Below is a transcript of the Multiple Sclerosis News Today interview with Dr. Peter Chin — principal medical director at Genentech — about the importance of the pending U.S. Food and Drug Administration (FDA) approval of a Biologics Licensing Application (BLA) for Ocrevus (ocrelizumab).
An an indepth article on this interview, looking Ocrevus and its potential impact on the MS community, can be found here.
Q: The BLA for Ocrevus is now being reviewed by the FDA, and an application is under review by the EMA [European Medicines Agency] as well. Are you anticipating approval? Can you please talk briefly about the journey Ocrevus has taken to reach this point?
Chin: We are working closely with the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) to bring ocrelizumab to people with relapsing forms of multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) as soon as possible. The FDA has indicated their intention to review the RMS and PPMS indications in parallel, with a targeted action date of March 28, 2017. We anticipate approval in the European Union (EU) around Q3 2017.
The journey of ocrelizumab in MS started about 15 years ago, when Genentech began collaborating with academic researchers at major universities to investigate the importance of B cells in MS and their potential as a therapeutic target. The first small proof-of-concept studies showed that CD20+ B cells appeared to play a more important role in MS than anybody previously thought.
At that time, we had a number of B-cell targeted anti-CD20 molecules in our portfolio with different properties. We advanced ocrelizumab, a humanized anti-CD20 antibody, into late stage development because we believed it had the best potential for efficacy and safety in people with MS, a disease where long-term treatment is warranted. A Phase 2 dose finding study provided preliminary evidence for ocrelizumab’s efficacy, showed a very low incidence of anti-drug antibodies, and informed selection of a dose for further investigation in Phase 3 clinical trials.
The Phase 3 clinical development program called ORCHESTRA included two studies (OPERA I and OPERA II) in people with RMS [i.e., relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) with relapses] and one study (ORATORIO) in people with PPMS. Currently, there are no approved medicines for PPMS.
Ocrelizumab is the first and only medicine to significantly reduce disease activity and slow physical disability progression in both RMS and PPMS in large Phase III studies.
This pioneering science redefines our understanding of the underlying biology of MS and shows that B cells, a type of immune system cell, play a central role in the disease. On December 21, 2016, the Phase III OPERA I, (NCT01247324), OPERA II (NCT01412333), and ORATORIO (NCT01194570) data were published online by the New England Journal of Medicine, and then in the same print issue on January 19.
Q: Knowing that Ocrevus is the first drug to show a significant impact on disease progression in primary progressive MS patients, could you elaborate on the importance of its pending approval?
Chin: In the past 20 years, we’ve seen a lot of progress in the fight against MS to help the 2.3 million people worldwide who have this disease. Despite these advances, people with RMS continue to need medicines that offer the potential for greater efficacy than standard-of-care interferons, while offering a favorable safety profile.
For people with PPMS, as you know, there are currently no approved treatments. PPMS is a debilitating form of the disease that affects 10-15% of people diagnosed with MS. People with PPMS have steadily worsening symptoms, typically without distinct relapses or periods of remission. Previous Phase III trials with investigational medicines have failed to demonstrate a significant effect on disability progression in PPMS.
Ocrelizumab is the first and only investigational medicine to show superior efficacy versus a comparator in both RMS and PPMS in clinical studies. In the OPERA I and OPERA II RMS studies, ocrelizumab consistently and significantly reduced disease activity and disability progression compared with a standard-of-care high-dose interferon (Rebif®). Ocrelizumab is the first investigational medicine to significantly reduce the progression of physical disability in primary progressive MS in a large Phase III study (ORATORIO).
With no approved treatments for PPMS, ocrelizumab has the potential to address an important unmet need in MS. We are committed to working with the FDA and EMA to make ocrelizumab an available treatment option for people with RMS and PPMS.
Q: How is Roche/Genentech working to ensure that as many eligible patients as possible are given access to the treatment, if approved?
Chin: Once FDA approved, we will have our Access Solutions service available to help people who are prescribed ocrelizumab navigate the access and reimbursement process, and to provide assistance to eligible patients in the United States who are uninsured or cannot afford the out-of-pocket costs for their medicine. To find more information about Access Solutions, please visit Genentech-Access.com.
Q: If the results seen in Phase 3 studies — reduced annualized relapse rates and a large proportion of patients reaching no evidence of disease activity — turn out to hold over a patient’s lifetime, how much impact do you foresee Ocrevus having on the natural course of MS?
Chin: Based on the pivotal study results of OPERA I, OPERA II and ORATORIO, ocrelizumab has the potential to change the way MS is treated. If approved, ocrelizumab would be the first and only treatment for RMS and PPMS, which affect approximately 95 percent of people with MS at diagnosis.
It is believed that early control of disease activity, including the reduction of clinical attacks and disease progression, plays a key role in preventing long-term accumulation of disability. No evidence of disease activity (NEDA) is a composite measure to assess the absence of clinical (relapses and disability) and MRI disease activity. NEDA in clinical studies enables determination of the prognosis for the long-term MS disease course. An independent publication on long-term NEDA status showed that NEDA at two years had a high positive predictive value for no progression at seven years.
Treatment with ocrelizumab resulted in a significantly higher proportion of patients achieving NEDA compared with interferon beta-1a in people with RMS. In exploratory analyses, ocrelizumab significantly increased the proportion of patients that achieved NEDA by 64% in OPERA I and 89% in OPERA II over 96 weeks compared with interferon beta-1a (both nominal p<0.001).
Scientifically speaking, projecting the effectiveness of a therapy for MS over time – or for any chronic condition that strikes young adults – is very challenging to do. Genentech is committed to further understanding the long-term effectiveness of suppressing disease activity with ocrelizumab through open-label extension studies of the OPERA and ORATORIO trials, as well as other studies.
Q: Targeting B cells in MS patients appears to be Ocrevus’ strength, but depleting B cells also raises safety concerns. Can you address these concerns for a moment, and future work your company is considering that might also address them?
Chin: The ocrelizumab Phase III studies have redefined our understanding of the underlying biology of MS and shows that B cells, a type of immune system cell, play a central role in the disease. CD20-positive B cells are a specific type of immune cell thought to be a key contributor to myelin (nerve cell insulation and support) and axonal (nerve cell) damage, which can result in disability in people with MS.
Ocrelizumab selectively binds to CD20, a cell surface antigen expressed by a subset of B cells. CD20 is not expressed on stem cells or antibody-producing plasma cells, and therefore pre-existing humoral immunity and the ability to reconstitute B cells may be preserved. Since the CD20 protein is not found on many other cells of the immune system, they can continue to fight infection and other illnesses.
The safety of ocrelizumab was assessed in the three pivotal Phase III studies (OPERA I and OPERA II in RMS, and ORATORIO in PPMS), in which the proportion of patients with serious adverse events and serious infections were similar to interferon beta-1a in the RMS studies and to placebo in the PPMS study. Ocrelizumab demonstrated a favorable safety profile in each Phase III study. Safety analyses continue in the open-label extension studies in both RMS and PPMS.
Q: Studies showed the Ocrevus-treated patients had a higher risk of tumors (0.40 per 100 patient-years of exposure) than non-treated patients. How significant do you consider this risk, and what is being done to address it? If Ocrevus is approved, will Genentech recommend that patients using it be monitored for signs of malignancies?
Chin: Patient safety is very important to us and we are committed to closely and continuously monitoring all safety data, including malignancy rates, in ongoing and future clinical studies. Although there was a numerical imbalance observed in the MS Phase III trials, we believe the totality of data does not support a causal relationship between ocrelizumab treatment and malignancy. Rates of malignancy with ocrelizumab treatment remain within epidemiological reports and no clear relationship between B cell suppression and malignancy has been established. Continued follow-up in the open-label extension studies have not shown increased risk of malignancy with additional exposure to ocrelizumab treatment.
We have submitted all ocrelizumab safety data to the FDA for consideration as they review the licensing application. We cannot speculate on post-approval monitoring at this time. We look forward to our action date of March 28, 2017, and hope to bring ocrelizumab to people living with RMS and PPMS as soon as possible.