Genmab will not file Arzerra for NHL after Phase III trial failure
This article was originally published in Scrip
Genmab will not file its lead drug candidate, the anti-CD20 monoclonal antibody drug Arzerra (ofatumumab), for what would have been its biggest indication to date – refractory follicular non-Hodgkin’s lymphoma (NHL) – after the pivotal Phase III trial in this population failed to meet its primary response rate endpoint. The result also led the company to cut its 2009 revenue forecast and to a 30% fall in its share price on August 18th.
Genmab said that it now expects its 2009 revenue to be approximately DKK 750 million ($143 million) compared with the previous estimate of DKK 1.2 billion. The reduction in revenue is primarily due to the exclusion of a milestone payment under the Arzerra collaboration with GlaxoSmithKline.
While Arzerra has already been filed in the US and the EU to treat refractory chronic lymphocytic leukaemia (CLL) – and is awaiting a decision from the FDA in late October – refractory follicular NHL would have been a much larger indication. The pivotal trial specifically tested Arzerra's efficacy in NHL patients who were refractory to Roche (Genentech's) blockbuster anti-CD20 NHL drug Rituxan/MabThera (rituximab), which would be Arzerra's biggest rival.
Ofatumumab, like rituximab, targets the CD20 antigen on the surface of normal and malignant B-cells. However, it is a fully human monoclonal antibody, while rituximab is chimaeric. It also targets a novel epitope of CD20, and preclinical studies have indicated that it was associated with greater complement-dependent cytotoxicity than rituximab.
GSK and Genmab said they remained committed to ofatumumab's development in NHL and continue to review the study results and discuss their development strategy. Genmab's chief executive, Dr Lisa Drakeman, admitted that the overall trial result was disappointing but pointed to the higher 22% response rate in the subgroup of patients in the trial who were refractory to prior rituximab monotherapy as "of interest" and "warranting further study".
There are also earlier phase clinical trials in earlier lines of treatment in NHL ongoing and in different subtypes of the disease. Genmab's chief scientific officer, Dr Jan van de Winkel, said that the company had planned to conduct head-to-head trials versus rituximab in subsets of NHL, and in combination with chemotherapy, and would update on these in the future.
Genmab and GSK highlighted that the highly refractory patient population may have been the reason for the trial's failure. Patients had had more prior rounds of therapy and more aggressive disease than the patients in Cephalon's trial of its approved chemotherapy drug Treanda (bendamustine HCl) in rituximab-refractory NHL, said Dr van de Winkel, and may have been too sick to be treated with any anti-CD20 drug.
"Clearly, this is a challenging patient population to treat with a single agent CD20 antibody,” said Kathy Rouan, vice-president and medicines development leader at GSK.
pivotal trial
A total of 116 patients were treated in the study, including 30 patients treated with 500mg of ofatumumab and 86 patients treated with 1,000mg of ofatumumab. Almost half of patients were refractory to their last chemotherapy treatment. They had previously received a median of four prior treatment regimens and had failed to achieve at least a partial response to rituximab in combination with chemotherapy, had disease progression while on rituximab or had disease progression following a response within six months of the last dose of rituximab.
The primary endpoint was objective response over six months from the start of treatment in the 1,000mg dose population. This was achieved by 10% of patients, including one complete response and eight partial responses. In addition, 50% of patients in the 1,000mg treatment arm had stable disease.
The objective response rate among the 27 patients who were refractory to prior rituximab monotherapy was 22%. For patients considered refractory to rituximab in combination with chemotherapy the response rate was 7%. The median duration of response in the 1,000mg treatment arm was six months and the progression free survival was six months.
disappointing
Analysts generally viewed the data as disappointing. Danske Markets analysts said they believed that the FDA had indicated a threshold value of an objective response rate of 20-25%, compared with the 10% observed. They added that a response rate of 30-35% and complete remissions of 5-10% was expected to be considered acceptable by the market.
UBS analysts said that the difference in response rate in patients refractory to chemotherapy and rituximab monotherapy suggests that patients refractory to rituximab plus chemotherapy could have been extremely severe patients.
Piper Jaffray analysts said that although not "strictly a fair comparison (particularly given a more refractory patient population) the data compare to response rates of between 68% and 74% for other approved drugs for Rituxan refractory NHL" –Treanda and the radiolabelled anti-CD20 monoclonal antibodies GSK's Bexxar (tositumomab) and Bayer's Zevalin (ibritumomab tiuxetan).
Several analysts viewed the trial as meaning that Arzerra would have to prove itself as better than Rituxan in order to be widely used. Those at Danske Markets held out hope that Arzerra would prove superior in first and second-line NHL studies, which they anticipated being scheduled.
Piper Jaffray analysts added, however: "Although our investment thesis is not based on Arzerra necessarily being superior to Rituxan on a head-to-head basis, it does depend on demonstration of differentiated activity, which we believed data from trials in refractory CLL had suggested. Unfortunately, the Rituxan refractory NHL study is the only trial to truly test whether Arzerra has activity where Rituxan doesn't. As such, it represents a severe blow to GSK's marketing plans and it may taint physician perception of the drug even in the CLL indication, for which we still anticipate approval."