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15 HD Insights, Vol. 13 Meet the Partner, cont... 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. Copyright © Huntington Study Group 2016. All rights reserved. H D I N S I G H T S 1 Southwell 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.