Clinical Alert - January 2023

TRENDING TOPICS

FDA APPROVES TEPLIZUMAB-MZWV (TZIELD™)

The FDA has approved a first-in-class CD3-directed monoclonal antibody therapy indicated to delay the onset of stage 3 type 1 diabetes (T1D) in adults and pediatric patients ≥ 8 years old with stage 2 T1D. Labeling recommends confirming stage 2 T1D through documentation of ≥ 2 positive pancreatic islet autoantibodies in patients with dysglycemia without overt hyperglycemia. An oral glucose tolerance test (OGGT) or alternative method should be used for diagnosing dysglycemia. Patients eligible for therapy should not have a clinical history suggestive of type 2 diabetes. Additional baseline labs include CBC and liver enzyme tests, as use is not recommended in certain patients with abnormal lab values or in patients with acute EBV or CMV infection or other active serious or chronic infections. Age-appropriate vaccination is also required prior to initiation of therapy, and premedication is recommended with an NSAID or acetaminophen, an antihistamine, and/or an antiemetic for at least the first 5 days of therapy.

Teplizumab-mzwv is administered once daily for 14 consecutive days as an IV infusion over ≥ 30 minutes with dosing based on BSA (day 1: 65 mcg/m2; day 2: 125 mcg/m2; day 3: 250 mcg/m2; day 4: 500 mcg/m2; day 5 through 14: 1,030 mcg/m2). Although there are no contraindications to use, teplizumab-mzwv carries warnings for CRS, serious infections, lymphopenia, and hypersensitivity reactions. A phase 2, randomized, double-blind, placebo-controlled trial (n=76) evaluated teplizumab-mzwv in patients 8 to 49 years with stage 2 T1D. The primary endpoint was the time from randomization to development of stage 3 T1D diagnosis. The median time to diagnosis was 48.4 months in the teplizumab-mzwv group and 24.4 months in the placebo group; stage 3 T1D was diagnosed in 43% of teplizumab-treated patients compared to 72% of placebo patients. Teplizumab-mzwv led to a significant delay in the development of stage 3 T1D (HR, 0.41; 95% CI, 0.22 to 0.78; p=0.006). The most common adverse effects with teplizumab-mzwv compared to placebo, respectively, were lymphopenia (73% versus 6%), rash (36% versus 0), leukopenia (21% versus 0), and headache (11% versus 6%).

REZVOGLAR™: INTERCHANGEABLE BIOSIMILAR

Insulin glargine-aglr (Rezvoglar) has been approved as an interchangeable biosimilar to Lantus® (insulin glargine). Rezvoglar was first approved in December 2021 as a biosimilar to reference product Lantus. In November 2022, the FDA approved interchangeability for the biosimilar— meaning Rezvoglar can be expected to produce the same clinical result as the reference product (Lantus) in any given patient, and the risk in terms of safety or diminished efficacy from alternating or switching between use of the reference product and interchangeable product is not greater than that from not switching. Rezvoglar is a long-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes and will be supplied as 100 units/mL in a 3 mL single-patient-use KwikPen® prefilled pen. It is the second interchangeable biosimilar insulin product to Lantus. Interchangeable biosimilars can be substituted for the reference product without the intervention of the prescriber, depending on state substitution laws.

COVID-19: NOTABLE DEVELOPMENTS

The FDA’s VRBPAC will convene on January 26, 2023 to discuss future vaccination regimens for COVID-19 and the composition of the primary doses and booster doses. The Agency has amended the EUAs of the bivalent COVID-19 vaccines from Moderna and Pfizer-Biontech to include use in children as young as 6 months of age. Specific details on eligibility criteria for these younger children are available from the FDA. Interim recommendations from the ACIP on the use of bivalent COVID-19 booster doses have also been published. Tocilizumab (Actemra®) has received FDA approval for certain hospitalized adults with COVID-19 who are receiving systemic corticosteroids and require respiratory support; tocilizumab retains EUA for certain hospitalized pediatric patients with COVID-19. The CDC has published data demonstrating a 51% lower hospitalization rate within 30 days following the diagnosis of COVID-19 among those adults who were prescribed nirmatrelvirritonavir (Paxlovid™) within 5 days of diagnosis, compared to those who did not receive Paxlovid. Please refer to the COVID-19 disclaimer at the end of the publication.

DRUG INFORMATION

HAPPENINGS & HIGHLIGHTS

• The CDC is reporting seasonal influenza-like illness (ILI) remains high but is decreasing in most areas for the week ending December 24, 2022. The majority of influenza viruses detected were A(H3N2) with 17% being A(H1N1). The FDA is currently reporting shortages for oseltamivir oral suspension and capsules from some manufacturers, and ASHP is also reporting shortages of oseltamivir capsules and oral suspension by multiple generic manufacturers.

• A liquid formulation of Rotarix® (rotavirus vaccine, live oral) supplied in an oral dosing applicator has been approved. This liquid formulation does not require reconstitution or dilution prior to administration. The oral dosing applicator provides a 1.5 mL dose that is administered orally. In contrast, the already available vial and oral dosing applicator presentation contain lyophilized vaccine that is reconstituted with the diluent before administration. After reconstitution of the lyophilized powder, the 1 mL dose is administered orally.

• The FDA has extended the duration of use for the levonorgestrel-releasing intrauterine system (Liletta®) from 6 years to ≤ 8 years. Liletta 52 mg is now indicated to prevent pregnancy for up to 8 years.

• GlaxoSmithKline has announced initiation of withdrawal of belantamab mafodotin-blmf (Blenrep ® ) from the market at the request of the FDA. The phase 3 confirmatory trial, DREAMM-3, did not meet the FDA’s Accelerated Approval requirements. Blenrep received FDA approval in August 2020 for the treatment of adults with relapsed or refractory multiple myeloma who have received ≥ 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

• Genentech has announced voluntary withdrawal for use of atezolizumab (Tecentriq®) for the treatment of adults with locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatincontaining chemotherapy and whose tumors express PD-L1 or are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. Other indications for atezolizumab remain.

• At the request of the FDA, GlaxoSmithKline has announced the second-line (recurrent) maintenance indication for niraparib (Zejula®) for ovarian cancer will be restricted to use only in patients with deleterious or suspected deleterious germline BRCA mutations. The first-line maintenance therapy indication remains the same.

DRUG INFORMATION HAPPENINGS

•

The International Antiviral Society (IAS)-USA Panel has issued the 2022 recommendations on antiretroviral drugs for treating and preventing HIV infection in adults; this updates the 2020 consensus recommendations.

•

The American Academy of Pediatrics (AAP) has published updated guidance on use of palivizumab (Synagis®) prophylaxis for prevention of hospitalization from severe RSV infection during the 2022 to 2023 RSV season.

•

The American Diabetes Association (ADA) has released the 2023 Standards of Care in Diabetes

• The CDC has published interim guidance for prioritization of antiviral therapy for influenza in the presence of decreased oseltamivir (Tamiflu®) availability.

• The FDA has updated its list of shortages for amoxicillin oral powder for suspension.

• The FDA has posted a Drug Safety Communication on the risk for severe hypocalcemia with potentially fatal outcomes in patients on dialysis treated with the osteoporosis drug denosumab (Prolia®).

PIPELINE NEWS

UPCOMING PRESCRIPTION DRUG/BIOSIMILAR USER FEE ACT (PDUFA/BsUFA) DATES

budesonide/albuterol

AstraZeneca

donanemab

Eli Lilly

pirtobrutinib

Eli Lilly

zavegepant Biohaven/Bristol-Myers Squibb

lecanemab Eisai/Biogen

• Inhaled

• Corticosteroid/shortacting beta agonist

• IV

• Amyloid beta protein inhibitor

• Oral

• Bruton’s tyrosine kinase inhibitor

• Intranasal

• Calcitonin generelated peptide (CGRP) receptor antagonist

• IV

• Amyloid beta protein inhibitor

Asthma

Jan−Feb 2023

Alzheimer’s disease (early) Jan−Feb 2023

Mantle cell lymphoma Jan−Feb 2023

Migraine treatment

Jan−Mar 2023

Alzheimer’s disease (early) 01/06/2023

RECENT FDA APPROVALS

DRUG NAME MANUFACTURER

methotrexate (Jylamvo®) Therakind

fecal microbiota, live-jslm (Rebyota™) Ferring

olutasidenib (Rezlidhia™) Rigel

DESCRIPTION

New Drugs

• 505(b)(2) NDA approval 11/29/2022; Standard Review

• Indicated for the treatment of adults with (1) acute lymphoblastic leukemia as part of a combination chemotherapy maintenance regimen, (2) mycosis fungoides, (3) relapsed or refractory non-Hodgkin lymphoma as part of a metronomic combination regimen, (4) rheumatoid arthritis, and (5) severe psoriasis

• Folate analog metabolic inhibitor

• Oral solution: 2 mg/mL

• Recommended starting dose for non-oncologic indications is 7.5 mg to 10 mg once weekly with escalation to achieve optimal response; dosage varies when administered as part of a chemotherapy regimen for neoplastic diseases

• Boxed warning for embryo-fetal toxicity, hypersensitivity reactions, and severe adverse reactions

• BLA approval 11/30/2022; Breakthrough Therapy, Fast Track, Orphan Drug

• Indicated for use in adults for the prevention of recurrence of Clostridioides difficile infection (CDI) following antibiotic treatment for recurrent CDI

• Not indicated for treatment of CDI

• Fecal microbiota suspension for rectal administration

• Rectal suspension: 150 mL dose contains between 1x108 and 5x1010 CFUs per mL of fecal microbes and ≤ 5.97 grams of polyethylene glycol 3350 in saline

• Recommended dosage is 150 mL rectally as a single dose administered by an HCP; administer 24 to 72 hours after the last dose of antibiotics for CDI

• NDA approval 12/01/2022; Orphan Drug, Standard Review

• Indicated for the treatment of adults with relapsed or refractory acute myeloid leukemia with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test

• IDH1 inhibitor

• Oral capsule: 150 mg

• Recommended dosage is 150 mg twice daily on an empty stomach until disease progression or unacceptable toxicity; for patients without disease progression or unacceptable toxicity, treat for ≥ 6 months to allow time for response

• Boxed warning for potentially fatal differentiation syndrome

RECENT FDA APPROVALS continued

DRUG NAME MANUFACTURER DESCRIPTION

New Drugs continued

adagrasib (Krazati™) Mirati

• NDA approval 12/12/2022; Accelerated Approval, Assessment Aid, Breakthrough Therapy, Fast Track, Orphan Drug, Standard Review

• Indicated for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received ≥ 1 prior systemic therapy; continued approval for this use may require demonstration of benefit in confirmatory clinical trials

• RAS GTPase inhibitor

• Oral tablet: 200 mg

• Recommended dosage is 600 mg twice daily until disease progression or unacceptable toxicity

adalimumab-aacf (Idacio®) Fresenius Kabi

latanoprost (Iyuzeh™) Thea Pharma

• BLA approval 12/13/2022; biosimilar to adalimumab (Humira®)

• Indicated for the treatment of adults with (1) moderately to severely active rheumatoid arthritis, (2) active psoriatic arthritis, (3) active ankylosing spondylitis, (4) moderately to severely active ulcerative colitis, (5) moderately to severely active Crohn’s disease, and (6) certain adults with moderate to severe chronic plaque psoriasis

• Indicated for the treatment of (1) moderately to severely active polyarticular juvenile idiopathic arthritis in patients aged ≥ 2 years and weighing ≥ 30 kg and (2) moderately to severely active Crohn’s disease in pediatric patients aged ≥ 6 years and weighing ≥ 40 kg

• Tumor necrosis factor (TNF) blocker; citrate-free formulation

• Single-dose prefilled pen and single-dose prefilled syringe: 40 mg/0.8 mL

• Recommended maintenance dosage is usually 40 mg administered SC every other week following recommended loading doses

• Boxed warning for increased risk of serious infections and malignancy

• Product availability is expected in July 2023

• 505(b)(2) NDA approval 12/13/2022; Standard Review

• Indicated for the reduction of elevated intraocular pressure in patients with openangle glaucoma or ocular hypertension

• Prostaglandin F2α analogue

• Ophthalmic solution: 0.005% (50 mcg/mL); preservative-free formulation

• Recommended dosage is 1 drop in the affected eye(s) once daily in the evening

• Product availability is expected in 2H 2023

nadofaragene firadenovec-vncg (Adstiladrin®)

Ferring

• BLA approval 12/16/2022; Assessment Aid, Breakthrough Therapy, Fast Track, Orphan Drug

• Indicated for the treatment of adults with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors

• Non-replicating adenoviral vector-based gene therapy

• Intravesical suspension: carton of 4 single-use vials with each vial containing a nominal concentration of 3 x 10¹¹ viral particles (vp)/mL and an extractable volume ≥ 20 mL

• Recommended dosage is 75 mL at a concentration of 3 x 10¹¹ vp/mL instilled once every 3 months into the bladder via urinary catheter; premedication with an anticholinergic is recommended before each instillation

• Product availability is expected in 2H 2023

RECENT FDA APPROVALS continued

DESCRIPTION

New Drugs continued

lenacapavir (Sunlenca®) Gilead

• NDA approval 12/22/2022; Breakthrough Therapy, Fast Track, Priority Review

• Indicated in combination with other antiretrovirals for treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations

• HIV-1 capsid inhibitor

• Oral tablet: 300 mg

• Solution for injection: 463.5 mg/1.5 mL (309 mg/mL) in SDVs

• Recommended maintenance dosage is 927 mg (2 x 1.5 mL) SC injection by an HCP into the abdomen once every 6 months following a starting dosage regimen that combines SC and oral dosing (further details are described in the prescribing information)

mosunetuzumab-axgb (Lunsumio™) Genentech

• BLA approval 12/22/2022; Accelerated Approval, Assessment Aid, Breakthrough Therapy; Orphan Drug, Priority Review

• Indicated for the treatment of adults with relapsed or refractory follicular lymphoma after ≥ 2 lines of systemic therapy; continued approval for this use may require demonstration of benefit in confirmatory clinical trials

• Bispecific CD20-directed CD3 T-cell engager

• Solution for injection: 1 mg/mL and 30 mg/30 mL in SDVs

• Recommended dosage is administered via IV infusion by qualified HCPs with appropriate medical support for managing serious reactions: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15, 60 mg on cycle 2 day 1, and 30 mg on day 1 in subsequent cycles; each treatment cycle is 21 days and therapy should be administered for 8 cycles unless patients have unacceptable toxicity or disease progression; patients with a partial response or stable disease can continue treatment up to 17 cycles

• Boxed warning for serious or life-threatening CRS

sodium phenylbutyrate (Olpruva™) Acer

• 505(b)(2) NDA approval 12/22/2022; Standard Review

• Indicated for adjunctive therapy to standard of care, which includes dietary management, for the chronic management of adult and pediatric patients weighing ≥ 20 kg with BSA ≥ 1.2 m², with urea cycle disorders involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase

• Not indicated for the treatment of acute hyperammonemia

• Nitrogen-binding agent

• Oral suspension: 2 g, 3 g, 4 g, 5 g, 6 g, 6.67 g pellets in packets for reconstitution

• Recommended dosage is 9.9 to 13 g/m²/day (maximum of 20 g/day) administered as 3 to 6 divided doses taken with food; plasma ammonia levels should be used to determine dosage adjustments; combine therapy with dietary protein restriction and, as needed, amino acid supplementation

RECENT FDA APPROVALS continued

DRUG NAME MANUFACTURER DESCRIPTION

New Drugs continued

ublituximab-xiiy (Briumvi™)

TG Therapeutics

• BLA approval 12/28/2022

• Indicated for the treatment of relapsing forms of multiple sclerosis in adults, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease

• CD20-directed cytolytic monoclonal antibody

• Solution for injection: 150 mg/6 mL (25 mg/mL) in SDVs

• Recommended dosage is 150 mg IV infusion over 4 hours for the first infusion, 450 mg IV infusion over 1 hour 2 weeks after the first infusion, then 450 mg IV infusion over 1 hour 24 weeks after the first infusion and every 24 weeks thereafter; infusions should be administered under the supervision of an HCP with experience and access to medical support for management of severe reactions; hepatitis B virus screening and quantitative serum immunoglobulin screening are required prior to the first dose, and premedication with methylprednisolone (or equivalent corticosteroid) and an antihistamine is required prior to each infusion

• Product availability is expected in 1Q 2023

505(b)(2) = FDA approval pathway that allows for submission of data from studies not conducted by or for the applicant.

COVID-19 Disclaimer: For the most current COVID-19 information, visit the FDA, CDC, NIH, NIH guidelines, and WHO websites. State and local health departments also provide valuable information regarding management in local communities. As the COVID-19 landscape is fluid, assumptions are subject to change.

Glossary:

ACIP Advisory Committee on Immunization Practices

ASHP American Society of Health-System Pharmacists

BLA Biologics License Application

BRCA BReast CAncer gene

BSA body surface area

CBC complete blood count

CD3 cluster of differentiation 3

CDC Centers for Disease Control and Prevention

CFU colony forming units

CI confidence interval

CMV cytomegalovirus

COVID-19 Coronavirus Disease 2019

CRS cytokine release syndrome

EBV Epstein-Barr virus

EUA Emergency Use Authorization

FDA Food and Drug Administration

GTP guanosine 5’-triphosphate

H half

HCP healthcare professional

HIV human immunodeficiency virus

HR hazard ratio

IV intravenous

NDA New Drug Application

NIH National Institutes of Health

References: aap.org cdc.gov diabetes.org fda.gov jamanetwork.com nejm.org

NSAID nonsteroidal anti-inflammatory drug

PD-L1 programmed cell death ligand 1

Q quarter

RAS Rat sarcoma

RSV respiratory syncytial virus

SC subcutaneous

SDV single-dose vial

US United States

USA United States of America

VRBPAC Vaccines and Related Biological Products Advisory Committee

WHO World Health Organization

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