondrial respiratory chain to trigger ROS in a cell and that ROS is linked to the binding of the drug to copper. As the company website explains, elesclomol kills cancer cells in which the mitochondrial electron transport chain is the dominant source of energy production. This can occur when oxygen conditions are normal (normoxic) but under low March 2011 | 23

Pharmaceutical Approvals Monthly

Elsevier Business Intelligence

oxygen (hypoxic) conditions, there is a shift toward producing energy from glucose into other byproducts (glycolysis), and away from mitochondrial energy production. High LDH is linked with tumor hypoxia, and in this environment elesclomol is not active. Conversely, low to normal levels of LDH are associated with a normoxic environment, “and this is where we see elesclomol activity,” the company explains. All in all, Synta had enough evidence to allow trials of elesclomol to resume. And the knowledge about the value of shifting away from glycolysis could impact selection and development of other candidates in the future.

Part Of Trend The elesclomol experience is part of a larger trend of research into disease activity helping to resurrect a drug after a trial failure. Synta considers it akin to Dendreon Corp.’s Provenge (sipuleucel-T), which suffered early clinical setbacks and ultimately got approved for prostate cancer as more was understood about how the drug works. Or, more recently, Human Genome Sciences Inc.’s Benlysta (belimumab) was cleared; the lupus drug failed in Phase II, but post-hoc analysis of the data gave HGSI and partner GlaxoSmithKline confidence to move forward (“Emerging Phase III Data Validate Clinical Trial Design In Lupus,” Pharmaceutical Approvals Monthly, September 2009).

“In both cases, a review of the data allowed a better understanding of the activity of the drugs,” Kloppenburg said. Debiopharm Group has put Pfizer Inc.’s CTLA-4 inhibitor tremelimumab back in the clinic in a Phase II trial, following a late-stage failure in melanoma (“Weak Result Stops Pfizer’s Tremelimumab Phase III Trial,” “The Pink Sheet,” April 3, 2008). As with elesclomol, the new study will use a biomarker to identify responders. Per a co-development deal between the two companies, Debiopharm will lead development and Pfizer will handle commercialization. As understanding of cancer improves, scientists are better able to learn from trial results and make adjustments that can help identify patient populations that can benefit from a particular therapy, Kloppenburg said. “Elesclomol is a tremendous example of this, where our improved understanding of the mechanism of action … combined with an improved understanding of [the role] hypoxia can play in activity has helped us design trials where we (and our collaborators) believe elesclomol can provide benefit to patients in diseases such as AML and ovarian cancer,” he said. If elesclomol is eventually approved, Glaxo will be eligible for a very small royalty on sales. At the time the SYMMETRY study was suspended, the company had earned $50 million in milestones from Glaxo.

INSIGHT AND ANALYSIS FROM ELSEVIER BUSINESS INTELLIGENCE With highlights from:

BUSINESS DEVELOPMENT FINANCE STRATEGY DRUG DEVELOPMENT REGULATION REIMBURSEMENT

“The Pink Sheet” “The Pink Sheet DAILY” IN VIVO Start-Up Pharmaceutical Approvals Monthly PharmAsia News “The Gold Sheet”

Elsevier Business Intelligence – publisher of "The Pink Sheet" and IN VIVO: The Business & Medicine Report — announce a complimentary resource on biopharmaceutical industry developments. Get insight and analysis covering crucial business-critical information on the new Biopharma Today Blog.

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24 | March 2011

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Uncertain Future For Otelixizumab In Type 1 Diabetes After Phase III Failure

Pharmaceutical Approvals Monthly

Otelixizumab had shown promising results in Phase II dosefinding studies where recipients received up to 48 mg of the drug, but for the Phase III program, a 3.1 mg dose was selected because of tolerability issues seen with higher doses, the firm explained.

JOSEPH HAAS j.haas@elsevier.com

laxoSmithKline and Tolerx announced March 11 that their humanized anti-CD3 monoclonal antibody, otelixizumab failed to meet the primary endpoint in the Phase III DEFEND-1 trial for type 1 diabetes, and they were halting recruitment and dosing in another Phase III trial, DEFEND-2, while they review the DEFEND-1 results. The primary endpoint was change in C-peptide, a marker for the individual’s natural insulin production, as measured 12 months after therapy.

The companies partnered on the antibody for development in type 1 diabetes and other autoimmune and immune-mediated inflammatory diseases in 2007 (“GSK Signs Deal For Tolerx Anti-CD3 Antibody For Type 1 Diabetes,” “The Pink Sheet” DAILY, Oct. 23, 2007). Although GSK had recently touted the low attrition rate for its late-stage pipeline, the poor DEFEND-1 results were not unexpected. Eli Lilly and MacroGenics’ teplizumab, another anti-CD3 antibody being studied in type 1 diabetes, missed its endpoint in a Phase III study last fall (“Lilly Sweet On MacroGenics’ Novel Diabetes Drug Teplizumab,” “The Pink Sheet” DAILY, Oct. 18, 2007). That study hinged on a composite measurement of a patient’s total daily insulin usage and HbA1c levels after 12 months.

This is the second anti-CD3 antibody to fail in type 1 diabetes: Lilly and MacroGenics’ teplizumab failed to meet its Phase III endpoint in 2010. “This is not overly surprising, given that Lilly failed a similar study with a similar agent in 2010,” wrote Leerink Swann analyst Seamus Fernandez in a March 11 note. He added that it remains unclear whether development will continue for either antibody in type 1 diabetes. However, in an e-mail, Tolerx cautioned that so far only top-line data from DEFEND-1 are available. “Tolerx and GSK need to better understand the results of the DEFEND-1 study before we can make any comment about the future clinical development plan for otelixizumab in type 1 diabetes,” the company said.

Dose Lowered Significantly For Phase III GSK said in its release that it would continue to explore additional dosing regimens to inform decisions about the antibody’s development future. Unauthorized photocopying is prohibited by law.

DEFEND-1 was a randomized, placebo-controlled study of 272 patients, aged 12-45, with new-onset type 1 diabetes. The trial investigated whether a single, eight-day intravenous course of otelixizumab administered within 90 days of diagnosis preserved the function of insulin-producing beta cells in the pancreas, as measured by C-peptide. Tolerx said measurement of C-peptide at 12 months after dosing is a well-established surrogate measure of beta cell function endorsed by FDA. Prior to partnering the antibody with GSK, Tolerx reported a Phase II study in which otelixizumab demonstrated the potential to preserve the function of insulin-producing beta cells in the pancreas and reduce the amount of administered insulin needed to control blood glucose levels after a single course of therapy. It does this by inhibiting T-effector cells, which attack the body’s own tissue in autoimmune disease states, and by prompting T-regulatory cells to suppress T-effector cell damage. The deal between Tolerx and GSK included a $70 million upfront payment, along with up to $155 million in future development cost funding and up to $525 million in development and sales milestones. Tolerx was responsible for conducting the Phase III trials in type 1 diabetes and held an option to co-promote the drug in that indication in the U.S. GSK took over development of the antibody in other indications and has advanced it to Phase I in both rheumatoid arthritis and Graves eye disease. During the pharma’s fourth quarter earnings call, CEO Andrew Witty noted that there were no discontinuations of late-stage pipeline products in 2010, although GSK had scrapped sleep drug almorexant early in 2011. Counting otelixizumab, GSK has 30 products in late-stage development, 10 of which entered Phase III last year, and 20 of which are new chemical entities or vaccines (“GSK Announces Share Buyback Program As Pretax Profits Fall by 52% In 2010,” “The Pink Sheet” DAILY, Feb. 3, 2011). Privately held Tolerx, based in Cambridge, Mass., has raised well over $118 million, last bringing in $35.6 million in a Series E round in 2006 led by FrontPoint Partners (“Tolerx brings in $35.6mm with its latest venture round,” Elsevier’s Strategic Transactions Database, August 2006). Focused on therapies that normalize immune responses, the firm has two other programs in clinical development, led by TRX518, an immunotherapy that targets and activates the glucocorticoid-induced tumor necrosis factor receptor (GITR) in Phase I in cancer. March 2011 | 25

Pharmaceutical Approvals Monthly

Regeneron Files BLA For VEGF Trap-Eye In Wet AMD; Second Filing Anticipated This Year SHIRLEY HALEY s.haley@elsevier.com

egeneron Pharmaceuticals Inc. is hoping to launch aflibercept ophthalmic solution in the fall with clinically equivalent trial results and a dosing advantage over Roche ‘s VEGF inhibitor Lucentis (ranibizumab), the current standard of care for “wet” agerelated macular degeneration. Regeneron announced Feb. 22 that it had filed a BLA for the VEGF Trap-Eye fusion protein product it is developing with Bayer HealthCare AG for AMD and asked FDA for a sixmonth priority review. Bayer plans a European filing for wet AMD in the first half of the year. In addition, the two companies, which are partnered on clinical development of aflibercept for intraocular indications, reported positive top-line results for the product in central retinal vein occlusion in December. They indicated they would speed up the timeline on a CRVO filing if the final results are positive, opening the door for a second 2011 filing (“Regeneron/Bayer Announce Positive VEGF Trap-Eye Data In A Second Eye Disease,” The Pink Sheet” DAILY, Dec. 20, 2010).

Second NDA could be filed in 2011, for central retinal vein occlusion.

Elsevier Business Intelligence

”If we do get out there, I think we can win that [choice] our fair share of the time,” Regeneron CEO Leonard Schleifer said Feb. 15 at the International Strategy & Investment conference in New York.

Preparing For Launch Regeneron plans to be “really ready to go” when an approval comes, Schleifer said. Retinal surgeons are very sophisticated, he said. They aren’t influenced by sending in a detail person, but matters such as reimbursement support, a safety net for patients and service issues are important. For that reason, he said he doesn’t envision a large detailing force for the product. Regeneron is sensitive to the pricing difference between Avastin and Lucentis, and, while all pricing options are on the table, one option is to price the product below Lucentis, Schleifer said. He said he doubts product loyalty will be an issue when two-thirds of the time Lucentis is losing to Avastin. “There’s nothing loyal about that from Roche’s perspective,” he quipped.

Taking On Lucentis/Avastin While VEGF Trap-Eye might offer an option for patients who are not helped by Lucentis/Avastin or who don’t want to continue with a monthly injection, the long-term success of the drug depends on winning new patients, not on getting established patients to switch, Schleifer said.

Coming study data could help build argument for switching established patients.

Market Could Hinge On Dosing Data The AMD BLA is based on positive results from the North American VIEW 1 study in 1,217 patients (sponsored by Regeneron) and the international VIEW 2 study in 1,240 patients (conduced by Bayer). In both studies, VEGF Trap-Eye was evaluated for its effect on maintaining and improving vision when dosed as a monthly intravitreal injection. Initial loading doses were given monthly for three months followed by dosing every two months compared to monthly ranibizumab, and the product was non-inferior at all dosing strengths, with a similar safety profile. Regeneron is counting on the dosing advantage as a wedge into the wet-AMD market, where it must compete not only with Lucentis but with off-label use of Roche’s cancer drug Avastin (bevacizumab), which can be administered in smaller, less-expensive doses than ranibizumab (“Regeneron/Bayer Bullish On Wet-AMD Drug But Commercial Success Is No Guarantee,” “The Pink Sheet” DAILY, Nov. 22, 2010). 26 | March 2011

The pending release of data from the CATT study, a Lucentis/Avastin comparison being conducted by NIH’s National Eye Institute, might offer Regeneron an advantage. The study includes arms testing the Roche drugs administered PRN, a test of the “treat and extend” regimen used off-label for both drugs in an attempt to push the monthly injections out to six or even eight weeks. Regeneron is assuming the two drugs will prove “about the same” when used monthly and that PRN dosing won’t be as effective, Schleifer said. In its year-end financial report Feb. 2, Roche management tried to reassure investors ahead of the CATT results – which are due in the first half – by pointing out that Lucentis accounts for only 3% of the company’s sales. Still, Lucentis generated CHF 1.46 billion in 2010, up 27% year over year (“Roche Looks Ahead To 2011, But Avastin Woes And Other Concerns Could Pose Challenges,” “The Pink Sheet” DAILY, Feb. 2, 2011).

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User Fee Goals For Recently Announced NDA/BLA Submissions For a complete list of user fee goals compiled by Pharmaceutical Approvals Monthly see our website, www. PharmaceuticalApprovals.com. User fee goals are calculated based on the date the application is received by FDA and the agency’s assignment to either standard (10 months) or priority (6 months) review. Resubmissions that contain significant new data or analyses have a six-month review goal.

Sponsor & Product

Class/Indication

Celgene

New indication for the histone deacetylase inhibitor for treatment of peripheral T-cell lymphoma patients who have received at least one prior therapy

Istodax Romidepsin a

Lundbeck Onfi Clobazam b

Merck/Santen Saflutan Tafluprost b

Submission/ Receipt Date

Advisory Committee Status

Estimated User Fee Goal

12/2010

6/17/2011 (Priority review)

1,5-benzodiazepine that binds to GABA-A 1Q 2011 receptors as adjunctive therapy for treating seizures associated with Lennox-Gastaut syndrome in patients two years of age and older

4Q 2011 (Standard review)

Preservative-free prostaglandin analog ophthalmic solution for reduction of elevated intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension

4Q 2011 (Standard review)

1Q 2011

Novo Nordisk Recombinant Factor XIII b (rFXIII)

Recombinant protein clotting Factor Announced XIII as an alternative to FXIII derived 2/23/2011 from human plasma as preventive once-monthly replacement therapy for patients with congenital FXIII deficiency

8/23/2011 or earlier if priority review; 12/23/2011 or earlier if standard review

Pfizer (FoldRx) Tafamidis meglumine b

First-in-class oral therapy for treatment 2/2011 of the genetic neurodegenerative disease transthyretin amyloid polyneuropathy

8/2011

Regeneron VEGF Trap-Eye b

Fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 to block VEGF-A and Placental Growth Factor for treatment of neovascular, or “wet,” age-related macular degeneration

Announced 2/22/2011

8/22/2011 or earlier (if FDA grants priority review request)

Seattle Genetics Brentuximab vedotin b

Antibody-drug conjugate comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to the cytotoxin monomethyl auristatin E for treatment of relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma

Announced 2/28/2011

8/28/2011 or earlier (if FDA grants priority review request)

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Sponsor & Product

Class/Indication

Shire (formerly Jerini)

Bradykinin B2 receptor antagonist for treatment of acute attacks of hereditary angioedema

Firazyr Icatibant b, inj.

Submission/ Receipt Date

Advisory Committee Status

Estimated User Fee Goal 8/28/2011 or earlier

Announced 2/28/2011(Class 2 resubmission in response to 4/2008 “not approvable” letter)

Takeda Fixed-dose combination of the Announced a angiotensin II receptor blocker (Edarbi) 2/23/2011 Azilsartan/chlorthalidone and the long-acting oral thiazide-like diuretic for treatment of hypertension

12/23/2011 or earlier

* Status as priority or standard review unknown a Submission for new use or new formulation of drug that sponsor already markets b New molecular entity or combination product with NME as component

NDAs/BLAs With User Fee Goals In February, March & April 2011 For a complete list of user fee goals compiled by Pharmaceutical Approvals Monthly see our website, www. PharmaceuticalApprovals.com. User fee goals are calculated based on the date the application is received by FDA and the agency’s assignment to either standard (10 months) or priority (6 months) review. Resubmissions that contain significant new data or analyses have a six-month review goal.

Submission/ Receipt Date

Advisory Committee Status

Estimated User Fee Goal

Inhibitor of VEGFR, EGPR, and RET pathways for oral treatment of advanced medullary thyroid cancer

Announced 9/23/2010

Advisory committee 12/2/2010 voted 10-0 in favor of requiring postmarketing studies to find optimal dose; 6 of 10 panelists favored limiting indication to progressive and/or symptomatic disease

4/7/2011 (Priority review) (FDA extended user fee goal from 1/7/2011 to review REMS)

Macrocyclic non-ionic gadolinium-based contrast agent for use in magnetic resonance imaging of the central nervous system

5/14/2010

Advisory committee 1/21/2010 voted 16-0 in support of approval

3/14/2011 (Approved 3/14/2011)

Boehringer Ingelheim/Lilly Linagliptin b

Dipeptidyl peptidase-4 inhibitor for oral, oncedaily treatment of type 2 diabetes

2H 2010

Bristol-Myers Squibb

Cytotoxic T-lymphocyte antigen-4 inhibitor for second-line treatment of metastatic melanoma

6/2010

Sponsor & Product

Class/Indication

AstraZeneca Zictifa Vandetanib b (formerly Zactima)

Bayer Schering Pharma AG (Bayer HealthCare Pharmaceuticals) Gadavist Gadobutrol, 1.0 molar concentration (formerly Gadovist)

Yervoy Ipilimumab b

28 | March 2011

4/2011 to 10/2011

Advisory committee review rescheduled for 2/9/2011 cancelled

3/26/2011 (Priority review) (User fee goal extended from 12/25/2010 for major amendment)

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Submission/ Receipt Date

Advisory Committee Status

Estimated User Fee Goal

Sponsor & Product

Class/Indication

Eisai

5/3/2010 Oral suspension formulation of the triazole derivative (approved as an oral tablet) for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children four years and older and adults

3/3/2011 (Approved 3/3/2011)

New weekly transdermal patch formulation of the cholinesterase inhibitor for treatment of mild, moderate and severe Alzheimer’s disease

6/30/2010

4/30/2011

Phosphodiesterase-4 inhibitor for once-daily, oral treatment to reduce the risk of chronic obstructive pulmonary disease exacerbations in patients with severe COPD associated with chronic bronchitis in patients at risk for exacerbations

8/30/2010 (Class 2 response to FDA’s 5/17/2010 “complete response” letter for NDA originally received 7/17/2009)

Prodrug of gabapentin with improved pharmacokinetics using high-capacity nutrient transport mechanisms in the GI tract to improve absorption, for treatment of moderate-to-severe primary restless leg syndrome

10/2010 (Class 2 response to 2/17/2010 “complete response” letter amends NDA from 505(b)(1) to 505(b) (2) so FDA can consider published gabapentin nonclinical data; NDA submitted 1/9/2009; original 9/2008 NDA withdrawn 11/2008 to reformat data)

New indication for the anticonvulsant for monotherapy of partial seizures in patients 13 and older

Late 3/2010

Banzel Rufinamide, oral suspension a

Eisai/Teikoku Pharma/Pfizer Aricept Donepezil, transdermal a

Forest/Nycomed Daliresp Roflumilast b (formerly known as Daxas)

GlaxoSmithKline/Xenoport Horizant Gabapentin enacarbil b (formerly Solzira)

GlaxoSmithKline Lamictal XR Lamotrigine, extended-release a

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Advisory committee 4/7/2010 voted 10-5 that overall risk/ benefit had not been shown for the original slightly broader indication; the revised indication was submitted 1/29/2010, too late for consideration

2/28/2011 (Approved 2/28/2011)

4/6/2011

Advisory committee 3/10/2011 voted 10-2 with 1 abstention and 1 absence that effectiveness had been shown and 14-0 that historical control trial design was acceptable

4/30/2011 (FDA extended PDUFA goal from late 1/2011 after requesting additional analyses)

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Submission/ Receipt Date

Sponsor & Product

Class/Indication

Horizon PharmaHZT-501 Ibuprofen/famotidine a (formerly Duexa)

3/2010 Fixed-dose tablet formulation of the NSAID and a high dose of the H2 antagonist to reduce the risk of development of upper gastrointestinal ulcers in patients with mild to moderate pain and arthritis

Human Genome Sciences/ GlaxoSmithKline

Monoclonal antibody that targets the protein B-lymphocyte stimulator for treatment of active, autoantibodypositive systemic lupus erythematosus patients who are receiving standard therapy

6/9/2010

Long-acting progesterone to reduce the risk of preterm birth in women who are pregnant with a single baby and had spontaneously delivered a single baby preterm in the past

Announced 7/13/2010 (Resubmission following FDA’s 1/2009 “complete response”; previously “approvable” 10/2006; 505(b) (2) NDA submitted 5/2006)

9/2010

Oral tablet formulation of the drug, which may interfere with lymphocyte proliferation, to reduce relapses in people with relapsing forms of multiple sclerosis

Announced 6/8/2010 (FDA refused to file an earlier submission 11/2009)

Benlysta Belimumab b

K-V Pharmaceutical/ Hologic Makena Hydroxyprogesterone (also known as 17 alphahydroxyprogesterone caproate or 17P)(formerly Gestiva)

Lilly (formerly Avid Radiopharmaceuticals) Amyvid Florbetapir F 18 b

Merck Serono (Merck KGaA) Cladribine

30 | March 2011

Advisory Committee Status

Estimated User Fee Goal 4/22/2011 (FDA extended user fee goal from 1/21/2011)

Advisory committee 11/16/2010 voted 13-2 for approval

3/10/2011 (Priority review) (FDA extended user fee goal from 12/9/2010) (Approved 3/9/2011)

4/13/2011 (FDA extended user fee goal from 1/13/2011 to review additional information submitted) (Approved 2/3/2011)

Advisory committee 3/17/2011 1/20/2011 recommended (Priority review) against approval 13-3 (“Complete response” letter announced 3/18/2011)

2/28/2011 (Priority review) (FDA extended user fee goal from 11/28/2010 to provide time for review of additional information) (“Complete response” letter announced 3/2/2011)

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Submission/ Receipt Date

Advisory Committee Status

Estimated User Fee Goal

Long-acting beta 2 antagonist for once-daily use as a bronchodilator for chronic obstructive pulmonary disease

10/1/2010 (Response to 10/16/2009 “complete response” letter, lowering the dose to 75 or 150 mcg from the 150 or 300 mcg in the NDA submitted 12/15/2008)

Advisory committee 3/8/2011endorsed the 75 mcg dose 13-4 but voted 12-5 against approval of Novartis’ preferred 150 mcg dose

4/1/2011

Novartis Panobinostat b (LBH-589)

Pan-deacetylase inhibitor for oral treatment of extensively pretreated Hodgkin’s lymphoma patients who relapsed or became refractory after an autologous stem cell transplant

4Q 2010

2Q 2011

Pfizer/Protalix

Plant-cell expressed recombinant form of human glucocerebrosidase for the treatment of the lysosomal storage disorder Gaucher disease

Completion of rolling BLA submission announced 12/9/2009, but FDA’s request for additional CMC data, announced 2/2/2010, kept the BLA open until 4/2010

2/25/2011 (Standard review) (“Complete response” letter announced 2/25/2011)

New indication for the high-dose 550 mg tablet formulation of the gut-selective antibiotic for treatment of nonconstipation irritable bowel syndrome and IBSrelated bloating

Announced 6/8/2010

3/7/2011 (Priority review) (FDA extended user fee goal from 12/7/2010 for additional review time) (“Complete response” letter announced 3/8/2011)

Sponsor & Product

Class/Indication

Novartis Arcapta Neohaler Indacaterol b (previously called Onbrez Breezhaler)

Uplyso Taliglucerase alfa b

Salix Xifaxan Rifaximin 550 mg tabs. a

Sanofi-Aventis Menactra Vaccine, meningococcal serotypes A, C, Y, and W-135 a

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Expanded population for 6/2010 the conjugate vaccine for meningococcal serogroups A, C, Y, and W-135 for infants aged 9-12 months

4/2011 Advisory committee scheduled to discuss immunological markers for meningococcal A, C, Y, and W-135 vaccines in children under age 2 on 4/6/2011

March 2011 | 31

Pharmaceutical Approvals Monthly

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Sponsor & Product

Class/Indication

Shire

New claim for the nonstimulant alpha2A agonist, approved as monotherapy, for adjunctive treatment of attention deficit hyperactivity disorder in children and adolescents ages 6-17 years in combination with longacting oral stimulants

Intuniv Guanfacine a

Shire

Submission/ Receipt Date

Advisory Committee Status

4/28/2010

Estimated User Fee Goal 2/28/2011 (Approved 2/25/2011)

Expanded indication for 6/14/2010 the anti-inflammatory for maintenance of remission in ulcerative colitis patients

4/14/2011

Spectrum Pharmaceuticals Fusilev Levoleucovorin a

New indication for the folate analog for use in combination chemotherapy for advanced metastatic colorectal cancer

4/29/2011

Takeda Edarbi Azilsartan b

Angiotensin II receptor 4/27/2010 blocker for use alone or in combination with drugs from other antihypertensive classes for treatment of hypertension

2/28/2011 (Approved 2/25/2011)

Winston

6/30/2010 Transient receptor potential vallinoid (TRPV-1) modulator, also known as civamide, that selectively depresses activity of type-C pain fibers for topical treatment of signs and symptoms of osteoarthritis of the knee as monotherapy or in combination with systemic pain relief medications

4/30/2011 (Sponsor predicts FDA action in the second half of 2011)

Lialda Mesalamine a

Civanex Zucapsaicin, 0.075% cream b

10/29/2010 (Class 2 resubmission to 10/2009 â&#x20AC;&#x153;complete responseâ&#x20AC;? letter)

* Status as priority or standard review unknown a Submission for new use or new formulation of drug that sponsor already markets b New molecular entity or combination product with NME as component

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The Lesson Of Jevtana: With A Survival Advantage, All Things Are Possible BRIDGET SILVERMAN b.silverman@elsevier.com

he expedited review and approval of Sanofi-Aventis’ oncologic Jevtana (cabazitaxel) shows the power of a clearly demonstrated survival advantage to overcome regulatory hurdles. The Jevtana review took only 11 weeks, despite issues of a scale that have been known to derail other NDAs: significant, even fatal, adverse reactions and a dose level that the FDA review team found too high. “Cabazitaxel is being recommended for approval based on a survival advantage, which is considered a gold standard in the field of oncology,” Division of Drug Oncology Products Deputy Director Amna Ibrahim said in a memo dated June 17, 2010, the day of Jevtana’s approval. Office of Oncology Drug Products Director Richard Pazdur explained that with the survival benefit, the review was expedited “due to an anticipated impact on public health” in his June 17, 2010, memo.

The “anticipated impact on public health” merited the expedited review, FDA’s Pazdur said. There were no treatment options that offered a survival benefit for the proposed hormone-refractory prostate cancer population, clinical reviewers Amy McKee and Ian Waxman pointed out in their June 2, 2010, review, noting that “the robust results in overall survival” for cabazitaxel would change that. Median overall survival for Jevtana patients in the pivotal 755-patient TROPIC trial was 15.1 months, compared with 12.7 months for mitoxantrone patients in the comparator arm (“With Jevtana Approved For Advanced Prostate Cancer, Sanofi Could See Expansion To First-Line Use,” “The Pink Sheet,” June 21, 2010).

Survival Benefit > Unusually Severe Toxicity Sanofi-Aventis, the NDA sponsor, helped FDA move Jevtana through the review process quickly, with “rapid responses … to FDA questions and concerns,” Ibrahim stated. The expedited review action goal date was June 18, 2010, less than three months after Jevtana’s completed submission on March 31, 2010. The regular PDUFA goal date was Sept. 30, 2010, a six-month timeline reflecting Jevtana’s priority review designation (see chronology of Jevtana clinical development). McKee and Waxman highlighted the strength of the clinical data; the medical review states that the overall survival results were robust, and “there were very few patients lost to follow-up or censored for other reasons.” Attesting to another aspect of the robustness of the NDA, Cross-Disciplinary Team Leader John Johnson reported in a June 17, 2010, memo that “there were no disagreements among review team members regarding risk/benefit assessment.” The strength of the survival benefit was vital to overcoming what Ibrahim called “the unusually high incidence and severity of toxicity” in cabazitaxel-treated patients in the pivotal trial. “Despite the increased toxicity and increase in deaths due to toxicity in the cabazitaxel arm relative to the control arm, there is still a survival advantage for the cabazitaxel treatment group,” Johnson agreed. Nonetheless, when the goal is palliation in a group of elderly men, the severity of toxicity is a factor. The median age of prostate cancer diagnosis is 72 years. “The risk/benefit ratio in the Phase III trial is favorable, but suboptimal,” he concluded.

A Setting In Need Hormone-refractory prostate cancer has been one of oncology’s more elusive targets. “Despite active research, it has been difficult to develop effective drugs to treat metastatic hormone-refractory prostate cancer,” Ibrahim stated. “There are few drugs available for the advanced form of this common cancer and none for this indication.”

Overall survival is especially important in HRPC, where surrogate endpoints are lacking. Pain, the most common stand-in for disease progression in prostate cancer, is a slippery element to measure, at best (“Why Survival Is The Fittest Enpoint For HRPC: The Problem With Pain,” Pharmaceutical Approvals Monthly, March 2011).

Jevtana is approved for a subset of advanced patients who have become refractory to the first line of attack in prostate cancer – medical or surgical castration – and who have then progressed on or become refractory to the first line of therapy for hormone-refractory disease, Sanofi-Aventis’ venerable taxane Taxotere (docetaxel). All the chemotherapies used in this setting have significant toxicities and are approved in combination with the steroid prednisone.

But even with the survival advantage, many stars had to align to put Jevtana in a position where an expedited review was appropriate.

Taxotere was approved for HRPC in 2004, and for the six years until the Jevtana approval it was the last line of therapy approved for these advanced patients.

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“For patients who have progression on or after docetaxel-based therapy, there are no treatments that have shown a survival advantage,” McKee and Waxman declared. “Mitoxantrone in combination with prednisone is labeled for pain palliation in this setting, but has not demonstrated a survival advantage,” they noted. Mitoxantrone was the comparator drug in both the pivotal Jevtana TROPIC trial and in the studies supporting docetaxel’s HRPC approval.

HRPC Drugs Are Few Despite Active R&D “Many single agents and combination regimens have been investigated in this setting but have shown unacceptable toxicity or unpromising response rates,” McKee said, listing a roll call of failed treatments: lenalidomide/paclitaxel, the histone deacetylase inhibitor romidepsin, pemetrexed, multi-kinase inhibitor sunitinib, gefitinib, microtubule inhibitor patupilone and bortezomib, among others. The clinical reviewers specifically cited the recent failure of GPC Biotech/Pharmion’s satraplatin, a next-generation oral platinum chemotherapy, to achieve the primary endpoint of overall survival as a second-line treatment for HRPC in

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the lare, placebo-controlled Phase III SPARC study (“GPC Biotech’s Satraplatin Fails To Meet Survival Endpoint In SPARC Trial,” “The Pink Sheet” DAILY, Oct. 31, 2007).

The history of HRPC R&D is littered with drugs and drug combinations with “unacceptable toxicity or unpromising response rates,” McKee said. Nonetheless, HRPC remains an active area for drug development. While 85% of prostate cancer patients respond to castration, either surgical or medical via gonadotropin-releasing hormone antagonists, prostate cancer is the most common cancer diagnosed in men, making the remaining 15% a not inconsiderable market. Additionally, the clinical reviewers noted, “responders will eventually become refractory to hormonal intervention.” In fact, Jevtana was actually the second novel HRPC therapy approved in 2010. Like Jevtana, Dendreon’s cancer vaccine

Jevtana Clinical Development Date

Action

IND Chronology (#56,999) 4/14/1999

IND activated

6/28/2006

End-0f-Phase II meeting

9/11/2006

Special Protocol Assessment request granted for pivotal study EFC6193

7/30/2008

“Dear Investigator” letter from sponsor directs clinical trial investigators to follow ASCO guidelines concerning use of G-CSF to reduce neutropenia risk

11/9/2009

Fast Track designation

12/18/2009

First sections of application submitted under rolling submission allowed fast track products

2/23/2010

Pre-NDA meeting

NDA Chronology (#20-1023) 3/31/2010

NDA submission completed

4/22/2010

Division of Drug Oncology Products requests consult with Study Endpoints and Labeling Development Team regarding the patient-reported outcome of pain intensity in Phase III

5/11/2010

Trade Name Jevtana found acceptable by Division of Medication Error Prevention and Analysis

6/17/2010

Approval

6/18/2010

Expedited review action goal

9/30/2010

PDUFA goal date (priority review)

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Provenge (sipuleucel-T) was approved on the basis of a survival advantage. However, Provenge’s indication is limited to metastatic HRPC patients with asymptomatic or minimally symptomatic disease, an earlier stage group of patients and a smaller population than Dendreon originally sought (“FDA Considered A Broader Indication For Dendreon’s Provenge,” Pharmaceutical Approvals Monthly, June 2010).

in the same class. There is no REMS or medication guide in Taxotere,” he explained.

The symptom of pain is widely used as a prognostic factor in prostate cancer. By limiting the Provenge indication to patients with little or no pain, FDA excluded the larger population of patients with more advanced disease.

As part of labeling discussions, “special attention was directed to clarity and content of the Boxed Warning, Contraindications, Warnings and Precautions sections. Emphasis was on neutropenia, febrile neutropenia, infection, diarrhea, hypersensitivity reactions and renal failure,” Johnson said.

The late-stage development candidates for HRPC are principally next-generation hormone therapies or alternative drugs to be used when hormone therapy fails (“Prostate Cancer Market Snapshot: More Than Provenge,” “The Pink Sheet,” Nov. 22, 2010). The FDA reviewers highlighted some promising new programs in the castration-resistant population, singling out two projects then in Phase III, One of the drugs is now one of the hottest new molecular entity prospects pending at FDA: abiraterone, a CYP17 inhibitor from Johnson & Johnson’s Cougar Biotech. J&J submitted an NDA for abiraterone late in 2010 for an indication similar to Jevtana’s in taxane-experienced metastatic advanced prostate cancer patients. The clinical reviewers also pointed to a Phase III trial using an Abbott Laboratories drug that famously stalled out with a “not approvable” letter for HRPC in 2005. The ongoing study highlighted by the reviewers combined Abbott’s atrasentan (Xinlay), an endothelin-A receptor antagonist, with docetaxel.

Familiarity Can Be An Asset Jevtana is a next-generation member of the same taxane class that includes two of the most well-established chemotherapies in the contemporary armamentarium, Bristol-Myers Squibb’s mainstay Taxol (paclitaxel) and SanofiAventis’ own vulnerable-togenerics Taxotere (docetaxel). Both Taxol and Taxotere are associated with a range of Medical toxicities, which have been managed through labeling. Statistics

The oncology setting in general is amenable to risk management through labeling and surveillance; treatment is usually closely supervised by a physician already experienced with managing the toxicity of chemotherapy, the primary reviewers noted.

Instead of focusing on communicating risk to the patient, as with a MedGuide, Jevtana risk management focuses on new studies to address FDA’s concerns. Indeed, the postmarketing requirements actually include more Phase III studies (two) than the NDA did (one).

The post-marketing program for Jevtana will include more Phase III studies than the pivotal program.

11 Weeks To Approval = 10 PMRs As FDA becomes more comfortable with the safety tools provided by the FDA Amendments Act, post-marketing requirements are increasingly being used as a tool to provide FDA with enough of a comfort level to approve drugs that nonetheless have issues requiring further exploration (“Out Of The Shadow Of REMS: FDA Review Documents Show Emerging Importance Of Post-Marketing Requirements,” Pharmaceutical Approvals Monthly, January 2011). In settings of unmet medical need, the assurance that FDA’s questions will be answered (or at least asked) even after the

Jevtana FDA Reviewers

There was no recommendation for a Risk Evaluation and Mitigation Strategy or medication guide for Jevtana, Deputy Division Director Ibrahim stated. “The issues for cabazitaxel are similar to the Taxotere label, another drug

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Amy McKee, M.D. (efficacy); Ian Waxman, M.D. (safety) Chia-Wen Ko, Ph.D.

Chemistry

Xiao-Hong Chen, Ph.D.

Clinical Pharmacology

Pengfei Song, Ph.D.

Pharmacology/Toxicology

Sachia Khasar, Ph.D.; Whitney Helms, Ph.D.

Study Endpoints and Label Development Ann Marie Trentacosti Regulatory Project Manager

Christy Cottrell March 2011 | 35

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drug has been released on the market has been critical to the approval of troubled products like Theratechnologies’ Egrifta (tesamorelin), the first product approved for HIVassociated lipodystrophy (“Egrifta Approval: FDA Balanced Modest Efficacy, Off-Label Use Potential With Unmet Medical Need,” Pharmaceutical Approvals Monthly, February 2011) or Takeda’s Uloric (febuxostat), the first new gout drug in decades (“Score One For FDAAA: Uloric Approval Was Clinched By Post-Market Powers,” Pharmaceutical Approvals Monthly, July 2010). Jevtana’s swift review and approval should not be read as FDA having full confidence in the drug. FDA was impressed by cabazitaxel’s robust survival data, but on the safety side of the equation, significant concerns loomed. And on those safety questions, the PMR provided a way for FDA to get an efficacious drug to patients without other options, while at the same time ensuring that possible ways to address the toxicity would be studied. One such study will look at reducing the dose.

The fast approval is not an indication that FDA is wholly confident. Other PMRs will fill in the clinical safety profile of the drug. PMRs will “evaluate the potential for intravenous infusion of particulate matter into the blood stream” and will “assess the signals of the serious risks of hepatic impairment, QT prolongation and drug-drug interaction,” Ibrahim summarized.

A Path To Reduced Toxicity: Dose Reduction As cross-disciplinary team leader Johnson noted, the cabazitaxel dose “causes considerable toxicity and may be unnecessarily high.” But there is no information from RCTs on any other cabazitaxel dose and thus no indication whether a lower dose would be effective. “Because the risk/benefit ratio is favorable and 25 mg/m2 is the only dose we have data on, we are stuck with this dose,” Johnson lamented. “Unfortunately, so are elderly men with HRPC.” Some signals in the data suggested that a lower dose could moderate the toxicity profile without sacrificing significant efficacy, making the dose issue a good candidate for a required post-marketing study. “We do not want to deny patients the potential benefit of this treatment while the study is ongoing,” the PMR development documents state. “Some Phase I data indicates that a lower dose could have been studied,” according to FDA’s PMR/PMC development templates for cabazitaxel. Clinical pharmacology data showed “evidence of an exposure-response” relationship for serious neutropenia, McKee and Waxman added. 36 | March 2011

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During the review, FDA and Sanofi-Aventis scoured the cabazitaxel safety database to find patients with cancers not of the prostate who had been treated with 20 mg/ m2, which could provide support to the idea that the lower dose was worth studying. They found 77 patients. The rate of grade 3-4 neutropenia rate was lower in the 20 mg/m2 dose patients than in the pivotal HRPC study’s 25 mg/m2 dose arm: 57.1% vs. 82.1%. “Of note, 50 of the 77 patients who received 20 mg/m2 dosing were breast cancer patients treated on protocol ARD6191,” Waxman pointed out. “Despite the lower rate of grade 3-4 neutropenia, patients on ARD6191 were found to have a higher overall exposure to cabazitaxel.” Following the suggestion that the lower dose level could provide adequate efficacy, FDA required two post-marketing Phase III trials testing the lower dose; both are expected to complete in 2017. One of the required Phase III post-marketing trials will take place in the first-line metastatic HRPC setting, comparing docetaxel with the approved 25 mg/m2 dose and the lower 20 mg/m2 dose of cabazitaxel. The primary endpoint of overall survival will evaluate the incidence of drug-related death as well as efficacy, the PMR development documents state. It will test a lower dose in a different prostate cancer population, as Johnson recommended. The other Phase III trial will take place in the same secondline population as TROPIC, metastatic HRPC patients previously treated with docetaxel, but will be larger: 1,222 patients compared with the pivotal trial’s 755. The secondline trial will have two dose arms, cabazitaxel 20 mg/m2 and 25 mg/m2, and will be “powered to preserve 50% of the treatment effect of cabazitaxel 25 mg/m2.” Both Phase III trial designs include interim analyses of efficacy based on “safety and overall survival,”

Another Path To Reduced Toxicity: G-CSF Data examined during the review also indicate that more aggressive use of granulocyte-colony stimulating factors like Amgen’s Neupogen (filgrastim) could provide another path to reducing toxicities related to neutropenia. “Post-submission analyses suggest that a proportion of patients who experience neutropenia benefited from G-CSF use or dose reduction,” clinical safety reviewer Waxman said. “Neutropenia led to more treatment discontinuations than any other adverse event on the cabazitaxel arm,” he reported, while the comparator arm had no neutropeniarelated discontinuations. “There was a clear relationship between neutropenia and grade 5 infection,” he continued. Infection was a leading cause of treatment-related deaths in cabazitaxel patients. “Due to the occurrence of four infection-related deaths during cycle 1 of cabazitaxel therapy, primary prophylaxis with G-CSF should be considered in patients at high risk for © 2011 F-D-C Reports, Inc., an Elsevier company. All rights reserved.

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neutropenia complications,” Waxman concluded. None of the five total patients with infection-related deaths were given G-CSF prophylactically, he added. Jevtana labeling, in the warnings and precautions, states that “primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features,” including being 65 years of age or older. Older patients “are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia,” the label notes. The recommendation for primary prophylaxis with G-CSF was not part of the TROPIC protocol. However, “based on the occurrence of fatal infections in patients >65 years of age, primary prophylaxis appears to be appropriate in this high-risk patient population,” Waxman concluded. The large majority of infection-related deaths (80%) occurred in the first treatment cycle.

The flood of Phase III data to come could position Jevtana for broader use. Sanofi-Aventis did try to bring the study’s criteria for G-CSF up to date with more recent American Society of Clinical Oncology recommendations, but Waxman speculated that the change came too late in the study to make a meaningful difference. On July 30, 2008, the sponsor issued a “Dear Investigator” letter reflecting the TROPIC independent data monitoring committee’s recommendation to review and follow ASCO guidelines on use of G-CSF. The “absence of infection-related deaths after the IDMC recommendation more likely reflects the timing of the recommendation rather than any changes in clinical practice,” Waxman said. Johnson injected a note of caution about the use of G-CSF for primary prophylaxis. “The necessity for almost 50% of patients to be supported by G-CSF is not what we would desire for this setting.” he said. The torrent of information that could come in from the 10 PMRs could help to obviate this and other concerns about Jevtana toxicity. The interim analyses of the Phase III PMR trials, in particular, could potentially lead to a lowering of the dose with a simultaneous lowering of neutropenia and associated complications. Perhaps, as the PMR data comes in, the robust efficacy that impressed the FDA review team will be matched with a less worrisome risk profile. With sizable Phase III data coming down the pike thanks to the extensive PMRs, the risk side of the benefit/risk calculation could help move Jevtana from a severely toxic last-ditch therapy to a more Unauthorized photocopying is prohibited by law.

mainstream chemotherapy – something like Taxotere, the soon-to-be generic taxane that Sanofi-Aventis would love to replace.

Why Survival Is The Fittest Endpoint For HRPC: The Problem With Pain BRIDGET SILVERMAN b.silverman@elsevier.com

anofi-Aventis’ Jevtana is notable for its 11-week expedited review, which made it as the speediest approval of 2010.

What is even more notable is that Jevtana (cabazitaxel) received full approval, unlike most of the fastest cancer drug approvals at the modern FDA – a feat owing in part to the lack of acceptable surrogate endpoints in hormone-refractory prostate cancer. Typical secondary endpoints in prostate cancer trials, like prostate specific antigen levels and pain, have multiple drawbacks that make them unsuitable for supporting important efficacy claims, FDA clinical reviewers Amy McKee and Ian Waxman show in their June 2, 2010 review. When Sanofi-Aventis looked for – and found – an effect on overall survival in the Jevtana pivotal trial, it didn’t have many other options. Thanks to the difficulty of “measuring response and progression in the metastatic HRPC population,” the clinical reviewers state, “the recommended endpoint in a Phase III trial is overall survival.”

The Allure Of Accelerated Approval Sponsors looking to get a promising oncologic for an unmet medical need onto the market post-haste often avail themselves of the accelerated approval pathway, also known as the Subpart H (for drugs) or Subpart E (for biologics) pathway. Under the accelerated approval regs, products can be submitted based on data from surrogate endpoints considered likely to predict a clinical outcome, while the sponsors commit to conduct confirmatory trials with survival or equivalent endpoints postmarketing. FDA can pull an accelerated approval if the confirmatory trial fails to show an advantage, or if the sponsor fails to conduct the trial. Most of the fastest oncology reviews in contemporary FDA history have gone to accelerated approval applications. Novartis’ pioneering targeted therapy Gleevec (imatinib) was famously cleared in 2.4 months in 2001. The next year, Sanofi-Aventis’ Eloxatin (oxaliplatin) received Subpart H approval for certain metastatic colorectal cancer patients in 1.5 months, and in 2003 Millennium’s Velcade (bortezomib)

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posted a 3.7-month review under an accelerated approval for an advanced multiple myeloma indication.

Bone Lesions Are Hard To Measure The bone lesions characteristic of metastatic prostate cancer elude easy measurement. Bone lesions “are not measurable by RECIST criteria,” McKee and Waxman note, and the most recent Prostate Cancer Clinical Trials Working Group consensus report (PCWG2) “recognizes that there are no validated criteria for response based on radionuclide scans of the bone.” One of the better-known surrogate measures for prostate cancer, prostate specific antigen levels, is undergoing a reevaluation after several recent studies questioned the value of PSA for screening and measuring response. PCWG2 recommends a lesser reliance on PSA levels to define progression on hormone refractory disease.

Pain Is Too Subjective Pain is frequently used in prostate cancer to measure both response and progression, McKee and Waxman noted, but “the difficulties in using the subjective measurement of pain to define progression” relegate it to secondary endpoint status. The PCGW2 expert consensus report states that ‘the assessment of pain progression is more difficult the subjectivity as to what constitutes a ‘clinically significant increase,’” the reviewers reported. Sanofi-Aventis probed the limits of what claims pain response data could support in labeling during the endof-Phase II meeting. The agency generally emphasized the pre-eminence of the overall survival endpoint, which Sanofi-Aventis had already agreed to use as the single primary endpoint, according to minutes of the June 29, 2006 meeting. A primary pain endpoint would require more data, FDA said: “If an improvement in survival is demonstrated, a single trial may be adequate. However, if the regulatory endpoint is pain improvement then a second controlled study would be required.” Ultimately, pain data from the secondary endpoints did not make it into the approved Jevtana labeling. The TROPIC trial’s secondary pain endpoint relied on a problematic patient-reported outcome, the Present Pain Intensity scale of the McGill-Melzack questionnaire, and failed to show a statistically significant effect on pain response or time to pain progression. The Division of Drug Oncology Products requested a Study Endpoints and Labeling Development team consult on one specific pain endpoint, the patient-reported outcome measure of pain intensity, which was used to define the secondary endpoints of progression-free survival, pain progression and pain response. 38 | March 2011

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“Open-label trials … are not adequately designed to support efficacy conclusions, based on subjective PRO measures, such as pain intensity,” SEALD reviewer Ann Marie Trentacosti declared May 10, 2010. Patient awareness of treatment assignment can produce both over-estimation and under-recognition of benefit. The pain intensity measure itself, the McGill-Melzack Pain Questionnaire present pain intensity scale, also “cannot effectively support efficacy claims,” she said. The PPI scale’s response options, which include “discomforting, distressing, horrible, and excruciating,” are “ambiguous and have not been shown to be interpretable and appropriate measures of t pain intensity.” Indeed, she continued, “the sponsor has not provided any information to justify that the pain progression and pain response definitions included in the trial are clinically meaningful.”

Disease Progression Stalls Out Over the past decade, two high-profile HRPC candidates gambled on disease progression endpoints to support efficacy. Both failed. GPC Biotech had a special protocol assessment with FDA that specified a progression-free survival endpoint for satraplatin in second-line HRPC, and filed an NDA based on PFS in February 2007 – only to withdraw the NDA several months later after an FDA advisory committee recommended basing any application on an overall survival endpoint. (“GPC Biotech To Resubmit Orplatna With Overall Survival Data,” “The Pink Sheet” DAILY, July 30, 2007). The ensuing overall survival trial, SPARC, failed to show an effect. Time-to-disease progression was the primary endpoint in the Phase III trial that Abbott tried to use as the centerpiece of its “not approvable” Xinlay (atrasentan) NDA in mHRPC. After Phase III failed to meet the TDP endpoint, Abbott submitted meta-analysis of a subset of the Phase III population and a failed Phase II study, but was smacked down by an advisory committee calling for overall survival data (“FDA Takes A More Conservative Approach To Quantifying Oncologic Benefit,” “The Pink Sheet,” Sept. 26, 2005). By sticking to the tried-and-true gold standard of overall survival, Sanofi-Aventis ensured that statistically significant data for the primary endpoint would not be a point of contention in the review. And with a clear demonstration of a survival advantage, even Jevtana’s high toxicity and holes in the data in drug interaction and other elements could not derail the expedited approval of the drug. Other issues could be addressed in required post-marketing studies while the drug provided the first option for docetaxel-experienced mHRPC patients (“The Lesson of Jevtana,” Pharmaceutical Approvals Monthly, March 2011). © 2011 F-D-C Reports, Inc., an Elsevier company. All rights reserved.

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