• Wave Life Sciences Ltd (NASDAQ: WVE) stock price rose 14.29% today. That is why.

The share price of Wave Life Sciences Ltd (NASDAQ: WVE) – a clinical-stage genetic drugs company committed to providing life-changing treatments for people battling devastating diseases – rose 14.29% today. Investors are reacting positively to the company’s announcement of a positive update to the ongoing FOCUS-C9 Phase 1b/2a trial of WVE-004, the company’s clinical candidate for amyotrophic lateral sclerosis associated with C9orf72 (C9-ALS) and frontotemporal dementia (C9-FTD). FOCUS-C9 (NCT04931862) is an adaptive assay that was designed to quickly optimize dose level and frequency based on early indicators of target engagement.

This trial update announced today is driven by the observation of potent and sustained reductions in poly(GP) dipeptide repeat proteins in cerebrospinal fluid (CSF) with single low doses of WVE-004. Poly(GP) is a key biomarker of C9-ALS/C9-FTD disease that, when reduced in CSF, indicates WVE-004 commitment to the target in the brain and spinal cord.

Reductions in poly(GP) were observed in all active treatment groups (10 mg, n=2 patients; 30 mg, n=4 patients; 60 mg, n=3 patients), reaching statistical significance compared to placebo (n=3 patients) after single doses of 30 mg, with a 34% reduction in poly(GP) at day 85 (p=0.011). And at the time of the analysis, none of the patients dosed at 60 mg had reached day 85.

As the poly(GP) reduction in the 30 mg single dose cohort does not appear to have plateaued, Wave will extend the observation period from approximately 3 months (85 days) to approximately 6 months to identify the reduction maximum poly(GP) ) and duration of effect of single low doses. Based on the durability and potency seen in the 30 mg cohort, FOCUS-C9 was scaled to include additional patients receiving single 20 mg and 30 mg doses of WVE-004.

Additional exploratory evaluations included CSF neurofilament light chain (NfL) monitoring and clinical outcome measures. And CSF NfL elevations were observed in some patients in the 30 mg and 60 mg single dose cohorts with no significant change in clinical outcome measures, although the data set and duration did not differ. sufficient to assess clinical effects. Exploratory evaluations will continue throughout the single-dose and multi-dose phases of the FOCUS-C9 trial.

Adverse events (AEs) were balanced between treatment groups, including placebo, and were mostly mild to moderate in intensity. 4 patients (including one on placebo) presented serious and/or serious adverse events; 3 were investigator-reported as ALS- or administration-related, and 1 was investigator-reported as study drug-related. And there were no treatment-associated elevations in white blood cell or CSF protein counts and no other notable laboratory abnormalities were observed.

Dosing in a multi-dose cohort at 10 mg per month is also well advanced, and additional single-dose and multi-dose data are expected throughout 2022. And the company anticipates that the additional single-dose and multi-dose data will be used to optimize dose level and frequency and allow for discussions with regulatory authorities later this year regarding the next phase of development.

Upcoming milestones for other Wave programs. In addition to WVE-004, Wave is advancing 2 other Phase 1b/2a clinical trials with its investigational candidates containing the next-generation PN chemistry: WVE-003 targeting SNP3 in Huntington’s disease (HD) – which is in progress. investigation in the SELECT-HD trial (NCT05032196) and WVE-N531 targeting exon 53 in Duchenne muscular dystrophy (DMD) (NCT04906460). Wave plans to share clinical data in 2022 for WVE-003 and WVE-N531 to better understand the clinical effects of PN chemistry and enable decision making for these programs.

Wave also continues to rapidly advance its alpha-1 antitrypsin deficiency (AATD) program, which is the company’s first program using its novel A-to-I(G) RNA base-editing oligonucleotides conjugated to the GalNAc (AIMers). And Wave plans to select an AATD development candidate and initiate IND-enabling toxicology studies in Q3 2022.

KEY QUOTES:

“ALS and FTD are serious, life-threatening disorders for which advances in disease-modifying treatments have been extremely limited. Although early, these data are encouraging and open up an opportunity to target the disease at the RNA level. Additionally, it is encouraging to see the benefits of the adaptive study design, where this early analysis has already helped to reduce the doses explored and allowed for more accurate, real-time exploration of dose-response and potency. ‘optimization.

— Merit Cudkowicz, MD, Chief of the Department of Neurology, Director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, and Chair of the FOCUS-C9 Clinical Advisory Board

“FOCUS-C9 was designed to provide an early indication of target engagement so that we can quickly optimize the dose and move to the next stage of development. Based on our preclinical PK/PD modeling, we expected that relatively low doses would engage the target; however, seeing this level of poly(GP) precipitation three months after a single 30 mg dose exceeded our expectations and we expect poly(GP) to decline further with repeated administrations. The next step is to identify a regimen that maximizes knockdown with repeat dosing, while potentially allowing quarterly or less frequent dosing. We are extremely grateful to the study patients, families, researchers and clinicians who helped us through this initial step and we look forward to their continued partnership as we work towards the completion of FOCUS- C9.

— Michael Panzara, MD, MPH, Chief Medical Officer and Head of Therapeutic Discovery and Development at Wave Life Sciences

“Wave was founded on the vision that rational drug design would enable us to realize the full potential of genetic medicines. This guiding principle has enabled the continued evolution of our PRISM platform and the discovery that PN chemistry dramatically improves the potency, durability and delivery of our therapeutic candidates. Today, these early FOCUS-C9 results demonstrate that our compelling preclinical data on PR-containing molecules is beginning to translate into the clinic. Additionally, these data reinforce our confidence that we will see the benefits of PN chemistry manifest in our other clinical programs – WVE-003 in HD and WVE-N531 in DMD – as well as our first RNA editing program in AATD. . We are on track to deliver meaningful therapies to patients and families. »

— Paul Bolno, MD, MBA, President and CEO of Wave Life Sciences

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