Roche's Actemra faces further delay in US for RA

Friday 5 December 2008
Malini Guha - Reporter

The US approval of Roche's novel biological rheumatoid arthritis drug Actemra (tocilizumab) has been further delayed after the FDA requested that Roche submit a risk evaluation and mitigation strategy (REMS) plan as well as additional preclinical studies.

On September 18th, the drug's user fee date, Roche said that the agency had issued it with a complete response letter for Actemra. However, it said then that the additional information requested by the FDA did not involve safety or efficacy issues, and no additional studies were needed.

Instead, the FDA requested additional documentation related to the manufacturing of Actemra and certain other outstanding components such as final labelling, the company said then, indicating that the issues would be resolved in the near future (Scrip Online September 19th, 2008).

However, Roche now says that it anticipates submitting the complete response for Actemra to the FDA in the third quarter of 2009. The FDA requires a REMS plan to help ensure that healthcare professionals prescribe and administer Actemra correctly, and that patients understand the potential benefits and risks associated with it. Additionally, based on the evolving requirements for approval of new biologics, the FDA has asked Roche to undertake preclinical studies to confirm that Actemra does not affect peri- and post-natal development, and fertility. The agency has not requested additional clinical studies before approval.

The FDA Office of Compliance has completed its evaluation of the manufacturing facility in Japan, and has indicated that it is acceptable to manufacture Actemra.

Despite the further delay, analysts at Collins Stewart said approval of Actemra, which they say is a potential blockbuster, is "highly likely" given that the FDA has asked for preclinical rather than clinical data, suggesting the issues are not serious; the clinical data so far have been very strong; Actemra is already approved in Japan, Switzerland and recommended in the EU; and the FDA approved Actemra's manufacturing facility.

On July 29th, the arthritis advisory committee of the FDA voted 10 to one to recommend approval of Actemra, while advising that patients be closely monitored for potential increases in lipid and liver enzyme levels and recommending rigorous postmarketing studies to track cardiovascular outcomes and infections.

It also said Roche's proposed monitoring regimen for hepatic injury was insufficient, particularly given that RA patients are likely to be taking other medicines that could affect liver function. The panel recommended liver enzyme tests with every other infusion, or every two months.

Roche suggested a dose of 8mg/kg intravenously once every four weeks, but the panellists instead supported a lower starting dose of 4mg/kg, with escalation if necessary.

Some committee members saw a niche for tocilizumab as salvage therapy in patients who failed anti-TNF agents.Roche told Scrip that initial use is expected largely to be in these patients as rheumatologists become more comfortable with the first-in-class agent, an IL-6 receptor-inhibiting monoclonal antibody.

Roche submitted the BLA for Actemra to the FDA on November 26th, 2007. It included results from five previously reported Phase III studies, which demonstrated that treatment with Actemra – alone or in combination with methotrexate or other disease modifying antirheumatic drugs (DMARDs)– significantly reduced RA signs and symptoms, regardless of previous therapy or disease severity, compared with current DMARDs alone. In all studies, a significantly higher proportion of subjects given tocilizumab achieved an ACR 20 response (a 20% improvement in symptoms) at 24 weeks compared with the control therapy.

Last month, tocilizumab received a positive recommendation from the EU's CHMP as RoActemra for the treatment of moderate to severe RA, in combination with methotrexate in adults who have either responded inadequately to, or who are intolerant to, previous therapy with one or more DMARDs or TNF inhibitors such as Wyeth's Enbrel (etanercept) and Centocor/Schering-Plough's Remicade (infliximab; Scrip Online, November 25th, 2008).

On December 3rd, the Swiss authorities approved RoActemra for patients who have not responded adequately to treatment with DMARDs or TNF inhibitors.

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