IHS Global Insight Perspective | |
Significance | Freshly published FDA documents have questioned the data supporting the regulatory application of chronic lymphocytic leukaemia (CLL) investigative treatment Arzerra. The FDA staff are wondering whether the supporting study can warrant fast-track approval. |
Implications | GSK and Genmab will need to wait for the FDA advisory committee's conclusion before they can get a better picture of their drug's regulatory fate. As it stands, it seems rather likely that Arzerra will not clinch regulatory approval, in one of the patient populations considered, this summer. Approval in the second patient population considered is more open-ended. |
Outlook | GSK and Genmab could see the market launch of their drug postponed by a few months. With the documents acknowledging the drug's anti-tumour activity, it seems that the timeliness of their application could be more in question than the approvability of their drug. Nevertheless, both the advisory committee and the FDA have yet to rule on the drug. |
A U.S. FDA briefing document freshly posted on the regulator's website has raised some questions with regards to GlaxoSmithKline's (GSK, U.K.) and Genmab's (Denmark) regulatory submission for chronic lymphocytic leukaemia (CLL) investigative drug Arzerra (ofatumumab; for full document, see here). While GSK is seeking regulatory approval for Arzerra as a single agent treatment in CLL patients, the company is hoping to secure approval in two patient populations: those irresponsive to treatment with fludarabine and alemtuzumab (Campath, Genzyme; U.S.; Double Refractory; DR), and those presenting bulky, fludarabine-refractory CLL (BFR). The submission is based on the single-arm, non-comparative Hx-CD20-406 interim analysis, which enrolled 154 patients.
On the one hand, the document questions whether the extent of Arzerra's activity, as measured by the objective response rate (ORR) and the duration of response (DOR), is "sufficient to be reasonably likely to predict clinical benefit". This concern may call off Arzerra's fast-track regulatory approval status as although the document acknowledges that Arzerra as a single agent displays anti-tumour activity in CLL patients, this observation on its own is insufficient to support fast-track status. Furthermore, the independent review committee questioned the manufacturer's analysis of the data, which concluded a 58% ORR in DR patients when the independent review committee estimated it at 42%.
On the other hand, the document concludes that BFR patients do not qualify as having an unmet clinical need and has requested that GSK undertake a comparative study in support of its regulatory application in this patient population. On safety, the FDA document concludes that on the back of the trial design, "it is not possible to determine the additional risk of infection posed by the administration" of Arzerra. The document was released ahead of the FDA Oncology Drug Advisory Committee (ODAC), which will be held on 29 May. The FDA is expected to rule on Arzerra by the end of July 2009.
Arzerra is a monoclonal antibody that targets a binding site on the CD20 molecule that is different from that targeted by the existing antibodies such as multi-blockbuster MabThera/Rituxan (rituximab; Roche, Switzerland). Arzerra has secured orphan drug designation in the treatment of CLL in the United States. Under the Orphan Drug Act of 1983, if it reaches the market, the drug should enjoy seven years of exclusivity. GSK acquired the global rights to the drug in December 2006 for a whopping US$2.1 billion. The company also recently acquired the full U.S. commercialisation rights to the drug (see United Kingdom – Denmark: 23 December 2008: GSK Takes on Full U.S. Marketing Duties for Genmab's Arzerra).
Outlook and Implications
The present document does not bode well for GSK and Genmab as it could delay regulatory approval for the drug. With regards to the drug's submission in the treatment of DR CLL patients, much hangs on the ODAC's conclusions as to whether the drug's anti-tumour activity as measured by the ORR and DOR is an acceptable measure of clinical outcome. If the ODAC concludes that it is not, Arzerra could be sent back to a 10-month standard regulatory approval. Although this does not preclude the drug from being approved in this patient population, it could delay market launch by at least a few months. In the worst-case scenario, GSK could be asked for further clinical data to support its application. With regards to the drug's approval in the BFR patient population, as it stands, the companies were required to provide further clinical data to support fast-track approval. As a result, it is highly likely that the drug will not clinch U.S. regulatory approval in this patient population over the summer.
As it stands, the ODAC has yet to form a recommendation on the drug. The outcome of tomorrow's meeting will be crucial for GSK and Genmab as the FDA tends to follow its committee's recommendations although it is not obliged to do so. What seems to be in the balance is the timing of the drug's regulatory approval rather than its approvability. If and when brought to the market, Arzerra would compete with Campath and Treanda (bendamustine hydrochloride; Cephalon, U.S.). GSK and Genmab are looking at extending Arzerra's indications in the treatment of follicular non-Hodgkin's lymphoma, diffuse B-cell lymphoma, rheumatoid arthritis and relapsing remitting multiple sclerosis. Financial analysts have pegged the drug's peak sales at an annual US$2 billion.