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* On July 3, 2014, GSK and Genmab announced that the European Commission has granted marketing authorization for a new indication for the use of Arzerra®, in combination with chlorambucil or bendamustine for the treatment of patients with chronic lymphocytic leukemia (CLL) who have not received prior therapy and who are not eligible for fludarabine-based therapy. The EC authorization of the first-line indication for Arzerra® (ofatumumab) is based on results from two trials:

A randomized, Phase III open-label, parallel-arm, multicenter, pivotal study (OMB110911, COMPLEMENT 1) evaluating the combination of ofatumumab and chlorambucil (N=221) versus chlorambucil alone (N=226) in CLL patients for whom fludarabine-based treatment is considered inappropriate. In this study, treatment with ofatumumab and chlorambucil demonstrated a statistically significant, 71 per cent improvement in median progression-free survival (PFS) compared to chlorambucil alone (22.4 months versus 13.1 months, respectively) (HR=0.57 [95 per cent CI, 0.45, 0.72].

A single-arm, multicenter, Phase II study (OMB115991) evaluating ofatumumab in combination with bendamustine in 44 patients with previously untreated CLL for whom fludarabine-based treatment was considered inappropriate. Results of this study demonstrated that ofatumumab in combination with bendamustine provided an overall response rate (ORR)of 95 per cent [95 per cent CI, 85, 99] and a complete response rate (CR) of 43 per cent.

Safety information for Arzerra (ofatumumab): The overall safety profile of ofatumumab in CLL (previously untreated and relapsed or refractory) is based on data from 511 patients in clinical trials. This includes 250 patients with relapsed or refractory CLL who were treated with ofatumumab alone and 261 patients with previously untreated CLL for whom fludarabine-based therapy was considered inappropriate and who were treated in combination with an alkylating agent.The most common undesirable effects for ofatumumab include adverse events associated with infusion reactions, cytopenias (neutropenia, anemia, febrile neutropenia, thrombocytopenia, leukopenia) and infections (lower respiratory tract infection, including pneumonia, upper respiratory tract infection, sepsis, including neutropenic sepsis and septic shock, herpes virus infection, urinary tract infection).

Special warnings and precautions for use of ofatumumab are summarized as follows:

1-Ofatumumab has been associated with infusion reactions leading to temporary interruption of treatment or withdrawal of treatment. Infusion reactions may include anaphylactoid events, cardiac events, chills/rigors, cough, cytokine release syndrome, diarrhea, dyspnea, fatigue, flushing, hypertension, hypotension, nausea, pain, pyrexia, rash, and urticaria. Infusion reactions occur more frequently on the first day of infusion and tend to decrease with subsequent infusions. Patients with a history of decreased pulmonary function may be at a greater risk for pulmonary complications from severe reactions.

2- In patients with CLL, tumor lysis syndrome (TLS) may occur with use of ofatumumab. Risk factors for TLS include a high tumor burden, high concentrations of circulating cells (>= 25,000/mm3), hypovolemia, renal insufficiency, elevated pre-treatment uric acid levels and elevated lactate dehydrogenase levels. Management of TLS includes correction of electrolyte abnormalities, monitoring of renal function, maintenance of fluid balance and supportive care.

3- Progressive multifocal leukoencephalopathy (PML) and death has been reported in CLL patients receiving cytotoxic pharmacotherapy, including ofatumumab. If a diagnosis of PML is suspected ofatumumab should be discontinued and referral to a neurologist should be considered.

4- Hepatitis B virus (HBV) infection and reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with drugs classified as CD20-directed cytolytic antibodies, including ofatumumab. All patients should be screened for HBV infection before initiation of ofatumumab treatment, patients previously exposed to HBV should be followed closely in consultation with an expert in this disease. Patients with evidence of prior HBV infection should be monitored for clinical and laboratory signs of hepatitis or HBV reactivation.

5- Patients with a history of cardiac disease should be monitored closely. Ofatumumab should be discontinued in patients who experience serious or life-threatening cardiac arrhythmias.

The effect of multiple doses of ofatumumab on the QTc interval was evaluated in a pooled analysis of three open-label studies in patients with CLL (N=85). Increases above 5 msec were observed in the median/mean QT/QTc intervals in the pooled analysis. No large changes in the mean QTc interval (i.e., >20 milliseconds) were detected.

* On 22 May 2014, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a variation to the terms of the marketing authorisation for Arzerra®. The CHMP adopted a new indication as follows:

 "Previously untreated chronic lymphocytic leukaemia (CLL): Arzerra in combination with chlorambucil or bendamustine is indicated for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy.

* On April 17, 2014, the FDA has approved ofatumumab (Arzerra® Injection, for intravenous infusion) in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabine-based therapy is considered inappropriate.The approval was based on the results of a multi-center, randomized, open-label trial comparing ofatumumab in combination with chlorambucil to single agent chlorambucil. The trial enrolled 447 patients for whom fludarabine-based therapy was considered to be inappropriate by the investigator for reasons that included advanced age or presence of co-morbidities. In the overall trial population the median age was 69 years (range: 35 to 92 years). The primary endpoint of the trial was progression free survival (PFS) as assessed by a blinded Independent Review Committee (IRC) using the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) update of the National Cancer Institute Working Group (NCI-WG) guidelines. Median PFS was 22.4 months (95% CI: 19.0, 25.2 months) for patients receiving Arzerra® in combination with chlorambucil compared to 13.1 months (95% CI: 10.6, 13.8 months) for patients receiving single-agent chlorambucil [hazard ratio 0.57 (95% CI: 0.45, 0.72), stratified log-rank p-value <0.001].

The most common adverse reactions (greater than or equal to 5%) with ofatumumab in combination with chlorambucil (greater than or equal to 2% more than in the control arm) were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia and upper abdominal pain. Overall, 67% of patients who received ofatumumab experienced one or more symptoms of infusion reaction. Ten percent of patients experienced a grade 3 or greater infusion reaction. The results of this randomized trial were adequate to fulfill the postmarketing requirement for GSK to verify the clinical benefit of ofatumumab and, therefore, the approval of ofatumumab was converted from accelerated approval to regular approval.The recommended dose and schedule for the approved regimen for ofatumumab in previously untreated CLL is: 300 mg on Day 1 followed 1 week later by 1,000 mg on Day 8 (Cycle 1) followed by 1,000 mg on Day 1 of subsequent 28 day cycles for a minimum of 3 cycles until best response or a maximum of 12 cycles.

* On December 17, 2013, GSK and Genmab have announced that the FDA has granted Priority Review designation to the supplemental Biologics License Application (sBLA) for the use of Arzerra® (ofatumumab) in combination with an alkylator-based therapy, to be used for treatment of CLL patients who have not received prior treatment and are inappropriate for fludarabine-based therapy.  The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target date of April 19, 2014 for the sBLA for Arzerra®.

* On October 18, 2013,  GSK and Genmab have announced the submission of a sBLA to the FDA for the use of Arzerra® (ofatumumab) in combination with an alkylator-based therapy, to be used for treatment of CLL patients who have not received prior treatment and are inappropriate for fludarabine-based therapy. The application is based on results from an international, multi-center, randomized Phase III study of Arzerra® in combination with chlorambucil versus chlorambucil alone in more than 400 patients with previously untreated CLL. Headline results from this trial were announced in May 2013 and the full study results are scheduled to be presented in two oral presentations at the 2013 American Society of Hematology Annual Meeting in December.