US FDA approves Roche's Actemra for previously treated RA
This article was originally published in Scrip
The US FDA has approved Roche's first-in-class IL-6-receptor inhibiting monoclonal antibody Actemra (tocilizumab) for the treatment of moderate-to-severely active rheumatoid arthritis (RA) in patients who are unresponsive to TNF inhibitors. The drug will be available in the US from January 18th.
"We are optimistic that working with the agency, we will be able to generate the additional data required to support approval in earlier lines of RA therapy," said Dr Hal Barron, executive vice president and chief medical officer of Roche. A number of additional Phase III trials are already underway.
The anti-inflammatory drug has been approved in Japan since April 2005, where it is currently approved for Castleman's disease, RA, systemic juvenile idiopathic arthritis (sJIA) and juvenile idiopathic arthritis. It was approved, as RoActemra, earlier last year for RA in the EU after receiving a positive opinion in 2008 (scripnews.com, November 25th, 2009).
It faced considerable delays attaining US approval, however. Despite a favourable vote of 10 to one by an arthritis advisory panel in 2008, the FDA issued a complete response letter that cited manufacturing and labelling concerns. The agency subsequently said that a risk evaluation and mitigation strategy (REMS) was needed, and requested preclinical studies to assess the peri- and postnatal development and fertility effects of the drugs. It was resubmitted in the US in August last year, at which time it was granted a six-month priority review (scripnews.com, August 6th, 2009).
Jefferies analyst Jeffrey Holford and his colleagues are optimistic about the future for the biologic with this new approval. "Due to what we see as the best risk/benefit profile of any rheumatoid arthritis drug to date (including the TNFa inhibitors) we believe Actemra has the potential to reach at least $3billion in peak sales potential," they write.
"We expect Actemra to eventually penetrate into first-line usage amongst the biologic agents once rheumatologists gain more experience with the drug and an injectable formulation reaches the market." RA is typically treated with non-steroidal anti-inflammatories and corticosteroids, followed by disease-modifying antirheumatic drugs (DMARDs) like methotrexate and then subcutaneous TNF inhibitors such as Amgen/Pfizer's blockbuster Enbrel (etanercept), Johnson & Johnson/Merck's Remicade (infliximab) and AstraZeneca/Abbott's Humira (adalimumab). Actemra, now a late-line resort, is currently administered as an intravenous infusion.
It was approved on the basis of five Phase III trials – RADIATE, OPTION, TOWARD, AMBITION and LITHE. These involved more than 4,000 patients and showed that Actemra, alone or in combination with methotrexate or other DMARDs reduced the signs and symptoms of RA compared with DMARDs alone. A head-to-head trial showed the Actemra was as effective as methotrexate in treatment-naïve patients, three trials tested the drug in patients who had failed DMARDs, and one tested the drug in those who had failed TNF inhibitors.
In RADIATE, for instance, 50% and 30% of patients who received Actemra 8mg/kg or 4mg/kg plus methotrexate, respectively, achieved the American College of Rheumatology 20% (ACR20) benchmark of improvement at week 24, compared with 10% of patients who received placebo plus methotrexate. Another trial – the LITHE trial – showed that the drug also reduced structural damage, as assessed by the Genant-modified Sharp score.
The drug's US labelling carries a black box warning on the risk of serious infections. "Serious infections leading to hospitalisation or death, including tuberculosis, bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving Actemra," it reads. The most common adverse events reported in clinical studies were upper respiratory tract infection, nasopharyngitis (inflammation of the nose and throat), headache, high blood pressure and increased liver enzymes.
Earlier last year, treatment was linked to 15 deaths among RA patients (0.3% of the total patient population) in Japan (scripnews.com, March 18th, 2009).
The drug was developed by Japanese firm Chugai Pharmaceuticals, which is controlled by Roche. Roche holds the rights to sell the drug outside Japan.
IL-6 is one of several cytokines that is linked with the inflammatory process, and its levels have been found to be elevated in patients with RA. In blocking the IL-6 receptor, Actemra is the first drug that specifically targets IL-6 activity. The only other IL-6 receptor inhibitor in clinical development is Regeneron's REGN-88, which recently completed Phase I trials for RA.