Interview on the PPMS ORATORIO Study
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People with primary progressive multiple sclerosis (PPMS) finally have something to cheer about in a potential disease modifying therapy. Genentech and Roche pharmaceutical companies announced the results of their studies of ocrelizumab in both relapsing remitting MS (RRMS) and PPMS, at the annual conference hosted by the European committee for the treatment and research in MS. (ECTRIMS), held in Barcelona, Spain.

Dr. Peter Chin, Principal Medical Director, for Genentech-Roche Global Neuroscience Development, took time out from the ECTRIMS meetings to discuss these study results with me. To understand the questions, you might first need more background information on ocrelizumab and ORATORIO. Scroll past the background information to get to my exclusive interview with Dr. Chin.

BACKGROUND:

Ocrelizumab is a humanized monoclonal antibody drug, and works by targeting B cells, which may be key to the destruction of the myelin and axonal damage experienced in MS. Ocrelizumab is a cousin of Rituximab, a drug that has quietly been used off-label for hard to treat cases of MS (think PPMS), but not so coincidentally also has a patent expiration date of 2015 (think small profit in generic drugs). Rituximab is commonly used for treating rheumatoid arthritis.

Ocrelizumab was studied in three separate trials named OPERA I, OPERA II, and ORATORIO. The OPERA studies looked at RRMS, and ORATORIO focused on PPMS. The OPERA studies showed positive results and plenty will also be written about them, but we have seen many RRMS drugs come into use over the past five years. We will take a closer look at OPERA results later – for now the spotlight should be on PPMS treatment.

What makes ORATORIO stand out is this is the first drug that has met the desired endpoints in PHASE III clinical trials for PPMS. ORATORIO was a double-blind, randomized study conducted at multiple sites around the world, and the study participants who received the real drug were given 600mg intravenously, in two separate 300mg doses, two weeks apart. There were 732 people in the trial and the study lasted 120 weeks for the subject on either Ocrelizumab or placebo.

The results of this Phase III study showed significant slowing of disease progression through an increase in walking speed, evidence on MRI with fewer lesions, and slowed brain volume loss.

The criteria for the study participants can be found through the clinical trials registry A Study of Ocrelizumab in Patients With Primary Progressive Multiple Sclerosis, but the following is a picture of the study population they used and the outcomes they hoped to meet.

The ORATORIO study was designed with these measures as their benchmarks for success:

“Primary Outcome Measures:

  • Efficacy: Time to onset of sustained disability progression, defined as an increase in Expanded Disability Status Scale (EDSS) score that is sustained for at least 12 weeks [ Time Frame: up to 5.5 years ]

Secondary Outcome Measures:

  • Time to sustained disability progression, defined as an increase in EDSS score that is sustained for at least 24 weeks [ Time Frame: up to 5.5 years ]
  • Change in timed 25-foot walk [ Time Frame: from baseline to Week 120 ]
  • Change in total volume of T2 lesions on magnetic resonance imaging (MRI) scans of the brain [ Time Frame: from baseline to Week 180 ]
  • Safety and tolerability: Incidence of adverse events [ Time Frame: up to 5.5 years ]

Inclusion Criteria:

  • Adult patients, 18-55 years of age
  • Primary Progressive Multiple Sclerosis (according to revised McDonald criteria)
  • Expanded Disability Status Scale (EDSS) 3 to 6.5 points
  • Disease duration from onset of MS symptoms < 15 years if EDSS > 5.0, < 10 years if EDSS >/= 5.0

Sexually active male and female patients of reproductive potential must use two methods of contraception throughout the study treatment phase and for 48 weeks after the last dose.”1

According to the official release from Genentech:

“The ORATORIO study met its primary endpoint, showing treatment with ocrelizumab significantly reduced the risk of progression of clinical disability sustained for at least 12 weeks by 24 percent compared with placebo, as measured by the EDSS (p=0.0321). Additionally, ocrelizumab was superior to placebo in significantly reducing the risk of progression of clinical disability for at least 24 weeks by 25 percent (p=0.0365) and the time required to walk 25 feet (Timed 25-Foot Walk, or T25-FW) over 120 weeks by 29 percent (p=0.0404). Ocrelizumab decreased the volume of hyperintense T2 lesions by 3.4 percent over 120 weeks, compared to placebo which increased T2 volume by 7.4 percent (p<0.0001). Ocrelizumab reduced the rate of whole brain volume loss over 120 weeks by 17.5 percent compared to placebo (p=0.0206).”

Exclusive Interview on Primary Progressive MS ORATORIO trial results

Peter Chin, MD, is Principal Medical Director for Genentech-Roche Global Neuroscience Development, and integral to the design and study of Ocrelizumab in both the OPERA and ORATORIO trials for the use of this drug in treating multiple sclerosis. Dr. Chin has treated people with MS where he learned more about the impact of this disease and its various stages. He took time from the proceedings of the ECTRIMS 2015 Congress to answer my questions.

Q: When will the results of the study ORATORIO be made available through formal papers so we might see all the results of this study?

Dr. Chin: We’re excited about the results of all three trials – the opera results in relapsing MS are also very good on many end points. And of course ORATORIO for primary progressive MS. The data is very fresh, it’s very new and many people at Roche worked very hard to get it to Congress (ECTRIMS) – we’re talking that these study results were just unblinded a couple weeks ago and so we may not yet have answers to all of your questions. It’s important for science to get the results without actually knowing what all of it will eventually show.

Q: ClinicalTrials.gov indicates these trials won’t be over until 2017. Can you explain how we have results now or if this study will continue?

Dr. Chin: The study design is complex. It was designed a number of years ago and progressive trials take a long time to complete. What that means from a clinical trial standpoint, there was no successful template how to complete a trial for PPMS. We designed the study to get the best chance for ocrelizumab to show efficacy against placebo, knowing there were many challenges and unknowns in developing this study. It is an event driven trial – when you power the study you can calculate the total number of confirmed disability disease progressions for the study to yield an answer as to whether the drug is effective or not. If you stop the study too short, not reaching that number, the study could fail not because the drug doesn’t work but because you designed the study wrong.

The ORATORIO study was against a true placebo. Very important was the patients were randomized in a 2:1 ratio, that means there are twice as many patients in the study treated with ocrelizumab than the placebo and that’s very important in looking at the data.

The study population was all people with PPMS; any person with a history of relapsing MS, secondary progressive or primary relapsing was not eligible for the study. The EDSS range was 3-5.

Q: The inclusion criteria shows you excluded people with a longer disease course. It seems the trial wasn’t looking at the older population of people with PPMS who have lived with this for 20-30 years.

Dr. Chin: This relates to my comments earlier about not having a template to follow for a PPMS trial. The reason for limiting the duration of the disease and a particular EDSS landmark has to do with the historical progression rate of an individual and this being an event driven trial. If patients have been stable for a very long time, their likelihood of progressing during the course of the trial, which is a limited time frame, is lower. When you need to demonstrate efficacy based on a number of events, it makes it harder to have a successful event if you have treatment arms that are not progressing and then you can’t show treatment over a period of time.

Q: Can you explain what would make ocrelizumab as a humanized monoclonal antibody more effective or useful than Rituximab, which is a chimeric (mouse) drug? And how much of this development is profit motivation and being answerable to investors and stockholders. Is there an advantage to this humanized version versus using Rituximab off-label?

Dr. Chin: The majority of the protein sequence in ocrelizumab is human, and that has certain advantages in therapy, particularly a chronic therapy that is used for a long time. The humanization is important because there is less likelihood an individual will generate antibodies against the drug itself. This is the basic reason humanization is preferred. Approximately 30% of the protein sequence of rituximab is mouse sequence and that has a higher potential to generate an anti-body. Injecting foreign protein gives a higher likelihood the body will generate antibodies and create problems. Taking that biology, when thinking about developing a drug for all autoimmune diseases, Genentech and Roche wanted to take this (ocrelizumab) forward because long term it has the best opportunity for efficacy and safety.

Q: If and when this is approved by the FDA, are there going to be specific things that will exclude certain people from taking ocrelizumab, such as a higher EDSS number or having taken a prior treatment that would expose them to other risks?

Dr. Chin: The short answer is those answers will come in time. From our perspective, we are mainly focused on getting complete data analysis, getting the  data analyzed and submitted to the global regulatory authorities (beyond just FDA). We are at the point of focus to get the data packaged and we will initiate discussions with the regulatory agencies.  It is way too early to speculate what they will do with our data, what the labels will look like, and how the use will be approved. But those will come in time.

Q: Are there any plans to do follow-on studies with ocrelizumab or further studies to expand its use?

Dr. Chin: as you noted we did the three studies and have a very robust data package to learn from. It is too early to speculate on other trials. We will try to understand the results from these three studies and have scientific discussions and see what else we might study from this.

Q: What prior therapies might a person have been on that would keep them from taking ocrelizumab or will there be a recommended washout period before starting this drug?

Dr. Chin: While I appreciate the question, what we can speak to now is the study data. Close to 90% of the study participants were not on a therapy prior to the trial. Those patients who were previously treated will be looked at closer for their data.

Q: Was there something that really grabs this headline when it was presented at ECTRIMS?

Dr. Chin: This is the first PPMS large study that has demonstrated efficacy on the end points. It is the first trial to show a positive effect on the EDSS but also on the other (secondard) outcomes. This is the first success.

The other thing is when looking at all three of our studies and the positive results, is the overall effect on B Cells. Genentech and Roche have always been committed to pioneering science and advancing understanding of treatments that work and open up new avenues of research. It also shows us the results of the trials teaches us something about the disease, about the physiology itself.

Q: The results clearly show efficacy in slowing and stopping disease progression but I don’t see anything in the results that shows the drug is also restorative. Am I correct that we are not looking at a drug that is capable of doing axonal or myelin repair?

Dr. Chin: So, the primary end point of the study was to continue firm disability progression and secondary endpoints as I mentioned. It is still very early and we just unblinded the study a couple weeks ago. We will do a lot of additional analysis to better understand the potential efficacy across different measures that you are highlighting but for now we are limited to what Dr. Montovan (trial lead) covered at this stage (at the official ECTRIMS presentation).

Q: If you have read any of my writings, you already know I have a love/hate relationship with the pharmaceutical companies. Like most of us, we need you and want to know the companies are doing right for us. I appreciate the time you have taken to talk with me and helped to answer a lot of my questions.

Dr. Chin: The last thing I want to say is hopefully this has been useful. Roche and Genentech have always been leaders in trying to develop innovative therapies that really transform medicine. I hope we can continue this dialogue and over time we can answer the rest of the questions you have once we have analyzed the data.

Postnote: stay tuned. There will be more to this story as the results are studied and the approval process moves forward.

Wishing you well,

Laura

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