Meet the Company



NAME: uniQure


SHARE PRICE AS OF 2/17/17: $6.31

52-WEEEK RANGE AS OF 2/17/17: $5.25-$16.40



Dr. Pavlina Konstantinova, a research scientist at uniQure, spoke with HD Insights about the company’s program to develop a gene therapy treatment for HD, using micro RNAs expressed from a DNA cassette delivered via an adeno-associated viral vector. The following is an edited transcript of the conversation.

HD INSIGHTS: Tell us about uniQure.

KONSTANTINOVA: uniQure is in a unique position because we have established a scalable manufacturing platform for adeno-associated virus (AAV) vector delivered gene therapies for commercial use. We started this a number of years ago when we were developing our first product, Glybera® (alipogene tiparvovec), which was developed in the mammalian system that a lot of other researchers are using.

However, during the Glybera® development period, we recognized that the process that we were using was not scalable and was also not really stable for commercial use. So we switched from a mammalian production system to an insect-based production system a number of years ago. At the moment, we think we are in a unique position, and we are the first company that has invested in developing this large-scale manufacturing platform for AAV vector delivered gene therapies that have commercial market potential.

Glybera® has been approved by the European drug regulatory agencies for treatment of familial lipoprotein lipase deficiencies. It is not available on the American market at the moment.

HD INSIGHTS: What are uniQure’s plans for HD therapeutics?

KONSTANTINOVA: uniQure started the HD program about six years ago. We combined our expert experience with AAV production and delivery with the micro RNA-based silencing approach. Prior to HD, we worked successfully to prove the concept of our gene silencing technology for liver disease, and we published a number of articles in peer-reviewed journals. After that initial work, HD seemed to be a good candidate for the gene silencing approach.

HD is a monogenetic disease with a very well-defined nature of the primary gene mutation that results in production of mutant huntingtin. But besides that, I think HD is a devastating disease, and no treatment is currently available. We saw an opportunity to try to develop a disease-modifying therapy that can eventually be a game-changer in management of HD. Reducing mutant huntingtin expression seems to us to be the most logical step to take because doing so can be expected to significantly contribute to slowing down disease progression.

At the moment, we are developing an RNA interferencebased approach. We have engineered small molecule RNAs known as micro RNAs (miRNAs) that target human huntingtin messenger RNA, expressed from a DNA cassette incorporated into AAV vector particles. This expression cassette will be delivered to the patient, with the aim of reducing the expression of the mutant gene that results in HD.

HD INSIGHTS: Other companies are also investigating gene silencing therapies for HD. Can you tell us how your approach is different or similar to theirs?

KONSTANTINOVA: First of all, companies that are silencing the mutant gene that causes HD are trying to lower the amount of mutant huntingtin. What distinguishes us from other companies is that we are proposing to use a single-time gene therapy, while the other approaches would require multiple administrations. Also, with the gene therapy approach using AAV, we can select the vector serotype to refine the targeting and safety of the delivery system, and we have been working on refining the administration procedure in order to have a very safe and efficacious profile. I think that is really our strength the combination of the mechanism of action, the vector serotype, production platform and the administration procedure that we have selected.

HD INSIGHTS: How and where would the therapy be administered?

KONSTANTINOVA: At the moment, we envision targeting the striatal structure in the brain. This would involve intraparenchymal injection using the convection-enhanced diffusion delivery method.

HD INSIGHTS: How is your preclinical work going? Have you applied this therapy to animal models, for example?

KONSTANTINOVA: We collaborate with others in our preclinical work. We have tested the therapy in a wide range of HD animal models. A number of years ago, we started a collaboration with Dr. Nicole Déglon from CHUV Lausanne, Switzerland, who has developed an HD rat model. The first proof-of-concept experiment was performed in this model, which typically displays very acute pathology. Neurodegeneration occurs very quickly, with very severe mutant huntingtin aggregate formation.

After these experiments, we moved to the humanized mouse model, working with Dr. Amber Southwell from University of British Columbia in Dr. Michael Hayden’s lab, and we performed a number of dose escalation studies in this model. The model is unique because it has two copies of the human huntingtin gene, one mutated, one wild-type, and no murine background huntingtin.

That makes it very suitable for a gene therapy approach like ours, where the huntingtin gene would be lowered, as well as looking at the tolerability of total huntingtin lowering. We also collaborated with Charles River Laboratories, where we are testing the functional improvement in the more standardized HD rodent models.

In the last two years, most of our experiments have been in large animals. We started our HD mini-pig experiments in collaboration with Dr. Jan Motlik from IAPG, Libechov, Czech Republic. This model was developed together with CHDI. In these experiments, we deliver our gene silencing therapy in a similar manner to how we envision delivery in our clinical program. We have obtained the first data from this HD mini-pig model, showing substantial total huntingtin knock-down, as well as very good vector distribution and miRNA expression. I think that so far, we have seen an adequate safety profile. And finally, we have performed tests in healthy non-human primates to refine the delivery procedure. We have injected different brain regions with increasing vector doses and looked at vector distribution, inflammation and neurodegeneration. Based on the outcome of those experiments, we are defining our therapeutic dose in patients aiming at approximately 50% huntingtin knock-down and no associated adverse events. As you can see, we have used several animal models of HD as well as healthy non-human primates to propel our preclinical program toward the development stage.

HD INSIGHTS: Can you tell us about the clinical effect you saw from your trials in the pig model?

KONSTANTINOVA: At the moment the pig model does not show clinical symptoms of HD, so the only parameters we could assess were mutant huntingtin lowering in the CNS, as well as vector distribution and safety. We looked at huntingtin lowering in the CSF at three months and saw a trend of reduction in the treated animals. In the blood, we looked mainly at markers for immune system activation, because this is a very important safety readout for our therapy. We found transient increase in some cytokines and interleukins in the treatment groups.  The study has not yet been published, but we are hoping to submit it for publication before the CHDI meeting.

HD INSIGHTS: Do you think it is feasible in humans to be able to look at huntingtin levels or to look for huntingtin-lowering effects in either the blood or CSF?

KONSTANTINOVA: I think if it were at all possible to have a positive readout for mutant huntingtin, it would be in the CSF. Because our therapy would be administered directly into the CNS, we do not expect leakage of the gene-silencing agent into the periphery, so all the changes in mutant huntingtin that we expect would be in the CSF. I am not aware of positive measurements of mutant huntingtin in the blood or in serum at the moment. We can envisage measuring mutant huntingtin levels in the CSF as it is a biomarker for therapeutic efficacy.

HD INSIGHTS: Researchers take both allele-specific and non-allele-specific approaches to gene silencing in HD. What is uniQure currently working on and why?

KONSTANTINOVA: We published a paper in Molecular Therapy – Nucleic Acids about our evaluation of both approaches, allele-specific and total silencing;1 however, our program development within the company has focused on total huntingtin silencing. Of course, we are working on the allele-specific approach as well, but the first therapy that we would like to bring to patients would be based on total huntingtin silencing.

HD INSIGHTS: When do you plan to start testing your therapy in humans?

KONSTANTINOVA: The program is progressing very well and we are working toward a company goal to begin a clinical trial in 2018.  At the moment, we are initiating our IND-enabling studies, and we are defining our regulatory pathway. To support our clinical program, we are creating a clinical network of key opinion-leaders in the HD field, but also neurosurgeons, experts in gene therapy delivery to the brain, and brain anatomy specialists who can help us and advise us on the development of our program.

HD INSIGHTS: Do you have early thoughts on the population of individuals affected by HD that you would see as most appropriate for initial investigations?

KONSTANTINOVA: We have talked about it a lot with our key opinion-leaders. As is well-known, brain atrophy in HD patients starts years before the onset of symptoms, and neuronal degeneration precedes decline in neuronal function. If we start from this standpoint, we think that to have a high likelihood of therapeutic efficacy, we would need to treat patients as early as possible, either at the time of diagnosis or shortly after the start of manifestation of symptoms. So I think for the first trial we would aim to go as early as possible in the course of the disease. To achieve maximum therapeutic benefit, we would need to go to patients at the time of genetic diagnosis.

HD INSIGHTS: Are there other things that you would like the community to know about your approach and your gene silencing therapies?

KONSTANTINOVA: Yes, I think we already have very promising results. Combined with the production platform that we have developed, I think we can make HD gene therapy a reality in the near future. So, I think that gene silencing as a disease-modifying treatment can really be a game-changer for HD patients.

HD INSIGHTS: Thank you and your colleagues at uniQure very much for all your efforts seeking and hopefully finding treatments that will make a huge difference for HD.

1Miniarikova J, Zanella I, Huseinovic A, et al. Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington’s Disease. Mol Ther Nucleic acids. 2016;5(3):e297.

Meet the Company: WAVE Life Sciences

Name: WAVE Life Sciences
Stock symbol: WVE
Share price as of 10/9/16: $30.27
Market capitalization: $574 million
U.S. Headquarters: Cambridge, MA


Brenda Jeglinski serves as the Director of Clinical Operations at WAVE. She enjoys spending her free time with her husband and children.

Wendy Erler, MBA is the Vice President of Patient Advocacy and Market Insights at WAVE. When she is not working to bring precision medicines to patients, she enjoys paddleboarding and spending time with her husband and their three children.

Wendy Erler, MBA is the Vice President of Patient Advocacy and Market Insights at WAVE. When she is not working to bring precision medicines to patients, she enjoys paddleboarding and spending time with her husband and their three children.


Michael Panzara, MD, MPH is the Franchise Lead for Neurology at WAVE. When he is not thinking about precision medicines for HD, he enjoys spending time at home with his family.

Precision Medicine for HD
WAVE Life Sciences, a preclinical biopharmaceutical company publicly traded since 2015, utilizes their proprietary platform to synthesize stereopure nucleic acid therapies for currently untreatable genetic diseases. HD Insights spoke with Brenda Jeglinski, Director of Clinical Operations, Wendy Erler, Vice President of Patient Advocacy and Market Insights, and Michael Panzara, Franchise Leader for Neurology, about the company’s work in HD. The following is an edited transcript of the conversation.

HD INSIGHTS: Thank you all for joining us today. Please tell us about WAVE Life Sciences.

JEGLINSKI: We are a small company, just starting our first clinical trials. We are currently working with investigators to develop our clinical trials, and identify where and when we can begin the first human dosing with our compounds.

ERLER: One of the exciting things about WAVE is that we have a number of people who have come into the company with past experience working in oligonucleotides, and that has really informed our HD program in particular.

HD INSIGHTS: How did WAVE first become interested in HD?

PANZARA: One of the unique aspects of our oligonucleotide platform is that we are able to control properties of each oligonucleotide, including specificity. This enables an allele-specific approach when targeting genetic diseases, making the mutation in HD an ideal target. In addition, WAVE is building a neurology franchise upon this platform. Neurological diseases are an area of high unmet need and our primary focus at WAVE. Combining our platform with our focus on this area of high unmet need, HD seemed liked the ideal place for us to begin to develop the next generation of therapeutics.

HD INSIGHTS: You mentioned that your approach is allele-specific. Other companies are developing non – allele-specific compounds. Can you talk about the possible relative advantages of allele specificity?

PANZARA: Healthy huntingtin protein (HTT) has many essential functions in the nervous system, while the presence of mHTT leads to neurodegeneration, so we thought that if we could develop an approach that targeted the gene product, the transcript of the mHTT allele specifically, while leaving the transcript for the healthy protein intact, we could potentially increase the benefits of treatment while minimizing risks. One of the strengths of controlling the stereochemistry of nucleic acid synthesis is that it allows us to specifically enhance and adjust properties of the nucleic acid, such as its stability, its activity, its immunogenicity, and most importantly, its specificity, which enables an allele-specific approach to treatment of the disease.

HD INSIGHTS: Can you talk about the preclinical evidence, and the importance of allele specificity?

PANZARA: The literature suggests that HTT has many important functions in preservation of neuronal health in the central nervous system, which is what prompted us to explore the potential to target mHTT in a selective way.1-4 By controlling stereochemistry, we have been able to design an antisense oligonucleotide that appears to discriminate between HTT and mHTT. We have done experiments in fibroblasts from HD patients known to have specific single nucleotide polymorphisms (SNPs) associated with their HD mutations. We have designed our oligonucleotides to target those SNPs, and demonstrated in this system that mHTT can be reduced significantly, while leaving healthy wild-type HTT relatively intact (WAVE preclinical data). Again, the overarching goal was to create a very specific effect on the detrimental protein, while leaving the wild-type protein intact, attempting to maintain normal neuronal function.

ERLER: To date, nucleic acid therapies have comprised complex mixtures of hundreds of thousands of chemical entities called stereoisomers. Some of those stereoisomers have therapeutic effects, while some are less beneficial, or have an unknown impact, and could contribute to undesirable side effects. With WAVE’s novel chemistry platform, we eliminate those complex mixtures, giving us control over the pharmacology by creating stereopure compounds. This rational, very specific design is what gives all the attributes just described specific to our HD candidates, but also allows us to use our oligonucleotides in other ways, such as exon skipping.

HD INSIGHTS: Tell us about your regulatory status.

PANZARA: We intend to file two INDs before year’s end, and we have been granted orphan drug designation in the USA. This should enable us to initiate studies in the early part of 2017 that focus on two distinct patient populations.

HD INSIGHTS: Can you tell us about the patient populations that you are looking to enroll in your first clinical trials?

PANZARA: Our compounds are developed to target the two most common SNPs associated with the mHTT allele which encompasses nearly two-thirds of the HD population. In addition, we are looking to enroll patients over 25 years old with early manifest HD.

ERLER: This is a really good opportunity to explain why there are two INDs being filed, since so many in the community have had exposure to other programs, specifically Ionis’s (see HD Insights, Vol. 13). Our planned INDs are, in fact, for two separate drug candidates for HD patients specifically targeted to two distinct SNPs (SNP 1 or SNP 2), so that means patients who are screened for these studies, will have a blood test to determine if they are eligible for SNP 1 or SNP 2 (see Meet the Compounds, p. 19). We plan to run both studies in parallel at the same trial centers.

PANZARA: In addition, an individual who does not want to know their CAG repeat number or their full genotyping can still participate in the study. The screening test would focus only on study eligibility, and the presence of either SNP 1 or SNP 2. From there, they would then have the opportunity to enroll, assuming they meet other inclusion and exclusion criteria.

JEGLINSKI: Another key factor is that because there is SNP 1 versus SNP 2, there are two different programs, but they are identical studies. There is no benefit or anything more enticing in one study versus the other.

HD INSIGHTS: It sounds as if WAVE is focusing on precision medicine, or personalized medicine – not only just focusing on a particular condition, but focusing on particular subpopulations within that condition.

PANZARA: Exactly. We see this as an important step towards precision medicine, designing the most appropriate drug for a given patient. We also see this as the start of an important part in the history of WAVE Life Sciences. These will be our first two clinical studies in precision medicine, but I think it epitomizes our approach to diseases with high unmet need: focusing on the most appropriate drug for a given patient.

HD INSIGHTS: Can you say when these precision medicine treatments will be investigated in clinical trials?

PANZARA: Our intention for HD is open both trials in the first part of 2017. These will be phase 1 safety studies.

HD INSIGHTS: This is WAVE’s first involvement in HD. Can you tell us a little bit about your impressions of the HD community? Any surprises or disappointments?

ERLER: I feel completely privileged and honored to have engaged with the HD community. It has been one of the most gratifying personal experiences of my career, because the community is incredibly open and warm, and very, very interested in sharing their stories so that we as an organization can better understand the true experience of living with HD, not just as a patient, but as a caregiver, or a spouse, son or daughter of someone who is living with HD. It has completely encouraged me to fight on behalf of these families, because I have just been so incredibly impressed with their fortitude and tenacity, and universal positive attitudes in light of their burden. At WAVE, we have been fortunate to have HD community members, patients and care givers, come to our office to meet with our team and share their stories and we have also been able to have WAVE employees participate in several HD fund raisers.
So while I knew this was a devastating disease, I was definitely surprised at just the sheer will and force these families have, and how positive they are, and how everybody without question comments about wanting to get involved with our clinical trials, not to help themselves, but to help future generations.

PANZARA: The only thing I would add is that because I am relatively new to WAVE and to this particular therapeutic area from a drug development standpoint, I have been extremely impressed by the sense of collaboration and purpose of the HD community. Everyone is universally focused on doing whatever they can for patients with this disease.

HD INSIGHTS: Thank you all very much for your efforts and for WAVE’s interest in developing precision treatments for HD. We wish you all the best, and great success in the future.

1. Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet. 2000;26(3):300-306.
2. Leavitt BR, van Raamsdonk JM, Shehadeh J, et al. Wild-type huntingtin protects neurons from excitotoxicity. J Neurochem. 2006;96(4):1121-1129.
3. Rigamonti D, Sipione S, Goffredo D, Zuccato C, Fossale E, Cattaneo E. Huntingtin’s neuroprotective activity occurs via inhibition of procaspase-9 processing. J Biol Chem. 2001;276(18):14545-14548.
4. Zhang Y, Leavitt BR, van Raamsdonk JM, et al. Huntingtin inhibits caspase-3 activation. EMBO J. 2006;25(24):5896-5906.

Antisense Oligonucleotides Enter Clinical Trials

Ionis Pharmaceuticals' HTTRx development team, from left to right: Roger Lane, Curt Mazur, Holly Kordasiewicz, Erika Paz, Kristin Balogh, Anne Smith, Tom Zanardi, Dan Norris, Eric Swayze, Tiffany Baumann, Kristina Bowyer, Gene Hung, Jose Mendoza, Frank Bennett (Not pictured: Gina Mc Mullen, Ed Wancewicz).

Ionis Pharmaceuticals’ HTTRx development team, from left to right: Roger Lane, Curt Mazur, Holly Kordasiewicz, Erika Paz, Kristin Balogh, Anne Smith, Tom Zanardi, Dan Norris, Eric Swayze, Tiffany Baumann, Kristina Bowyer, Gene Hung, Jose Mendoza, Frank Bennett (Not pictured: Gina Mc Mullen, Ed Wancewicz).



NAME: Ionis Pharmaceuticals


SHARE PRICE AS OF 2/5/16: $35.25




Meet the team behind IONIS-HTTRx, the antisense oligonucleotide therapy with the potential to transform HD treatment

Ionis Pharmaceuticals has been developing antisense-based therapies for a variety of conditions since 1989. The company has developed an antisense oligonucleotide (ASO) that targets huntingtin messenger RNA. In July 2015, they began a first-in-man, Phase I/IIa trial on IONIS-HTTRx in early manifest HD patients to evaluate the safety, tolerability, and pharmacokinetics of intrathecal administration of the drug. HD Insights sat down with four of the individuals involved in the development of HTTRx to find out more. The following is an edited transcript of the conversation.

HD INSIGHTS: Dr. Kordasiewicz, tell us about the rationale for ASOs in HD and what you learned in animal models.

HOLLY KORDASIEWICZ: It is pretty straightforward. The idea is to go after the source of the disease, which we know is mutant huntingtin protein (mHTT). We can use ASOs to selectively lower huntingtin RNA, which reduces the total amount of huntingtin protein (HTT), including mHTT. By lowering mHTT in patients with HD, we can hopefully stop the course of the disease. With the work that we have done in animal models, we lower mHTT using ASOs, and some aspects of the animal disease—which are similar to what we see in HD patients—are reversed, and the animals begin to do better in a number of different ways.

These animal studies have been a collaborative effort with the group here at Ionis, Dr. Don Cleveland’s laboratory at UCSD, CHDI and also Genzyme, particularly Dr. Lisa Stanek, who was responsible for the work done in the YAC128 mice. We have looked at the R6/2 mouse, the YAC128 mouse, as well as the BACHD mouse.1,2 All of those mice express either fragments or the whole human mutant Huntingtin gene (mHTT).

HD INSIGHTS: How did you deliver the drug in the mouse models and how might that differ in humans?

KORDASIEWICZ: In human patients we deliver the drug intrathecally, directly into the cerebrospinal fluid (CSF), so that the drug can access the full brain. It is very difficult to do intrathecal delivery in mice because they are so small, so we use intraventricular delivery instead. We go into the mouse right lateral ventricle, which is just a little bit of a larger space so it is easier for us to access.

HD INSIGHTS: Two of the concerns with this approach are the potential need to give repeated injections and the possible need for allele selectivity. Could you comment on those concerns?

KORDASIEWICZ: When we started this approach, we did not realize how long ASOs and their effects last once you introduce them into the brain. About two weeks after we deliver the drug, we have maximum RNA reductions, and then those levels start to come back to normal. In mice, it takes about 12 to 16 weeks for levels to return to normal after a single injection, so in the human Phase I study we are trying monthly dosing. Eventually we could be looking at less frequent dosing, based on the characteristics of the drug.

ROGER LANE: The monthly dosing in the initial Phase I study is just to get concentrations up during the three-month dosing period.

KORDASIEWICZ: We spent a lot of time looking at allele selectivity. We did a collaboration, initiated by Dr. Frank Bennett, with Dr. Michael Hayden’s group to look at allele-selective approaches. The chemists here also worked with Dr. David Corey’s group at UT Southwestern, looking at using different antisense mechanisms to achieve allele selectivity. The work that I did in the mouse models examined the consequences of lowering only mutant human HTT, or both mutant human HTT and wild-type mouse Htt. In the mice, we found that we did not attenuate our benefits by lowering both the mutant human and the wild-type mouse protein; it was very similar to lowering just mutant human huntingtin alone. Because of that, we have gone forward with the nonallele-selective approach, but we have spent a lot of time working to find potential allele-selective approaches.

HD INSIGHTS: Did any safety issues emerge in your animal models?

KORDASIEWICZ: We looked at a number of endpoints and we followed animals for a year after dosing. We did not see any safety issues either in the wild-type mice or non-human primates resulting from lowering wild-type huntingtin.

HD INSIGHTS: Dr. Smith and Dr. Lane, what led you to determine that the drug was ready for study in humans?

LANE: Well, if you have a very good mechanistic rationale for a drug, support from good animal models of the disease, confidence that it can distribute to its target tissues and engage its target, and you have a means of measuring that target engagement, then you have a rational basis for a clinical development program.

HD INSIGHTS: Can you tell us about your Phase I/IIa clinical study?

ANNE SMITH: We can discuss it in general, but since it is ongoing, we will not discuss any data that is accruing. It is a small study, intending to enroll about 36 patients at sites in Canada, the UK, and Germany. We began dosing midyear, and the study is going well. Our sites are run by investigators at institutions who have been involved in helping us shape this program for many years. They are thought leaders in the area.

LANE: It is a multiple ascending dose study where patients are being treated with four intrathecal injections over a three-month period, then followed up for four months after that.

SMITH: Drug development is a long process. This is the first trial in humans, so we have planned several stops along the way where we have an independent group look at safety and help guide us if any changes are needed. So far, the study is proceeding according to plan.

HD INSIGHTS: From your listing, it seems that you are focusing on individuals with early manifest HD. Can you explain your rationale for that, and discuss the decision not to look at individuals with, for example, prodromal HD?

SMITH: Yes, we are indeed limiting participation in the study to early manifest patients. In later manifest HD patients, we had concerns about ability to consent. In prodromal patients, it would be a different sort of clinical development program. It is an area that we are very interested in going into, but if you are looking at patients who do not yet have motor symptoms, it changes the clinical endpoints that you would use in that study.

C. FRANK BENNETT: In this population, we felt the risk-benefit ratio was appropriate. We were concerned about enrolling individuals too early in the course of the disease in a first-in-man study. Without any experience with the drug in humans, we felt that the risk was too high for those patients. We identified individuals with early manifest HD as the ideal patient population.

HD INSIGHTS: What clinical endpoints are you looking at in this study?

SMITH: This first study is a safety and tolerability study, so the primary endpoints are a battery of safety endpoints. We are looking at a number of exploratory markers of disease in hopes of seeing a signal, but this is a short study in a small number of patients and it is certainly not designed, nor powered, to detect any changes in those types of endpoints.

LANE: We have a secondary endpoint to make sure that we are achieving the concentrations of ASO in the CSF that we are expecting, and then we are looking at target engagement whether we reduce mHTT in the CSF. We have a variety of other markers we are using to look at whether we are having a biological effect on the disease, including other CSF markers, EEG, neuroimaging, etc. We have some clinical measures, which we do not expect to be impacted in such a short-term study, but which we want to monitor for any deterioration. There is just a tiny chance that they could show something positive as well.

SMITH: These markers may also be useful in planning later studies if we see any small changes in this preliminary study.

HD INSIGHTS: I believe this will be the first clinical trial that investigates CSF markers. You mentioned that you are looking at mHTT in CSF. Can you talk about the reliability of CSF markers in HD and what you expect to find in the study?

SMITH: Well, there are challenges in being first. Assays for mHTT levels have been explored in several publications, and it is such a clear, obvious marker for our product and we are optimistic that we will be able to see changes with that marker.3,4 The other CSF markers we are using, such as neurofilament light chain and synaptic health markers, are definitely exploratory. Being first, we do not know what happens to these markers when you have modified the disease, so ask us when the study is over!

HD INSIGHTS: TRACK-HD and other studies have looked at brain volumetric MRI over time and found it has potential as a biomarker in HD. Are you looking at volumetric MRI or other outcome measures?

SMITH: We are looking at volumetric MRI, yes. TRACK-HD and other studies have given us beautiful natural history data that has helped a lot with our program and designing our study. Again, it is a short study, so we do not expect to see positive changes. We will use these markers primarily to assess whether there is deterioration in the trial participants.

HD INSIGHTS: For clinical assessments, you are using the HD Cognitive Assessment Battery (HD-CAB) developed by Dr. Julie Stout and colleagues. Are there other clinical measures that you are looking at, such as the Q-motor?

SMITH: The HD-CAB is our primary cognitive measure and again, being early, there really is not longitudinal data in that one either, so it will be interesting to see how that performs longitudinally. We do not have the Q-motor in the study.

HD INSIGHTS: When do you expect the initial results of the study to be available?

SMITH: We are on pace to meet the timeline we initially set, with a primary completion date of March 2017, and a study completion date of September 2017.

HD INSIGHTS: What has been the response of the HD community to the study? Have they been receptive? Was education required?

SMITH: We have wonderful support from our principal investigators. My understanding through them is that there has been a lot of interest in participating in the study, including “cold calls” from patients they know, to them and to us. Enrolling this study is probably not going to be a challenge because the community is very well educated about what is available to them now and what is coming. There is a lot of excitement around this product.

HD INSIGHTS: Are there other topics or questions that you would like to address related to your efforts?

BENNETT: Just that although our initial study is being done in Canada, the UK and Germany, subsequent studies would probably involve patients from more countries, including the USA. We are doing everything we can to accelerate the development, making sure that we are staying on track. And that if the drug is successful, we will start further studies as expeditiously as we can.

SMITH: I just want to remind people that it is a lengthy process and it is going to be a long timeline. There is a lot of anxiety in the community because people feel that they are missing something, even though its development has just barely started. Making sure we maintain realistic expectations is important.

HD INSIGHTS: What are your plans for future development should the initial studies go well?

BENNETT: We do not have very firm, locked-in plans, but the thought is that the next studies would test longer-term exposures with a larger group of patients, really Phase II studies.

LANE: The next studies may involve patients at earlier stages of HD. In addition, with this approach we can start thinking of prevention. At the moment, HD is diagnosed at the stage of clinical manifestations of brain pathology, but patients have had brain pathology developing for a long time before this stage. With genetic testing and the inevitability of the disease once the pathology has started, we have the prospect of going back to earlier points, when patients are not yet exhibiting symptoms, and treating them to prevent or delay the development of the disease. That may be some way in the future.

HD INSIGHTS: Thank you all for your efforts.

C. Frank Bennett, PhD: Dr. Bennett is the Senior Vice President of Research at Ionis Pharmaceuticals. He contributed his thoughts on the earlier stages of IONIS-HTTRx’s development to HD Insights, Vol. 3, and has continued to oversee this and other ASO programs at Ionis since that time.

Holly Kordasiewicz, PhD: Dr. Kordasiewicz is the Director of Neurological Drug Discovery at Ionis Pharmaceuticals, where she has worked since 2011 after completing her postdoctoral fellowship in the lab of Dr. Don Cleveland. She focuses on the preclinical development of novel drug candidates, investigating compounds in animal models and then characterizing the compounds prior to clinical development.

Roger Lane, MD, MPH: Dr. Lane is the Vice President for Clinical Development at Ionis Pharmaceuticals, a position he has held since January 2014. He leads clinical development efforts in the neurological therapeutic area at Ionis.

Anne Smith, PhD: Dr. Smith is the Director of Clinical Development at Ionis Pharmaceuticals, and serves as the Project Team Leader for IONIS-HTTRx.

1Kordasiewicz Holly B, Stanek Lisa M, Wancewicz Edward V, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron. 2012 Jun 21;74(6):1031-1044.

2Stanek LM, Yang W, Angus S, et al. Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington’s disease. J Huntingtons Dis. 2013;2(2):217-28.

3Wild EJ, Boggio R, Langbehn D, et al. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. J Clin Invest. 2015 May;125(5):1979-86.

4Southwell 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 Jul 15;5:12166.

Meet the Company

Approved Raptor Logo with (R) -04042014






NAME: Raptor Pharmaceuticals


STOCK PRICE AS OF 10/15/2014: $10.19

52 WEEK RANGE: $7.12-$17.72



APPROVED COMPOUNDS: Cysteamine bitartrate delayed-release capsules (PROCYSBI®), FDA- approved in 2013 for treatment of nephropathic cystinosis in adults and children age 6 and older.

Meet the Company

auspexhomeVITAL SIGNS

NAME: Auspex Pharmaceuticals


STOCK PRICE AS OF 2/13/2014: $22.20


EMPLOYEES: about 20

Pratik Shah, PhD, MBA, is the President, Chief Executive Officer, and Director of Auspex Pharmaceuticals. He came to Auspex in 2007 as an investor, and has since led the company as Chairman or Executive Chairman to shape its focus on Huntington disease and other orphan indications. “I first got involved in Auspex because I was intrigued by the possibility of improving drugs using a new technology (deuteration),” he said. “I was compelled by the opportunity to bring SD-809 to the market. It’s rare to get a chance to be involved all the way from the discovery of the drug to its ultimate commercialization. I consider this a blessing.” Dr. Shah recently shared with HD Insights Auspex’s current work, its recently completed Initial Public Offering (IPO) and his hope for the company’s future. Below is an edited transcript of his thoughts.

HD INSIGHTS: What is the value of deuteration of pharmacological agents?

SHAH: The side-effects, problematic drug-drug interactions, and patient to patient variability of certain drugs are driven by their short half-life, and removal from the body by liver enzymes. These issues can create challenges for patients and physicians.

It’s really remarkable how a small change of hydrogen to its heavy isotope deuterium, when engineered into exactly the right molecule at exactly the right positions, doesn’t just change the drug – it has the potential to transform the drug. It does so by slowing down the elimination of the drug from the body, reducing fluctuations in blood levels. These transformations can be achieved without changing the drug’s binding to the target, and therefore its efficacy. If a drug is better tolerated or is needed fewer times per day, it can be used by more patients, and create a better experience for patients and families.

HD INSIGHTS: Why deuteration of tetrabenazine?

SHAH: While tetrabenazine is a very efficacious drug, it is a textbook case of a short half-life drug with resulting limitations. Our Chief Medical Officer was the head of development at Prestwick Pharmaceuticals, and led the effort to receive FDA approval of tetrabenazine. He recognizes that there is more work to be done for treating patients with chorea. Auspex has been working to use deuteration to solve these challenges, and while deuteration has been applied to other treatments by a number of companies in various stages of clinical development, we believe that Auspex’s SD-809 program is the most advanced so far.

Possible benefits of deuteration of tetrabenazine include lower dose, less frequent administration, the potential for better tolerability & safety, reduced drug-drug interactions, reduced need for genotyping, reduced inter-patient variability, and reduced potential for QT prolongation. As a result, we hope to be able to take SD-809 into areas where tetrabenazine was never formally developed such as Tourette syndrome and tardive dyskinesia. In addition to a Phase 3 clinical trial with individuals with HD, we are embarking on a Phase 2/3 trial in tardive dyskinesia, and a Phase 1b preliminary safety & efficacy study in adolescents with tics associated with Tourette syndrome. We have seen promising data with our human studies comparing SD-809 to tetrabenazine so far. These results have been encouraging, and we are hoping to further understand the impact of deuteration by conducting the First-HD and ARC-HD clinical trials.

HD INSIGHTS: On February 5, 2014, Auspex completed an IPO listing on the NASDAQ Exchange. On the first day of trading, the company’s stock price opened at $15.00 and closed at $15.66 and raised $84 million for the company. What does the IPO mean for Auspex?

SHAH: This important milestone in the progress of our company further enables us to deliver on our mission to develop and commercialize new therapies for patients with HD, a variety of movement disorders and other orphan diseases. The IPO also makes more visible our long-term commitment to develop treatments for HD, and gives the company additional resources to support education and awareness initiatives.

Meet the Company









NAME: Pfizer, Inc.


STOCK PRICE AS OF 8/28/13: $28.00

52 WEEK RANGE: $23.55 – $31.15



Pfizer, Inc. is a research oriented, global pharmaceutical company. In collaboration with CHDI and the ICM in Paris, Pfizer Neuroscience’s HD team has been working to understand the role of phosphodiesterase 10A (PDE10A) inhibitors in the treatment of HD, and to develop clinical measures of their effectiveness and safety.

Phosphodiesterase (PDE) inhibitors are a class of compounds currently being evaluated for a new use in HD therapy1. Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in medium spiny neurons of the striatum, and mouse models of HD and human HD patients demonstrate that PDE10A levels decline with progression of HD. However, promising preclinical studies on the use of PDE10A inhibitors for HD therapy are showing that paradoxically, PDE10A inhibition may represent an effective therapy.2-4

HD Insights spoke with Pfizer Global Clinical Lead Spyros Papapetropoulos, MD, PhD, and Pfizer Neuroscience HD Project Leader Margaret Zaleska, PhD, about the company’s work with PDE10A inhibitors in HD.

HD INSIGHTS: Can you tell us a little bit about Pfizer’s interest in developing new treatments for HD?

PAPAPETROPOULOS: HD research is supported across the Pfizer organization, as part of Pfizer’s commitment to orphan indications. We are working with CHDI on many options for HD and scanning the landscape for opportunities at different levels of development. It’s a very exciting time, for the clinical team, the research team, CHDI, and, I hope, the Huntington community. We have assembled an A-team of about 20 folks here, actively engaged in HD programs.

ZALESKA: Our pursuit of phosphodiesterase inhibitors is in close collaboration with CHDI. This is a scientifically fulfilling and successful way of approaching this unmet medical need: combining Pfizer’s expertise in medicinal chemistry and neuropharmacology with CHDI’s focused efforts to apply the molecules that we make to HD.

HD INSIGHTS: Dr. Zaleska, what is PDE10A?

ZALESKA: PDE10A is a phosphodiesterase that catabolizes cyclic nucleotides. It is a dual substrate phosphodiesterase, meaning that the enzyme’s substrates are both cyclic GMP (cGMP) and cyclic AMP (cAMP). The enzyme is important in cyclic nucleotide signaling cascades, which are involved in the functioning of many neuronal pathways. PDE10A is found almost exclusively in the medium spiny neurons of the striatum, the primary area of the brain affected in HD. Aggregates of mutated huntingtin have been found to impair cAMP signaling and cAMP responsive-element binding protein (CREB) mediated transcription of genes responsible for neurotransmitter synthesis, release and signaling pathways, as well as the production of brain derived neurotrophic factor (BDNF). The resulting degeneration affects many other areas of the brain, causing the behavioral, cognitive and motor impairments that are characteristic of HD.

HD INSIGHTS: You say that PDE10A levels are reduced in individuals with HD. How do you measure that?

ZALESKA: We measure that using imaging of the PDE10A selective PET ligand binding. We studied about ten individuals with different stages of HD in the pilot study. We found that their enzyme levels were between 50 and 55 percent of levels in controls.

HD INSIGHTS: PDE10A levels are reduced in HD patients, so why would an enzyme inhibitor be beneficial?

ZALESKA: PDE10A levels are most likely diminished by a compensatory biological response, an attempt to preserve cyclic nucleotide signaling at higher levels. Because PDE10A destroys cyclic nucleotide signaling, it diminishes with the disease. We know from animal models of HD that by inhibiting PDE10A, we can increase the level of cGMP and cAMP in the basal ganglia. Inhibition of PDE10A has been found to modulate striatal signaling in neuroprotective pathways, to decrease neurodegenerative changes in the striatum of animal models of HD, and to restore cAMP-dependent CREB signaling, which results in improved cortico-striatal communication.

PAPAPETROPOULOS: The way that I see it as a physician scientist is we’re basically helping nature. I know that is a paradox, but it has made a difference when it comes to electrophysiological signatures, especially improving the crosstalk between the cortex and the striatum which is so much affected in HD. I’ll give you another example, which I borrow from my friend, Dr. Bernhard Landwehrmeyer. When I was first engaging with the program, I asked him, “Bernhard, what do you think we are doing here?” And he replied with a very simple analogy. “In HD the striatum is like a broken radio. No matter how much you try to crank up the volume, the radio can only produce a certain level of sound. What we’re doing is amplifying this level of sound so the cortex can hear the basal ganglia better.”

HD INSIGHTS: You said that inhibition of PDE10A has a stimulating effect on the medium spiny neurons in the basal ganglia. Do PDE10A inhibitors prevent neuronal death of spiny neurons?

ZALESKA: We do not have evidence of that. But, we have evidence that after dosing a transgenic mouse model of HD with PDE10A over four months, electrophysiological responses from medium spiny neurons following cortical stimulation are very significantly improved, compared with placebo-treated transgenic mice. We have evidence that the beneficial effects last beyond the presence of the drug in brain tissue, but we are very cautious about interpreting that as evidence of disease modification. At this moment we are focusing on potential treatment of symptoms, hoping that the improved cortico-striatal function will translate to clinically relevant effects in HD patients.

HD INSIGHTS: Dr. Papapetropoulos, what are the plans for human clinical trials of phosphodiesterase inhibitors?

PAPAPETROPOULOS: From a clinical perspective, we have multiple goals before we can safely move to a larger study. Our first goal is to answer the major question that Dr. Zaleska alluded to: Is PDE10A adequately expressed in HD? If the answer is yes, what areas are affected, and what are the clinical factors associated with different enzyme levels in HD? These are key questions in developing the right therapeutic approach for HD. The next question is: what are the treatment implications at the human brain circuit level? We have encouraging electrophysiological data that supports improved cortico-striatal connectivity, generated through our collaboration with CHDI. We want to replicate and sufficiently translate this dataset in a human cohort. We have established a collaborative study with the ICM at the Hôpital Salpétière in France, where we plan to dose early HD patients with our PDE10A inhibitor, and then scan these patients to detect PDE10A levels. This is a double blind, randomized, placebo controlled study with a sequential cohort design. It will be conducted at ICM in Paris, and we anticipate beginning to screen participants in the fall of 2013. We will use the monetary incentive delay task in an fMRI setting to look at potential differences between placebo and active drugs in brain activation. Abnormal activation in certain brain regions is known to occur starting in pre-symptomatic stages of HD with this task. This is work that was published by Enzi et al in 2012.5 We will also collect some additional endpoints. Although this study is not designed to answer any motor, behavioral, or cognitive questions, we have included a variety of exploratory endpoints that range from new innovative, objective measures of neuromotor function and tests of striatal activity to traditional endpoints, such as the UHDRS, apathy scales, both for safety purposes and also in the event that we can pick up signals of efficacy.

PAPAPETROPOULOS: By combining ICM’s expertise with our medicinal chemistry and clinical experience, we are hoping to directly translate the circuitry level data acquired in our preclinical trials into HD patients. We are also looking at safety, because this will be the first time that our PDE10A inhibitor, or any PDE10A inhibitor, will be administered to HD patients. Details about the study are listed at 6. The design of the study was presented at the recent CHDI meeting in Venice, and there is a lot of enthusiasm at Pfizer for this study.

HD INSIGHTS: It sounds like you’re doing lots of novel things in this trial. The first is that you’re investigating a novel class of compounds for HD. And the second is that you’re including some novel techniques to measure connectivity, including functional MRI. I don’t believe fMRI has been used before as a technique in HD clinical trials.

PAPAPETROPOULOS: That is correct. This is our attempt to humanize clinical research and look at circuits rather than symptoms. We believe that circuits are more preserved than behaviors, so they are easier to translate. And when we see congruency between human clinical patients and animal models, our confidence increases. The question remains whether a signal in the circuit will translate into a clinical patient benefit, but that is still to be addressed in future trials.

HD INSIGHTS: Dr. Zaleska, Dr. Papapetropoulos, thank you for your contributions to HD research and for taking the time to share them with HD INSIGHTS.


Spyros Papapetropoulos, MD, PhD,

Spyros Papapetropoulos, MD, PhD, is a neurologist and movement disorder specialist trained at the National Hospital for Neurology and Neurosurgery, Queen Square, London UK, who leads Pfizer’s HD clinical program. He holds an academic appointment with the University of Miami Miller School of Medicine. He has spent his entire academic career studying movement disorders, and since transitioning to industry, he has focused on migraine and pain, neurodegeneration, and neurorehabilitation. When Dr. Papapetropoulos is not working to develop drugs for HD, he focuses on medications for Parkinson disease. He is also an avid tennis player.





zaleskaMargaret Zaleska, PhD is a neuroscientist who leads the PDE10 inhibitor for HD research project in the Pfizer Neuroscience division. She earned her PhD in Biochemistry at the Polish Academy of Science in Warsaw, Poland, and then completed post-doctoral programs focused on neuroscience research at SUNY in the Department of Pharmacology and Experimental Therapeutics, and at the Oklahoma Medical Research Foundation. She was a member of the research faculty of the Perelman School of Medicine at the University of Pennsylvania, then joined Wyeth Research’s Neuroscience Division in Princeton, NJ in 1993. When Pfizer acquired Wyeth in 2009, Dr. Zaleska became a member of the Pfizer Neuroscience team. In her spare time, Dr. Zaleska enjoys exploring Pfizer Neuroscience’s new hometown of Cambridge, Massachusetts.



1 Kleiman RJ, Kimmel LH, Bove SE, et al. Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington’s disease. J Pharmacol Exp Ther. 2011 Jan; 336(1):64-76.

2 Kleiman RJ, Schmidt CJ, Harms J et al. Phosphodiestrase inhibitors rescue deficits in synaptic plasticity and medium spiny neuron excitability in transgenic Huntington’s Disease mouse model. Soc Neurosci. 2011 Abstract 148.15

3 Giampà C, Laurenti D, Anzilotti S, et al. Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington’s disease. PLoS One. 2010 Oct 15;5(10):e13417.

4 Strick CA, James LC, Fox CB, et al. Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A. Neuropharmacol. 2010 Feb; 58(2): 444-51.

5 Enzi B, Edel MA, Lissek S, et al. Altered ventral striatal activation during reward and punishment processing in premanifest Huntington’s disease: a functional magnetic resonance study. Exp Neurol. 2012 May;235(1):256-64.

6 term=PF-02545920&rank=8

Meet the Company










NAME: Teva Pharmaceutical Industries, Ltd.

HEADQUARTERS: Petah Tikva, Israel

STOCK PRICE AS OF 3/5/13: $37.25

52 WEEK RANGE: $36.63 – $46.38


EMPLOYEES: ~46,000

HD INSIGHTS: How did you first become interested in Huntington disease (HD)?

MICHAEL HAYDEN: My interest in HD goes back to my life as a medical student in the middle of the 1970s, when I first saw patients in South Africa who had HD. At the time, HD was not diagnosed because it was thought not to occur in Africa. I realized that not only did HD in fact occur in Africa, but in people of Caucasian or mixed-race background it occurred at a similar rate to that seen in Europe. By contrast, HD was rare in the black populations of Southern Africa. I was drawn to HD. I traveled to every one of the 16 psychiatric and neurological hospitals in South Africa. I examined every single patient with chorea, and from this I compiled a list of 400 to 500 patients with a family history of HD. People in South Africa with HD were discriminated against. Many were of mixed race. Our cardinal observations were that there was a high frequency of juvenile HD in South Africa, and the incidence of HD in people of Caucasian and mixed-race background was similar to the incidence of HD in Europe. We traced the introduction of the HD gene mutation back to Dutch settlers who came to South Africa in the mid-1600s. We started documenting the difficult social and psychological impact of HD on the family. In 1978 we started the first HD clinic in Africa, and we provided an integrated model of HD – comprehensive neurology, psychiatry, social work and physiotherapy. The clinic was integrated in every way; not only by virtue of the specialties to treat HD patients, but also racially. This was the first multiracial clinic at the Groote Schuur Hospital in Cape Town, where ten years previously the first human heart transplant had been done. We wanted to provide support for all families with HD irrespective of their race and irrespective of their past. In the late 1970s we also formed the first lay HD organization in Africa. Just as we established a multiracial clinic for HD, I wanted to integrate the experience of medical students of different racial backgrounds in hospital wards in Cape Town. Generally, white medical students did not see black patients and black medical students were barred from seeing white patients. Inevitably at that time, this put me into conflict with the authorities. I met Marjorie Guthrie in San Diego in 1977 at the Second International Congress on HD. Marjorie and I became close buddies. I told her that I was very worried about my future. I had to choose which struggle I was going to dedicate my life to – was it the struggle to change South Africa, or was it the struggle to have an impact on families with HD and do something for them? Marjorie persuaded me to come to the United States, and helped organize my move. The late Senator Ted Kennedy wrote a letter to the Immigration Department to support my application for immigration on a Green Card. I thought that after I left South Africa I could never go back, and needed to find a home. Senator Kennedy recommended that I go to Boston, so I interviewed at the Children’s Hospital and was accepted into the genetics program. I arrived in Boston in June 1980 as a post-doc. At that time there were no reference books on HD. There had not been a single monograph on HD. I took my thesis of 1979 which formed the basis of the first single-author monograph on HD. This was published while I was in Boston in 1981. I dedicated the monograph to my research assistant at the time, who later became my wife, and Marjorie. Those were the two people who really had played a key role in me being able to complete that work.

INSIGHTS: What was the next step for you?

HAYDEN: As I came to the end of my fellowship, I was asked to go to Vancouver, Canada. Judith Hall, President of the American Society of Human Genetics, was there, Tom Perry Sr., a major researcher in HD, was there. Marjorie encouraged me to look at this opportunity. They welcomed me, and the HD family welcomed me. I had a deeply ingrained commitment to HD. I had seen the plight and difficulties but had also witnessed the courage and dignity of HD patients. I established my lab to make inroads into HD. We have had huge support from families all over North America. In 1986 we did the first predictive test for HD, and contributed to the guidelines for HD predictive testing. We worked on really understanding how, at a molecular and biochemical level, HD occurs. The key question was: How do we develop therapies for HD? We created a full-length animal model for HD. We did the first PET scans in patients, and we created an integrated HD clinic, the first in Canada, that today sees patients contributing to trials around the world. We defined the epidemiology and the incidence of HD, showing that it is more frequent than people have realized in the past. We also defined mechanisms that lead to HD, which is ongoing work for my lab in Vancouver and Singapore too. Many of my post-docs have now gone on to be leaders in the lab in Singapore with a major focus on HD.

INSIGHTS: Why did you make the transition to Teva?

HAYDEN: I could only go to a certain point with academic lab work. To develop therapies for HD, I would have to be open to other possibilities. I worked very hard trying to engage pharma. I met with large pharmaceutical companies, informing them about the importance of this disease, but I was not able to convince them to make the investments needed to commit to developing medicines that could possibly change the course of the lives of patients and families. Then I was approached to consider the job of President of Global R&D at Teva. During the recruitment process we discussed my launching a focus on neurodegeneration using HD as the model. I think that HD could inform studies on many forms of neurodegeneration, including Alzheimer’s disease. We needed to start somewhere, and the CEO, Jeremy Levin, was willing and enthusiastic to commit to that. And so I joined. My labs continue to do basic research that can feed the pipeline with new ideas. I go back to Vancouver very frequently as well as to Singapore to support that work. The very first acquisition with me at Teva was the purchase of a Phase III asset, the drug Huntexil from Neurosearch. This drug was not going to change the course of HD, but provide symptomatic relief. We are now working to start definitive trials with Huntexil in the next few months.

INSIGHTS: What about other approaches for HD?

HAYDEN: As president of R&D at Teva, we have a commitment to refocus the pipeline to diseases of the central nervous system, including MS, Parkinson’s, Alzheimer’s, Pain and, of course, HD. We are hiring people from around the world who know about HD. Teva is a company committed to making a change in the lives of patients with neurodegenerative disorders.

INSIGHTS: What do you think are the greatest future opportunities for new treatments for HD?

HAYDEN: We believe that the inflammatory pathways are important targets. Inflammation is an early feature of this disease, and it occurs both centrally and peripherally. The neurons may be secondarily involved. Astrocytes and microglia secrete various inflammatory cytokines that could cause damage. We are looking into drugs that influence those pathways. In the end, it is likely that you will need combination therapy for this disease: To retard disease progression and also to protect neurons that are already damaged. In HD, the cellular and biochemical disease process starts very early, and often, by the time you have clinical symptoms, there has already been a lot of damage.

INSIGHTS: Dr. Hayden, thank you for your time. Do you have any final thoughts?

HAYDEN: HD is now recognized as being present globally. It is present wherever people have migrated, and the burden of the disease is very similar irrespective of politics, irrespective of race, irrespective of borders and boundaries. The impact on people’s lives is profound. We have the chance to do something. This is an opportunity to impact the lives of patients not only with HD, but also with other forms of neurodegenerative disease.

Meet the Company

isis pharm






Dr. C. Frank Bennett


NAME: Isis Pharmaceuticals

HEADQUARTERS: Carlsbad, California

STOCK PRICE AS OF 8/21/12: $13.67

52 WEEK RANGE: $6.25 – $14.05

MARKET CAPITALIZATION AS OF 8/21/12: $1.4 billion

EMPLOYEES: Approximately 340

Isis Pharmaceuticals is a biotechnology company that develops therapeutic agents that target and modulate RNA. Isis’s primary platform is exploiting antisense oligonucleotide technology to selectively reduce the expression of a target RNA. Co-founder and Senior Vice President of Research, Dr. C. Frank Bennett, spoke with HD Insights about Isis’s RNA-based targeting in HD. Edited excerpts from the discussion are below.


INSIGHTS: Can you tell us a little bit about Isis?

BENNETT: The focus of the company since its inception has been on novel therapeutic agents that target RNA. We use a technology called antisense oligonucleotides (ASOs) that uses short synthetic nucleic acid analogs designed to bind to a target RNA via Watson-Crick base pairing. Once our ASOs bind to the target RNA, they can then be a part of a range of mechanisms to modulate the RNA. For the Huntington disease (HD) Project, the primary mechanism that we’re exploiting is through an enzyme called RNase H. RNase H selectively degrades the RNA that is bound by the oligonucleotide. Wherever the oligonucleotide binds, it recruits RNase H to that RNA, and the RNase degrades the RNA. The oligonucleotides are then recycled within the cell. This is a novel catalytic mechanism that we are using to very selectively reduce the expression of a target RNA. In this case, we’re targeting RNA that is expressed by the huntingtin gene.

INSIGHTS: Since most humans have two copies of the huntingtin gene and in HD-affected individuals only one allele has the CAG expansion, how can you target the production of mutant huntingtin and not wild-type huntingtin?

BENNETT: We’re taking several different mechanistic approaches. The most advanced project we are using does not distinguish between wild-type and mutant huntingtin. Our pre-clinical research, performed in collaboration with Dr. Don Cleveland at University of California San Diego, suggests there are no deleterious effects associated with reducing wild-type huntingtin, and published research supports our understanding that wild-type huntingtin protein is essential for normal development before birth, but has a largely undefined role in adults. So we are counting on humans having some tolerance for reduced expression of both mutant and wild-type huntingtin. However, we also have two different approaches that we’re using to get selectivity in case it’s needed. One approach is a project with Dr. Michael Hayden and his colleagues at the University of British Columbia, in which we are targeting single nucleic-type polymorphisms that co-associate with the expanded CAG triplet on the mutant allele. We are able to distinguish a single nucleotide- change, which causes the loss of the mutant allele while sparing the wild-type allele. In our preclinical studies we have been able to demonstrate a greater than 50-fold selectivity of the mutant versus wild-type, based upon that same nucleotide- change. The caveat is that there are a number of haplotypes that all have expansions of repeats, so a single drug would at best treat about 50 percent of HD patients. Multiple drugs must be available to treat all the patients who would be amenable to this therapy. Another approach is to use all the oligonucleotides that bind to the expanded CAG repeat itself. Working with another collaborator, Dr. David Corey, at University of Texas Southwest Medical Center, we have shown that the expansion of that CAG repeat provides more binding sites for the oligonucleotide. Using this technology, we are able to distinguish between wild-type CAG repeat links and the expanded CAG repeat that occurs in a disease. This technology has an advantage that could treat a larger number of patients with a single drug, but there is also concern because other genes have CAG repeats. We are currently working to identify or characterize the risk of the CAG targeting approach versus the polymorphism approach.

INSIGHTS: What are the specific opportunities for antisense oligonucleotide therapies for HD?

BENNETT: Our technology can be broadly applicable to a variety of human diseases. We have demonstrated that intrathecal dosing results in a very broad distribution of a drug into CNS tissues and can influence expression of mutant huntingtin in the areas of the brain that are affected in HD. INSIGHTS: A number of these therapies you mentioned are further along in development. What is holding back development of therapies for HD? BENNETT: Mainly it is determining the optimal drug to take forward. Clinical trials are quite expensive, and we want to bring forward the drug that has the best chance of being successful in the clinic. We have narrowed down the list to a small number of drug candidates, and we are doing additional studies to characterize the behavior of those candidates in our preclinical studies. Our hope is that we’ll have that completed by early next year and then start the process of doing the toxicology studies that are necessary to bring that drug forward into the clinic.

INSIGHTS: Thinking about the clinical development of a drug for HD, are there any specific challenges in HD that are different to other conditions?

BENNETT: I think there are two separate endpoints that we would concentrate on: deciding which drugs make more sense for early clinical programs to show proof of concept, and then which clinical measures would make the most sense for demonstrating that the drug is clinically effective.

INSIGHTS: What do you envision would be the clinical population to which the drug would first be given, in terms of development of clinical HD symptoms?

BENNETT: Since this drug is delivered by intrathecal dosing, we would likely start clinical trials in currently symptomatic patients rather than in volunteers who are in the pre-sympotmatic stages of HD. The question is just how advanced would the disease be in patients we would be comfortable in selecting for dosing.

INSIGHTS: You mentioned dosing. How frequently do you think an ASO therapy would need to be dosed in a disease like HD?

BENNETT: Based on our work in other programs, I hypothesize that at a minimum, it would be an intrathecal injection every three months.

INSIGHTS: In those symptomatic patients, what clinical endpoints do you think are best for consideration?

BENNETT: I think we have to build in cognitive changes, maybe imaging measures, and then some motor function measures as well. A big challenge for the project right now is identifying clinical measures that correlate with reduction in intracellular levels of mutant huntingtin.

INSIGHTS: Are there any safety concerns?

BENNETT: At this point in the program it’s too early to say. We haven’t identified any safety concerns with our preclinical studies, and it’s something that we are investigating in our toxicology studies. The purpose of those studies is to help identify if there are any safety concerns that we would need to monitor in the clinic. However, ASO therapies have been very well tolerated in our amyotrophic lateral sclerosis drug and our spinal muscular atrophy drug. In our clinical programs we see a relatively low incidence of spinal headaches in patients dosed intrathecally. These events are more procedure-related than drug-related.

INSIGHTS: What message do you have for HD patients about the promise of ASOs for HD?

BENNETT: Again, it’s important to keep in mind is this is one of many therapies being developed by companies right now. I would not look at any of these therapies as a cure for HD. They may either slow down the process of the disease or mitigate some of the symptoms that patients experience. Ultimately, Isis can develop one of several drugs that will make a big impact in the lives of individuals with HD.

INSIGHTS: How can the research community help you and Isis develop therapies for HD?

BENNETT: One of the big challenges that we and other companies developing therapies for HD face is finding early, measurable clinical biomarkers that correlate with the effects of the drug. I think results from natural history studies will be important for developing drugs and helping us design our clinical trials. We’re excited to move these therapies forward. We would like to thank CHDI, the Hereditary Disease Foundation, and the Huntington’s Disease Society of America for their support of our efforts.

Meet the Company







NAME: Prana Biotechnology

HEADQUARTERS: Parkville, Victoria, Australia

STOCK PRICE AS OF 10/05/11: $1.59

52 WEEK RANGE: $1.13-4.50

MARKET CAPITALIZATION AS OF 10/05/11: $42.4 million

EMPLOYEES: Approximately 10

Prana Biotechnology’s research is driven by the hypothesis that metal protein attenuating compounds bind transition metals and prevent oligomerization of amyloid proteins in Alzheimer disease and of the huntingtin protein in Huntington disease. Prana Biotechnology CEO Geoffrey Kempler sat down with HD InsightsTM at the World Congress on Huntington’s Disease to discuss Prana’s research in neurological disease modification. Excerpts from the discussion are below.

INSIGHTS: Could you tell us a little bit about Prana?

KEMPLER: Prana began in 1997 as a private company through some seed capital financing that came in from myself and a friend of mine, Barry Lieberman. We became interested in some work that was happening at Harvard Mass General. The work was on the amyloid protein and the role of metals in facilitating the aggregation of this protein into oligomers and plaques. What we were doing was considered heretical because we were really the first group to start to understand the metal binding sites on these proteins, and that these metals were driving the aggregation of the proteins. We supported our research very privately. We had a peripheral concept growing that was already available in the market and matched our scientific theory. There, we could do that concept work. By us understanding the mechanism that’s behind protein aggregation, we’ve been able to drive an enormous amount of academic publications through our support laboratories at Harvard, here in Melbourne at the Mental Health Research Institute and the University of Melbourne, and at some other collaborations we’ve had in various parts of the world.

INSIGHTS: It makes a lot of sense that a company like yours might be interested in Alzheimer disease, which has a very large market. Tell us why you are interested in Huntington disease.

KEMPLER: You imagine that companies always look at market size and market opportunity, and that’s true. I don’t want in any way diminish that as a focus. We know that cognition is one of the key areas of deficit in Huntington disease patients. We know that it’s a major aspect of Alzheimer disease, but we also know that there’s some normal cognitive decline that comes just with the aging process even if you don’t have either of these diseases. In the animal experiments that we’ve done, we’ve demonstrated that our drug PBT2 actually had profound effects on a memory test that we gave to old mice that were not transgenically modified to have either Alzheimer disease nor Huntington disease. These mice were able to effectively complete the task post-treatment with the drug as effectively as young healthy mice. It told us that the drug would be useful wherever there is a cognitive deficit, particularly where that cognitive deficit emphasizes executive function deficit, such as early in the disease process.

INSIGHTS: So among the disorders that affect cognition, what attracted you specifically to Huntington disease?

KEMPLER: I think it was the advocacy of the Huntington disease researches. We have been approached by different researchers and different diseases, and we’re a little company so we can’t take on everything. But the people in Huntington disease were able to instill their confidence of our own drug in this indication. From a pragmatic perspective we saw that it was a disease where we could come along, present our case, get some attention, and actually see if we can bring benefit to patients.

INSIGHTS: Where there any researchers in particular who were especially strong advocates?

KEMPLER: I think I would have to certainly begin with Professor Ira Shoulson from Georgetown University, who had a lot of influence in our thinking, as well as Steve Hersch from Massachusetts General Hospital in Boston.

INSIGHTS: What did they do to persuade you?

KEMPLER: They were able to look at our data, explain the relevance of it to Huntington disease patients, and work with our scientists to generate new data. They were able to prepare feedback on what we’d produced and what others had produced, and really helped us understand that we might have a unique position with our drug.

INSIGHTS: There’s only one FDA approved treatment for HD right now. You are also aware that the Dimebon study failed to show benefit on cognition relative to placebo. How did that affect your thinking about coming into with a new compound to look at cognition in Huntington disease?

KEMPLER: We’ve spent so long on the outside of the accepted paradigms that we’re quite comfortable living in that little space. We feel that we’re likely to be in a pretty small group if not a bit unique amongst the drugs that actually have some promise.

INSIGHTS: Looking forward, what are your hopes for Prana and for Huntington disease?

KEMPLER: My big hope for Prana is that the many, many years of dedicated effort by outsiders, our staff, the investors, and by the community patient groups that have cooperated in our clinical trials and in our advocacy will be rewarded by PBT2 in the first instance. Getting approval for a drug that could bring cognitive benefit to patients with Huntington disease will parallel our ongoing important work in Alzheimer disease. We actually have an entire strategy that’s probably gone for the very high bar, and that’s to deal with the actual underlying disease process that’s behind each of these diseases. My hope for Prana in the very short-term is that we’ll be seen by the Huntington disease community as the drug in Phase II that appeared out of nowhere because it was from an Alzheimer universe.