ArzerraTM (Ofatumumab) from Approval to Post-marketing Compliance

By Payam Javanmardi

Academy of Applied Pharmaceutical Sciences

Canada, Toronto, December 2014

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On Jan 30, 2009 GlaxoSmithKline (GSK) andGenmab A/S submitted a Biologics LicenseApplication (BLA) to the FDA for ArzerraTM

(Ofatumumab)

ArzerraTM (Ofatumumab) is used to treat patients whose Chronic Lymphocytic Leukemia (CLL) is resistant to previous therapies.

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CLL is the most common form of adult leukemia in the western world.

Based on 2007 worldwide estimates, leukemia accounted for more than 330,000 new cases and more than 245,000 deaths.

154 patients with limited or no response to both fludarabine and alemtuzumab and patients who were refractory to fludarabine and considered inappropriate candidates for alemtuzumab

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Clinical Efficacy

The overall response rate was 58% for fludarabine alemtuzumab refractory group (n=59) and 47% for the fludarabine refractory group (n=79).

The most common AEs seen with Arzerra were related to infusion reactions and infections (≥ 10% of patients):

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Clinical Safety

Fever, cough, diarrhea, rash, low white blood cell counts, fatigue, pneumonia, anemia, shortness of breath, nausea

One case of Progressive Multifocal Leukoencephalopathy

One cased of Tumor Lysis Syndrome

There were further clinical trials being initiated at the time of submission.

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The companies intended to submit an application for marketing approval in Europe shortly.

On April 3, 2009 Genmab announced that the FDA had accepted the application (BLA) for ArzerraTM

(Ofatumumab).

In addition, the FDA had granted Ofatumumab orphan designation for the treatment of CLL.

Under priority review, the FDA set the target date for a decision from regulators at six months, rather than the standard 10-month review.

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On May 29, 2009 the companies announced that the FDA Oncologic Drugs Advisory Committee (ODAC) voted 10 to three that the Arzerra data were reasonably likely to predict benefit for patients with refractory CLL.

On June 16, 2009 the FDA informed companies that the agency had extended the action date for the Ofatumumab BLA application by three months to review additional chemistry and manufacturing information submitted on 5 June.

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On October 26, 2009, the FDA approved ArzerraTM

(Ofatumumab) for patients with CLL, whose cancer was no longer being controlled by other forms of chemotherapy.

On April 19, 2010 the European Commission granted a conditional marketing authorization valid throughout the European Union for Arzerra.

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The companies committed to carry out a study comparing treatment with Arzerra to treatment with other medicines chosen by the doctors, in patients with CLL whose previous treatment with fludarabine had failed.

The companies also committed to develop a Risk Management Plan (RMP) to:

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Ensure that Arzerra is used as safely as possible

Include safety information in the summary of product characteristics and the package leaflet

Include the appropriate precautions to be followed by healthcare professionals and patients

Provide additional information on the effectiveness and safety of Arzerra by the companies after marketing

On January 21, 2011 GSK submitted a New Drug Submission (NDS) to seek approval for the marketing of Arzerra.

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On March 9, 2012 Health Canada issued a Notice of Compliance with conditions (NOC/c) to GSK.

The safety of Arzerra was evaluated in 250 patients with relapsed or refractory CLL in two open-label, single arm studies.

The assessment of the safety of Arzerra was difficult due to the uncontrolled, unblinded design of the pivotal study.

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Given the single arm design, it was impossible to discern whether causal relationships existed between AEs and exposure to Arzerra.

Furthermore, the number of patients treated within the pivotal study was small, making the detection of rare events difficult.

Overall, 59% of patients experienced SAEs.

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A total of 17% of patients had SAEs that were considered to be drug-related.

The most common drug-related SAEs were neutropenia, pneumonia, and sepsis.

Of the 223 patients enrolled in the study, 138 died as of the safety analysis cut-off date.

Development of infections was a common occurrence during treatment with Arzerra and subsequent follow-up.

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The most frequent type of infections reported were of the respiratory tract, with lower respiratory tract infections being more common than upper.

Infection was the most common reason for drug discontinuation.

Infusion reactions were notably observed in both the pivotal and supportive studies:

Anaphylactic reactions, bronchospasm, cardiac events, chills/rigors, cough, cytokine release syndrome, diarrhea, dyspnea, fatigue, flushing, hypertension, hypotension, nausea, pain, pyrexia, rash, and urticaria

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In the majority of cases, infusion reactions did not require study withdrawal.

Furthermore, none of the infusion reactions resulted in death.

Neutropenia (hematologic AE) occurred in 17% of patients and was considered by investigator to be related to treatment in 13% of patients.

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Neutropenia is common in heavily treated CLL patients.

Therefore, it may be important to manage this complication in patients that present with baseline neutropenia and those that develop neutropenia to prevent infections from occurring.

Serious and Fatal cardiovascular events were reported following administration of Arzerra.

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Patients with a history of cardiac disease should be monitored closely during and after infusions and resuscitative measures should be readily available.

Post-marketing commitments

Under the NOC/c Policy, GSK agreed to submit additional documents:

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Data from currently undertaking or completed clinical studies

Any other analyses that have been designed as post-marketing commitments to other international authorization granting agencies

Provide information in relation to communications and consultations with other agencies, when applicable

Provide reports of all SAEs occurring in Canada and all SAEs occurring outside of Canada within 15 days to Health Canada

Post-marketing commitments

Submit Periodic Safety Update Reports (PSURs) for Arzerra on a semi-annual basis until such time as conditions associated with the market authorization are removed.

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Implement the Risk Management Plan (RMP) in Canada and provide any updates to the RMP when available

The sponsor should comply with the recommendations of Marketed Health Products Directorate (MHPD) in regards to the RMP

On April 17, 2014 GSK and Genmab received FDA approval for Arzerra as first-line treatment in combination with chlorambucil for patients with refractory CLL.

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The safety and effectiveness of Arzerra in children has not been established and should not be used in children unless the benefit outweighs the risks.

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Special Populations and Recommendations

There are no data from the use of Arzerra in pregnant women. The effect on human pregnancy is unknown.

Arzerra should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the fetus.

The safe use of Arzerra in humans during lactation (nursing women) has not been established.

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Special Populations and Recommendations

No clinically meaningful differences in the efficacy of Arzerra plus chlorambucil were observed between older ( > 65 years of age) and younger patients.

There were also no clinically significant differences in the common Adverse Reactions between older and younger patients.

No formal studies of Arzerra in patients with renal and hepatic impairment have been performed.

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Special Populations and Recommendations

Cytopenias, including prolonged and late-onset neutropenia have been reported during Arzerra therapy.

Complete blood counts should be obtained prior o therapy and at regular intervals during therapy and more frequently in patients who develop cytopenias.

Appropriate management should be considered should cytopenias occur.

FDA searched its Adverse Event Reporting System (FAERS) database for reports submitted between the time of market approval of Arzerra (October 2009) and August 2012 of patients treated with Arzerra who had fatal hepatitis B-related acute liver injury.

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FDA post-marketing risk identification

The search identified 3 cases.

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FDA Drug Safety Communications

On September 25, 2013 the FDA through a safety announcement (alert) has approved changes to the prescribing information about the risk of reactivation of hepatitis B virus (HBV) infection.

The revised label also will include additional recommendations for screening, monitoring, and managing patients to decrease this risk.

A post-marketing case of fatal infusion reaction has occurred during administration of the first dose of Arzerra to a 71-year old male with CLL and no known history of cardiac disease.

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MHRA and EMA communication

On July 25, 2014 GSK in agreement with the European Medicines Agency (EMA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) informed healthcare professionals of risk of Serious and Fatal infusion reaction.

Recommendations:Ofatumumab should only be administered under the supervision of a physician experienced in the use of cancer therapy and where facilities to monitor and treat infusion reactions are available.

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Patients should receive premedication agents 30 minutes to 2 hours prior to each infusion of Ofatumumab, according to the protocol in the Ofatumumab Summary of Product characteristics (SMP).

Despite premedications, infusion reactions may still occur. In cases of severe infusion reaction, the infusion of Ofatumumab must be interrupted immediately and symptomatic treatment instituted.

On August 6, 2014 GSK in consultation with Health Canada, endorsed the safety issue of fatal infusion reaction to Canadian Healthcare professionals and made recommendations as agreed.

The product monograph is revised accordingly.

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Health Canada communication

Referenceshttp://www.drugs.com/history/arzerra.htmlhttp://www.drugs.com/history/arzerra.htmlhttp://www.drugs.com/newdrugs/fda-approves-arzerra-ofatumumab-chronic-lymphocytic-leukemia-1750.htmlhttp://www.drugs.com/nda/arzerra_090130.htmlhttp://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_arzerra_128188-eng.phphttp://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/001131/WC500093092.pdfhttp://www.gsk.ca/english/docs-pdf/product-monographs/Arzerra.pdfhttp://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/40851a-eng.phphttp://www.fda.gov/downloads/Drugs/DrugSafety/UCM369436.pdfhttp://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm369846.htm

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