Investigational medicine to show positive study results in primary progressive and relapsing MS

Ocrelizumab is the first and only treatment to show positive results in primary progressive multiple sclerosis (MS) Phase III clinical study, (1) where all previous Phase III studies with MS medications have been negative. In relapsing MS, 46% and 47% reduction in relapse rate and delay onset of disability progression by 40% showing superiority to an established treatment, interferon beta-1a, not placebo (2). Findings from three Phase III studies, recruiting MS patients from eight UK study sites, (3,4,5) reinforce that B-cells are important in treatment of MS

Three phase III studies being presented at the European Committee for Treatment Research in Multiple Sclerosis (ECTRIMS) congress demonstrate that treating MS with ocrelizumab reduces relapse rate and delay onset of disability progression compared to interferon beta-1a (Rebif®) in relapsing forms of MS (RMS) (OPERA I and OPERA II studies) and disability progression in primary progressive MS (PPMS) (ORATORIO study) compared to placebo. (1,2)

Ocrelizumab is an investigational therapy that selectively targets B-cells, (6) one of the two immune cells implicated in the inflammatory and neurodegenerative process of MS, (7,8) which affects approximately 100,000 people in the UK. (9)

Professor Gavin Giovannoni, Chair of Neurology at the Blizard Institute, Barts and The London School of Medicine and Dentistry, said, “The Phase III ocrelizumab results for both PPMS and RMS, in my opinion, are a game changer for the clinical community. These data demonstrate that B-cell targeting can significantly modify the disease, which in effect means a more positive outlook for patients. The important next step is for regulators to enable the use of ocrelizumab across the spectrum of PPMS and RMS, and for treatment to be provided as soon after diagnosis as possible to provide optimal outcomes, with the potential to improve patients’ quality of life in the long-term.”

The Phase III ORATORIO study in PPMS included five UK sites (3) and met its primary endpoint in this progressively disabling form of MS, which currently has no approved treatments. (1,10) Top-line results being presented as a late-breaking abstract at ECTRIMS have shown a reduction in the progression of clinical disability with ocrelizumab of 24% compared with placebo sustained for at least 12 weeks, as measured by the Expanded Disability Status Scale (p=0.0321). (1)

Commenting on the ORATORIO data, a UK Investigator Dr Klaus Schmierer, Reader in Clinical Neurology at the Blizard Institute, Queen Mary University of London, and Consultant Neurologist at The Royal London Hospital (Barts Health NHS Trust) said, “It is exciting to see the results of ocrelizumab in primary progressive MS (PPMS). People with PPMS and clinicians alike have been eagerly waiting for an effective treatment to slow the path of relentless deterioration in PPMS. This is great news for everybody affected by MS, and society as a whole.”

Also presented at ECTRIMS are the Phase III OPERA I and II studies, which included six study sites in the UK. (4,5) For patients treated with ocrelizumab, the reduction in frequency of their relapses (known as annualised relapse rate [ARR]) was 46% (p=0.0001) in OPERA I and 47% (p=0.001) in OPERA II compared to patients treated with interferon beta-1a. (2)

Ocrelizumab also significantly delayed the progression of clinical disability with a relative risk reduction of 40% (p=0.006) across the two studies (OPERA I: 43%, p=0.0278; OPERA II: 37%, p=0.0370) compared to interferon beta-1a. (2) This is the first time a single treatment has met this endpoint in two separate phase III studies. Furthermore, treatment with ocrelizumab led to a reduction of the total number of T1-gadolinium-enhancing lesions on the brain by 94% (p=0.0001) in OPERA I and 95% (p=0.001) in OPERA II compared with interferon beta-1a. (2)

This is important because an increased number of lesions reflects disease activity. (4,5) In more serious cases with specific types of lesions, an increase can result in brain damage, affecting a patient’s mobility, visual coordination, and cognition. (11,12)

Commenting on the OPERA I and II data, Dr Ben Turner Consultant Neurologist and Honorary Senior Lecturer at Barts and The London NHS Trust and UK Chief Investigator of one of the OPERA studies said, “Two phase III studies have shown the benefit of ocrelizumab in relapsing forms of MS. This is a significant step forward in the treatment of this challenging disease. Ocrelizumab provides a new mechanism of action and therefore new approach to treating MS.”

Approximately 95% of all cases of MS are in the relapsing and primary progressive forms of this debilitating disease at diagnosis. (13) Characterised by relapses or flare-ups (attacks) of symptoms, RMS forms approximately 85% of all cases. (13) Approximately a further 10–15%present with PPMS, which is characterised by steadily worsening neurologic function from the beginning with no distinct relapses or remissions. (13) To date, no treatment has been shown to be effective. (10)

Dr Dan Thurley, Medical Director Roche UK, said, “This pioneering science redefines our understanding of the underlying biology of MS with a clear focus on the role of B-cells in the disease. This is the result of our investment in following the science and we look forward to continuing further research of new treatment options for patients with chronic and potentially devastating diseases. We are excited to be re-entering the neuroscience space with the aim to improve the lives of patients.”

In the ORATORIO study, the incidence of adverse events associated with ocrelizumab was similar to placebo (95.1% versus 90.0%, respectively); the most common adverse events were mild-to-moderate infusion-related reactions (39.9% versus 25.5% for placebo). The incidence of serious adverse events associated with ocrelizumab, including serious infections, was also similar to placebo (20.4% versus 22.2%, respectively). (1)

Overall, the results of the OPERA I and II studies in relapsing MS did not show any unexpected safety findings, with adverse events being similar to those seen in the interferon beta-1a arm of the studies (83.3% in each treatment group). The most common treatment-related adverse event associated with ocrelizumab was infusion-related reactions (IRR), which were mostly mild to moderate in severity (34.3%of patients who received ocrelizumab experienced at least one infusion-related reaction versus 9.7% for interferon beta-1a). The proportion of patients in the ocrelizumab group with serious adverse events, including serious infections, was also similar to interferon beta-1a (6.9% versus 8.7%, respectively). (2)

References:

1. Montalban X. (2015) Efficacy and safety of Ocrelizumab in primary progressive multiple sclerosis – results of the placebo-controlled, double-blind, Phase III ORATORIO study. Abstract #228. ECTRIMS presentation on Saturday 10 October at 8:52am.
2. Hauser SL. (2015) Efficacy and safety of Ocrelizumab in primary progressive multiple sclerosis – results of the interferon – beta – 1a – controlled, double-blind, Phase III OPERA I and II studies. Abstract #190. ECTRIMS presentation on Friday 19 October at 14:40pm. F. Hoffmann-La Roche. ClinicalTrials.gov NCT01194570. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT01194570. Last accessed October 2015.
3. F. Hoffmann-La Roche. A Study of Ocrelizumab in Patients With Primary Progressive Multiple Sclerosis. ClinicalTrials.gov NCT01194570. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT01194570. Last accessed October 2015.
4. F. Hoffmann-La Roche. A Study of Ocrelizumab in comparison with Interferon Beta1a (Rebif) in patients with relapsing multiple sclerosis. ClinicalTrials.gov NCT01247324. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT01247324. Last accessed October 2015.
5. F. Hoffmann-La Roche. A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Patients with Relapsing Multiple Sclerosis. ClinicalTrials.gov NCT01412333 National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT01412333. Last accessed October 2015.
6. Roche. Product Development Portfolio. Available from: http://www.roche.com/research_and_development/who_we_are_how_we_work/pipeline.htm. Last accessed October 2015.
7. Disanto et al. The evidence for a role of B cells in multiple sclerosis. Neurology 2012;78(11):823–32.
8. Magliozzi R, et al. A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010;68(4):477–93.
9. Multiple Sclerosis Society. What is MS? Available from: http://www.mssociety.org.uk/what-is-ms. Last accessed October 2015.
10. National MS Society. Treating Primary Progressive MS. Available from: http://www.nationalmssociety.org/What-is-MS/Types-of-MS/Primary-progressive-MS/Treating-Primary-Progressive-MS. Last accessed October 2015.
11. Bakshi R. Multiple Sclerosis: Hyperintense Lesions in the Brain on Nonenhanced T1-weighted MR Images Evidenced as Areas of T1 Shortening in Radiology. 2007;244(3).
12. MS International Federation. What is MS? Available from: http://www.msif.org/about-ms/what-is-ms/. Last accessed October 2015.
13. National MS Society. What is MS? Available from: http://www.mssociety.org.uk/what-is-ms. Last accessed October 2015.