CLL Training

ARZERRA: ANNOTATED SALES AID An annotated guide to help you discuss the sales aid for ARZERRA with your customers

FOR SALES TRAINING PURPOSES ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. SEPTEMBER 2010

AZA212R0

ARZERRA: ANNOTATED SALES AID

You have the opportunity to help physicians see how ARZERRA can expand their treatment options for patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.

The sales aid for ARZERRA will help you educate your customers about ARZERRA and get them excited about the benefits ARZERRA may offer to their patients. It will also help you present Important Safety Information for ARZERRA in a clear and understandable manner.

This annotated sales aid is designed to help you succeed in reaching your goals by providing helpful insights, selling ideas, and key discussion questions.

FOR SALES TRAINING PURPOSES ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS.

ARZERRA: ANNOTATED SALES AID

Each annotated page includes: • Insights into ARZERRA Background information, including market research results or key learnings from the brand team. The information in this section is FYI ONLY and cannot be shared with customers • Explanations of key selling points How-to-use and other selling tips, including suggested dialogue • Engaging questions for physicians Sample questions to initiate productive, 2-way dialogue with customers • Transitions between spreads For effortless navigation spread to spread

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FRONT COVER

Insight into ARZERRA During market research, most respondents reacted positively to ARZERRA and this new core visual aid. The imagery was viewed as eye-catching and made them want to learn more about the product. Use this sales aid with confidence. ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab. ARZERRA is the only treatment specifically indicated for patients refractory to both those agents. The effectiveness of ARZERRA is based on the demonstration of durable objective responses.

No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Remember, although no other product has this specific indication, there are other products with indications broad enough to include FA-refractory CLL patients (ie, Rituxan and Treanda) and you must state so if you mention that ARZERRA is the “ONLY” product with this specific indication.

Physicians also reacted positively to the mechanism of action for ARZERRA, thus this is another key message.

The headline, “Expand Your Options,” is the real-world benefit of ARZERRA as it informs physicians that they now have another option for their patients with CLL refractory to fludarabine and alemtuzumab.

When introducing ARZERRA, it is important to let your customers know that it is an anti-CD20 monoclonal antibody for the treatment of patients with CLL refractory to fludarabine and alemtuzumab. It is also important that you share the full Indication with your customers so they understand the limitations of the data (ie, that the effectiveness of ARZERRA is based on the demonstration of durable objective responses and that no data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA).

When discussing ARZERRA, please be sure to review the Important Safety Information. It’s okay to begin by stating the warnings listed here, but also let your customers know that you will be reviewing important details of this information throughout the presentation.

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FRONT COVER

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• “There are many treatment options that can be used for treating CLL. Which agents do you prefer in FA-refractory CLL?” • “When treating patients with CLL, how do you define them as being unresponsive or refractory to treatment?”

“Doctor, thanks for providing me the opportunity to discuss ARZERRA.” “ARZERRA is an anti-CD20 monoclonal antibody that is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. In fact, it is the only treatment specifically indicated for patients refractory to fludarabine and alemtuzumab. The effectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Although ARZERRA is the only product with this specific indication, there are other products, such as Treanda and Rituxan, which have indications that are broad enough to include this patient population.”

“My objective for our discussion today is to review the pivotal study that led to the accelerated approval of ARZERRA last October and to review the mechanism of action for ARZERRA. I will also review some Important Safety Information regarding infusion reactions, cytopenias, PML, and hepatitis B reactivation, intestinal obstruction, and immunizations. We will also cover the most common adverse reactions and the most common serious adverse reactions.”

“Let’s start with the clinical data.”

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PAGE 2: STUDY DESIGN

Insight into ARZERRA It is important to share with your customers the study design of the clinical trial for ARZERRA. In market research, physicians were particularly interested in the study design.

It is particularly important to share the key characteristics of the patients studied: • All patients were refractory to both fludarabine and alemtuzumab • The median number of prior therapies the patients received • The percentage of patients who previously had received rituximab What can you say about the study design? It is important to share with your customers the facts of the pivotal study, and therefore it is important to tell them that ARZERRA was studied in a single-arm, multicenter trial of 154 patients with relapsed or refractory CLL. You must also state that of these 154 patients, a subset of 59 patients with CLL refractory to fludarabine and alemtuzumab comprised the efficacy population for ARZERRA. If your physician asks for further information about the other patients in the pivotal study, please ask him or her to contact Medical Information (MI) or set up an appointment with your RMS. What can you not say about the study design? You cannot use the study design to suggest that ARZERRA should be used in a patient population that is broader than its FDA-approved indication. For example, you cannot say: • Not only has ARZERRA been studied in FA-refractory CLL patients, but it has also been studied in the relapsed or refractory CLL setting OR • I understand that you don’t see many alemtuzumab-refractory patients, but ARZERRA has been studied in the relapsed or refractory CLL setting OR • Not only has ARZERRA demonstrated efficacy in the FA-refractory CLL setting, but anti-tumor activity has also been observed in the relapsed or refractory CLL setting NOTE: All 3 of these examples violate the policy of GSK against off-label promotion. To avoid this risk, you should closely follow the language in the sales aid when discussing the pivotal study design.

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PAGE 2: STUDY DESIGN

“Doctor, in the pivotal single-arm, multicenter trial of 154 patients with relapsed or refractory CLL, 59 patients with CLL refractory to fludarabine and alemtuzumab comprised the efficacy population for ARZERRA. This was a patient population in need of additional treatment options.”

“Drug refractoriness was defined as failure to achieve at least a partial response to, or disease progression within 6 months of, the last dose of fludarabine or alemtuzumab, and the main efficacy outcome was durable objective tumor response rate.”

“Every patient was refractory to both fludarabine and alemtuzumab, the vast majority had previously received alkylating agents, and more than half previously received prior rituximab. The median number of prior therapies was 5.”

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• “Doctor, looking at this profile of the baseline characteristics of patients and taking into consideration the number and type of prior therapies, what type of response would you expect to see as a result of subsequent therapy?”

• “What efficacy rate would you expect from a single agent?”

“Bearing in mind that this patient population had a median of 5 prior therapies, let’s look at the clinical efficacy demonstrated by ARZERRA as monotherapy.”

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PAGE 3: EFFICACY

Insight into ARZERRA Market research has shown that most physicians expect a 15% to 20% response rate in the ARZERRA patient population. Remember that you cannot share these data externally.

Nevertheless, it is important for you to understand the marketplace expectations so you can understand the importance of the efficacy data for ARZERRA. ARZERRA demonstrated a 42% overall response rate, although there were no complete responses or data demonstrating improvement in disease-related symptoms or increased survival.

The complete Indication statement must be included as part of every sales call when discussing efficacy. Moreover, physicians were also impressed with the fact that 88% of patients received at least 8 infusions of ARZERRA and more than half (54%) received all 12 infusions.

This is an important page in your sales aid because it conveys the key efficacy messages.

Throughout this sales aid are sections of the Important Safety Information for ARZERRA. The full ISI can also be found on pages 10 and 11. In longer discussions with customers, you must provide all of the information found in the ISI. However, you do not need to repeat the information that you have already covered just because it appears on more than one spread. For shorter interactions with customers, you must provide at least all of the information in the highlights of Warnings and Precautions, which can be found on the front and back covers. You should also familiarize yourself with the safety information that is not in the sales aid but in the PI (eg, contraindications, immunogenicity, drug interactions, use in specific populations) so you can respond to questions about those topics. All unsolicited safety questions that cannot be answered in the sales aid or PI should be referred to MI.

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PAGE 3: EFFICACY

“Doctor, patients with CLL refractory to fludarabine and alemtuzumab who were treated with ARZERRA as monotherapy achieved a 42% overall response rate. Please note that there were no complete responses.”

“Doctor, I would also like to point out that in the pivotal study, 88% of patients received at least 8 of the 12 infusions of ARZERRA and 54% received all 12 infusions.”

“Doctor, the National Comprehensive Cancer Network (NCCN) guidelines include a recommendation for using ARZERRA according to its approved indication: CLL that is refractory to fludarabine and alemtuzumab.” Note, however, that you must refer physicians to MI if they ask for elaboration on the NCCN guidelines.

“Doctor, as I mentioned previously, I'm going to cover the Important Safety Information for ARZERRA throughout our discussion. The first warning I'd like to discuss relates to cytopenias. Prolonged and severe neutropenia and thrombocytopenia can occur with ARZERRA. In the pivotal study, of the 108 patients with normal neutrophil counts at baseline, 42% developed Grade 3 or greater neutropenia and 18% developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia that was greater than 2 weeks in duration. To manage this risk, the Prescribing Information states that you should monitor CBC counts and platelet counts at regular intervals during therapy and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.”

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“Doctor, what do you think about the efficacy data that I’ve presented?”

“Now that we've discussed the efficacy results for ARZERRA, I'd like to share with you the most common adverse events seen in the pivotal study. Keep in mind that many of the most serious risks that can occur with ARZERRA—infusion reactions, PML, and hepatitis B reactivation— will be discussed in more depth later.”

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PAGE 4: ADVERSE EVENTS PROFILE

Insight into ARZERRA In addition to efficacy, physicians make treatment decisions based on safety. As such, it is vitally important that physicians know the safety information for ARZERRA so they can be prepared to manage patients accordingly.

Please remember that when presenting safety information, you cannot state that "the safety profile is to be expected given the characteristics of the patient population.” You also should not suggest that any of the adverse events seen with ARZERRA were attributable to prior therapies that these patients received. Your presentation of safety should never minimize the safety information for ARZERRA. It is important that you understand how to articulate the information here to correctly identify the patient population studied. The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, nonrandomized studies. The adverse reactions that are listed in the table on this page, however, are derived from the 154 relapsed or refractory CLL patients in the pivotal study and from the fludarabine- and alemtuzumab-refractory subset of patients in that study. If your customers have any further questions, please refer them to MI.

“Doctor, the safety of ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, nonrandomized, single-arm studies. In Study 1 (N=154), the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia.”

NOTE: You may state this number (181), but may not mention the efficacy (n=154) number.

“In Study 1, ARZERRA was administered at 2000 mg beginning with the second dose for 11 doses. The most common adverse events occurring in ≥5% of patients in Study 1 are listed in this table. The 2 columns in the middle refer to the 154 patients from Study 1 and the last 2 columns refer to the fludarabine- and alemtuzumab-refractory subset of patients from Study 1.”

“The most common AEs (≥10%) in Study 1 were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections.”

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PAGE 5: ADVERSE EVENTS PROFILE

Insight into ARZERRA Although infusion-related adverse reactions are listed in this table, this topic is covered in more detail on pages 7 and 10.

“Doctor, a majority of infections seen with ARZERRA were Grade 1 or 2 in severity. In Study 1, 70% of patients experienced bacterial, viral, or fungal infections. Of these, 29% experienced Grade 3 or greater infections and 12% of the infections were fatal. In the fludarabine- and alemtuzumab-refractory group, 17% of infections were fatal.”

“Before we go into additional Important Safety Information for ARZERRA, I would like to walk you through some important information about dosing and administration of ARZERRA.”

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PAGE 6: DOSING

Insight into ARZERRA Market research confirmed that physicians find it important to understand the dosing schedule for ARZERRA. They also want to know that their oncology nurses, who would most often infuse ARZERRA, are comfortable with this schedule and clear on how the drug should be administered to manage potential adverse reactions.

This page also presents an opportunity to provide an in-service and involve a clinical educator. Use during in-services and other situations in which an extended sales call is appropriate. You can also use the dosing card as a leave-behind for the infusion staff.

Note that when presenting dosing information, you should also present information regarding infusion reactions. And if you do not cover the dosing information in your discussion, you must still present the information regarding infusion reactions.

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PAGE 6: DOSING

“Doctor, the premedication schedule for ARZERRA includes IV corticosteroids, oral analgesics, and oral or IV antihistamines.”

“On infusion 1, ARZERRA should be dosed at 300 mg, IV corticosteroids at 100 mg of prednisolone or equivalent, oral acetaminophen at 1000 mg or equivalent, and IV or oral cetirizine at 10 mg or equivalent. The dose of ARZERRA then increases to 2000 mg for the remaining infusions, and the corticosteroid doses may be gradually reduced with successive infusions for Doses 3 through 8 if a Grade 3 or greater infusion reaction did not occur with the preceding dose. Also, prednisolone 50 to 100 mg or equivalent may be administered for Doses 10 through 12 if a Grade 3 or greater infusion reaction did not occur with Dose 9. Cetirizine and acetaminophen maintain the same dosages throughout.”

“It is important to note that for the first 2 weekly treatments (Doses 1 and 2) and for the first monthly treatment (Dose 9) of ARZERRA, the corticosteroid dose should not be reduced given the risk of infusion reactions.”

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Physicians and nurses will be interested in knowing the total duration of therapy will be 24 weeks with 12 total infusions. The approximate infusion duration of Doses 1 and 2 is a minimum of 6.5 hours and a minimum of 4 hours for Doses 3 to 12. Infusion duration is based on the absence of infusion toxicity and may not be the duration for all patients.

This is a great point to discuss during in-services with nursing staff.

Refer to Table 1 of the PI and note that in the absence of infusion toxicity, the rate of infusion may be increased every 30 minutes as described in Table 1.

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PAGE 7: DOSING

“ARZERRA should never be administered as an IV push or bolus injection and should always be administered using an infusion pump with the provided in-line filter and PVC administration sets.”

“All doses should be prepared with 1000 mL of 0.9% sodium chloride.”

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Key Point: Note the increase in the rate of infusions, which can be increased every 30 minutes in the absence of infusional toxicity as described in the PI. It’s important to remind physicians of these increased rates. Quicker infusion rates, per the recommendations in the PI, free up healthcare resources and could save patients time and money.

“It is important for you to know that ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema.”

“Interrupt infusions for infusion reactions of any severity and institute medical management for severe infusion reactions.”

“In a study of patients with moderate to severe COPD, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion.”

“Infusion reactions with ARZERRA occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2000 mg), and less frequently during subsequent infusions.”

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Key Point: Infusion reactions were the most common serious adverse reactions seen in the pivotal trial for ARZERRA. Therefore, whenever time permits, you should present all of the warning information regarding infusion reactions. (You must, at a minimum, always present all of the safety information from the highlights of the Warnings and Precautions section.)

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PAGE 7: DOSING

“If you would like, I can schedule a clinical educator to come in and teach your team about the dosing schedule, appropriate premedication requirements, length of infusions, and potential side effects.”

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“Do you have any questions about the dosing and administration of ARZERRA?”

“Doctor, I would like to walk you through the mechanism of action for ARZERRA.”

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PAGE 8: MECHANISM OF ACTION

Insight into ARZERRA In market research, physicians were particularly interested in understanding the targeted MOA of ARZERRA and the fact that it binds to both the small and large extracellular loops of the CD20 molecule. NOTE: When discussing the MOA of ARZERRA, you cannot specifically compare the MOA of rituximab. You can say that ARZERRA is an antiCD20 monoclonal antibody that targets both the small and large extracellular loops on the CD20 molecule. You must always point out, however, that the CD20 molecule is expressed on normal B lymphocytes (pre-B to mature B lymphocytes) and on B-cell CLL. Remember that the MOA of ARZERRA is not definitively known. Instead, it is presumed based on in vitro data. You must always point out that the presumed MOA is based on this type of data when discussing MOA. You should never overstate our understanding of the MOA or compare the MOA of ARZERRA with the MOA of any other product.

Remember, any MOA questions that go beyond the information in the sales aid and PI must be referred to MI.

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PAGE 8: MECHANISM OF ACTION

“Doctor, the Fab domain of ARZERRA binds specifically to both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre-B to mature B) and on B-cell CLL. The CD20 molecule is not shed from the cell surface and is not internalized following antibody binding. After binding, the Fc domain mediates immune effector functions to result in B-cell lysis in vitro. In vitro data suggest that possible mechanisms of cell lysis include CDC and ADCC.”

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You should finish discussing safety before discussing CARES by GSK™, unless you receive an unsolicited question about reimbursement support or the PAP. Also, remember that you must save enough time in longer details to cover all of the Important Safety Information for ARZERRA.

“Now that I’ve shared the efficacy, dosing, and MOA of ARZERRA with you, I’d like to finish discussing the safety information for ARZERRA.” [Skip ahead to pages 10 and 11.]

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PAGE 9: REIMBURSEMENT

Insight into ARZERRA More than ever before, physicians are increasingly sensitive to reimbursement for oncology products.

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“It is a challenging reimbursement landscape that exists today. Are you familiar with CARES by GSK™?”

“Doctor, GSK is proud to offer reimbursement support through our CARES by GSK™ program. If you would like more information, please call 1-888-ONE-GSKCARES (1-888-863-4752) or visit online at caresbygsk.com to learn more. I can also follow up with your office manager.”

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• CARES by GSK™ is committed to helping people find reimbursement for and access to its oncology and specialty medicines • CARES by GSK™ offers a variety of programs and levels of assistance to help patients get the therapy they need, including: ­ Reimbursement support, including benefits verification ­ Patient assistance programs, which provide free prescription medicines and GSK co-pay assistance to people with income limitations • Instruct physicians to contact the LASH group by calling the CARES by GSK™ number or their PRM

“Doctor, I know we’ve covered a lot of information today, but I’d like to briefly summarize the key points about ARZERRA with you.”

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PAGES 10 & 11: IMPORTANT SAFETY INFORMATION

Insight into ARZERRA Before prescribing any new drug, physicians are particularly interested in knowing its Important Safety Information. At a minimum, you must provide the highlights of the Warnings and Precautions on every sales call. For longer details, you must provide all of the Important Safety Information.

“Doctor, we've already talked about the Important Safety Information regarding infusion reactions and cytopenias. We've also covered the most common adverse reactions and the most common serious adverse reactions seen in the pivotal study. Now, I'm going to cover the remaining Important Safety Information for ARZERRA.” “Progressive multifocal leukoencephalopathy, including fatal PML, can occur with ARZERRA. The PI states that you should discontinue treatment with ARZERRA if PML is suspected and initiate evaluation for PML, including consultation with a neurologist, a brain MRI, and a lumbar puncture.”

“As you may know, hepatitis B reactivation, including fulminant hepatitis and death, occurs with other monoclonal antibodies directed against CD20. Therefore, the PI states that you should screen patients at high risk of hepatitis B virus (HBV) infection before initiation of ARZERRA. It also states that you should closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection. This monitoring should be done during treatment with ARZERRA and for 6 to 12 months following the last infusion. Finally, you should discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis and institute appropriate treatment. Insufficient data exist regarding the safety of ARZERRA in patients with active hepatitis.”

“Obstruction of the small intestine can also occur in patients receiving ARZERRA. The PI states that you should perform a diagnostic evaluation if obstruction is suspected.”

“The last safety topic that I'm going to mention relates to immunizations. The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied, therefore it is recommended that you should not administer live viral vaccines to patients who have recently received ARZERRA. In addition, the ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.”

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PAGES 10 & 11: IMPORTANT SAFETY INFORMATION

“Doctor, I know that we've covered a lot of safety information, but I want to make sure that you understand the full efficacy and safety profile of ARZERRA. Do you have any questions regarding the information that I've presented?”

“Doctor, in the event that you have a patient who you feel is appropriate for ARZERRA, I'd like to mention our reimbursement support program.” [Go back to page 9.]

Remember to always provide the PI.

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BACK COVER

Insight into ARZERRA The back cover provides a nice summary and is also a good resource for shorter details.

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Key Points: • EFFICACY ­ “ARZERRA provided a 42% overall response rate in CLL patients who were refractory to both fludarabine and alemtuzumab. There were no complete responses. The patients in this study had a median of 5 prior therapies, and more than half previously received rituximab” • MOA ­ “ARZERRA is a monoclonal antibody that targets both the small and large extracellular loops on the CD20 molecule. CD20 is expressed on both normal, healthy B cells and on B-cell CLL. In vitro data suggest 2 possible mechanisms of cell lysis, CDC and ADCC” • SAFETY ­ “ARZERRA can cause serious infusion reactions. Premedicate with an IV corticosteroid, an oral analgesic, and an oral or IV antihistamine. Monitor patients closely during infusions and interrupt infusion if infusion reactions occur” ­ “Prolonged and severe cytopenias can also occur with ARZERRA. Monitor blood counts at regular intervals for neutropenia and thrombocytopenia” ­ “PML, including fatal PML, can occur with ARZERRA. Monitor neurologic function and discontinue ARZERRA if PML is suspected” ­ “Because of the risk of hepatitis B reactivation, you should screen high risk patients and discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis”

Be sure to review the Important Safety Information for ARZERRA on every call.

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“Doctor, we have discussed the efficacy and safety of ARZERRA in patients with CLL refractory to fludarabine and alemtuzumab. Can you think of any patients with FA-refractory CLL in your practice who would benefit from ARZERRA?”

FOR SALES TRAINING PURPOSES ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. AZA212R0