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
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.