Huntington’s disease (HD), also known as Huntington’s chorea, is an inherited genetic disorder that kills brain cells. The Huntington Disease Society of America describes the disease as “a fatal genetic disorder that causes the progressive breakdown of nerve cells in the brain.”

The symptoms of HD are described as having ALS, Parkinson’s and Alzheimer’s simultaneously. Symptoms usually appear during prime working years – between the age of 30 and 50 – and worsen over a 10- to 25-year period. Over time, HD affects the individual’s ability to reason, walk and speak. The disease affects men and women equally and children born to a parent with HD have a 50/50 chance of inheriting the faulty gene.

There is currently no cure or treatment which can halt, slow or reverse the progression of the disease. Full-time care is required in the later stages of the disease. Treatments can relieve some symptoms and, in some, improve quality of life. Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Disease complications and injury from falls reduce life expectancy. Suicide is the cause of death in about 9% of cases. Death typically occurs 15–20 years from when the disease was first detected. 

According to the Huntington Disease Society of America,“there are approximately 41,000 symptomatic Americans and more than 200,000 at-risk of inheriting the disease.”

While only a handful of biopharmaceutical companies are researching new therapies for HD, Maurice Zauderer, President and CEO of Vaccinex, a clinical stage biotech company based in Rochester NY is optimistic the company’s late stage drug pepinemab may be the first effective therapy for HD patients.

Ironically, cancer research led Vaccinex to utilize the same technology to target HD.

As part of its ongoing series exploring the challenges of rare disease research, Wuxi AppTec Communications spoke with Dr. Zauderer about why he believes pepinemab can make a difference.

Dr. Zauderer, Ph.D. has served as President and Chief Executive Officer and a member of the Vaccinex’s board of directors since its inception in April 2001. Prior to founding the company, Dr. Zauderer was an Associate Professor at the University of Rochester and has also held senior faculty positions at Columbia University. During his academic career, Dr. Zauderer held the position of visiting scientist at the Laboratory of Cell Biology, the Ontario Cancer Institute and the National Cancer Institute. Dr. Zauderer received a B.S. in Physics from Yeshiva University and a Ph.D. in Cell Biology from the Massachusetts Institute of Technology.

WuXi AppTec: What are the major  differences between developing drugs for rare diseases and for more common diseases? What are some of the unique rare disease regulatory and business challenges?

Maurice Zauderer: In general, larger clinical trials and greater financing are required to achieve regulatory comfort for indications that affect large numbers of people. To a large extent, this reflects the inherent diversity of large human populations. In principle, identification of biomarkers that allow functional segmentation could facilitate development. On the science and investment side, there is usually not as much research and knowledge to draw on for rare and orphan diseases, and, importantly, there is often no precedent for therapeutic success. As a result, investors may not be confident that the reward merits the risk. Fortunately, greater pricing tolerance on the part of payers for rare and orphan diseases alleviates some of these concerns.

WuXi AppTec:  Many biotech companies are involved in cancer research how did you choose to target Huntington’s?

Maurice Zauderer: We are actually developing our lead drug, pepinemab, both as a combination therapy with a checkpoint inhibitor in cancer and as a single agent in neurodegenerative disease. What we learned about the mechanism of action of our drug in cancer actually informed our understanding of its potential in Huntington’s and other neuroinflammatory/neurodegenerative diseases. Our lead antibody, pepinemab, blocks the activity of SEMA4D, a molecule that binds to high affinity plexin receptors to trigger dissociation of the cell cytoskeleton. The cell cytoskeleton gives cells shape, but, more importantly, it makes it possible for cells to change shape. Cells need to change shape in order to extend projections that enable movement in a desired direction. This is, for example, essential for immune cells to infiltrate and attack tumors. Tumors have learned to exploit this pathway as one of several means of evading anti-tumor immune responses. They express high levels of SEMA4D at their margin and this serves to immobilize immune cells that constitutively express the plexin receptors for SEMA4D.

Wuxi AppTec: So how did this discovery lead to a potential therapy for Huntington’s?

Maurice Zauderer: Based on our understanding of the biochemistry and cell biology of the SEMA4D/plexin pathway, we came to recognize that similar cytoplasmic projections are required for cells to make contacts that enable direct interactions with other cells. Such contacts are central to the normal function of astrocytes in the brain. Astrocyte projections completely cover blood vessels that feed the brain. These projections express glucose transporters, the main source of energy for the brain, and facilitate uptake of glucose from circulation. Similar astrocyte projections cradle synapses and express glutamate receptors that recycle and allow efficient use of the free excitatory transmitter. In response to brain injury, the astrocyte cytoskeleton collapses, they abandon these normal functions and switch over to secretion of inflammatory cytokines. This is an interaction mediated by diffusion of soluble molecules rather than direct cellular contact. We asked what might trigger this important inflammatory transformation, and we wondered whether the SEMA4D/plexin pathway could be involved. Indeed, we discovered that SEMA4D is upregulated on neurons in response to stress or damage during underlying disease progression, and that astrocytes express plexin receptors that, in response to SEMA4D, trigger inflammatory transformation. We determined that SEMA4D blocking antibody ameliorated disease pathology in several animal models of neuroinflammatory/neurodegenerative disease, including Huntington’s, Alzheimer’s and multiple sclerosis.

WuXi AppTec: Were there other factors that led to looking at Huntington’s?

Maurice Zauderer: In addition to these mechanistic insights, we were motivated to focus on Huntington’s disease because it is an important unmet medical need with unambiguous diagnostic clarity of clinically manifest and asymptomatic gene carriers. The clinical trial experience of our colleagues in the Department of Neurology at the University of Rochester School of Medicine and in the Huntington Study Group were important support for the soon to be completed, potentially pivotal, SIGNAL study of pepinemab as a treatment for Huntington’s disease.

WuXi AppTec: How important are government regulatory incentives to encourage rare disease research in general? And as a follow-up, are patient groups also an important driver in Huntington’s?  

Maurice Zauderer: It is very important that regulatory agencies recognize the special difficulties of performing clinical trials in rare or orphan diseases and make reasonable accommodation to facilitate such studies. The rare disease community has been historically overlooked and under-researched, and we’re pleased to see that regulatory incentives have played a role in beginning to change this. In addition to the fact that HD is an important unmet need that is devastating to patients and families, a more rapid regulatory pathway motivated us to initially focus on HD, rather than a more prevalent neurodegenerative disease such as Alzheimer’s. The favorable regulatory environment has allowed us to safely and efficiently develop and advance pepinemab, with the hope of being able to rapidly deliver this new therapy to a community that currently has no treatment options, beyond those that address some symptoms of the disorder.

Additionally, choosing to address HD first has enabled us to expand our research and help more patients than might not have been possible otherwise. Our promising data in HD has led to welcome support from the Alzheimer’s Association and the Alzheimer’s Drug Discovery Foundation for a phase 1 Alzheimer’s study that we plan to initiate in the second half of 2020.

WuXi AppTec: Why is it so difficult to develop effective therapies for Huntington’s Disease?

Maurice Zauderer: All neurodegenerative diseases are challenging because there are numerous important but not well understood interactions between different cell types in the brain. As an orphan disease, HD does not enjoy the concentration of research invested in other slowly progressive neurological diseases such as Alzheimer’s and multiple sclerosis. Fortunately, much can be learned from common pathways and parallel mechanisms in these different brain diseases. A broader perspective can accelerate therapeutic development.

WuXi AppTec: How do you overcome patient recruitment challenges in rare disease research when you have much smaller patient populations

Maurice Zauderer: In our experience, it has been important to work with a CRO that has well-established relationships with investigators and clinical coordinators at a large number of sites. The Huntington Study Group has served us well.

WuXi AppTec: How much progress has been made in Huntington’s disease drug research and development over the last 20 years? 

Maurice Zauderer: Not enough. The only currently approved drugs for HD are symptomatic treatments like tetrabenazine that suppresses involuntary movements but does not slow disease progression.

WuXi AppTec: We have been talking about Huntington’s research in general. I would like to switch to your specific drug program. What phase is it in? What results have you seen so far? And will it treat all stages of the disease?

Maurice Zauderer: As discussed above, the SIGNAL study is based on the relatively recent understanding of the key role of astrocytes in neuroinflammation. Much of this work was pioneered by the outstanding late neuroscientist, Ben Barres and his colleagues at Stanford University.

Our contribution has been to identify a specific molecular pathway that activates astrocytes. The Vaccinex drug, pepinemab, blocks this pathway and ameliorates the pathology. The soon to be completed SIGNAL study in HD enrolled 265 subjects of whom two thirds had manifest disease and one third were prodromal, that is they were known to have inherited the Huntingtin mutation but did not yet have diagnostic symptoms. Subjects were randomized 1:1 drug to placebo and received 18 monthly treatments of a relatively high concentration of pepinemab antibody administered intravenously.

The antibody concentration was calibrated to achieve a targeted biologically effective dose in the brain even though antibodies do not efficiently pass through the blood-brain barrier. This avoided the need for more invasive interventions like intrathecal injections into the spinal cord or intavesicular injection directly into the brain.

WuXi AppTec: What were the results you saw first?

Maurice Zauderer: In an initial 36 subject phase 2 arm of this study, we determined that pepinemab treatment has a dramatic effect on preserving and even increasing glucose transport as reflected in FDG-PET imaging. This was an exciting observation because we know that glucose transport is a normal function of astrocytes that is abandoned upon inflammatory transformation. Our interpretation, supported by a variety of other evidence, is that our drug blocks reactive transformation of astrocytes. The SIGNAL study will now determine whether pepinemab treatment confers clinical benefit to subjects with early HD including both manifest disease and, potentially, prodromal subjects.

WuXi AppTec: When do you think it may be available to patients?

Maurice Zauderer: We anticipate completing the SIGNAL study in late June/early July 2020, at which time we will begin the process of locking the database, leading to analysis and topline data in the Fall. This is a potentially pivotal study for FDA registration, and we have already begun to prepare to scale up manufacture and the infrastructure for commercialization should results prove to be positive. Pepinemab has the potential to be the first disease-modifying therapy for HD.

WuXi AppTec: Why do you think your approach can be more successful than other companies’ drug programs in this disease? 

Maurice Zauderer: I think that what is most important about the Vaccinex treatment strategy for HD is that it targets a pathogenic mechanism rather than just a biomarker of the disease. Biomarkers are useful to identify disease susceptibility and progression, but, as we have seen in many failed trials in Alzheimer’s disease, they are not necessarily effective targets. There is a lot of evidence for the pathogenic role of astrocytes and chronic inflammation in multiple neurodegenerative diseases and these research advances have informed our strategy for HD.

WuXi AppTec: Do you see a time when we will have a cure for this disease? What scientific advances are needed to reach this goal? Any predictions when this might happen?

Maurice Zauderer: There are multiple new approaches employing novel technologies in development. A lot of good things could happen in the next few years, including potential combination therapies. I am optimistic.

WuXi AppTec: Anything we haven’t touched on that you would like to add? 

Maurice Zauderer: One of the very rewarding aspects of working in HD is that the Huntington’s disease community, patients and their families, have seen and understand the devastation of this disease. They are wonderfully supportive of each other and of efforts to develop new and effective treatments. It is inspiring to experience and share in the determination and commitment of this community.