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HD InsightsMeet the Partner

Dr. Scott Schobel
Dr. Scott Schobel


NAME: Scott Schobel, MD, MS

TITLE: Translational Medicine Leader, Hoffmann-La Roche Pharmaceuticals

EDUCATION: BA, Japanese, University of Minnesota; MD, University of North Carolina-Chapel Hill; MS, Columbia University Mailman School of Public Health

HOBBIES: Skiing; studying languages (currently German); chasing after his three sons

Dr. Scott Schobel, former Professor of Psychiatry at Columbia University School of Medicine, currently leads clinical efforts at Roche to develop Ionis Pharmaceuticals’ IONIS-HTTRx, the first huntingtin-lowering therapy being evaluated in humans. He took a few moments to share his thoughts with HD Insights on the compound, Roche, and the future of HD therapeutics. The following is an edited transcript of the conversation.

HD INSIGHTS: Can you tell us how Roche became interested in Ionis Pharmaceuticals?

SCHOBEL: Roche’s strategy of innovation is to follow the science and disease areas in which we believe we can make the greatest difference in peoples’ lives. We consider our collaboration with Ionis Pharmaceuticals in HD to be true to this strategy.

The particular thing that attracted us is that Ionis has generated a huntingtin antisense oligonucleotide (ASO). This is a second-generation antisense therapy—the first to enter clinical development—designed to reduce the production of all forms of HTT, including mHTT. The life-transforming potential of this ASO made it a very attractive opportunity for us.

HD INSIGHTS: HTTRx recently began a clinical trial with a Phase I study in individuals with early HD. Can you tell us about that?

SCHOBEL: First, I should say that Ionis is running the trial. They are in charge of development until the end of Phase I. In the Phase I trial, we are seeking to better understand the ASO. The two key parameters we are interested in are that it is safe and well tolerated, and whether its expected huntingtin-lowering action is proven through the lowering of protein levels in participants’ cerebrospinal fluid (CSF).

HD INSIGHTS: Can you tell us about measuring HTT levels in the CSF? The assay has not been widely used, and has never been used in a clinical trial.

SCHOBEL: What is known is coming out of the collaboration with CHDI and the labs of Dr. Ed Wild and Dr. Amber Southwell. They have shown in clinic that one can measure mHTT in the CSF, which is a very exciting development. These assays appear to be ready for prime time. The other exciting aspect of the assays is that they track disease stage, and associate with clinical severity, at least in cross-section. We want to learn more about how those assays perform longitudinally in terms of their test-retest reliability. A forthcoming study – the HDClarity study – will hopefully elucidate that. In the Phase I study of HTTRx, we are looking to see whether HTTRx can change the levels of mHTT and total HTT in the CSF from baseline. That would be a very exciting first-in-human clinical accomplishment.

SCHOBEL: The final thing to say is that published preclinical results from Amber Southwell’s work have shown the proof of principle that lower levels of mHTT in the CSF reflect lowering of mHTT in the brain.1 That link has now been empirically established in rodent models, and is a light for us to follow into the clinic.

HD INSIGHTS: The Phase I study is investigating whether monthly intrathecal infusions are safe, well-tolerated, and lower both total HTT and mHTT levels in the CSF. Are there any other major outcomes of interest?

SCHOBEL: Those are the key outcomes. Any other positive outcomes we might observe in Phase I would be a pleasing upside. The treatment duration is probably insufficient to result in disease modification. The sample size is also very small, so I think that any effects we might see on motor or cognitive functioning, or an overall sense of well-being, for example, would be pleasing, but not what we really expect.

HD INSIGHTS: Can you tell us about your plans beyond Phase I?

SCHOBEL: We are now in an option-planning period. First of all, we are learning from our partner’s considerable efforts and prior knowledge from having developed the ASO to date, and taken the lead on Phase I. From there, we are looking together towards the future of the program, what an integrated program may look like, as well as clinical development options.

I consider this to be a process. We are engaging in collaborative discussions with stakeholders and therapeutic experts. We are also actively engaged in a disease-modeling effort to help us better design clinical efficacy trials. This has been made possible in part through generous sharing of datasets from academic investigators, including Dr. Sarah Tabrizi of University College, London, and Dr. Jane Paulsen of the University of Iowa.

HD INSIGHTS: Are there plans to start a subsequent clinical trial?

SCHOBEL: The partnership is structured such that at the end of Phase I we have an option to opt-in for full development. We are planning for success now and in the future, but of course we are waiting for the Phase I data to formally trigger planning of later trials. We are mapping it out right now.

HD INSIGHTS: You recently came to Roche from academia. Can you tell us what brought you here?

SCHOBEL: I came to Roche from academia because I became convinced that investigating first-in-class or first-in-man drug candidates would be a very good way to make a big difference in patients’ lives. I can happily report that my expectations have been met in every way in that regard. I have found that at Roche I can do every bit of the science, and work with these fantastically exciting novel molecular entities to try to help to make a difference. That is what brought me, and that is what I am doing, so it is a happy report. I am in charge of clinical development plans for the program on the Roche side. That involves everything involved in planning clinical efficacy studies, by integrating what we think the preclinical package is telling us with the early clinical experiments, then planning the efficacy studies.

HD INSIGHTS: What would you view as a success for this partnership? Where would you like the partnership to be? And where would you like this ASO to be?

SCHOBEL: Well, everybody’s hope and expectation is that we could see a safe, well-tolerated ASO administered intrathecally that could lower mHTT in the CNS, as measured by levels in CSF. That would set us up to conduct efficacy studies to see whether this will translate into a safe and well-tolerated therapy that makes a difference in peoples’ lives. However, even short of that, the fact that we are in the clinical field with a huntingtin-lowering therapy is an important aspect of this program. We hope for the best for this particular therapy, but we should consider it a first shot on goal for this type of therapy in this field. We anticipate that the field will deliver on other promising methods of lowering mHTT over the next five to ten years. We are very excited for this program and hope for the best, but it is really just the beginning of what we hope will be a whole next-generation wave of therapies that can impact patients’ lives by limiting disease progression, which is really our ultimate goal.

HD INSIGHTS: Thank you very much.

1Southwell AL, Smith SE, Davis TR, et al. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci. Rep. 2015;5:12166.

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Our mission is to promote, disseminate, and facilitate research on Huntington’s disease. To fulfill this mission, we are guided by an outstanding editorial board that includes representatives from three continents, academia, industry, and the HD community.