Ocrelizumab (Roche) was the undisputed main attraction of the 2015 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting, which was held on 7–10 October 2015 in Barcelona, Spain. Roche presented detailed clinical data for the drug from three Phase III trials: OPERA I and II in relapsing-remitting multiple sclerosis (RRMS) patients and ORATORIO in primary progressive multiple sclerosis (PPMS) patients. The CD20 antibody showed impressive efficacy across the entire pivotal clinical trial program, with the PPMS data most notable considering the absence of any approved treatment options in this patient population. With no safety signal yet emerging that might jeopardize its regulatory approval, Datamonitor Healthcare now expects ocrelizumab to be a very competitive drug for RRMS patients, where it will predominantly target the $2bn market segment currently occupied by Biogen’s Tysabri (natalizumab). Furthermore, as the first effective drug for PPMS patients, ocrelizumab will provide true growth to the wider market and reinvigorate drug development for this underserved population.
The two OPERA trials showed ocrelizumab to have among the best-in-market efficacy for reducing annualized relapse rate (ARR), while also having a relatively benign safety profile. Drug treatment reduced ARR by 46–47% compared to interferon beta-1a, which is an established standard-of-care for multiple sclerosis (MS). This result potentially places ocrelizumab at a slight advantage to Tysabri, which has demonstrated ~60% ARR reduction against placebo, and is almost identical to the 45% ARR reduction over interferon beta-1a shown by fellow pipeline drug Zinbryta (daclizumab; Biogen/AbbVie) at ECTRIMS 2014. Ocrelizumab’s effect on relapses was also accompanied by a 37–43% reduction in the risk for confirmed disability progression, and highly significant reductions on magnetic resonance imaging (MRI) measures of disease activity. Importantly, ocrelizumab had a lower rate of serious adverse events than interferon beta-1a (6.9% vs 8.7%), including serious infections (1.3% vs 2.9%). The most common treatment-emergent adverse event for ocrelizumab was infusion-related reactions, which occurred in 34.3% of patients. There were no reported cases of progressive multifocal leukoencephalopathy, which have restricted Tysabri’s use to later lines of therapy.
Roche’s 732-patient PPMS trial of ocrelizumab, ORATORIO, met its primary endpoint, with drug treatment showing a significant 24% reduction in the risk of 12-week sustained disability progression compared to placebo. Additionally, ocrelizumab was superior to placebo on a range of secondary endpoints, including 24-week sustained disability progression, timed 25-foot walk, and MRI measures of disease activity. Ocrelizumab was again associated with infusion-related reactions, which occurred in 39.9% of patients, but drug treatment was similar to placebo for the incidence of serious adverse events (20.4% vs 22.2%), including serious infections. These data are harder to place into context considering the lack of comparator therapies, although this fact also makes the results extremely important. Assuming ocrelizumab is approved by the various regulatory agencies, PPMS patients will, for the first time, have a treatment that will slow the course of their disease. The prognosis for patients diagnosed with PPMS is currently poor, as patients experience an inevitable worsening of symptoms with the only respite coming from symptomatic treatments such as those for pain, spasticity, and bladder problems.
After completing its pivotal trial program, Roche now anticipates filing ocrelizumab for approval in early 2016, meaning potential commercial availability from Q4 2016 or Q1 2017. Upon its launch, ocrelizumab will enter the highly competitive RRMS market, where its efficacy and intravenous delivery will place it in competition with other antibody therapies such as Tysabri, Lemtrada (alemtuzumab; Sanofi/Bayer), and potentially Zinbryta. Although Roche is a newcomer to the MS market, it is heavily investing in neurology research and development (R&D), and Datamonitor Healthcare expects that physicians will be very receptive to ocrelizumab. The drug’s benign safety profile will threaten the position of Tysabri, which generated sales of $2bn in 2014.
Furthermore, as the first disease-modifying drug for PPMS, ocrelizumab will introduce new, previously untreated patients to the world of high-cost MS therapies. Roche would rightly be justified in setting a price premium for ocrelizumab, considering the improvement it represents over current treatments and its efficacy for the rare PPMS subtype. However, the commercial dynamics of the RRMS market may force Roche to set its pricing in line with existing therapies as this market is likely to be where the bulk of its ocrelizumab revenues will derive. This would equate to annual US pricing in the region of $60,000–70,000. PPMS patients only account for around one in 10 of new diagnoses, with the vast majority being diagnosed with RRMS. Although not yet tested in the indication, ocrelizumab may also have greater benefits for those RRMS patients who go on to develop secondary progressive MS, which is characterized by a progressive disease course that may also be accompanied by relapses.
Ocrelizumab’s broad efficacy profile provides strong evidence for the role of B cells in MS pathology and will help to reshape future drug development. Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells, which are thought to be contributors to myelin and axonal damage. It follows on from Rituxan (rituximab; Biogen/Roche/Chugai/Zenyaku Kogyo), a first-in-class CD20 antibody predominantly used for hematological indications, which only revealed a marginal clinical effect in a 430-patient PPMS trial completed in 2009.
Companies with CD20-targeting products already in development for MS will be looking to broaden their clinical programs to include the previously difficult-to-treat progressive patients. This includes ofatumumab, which Novartis recently acquired as part of its asset swap with GlaxoSmithKline. Furthermore, those with CD20 antibodies for hematological indications may be tempted to expand into MS as an added differentiator. TG Therapeutics has started recruiting for a trial of ublituximab in acute optic neuritis, which has shared pathology with MS and is also being targeted by Biogen’s next big hope for MS, its anti-LINGO-1 antibody BIIB033.
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