Wave Life Sciences Announces Positive Update from Phase 1b/2a SELECT-HD Trial with Initial
Results Indicating Allele-Selective Target Engagement with WVE-003 in Huntington’s Disease
September 20, 2022
Single doses of WVE-003 appear generally safe and well-tolerated
CSF mutant huntingtin (mHTT) protein was reduced following single doses of 30 or 60 mg; mean mHTT reduction across both cohorts was 22%(median reduction 30%) from baseline 85 days post-single dose
Wild-type huntingtin (wtHTT) protein levels through day 85 appear consistent with allele-selectivity
Expanding single dose cohorts to optimize dose level with data expected in 1H 2023
Continued clinical validation of PRISM platform and PN stereochemistry
Wave to host investor conference call and webcast at 8:30 a.m. ET today
CAMBRIDGE, Mass., Sept. 20, 2022 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic medicines company
committed to delivering life-changing treatments for people battling devastating diseases, today announced a positive update to the ongoing Phase
1b/2a SELECT-HD clinical trial of WVE-003, the company’s clinical candidate for Huntington’s disease (HD). SELECT-HD ( NCT05032196) is anadaptive trial designed to rapidly optimize dose level and frequency based on early indicators of target engagement. The trial update announced today
is being driven by the observation of reductions in mutant huntingtin (mHTT) protein in cerebrospinal fluid (CSF) after study participants received eithera single 30 or 60 mg dose of WVE-003. Additionally, wild-type huntingtin (wtHTT) protein was preserved, which appears consistent with alleleselectivity.
“These preliminary data suggest WVE-003 is working as intended: to selectively reduce the toxic mHTT protein while avoiding targeting the healthy,
wild-type huntingtin protein, thereby preserving its beneficial effects in the central nervous system,” said Ralf Reilmann, MD, founder of the GeorgeHuntington Institute, Muenster, Germany and member of the SELECT-HD Clinical Advisory and Dose Escalation Committees. “Additionally, I amencouraged by the safety and tolerability data. Taken together, WVE-003 appears to have a unique profile with the potential to overcome priortherapeutic challenges in this field. Furthermore, as a clinician and researcher focused on HD, it is my hope that innovative adaptive trial designs like
SELECT-HD become more commonplace to optimize dosing in early proof-of-concept studies. It is also exciting to finally see an assay measuring
wtHTT being developed and used successfully in a clinical trial – a long awaited, big step forward for the HD research community. The availability ofthis assay has potential to significantly increase our understanding of how best to treat this challenging disease.”“Based on these initial data, it appears that our preclinical data for WVE-003 are translating in the clinic,” said Michael Panzara, MD, MPH, Chief
Medical Officer and Head of Therapeutics Discovery and Development at Wave Life Sciences. “We are encouraged to see a mean CSF mHTT
reduction from baseline of 22% at day 85 after participants received just a single dose of WVE-003, demonstrating a compelling pharmacological
profile for individuals with HD. We are grateful to the HD community, including the SELECT-HD participants, study sites and advisors, for theircontinued partnership and support of this program. We look forward to continuing to expand this study and sharing additional data next year.”
Eighteen (18) participants have been dosed in the SELECT-HD trial (30 mg, n=4; 60 mg, n=4; 90 mg, n=4; placebo, n=6). Participants enrolled at 30mg, 60 mg and placebo had adequate follow-up to day 85 for biomarker analysis. At the time of analysis, none of the participants dosed with 90 mg
had reached day 85 so this cohort is not included in the biomarker analysis.
Key observations include:

Single doses of WVE-003 up to 90 mg appeared generally safe and well-tolerated
Adverse events (AEs) were balanced across treatment groups, including placebo, and all were mild to moderate inintensity
No serious adverse events (SAEs) were observed
No participants discontinued from the study
Among participants in the 30 and 60 mg WVE-003 cohorts, the mean reduction in CSF mHTT from baseline was 22%(median reduction 30%) at 85 days following a single dose
The difference in the mean reduction in CSF mHTT compared to placebo was 35% at 85 days post-single dose
For these analyses, the 30 and 60 mg single dose cohorts were pooled as there was no apparent dose response
between these two cohorts. Wave will continue to evaluate dose response in the expanded single dose cohorts
In the 30 and 60 mg cohorts, wtHTT protein was preserved, which appears consistent with allele-selectivity
Increases in neurofilament light chain (NfL) from baseline were observed in some participants. Wave will continue tomonitor trends in NfL as SELECT-HD advances
There were no clinically meaningful elevations in CSF white blood cell counts or protein that would indicate inflammation inthe CNSThere were no meaningful changes in clinical outcome measures, although the dataset and duration were not sufficient toassess clinical effects
Based on these data, Wave is adapting the SELECT-HD clinical trial to expand the single dose cohorts and will also continue advancing the 90 mg
cohort for biomarker analysis at day 85. Additional single dose biomarker and safety data are expected in the first half of 2023.
Wave’s approach to HD is guided by the recognition that, in addition to a gain of function of the mHTT protein, people with this disease have lost one
copy of the wtHTT allele, leaving them with a smaller protective reservoir of healthy protein than unaffected individuals. wtHTT protein is critical forneuronal function and suppression may have detrimental long-term consequences.
WVE-003 is the only allele-selective HD candidate in clinical development. It is designed to preferentially lower mHTT by targeting a single nucleotide
polymorphism (SNP3) that appears on the mHTT allele and is not present on the wtHTT allele. Based upon scientific literature, it is estimated thatapproximately 40 percent of adults with HD carry SNP3 in association with the HD mutation.
“These SELECT-HD data are the first to support the feasibility of allele-selective mHTT knockdown in the clinic – a precision approach enabled by ourPRISM discovery and drug development platform,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences.
“SELECT-HD is the second clinical trial this year to demonstrate clinical translation of Wave’s PN backbone chemistry modifications, as well as theimpact of rational design through control of stereochemistry, increasing our conviction in our platform. We look forward to sharing data from oursplicing clinical program in muscle – WVE-N531 for exon 53 skipping in Duchenne muscular dystrophy – in the fourth quarter of 2022.”
Investor Conference Call and Webcast
Wave management will host an investor conference call today at 8:30 a.m. ET to discuss the SELECT-HD clinical trial update. The webcast of theconference call may be accessed by visiting “Events” on the investor relations section of the Wave Life Sciences corporate website:
ir.wavelifesciences.com/events-and-presentations. Analysts planning to participate during the Q&A portion of the live call can join the conference callat the audio conferencing link available here. It is recommended that participants register at least 15 minutes in advance of the call. Once registered,participants will receive the dial-in information. Following the live event, an archived version of the webcast will be available on the Wave Life Scienceswebsite.
About the SELECT-HD Clinical Trial
The SELECT-HD trial is a global, multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety andtolerability of single- and multiple-ascending intrathecal doses of WVE-003 in people with a confirmed diagnosis of HD who are in the early stages ofthe disease and carry SNP3 in association with their cytosine-adenine-guanine (CAG) expansion. Additional objectives include assessing the plasma
pharmacokinetic profile and exposure in the cerebrospinal fluid, as well as exploratory pharmacodynamic (mHTT, wtHTT and neurofilament lightchain) and clinical endpoints. The SELECT-HD trial is expected to enroll approximately 36 participants. It is designed to be adaptive, with dose
escalation and dosing frequency being guided by an independent committee.
About Huntington’s Disease
Huntington’s disease (HD) is a debilitating and ultimately fatal autosomal dominant neurological disorder, characterized by cognitive decline,
psychiatric illness, and chorea. HD causes nerve cells in the brain to deteriorate over time, affecting thinking ability, emotions, and movement. HD iscaused by an expanded cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin (HTT) gene that results in production of mutant HTT (mHTT)
protein. Accumulation of mHTT causes progressive loss of neurons in the brain.
Approximately 30,000 people in the United States have symptomatic HD and more than 200,000 others are at risk for developing the disease. Thereare currently no approved disease-modifying therapies available.
About PRISM™
PRISM is Wave Life Sciences’ proprietary discovery and drug development platform that enables genetically defined diseases to be targeted withstereopure oligonucleotides across multiple therapeutic modalities, including silencing, splicing, and editing. PRISM combines the company’s uniqueability to construct stereopure oligonucleotides with a deep understanding of how the interplay among oligonucleotide sequence, chemistry andbackbone stereochemistry impacts key pharmacological properties. By exploring these interactions through iterative analysis of in vitro and in vivo
outcomes and machine learning-driven predictive modeling, the company continues to define design principles that are deployed across programs torapidly develop and manufacture clinical candidates that meet pre-defined product profiles.
About Wave Life Sciences
Wave Life Sciences (Nasdaq: WVE) is a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battlingdevastating diseases. Wave aspires to develop best-in-class medicines across multiple therapeutic modalities using PRISM, the company’s
proprietary discovery and drug development platform that enables the precise design, optimization, and production of stereopure oligonucleotides.
Driven by a resolute sense of urgency, the Wave team is targeting a broad range of genetically defined diseases so that patients and families may
realize a brighter future. To find out more, please visit www.wavelifesciences.com and follow Wave on Twitter @WaveLifeSci.
Forward-Looking Statements
This press release contains forward-looking statements concerning our goals, beliefs, expectations, strategies, objectives and plans and otherstatements that are not necessarily based on historical facts, which are within the meaning of the Private Securities Litigation Reform Act of 1995, asamended, including, without limitation, statements regarding: our belief as to what our initial WVE-003 data indicating allele-selective target
engagement announced above portend for our ability to deliver meaningful therapies for people living with HD and their families; the first-in-classnature of our initial WVE-003 data to support the feasibility of allele-selective mHTT knockdown in the clinic; the continued dosing and generation ofdata to complete our SELECT-HD adaptive study and the announcement of such events; our expectations regarding the timing of additional data in theSELECT-HD study; the potential of our in vitro and in vivo preclinical data and modelling to predict the relevant dosing and behavior of our compounds
in humans; the potential benefits of PRISM, including our novel PN backbone chemistry modifications and the impact of rational design through controlof stereochemistry; and our expectations regarding the timing of sharing data from our third clinical candidate containing PN chemistry, WVE-N531 forexon 53 skipping in Duchenne muscular dystrophy. Actual results may differ materially from those indicated by these forward-looking statements as aresult of various important factors, including the following: our ability to finance our drug discovery and development efforts and to raise additional
capital when needed; the ability of our preclinical programs to produce data sufficient to support our clinical trial applications and the timing thereof; theclinical results of our programs and the timing thereof, which may not support further development of product candidates; actions of regulatoryagencies, which may affect the initiation, timing and progress of clinical trials, including their receptiveness to our adaptive trial designs; oureffectiveness in managing future clinical trials and regulatory interactions; the effectiveness of PRISM, including our novel PN backbone chemistrymodifications; the effectiveness of our novel ADAR-mediated RNA editing platform capability and our AIMers; the continued development andacceptance of oligonucleotides as a class of medicines; our ability to demonstrate the therapeutic benefits of our candidates in clinical trials, including
our ability to develop candidates across multiple therapeutic modalities; our dependence on third parties, including contract research organizations,contract manufacturing organizations, collaborators and partners; our ability to manufacture or contract with third parties to manufacture drug material
to support our programs and growth; our ability to obtain, maintain and protect our intellectual property; our ability to enforce our patents against
infringers and defend our patent portfolio against challenges from third parties; competition from others developing therapies for similar indications; ourability to maintain the company infrastructure and personnel needed to achieve our goals; the severity and duration of the COVID-19 pandemic andvariants thereof, and its negative impact on the conduct of, and the timing of enrollment, completion and reporting with respect to our clinical trials; andany other impacts on our business as a result of or related to the COVID-19 pandemic, as well as the information under the caption “Risk Factors”
contained in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in other filings we make with
the SEC from time to time. We undertake no obligation to update the information contained in this press release to reflect subsequently occurring
events or circumstances.
Investor Contact:
Kate Rausch617-949-4827
krausch@wavelifesci.com
Media Contact:
Alicia Suter
617-949-4817
asuter@wavelifesci.com
HD Community Contact:
Chelley Casey774-276-8738
ccasey@wavelifesci.com

Source: Wave Life Sciences USA, Inc.