Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications
Risk of serious infections has hampered mAb’s development in RA and LE, but drug is still being tested in MS.
On March 8, Roche and Biogen Idec said that they were suspending treatment of rheumatoid arthritis (RA) patients with Ocrelizumab. It reportedly caused serious and opportunistic infections, several of which were fatal in some of the 2,400 patients treated in trials in more than 30 countries. Neither Roche nor Biogen Idec revealed how many patients died from infections related to the antibody.
Ocrelizumab is a humanized anti-CD20 mAb characterized by some as the “next-generation Rituxan” or the “son of Rituxan.” The antibody made it into Phase III trials for RA and lupus erythematosus (LE) and Phase II studies for multiple sclerosis (MS) and hematologic cancers. Besides canceling four RA-related trials (SCRIPT, FEATURE, FILM, and STAGE), the companies also terminated the BELONG trial for LE. The companies are continuing their Phase II testing of ocrelizumab in the treatment of relapsing-remitting MS.
In December 2009, Roche reported that the Phase III STAGE study of Ocrelizumab with methotrexate (MTX) met its primary endpoint. But an analysis by the independent Data and Safety Monitoring Board (DSMB) of all four RA studies and the two LE trials revealed too many riskz for RA patients. The FILM study, conducted in MTX-naïve RA patients, had already been placed on clinical hold.
The BELONG study in lupus patients had also previously been halted due to signs of serious and opportunistic infections. This study was designed to evaluate the efficacy and safety of Ocrelizumab added to standard of care (SOC) comprising corticosteroid plus one of two immunosuppressant regimens compared with placebo added to SOC.
Ocrelizumab Out of the RA Game
Biogen Idec may be less disappointed than Roche in the trial discontinuations for Ocrelizumab in RA, as this will likely prolong the sales life of Rituxan, which treats RA, LE, as well as hematologic cancers and was developed by Genentech, now part of Roche, and Biogen Idec. Biogen Idec draws a higher share of revenue from Rituxan sales than it would from the new drug.
The operating profits for Rituxan are currently split 60–40 between Roche and Biogen Idec, respectively. But profits for Ocrelizumab would be split 70–30 in Genentech’s favor, accounting for Genentech’s enthusiasm to move ahead with the development of Ocrelizumab in MS, at the expense of Rituxan, which loses patent protection in 2015.
Rituxan remains a significant source of revenue, with Biogen Idec reporting net U.S. sales of almost $2.67 billion in 2009. Overall sales in 2009 rose 6% to CHF 6.1 billion, or $5.73 billion. Sales in the RA segment were an estimated CHF 900 million (about $845.9 million), or 15% of the product’s total sales.
mAb Still in Play for MS
A win with Ocrelizumab would strengthen Biogen Idec’s franchise in MS and take some of the edge off Tysabri’s upcoming loss of patent protection in 2015. Besides Tysabri, the firm also owns Avonex, but the drug goes off patent in 2011.
Tysabri, an anti-α4integrin mAb used to treat MS in patients who do not respond to other drugs, was developed by Elan and is co-marketed with Biogen Idec in a 50–50 partnership. Despite 35 cases of and eight deaths among MS patients due to progressive multifocal leukoencephalopathy (PML), Tysabri remains a source of future growth for both companies. Its sales have indeed been slower than originally hoped amid concerns about PML, which led to its 18-month market withdrawal beginning in 2005.
The most recent update in PML cases, disclosed by Biogen Idec in February, translates to about 1.56 cases per 1,000 patients on Tysabri for between two and three years. By contrast, the incidence is about 0.54 case per 1,000 patients in those using the drug for one to two years, and it is almost nonexistent in patients using less than a year. Should the incidence climb, analysts say sales could fall as the risk of PML to patients becomes increasingly unacceptable.
Among patients with secondary progressive MS, a subgroup of chronic progressive MS patients, Tysabri will most likely remain “a proprietary clinical gold standard” through 2018, according to Decision Resources. “Surveyed neurologists told us that a drug’s effect on long-term disability progression is the attribute that most influences their prescribing decisions in chronic progressive multiple sclerosis,” reports Bethany Kiernan, Ph.D., Decision Resources’ director.
“Although Tysabri’s robust therapeutic effects have been demonstrated only in relapsing-remitting multiple sclerosis patients, not chronic progressive multiple sclerosis patients, experts’ positive perception of the drug’s efficacy extends beyond the relapsing-remitting population. Taken together, these clinical data and the opinions of interviewed thought leaders indicate that Tysabri has advantages over the chronic progressive multiple sclerosis sales leader, Betaseron, on this attribute.”
Benlysta Remains Front-Runner in LE
Ocrelizumab may remain a viable candidate for MS treatment, given the precedent for serious infection as an acceptable risk in this patient population. But for LE, a chronic autoimmune disorder affecting more than 1.5 million Americans, mostly women of childbearing age, the antibody candidate to beat may be Human Genome Sciences (HGS) and GlaxoSmithKline’s (GSK) Benlysta. Given that the mAb is already in Phase III, if successful, the treatment will become the first new therapy approved for LE in about 50 years.
In November 2009, HGS and GSK announced that the antibody met the primary endpoint in BLISS-76, the second of two Phase III trials in seropositive LE (SLE). Study results through 52 weeks showed that Benlysta 10 mg/kg plus standard of care achieved a statistically significant improvement in patient response rate compared with placebo plus standard of care.
In addition to reduced lupus symptoms, patients noted fewer flare-ups, less fatigue, better quality of life, and an ability to decrease typical steroid dose. The study also showed that the antibody was generally well tolerated, with rates of overall adverse events and infections as well as discontinuations due to adverse events comparable between both treatment arms.
Upon news of the successful clinical trial results, Leerink Swann research analyst Joseph P. Schwartz reaffirmed an Outperform rating for HGS, saying that he expected Benlysta to gain regulatory approval and then reach the market by the second half of 2010. He boosted his fair value outlook for the stock to $40 from $30 and expects the company to present full results from BLISS-76 at an upcoming medical conference.
Ocrelizumab may be out of the game in LE, but for Biogen Idec, with its significant franchise in MS, positive results with Benlysta really matter. Roche and Biogen Idec are thus continuing with one clinical trial testing Ocrelizumab in MS.
The most advanced results from the drug in this indication came last December. The companies reported that the antibody produced significant reductions in signs of disease activity among 220 treatment-naïve and previously treated patients with the relapsing-remitting form. The aim is to get a potentially safer but equally effective drug as Tysabri, which will extend Biogen Idec’s MS franchise.
Patricia F. Dimond, Ph.D., is a principal at BioInsight Consulting. Email: firstname.lastname@example.org.