Wave Life Sciences Announces Initiation of Dosing in Phase 1b/2a FOCUS-C9 Clinical Trial of WVE-004 in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
First clinical dosing of a compound using PN backbone chemistry modifications
Enrolling participants with C9-ALS, C9-FTD or mixed phenotype
FOCUS-C9 is adaptive to enable rapid optimization of WVE-004 dosing
Clinical data to enable decision-making on next steps for WVE-004 program expected in 2022
“ALS and FTD are devastating illnesses where therapeutic progress has been extremely limited. Advancing discovery and development of new treatments for ALS and FTD is an urgent need that requires creativity, expediency and innovative thinking,” said
C9-ALS and C9-FTD are believed to be caused by multiple factors related to the G4C2 expansion. The expansion may lead to accumulation of repeat-containing RNA transcripts and aberrantly translated dipeptide repeat proteins (DPRs) leading to neurotoxicity, as well as insufficient levels of C9orf72 protein, affecting normal regulation of neuronal function and the immune system.
Preclinical studies of WVE-004 demonstrated potent and durable knockdown of repeat-containing transcripts in spinal cord and cortex, as well as knockdown of more than 90% of DPRs in the spinal cord and at least 80% of DPRs in the cortex, an effect that persisted for at least six months. C9orf72 protein was relatively unchanged over the same time period.
The FOCUS-C9 trial is a global, multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety and tolerability of single- and multiple-ascending intrathecal doses of WVE-004 for people with C9-ALS and/or C9-FTD. Additional objectives include measurement of polyGP DPR proteins in the cerebrospinal fluid (CSF), plasma and CSF pharmacokinetics (PK), and exploratory biomarkers and clinical outcomes. The FOCUS-C9 trial is expected to enroll approximately 50 participants. It is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee.
WVE-004 incorporates Wave’s novel PN backbone chemistry modifications (PN chemistry), which have been shown in preclinical studies to enhance potency, exposure, and durability. In addition to WVE-004, Wave is advancing two other proof-of-concept trials with PN chemistry-containing investigational candidates: WVE-003 targeting SNP3 in Huntington’s disease and WVE-N531 targeting exon 53 in Duchenne muscular dystrophy.
About Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which the progressive degeneration of motor neurons in the brain and spinal cord leads to the inability to initiate or control muscle movement. People with ALS may lose the ability to speak, eat, move and breathe. ALS affects as many as 20,000 people in
Frontotemporal dementia (FTD) is a fatal neurodegenerative disease in which progressive nerve cell loss in the brain's frontal lobes and temporal lobes leads to personality and behavioral changes, as well as the gradual impairment of language skills. It is the second most common form of early-onset dementia after Alzheimer’s disease in people under the age of 65. FTD affects as many as 70,000 people in
ALS and FTD can be caused by mutations in the C9orf72 gene, which provides instructions for making protein found in various tissues, including nerve cells in the cerebral cortex and motor neurons. In
PRISM is Wave Life Sciences’ proprietary discovery and drug development platform that enables genetically defined diseases to be targeted with stereopure oligonucleotides across multiple therapeutic modalities, including silencing, splicing and editing. PRISM combines the company’s unique ability to construct stereopure oligonucleotides with a deep understanding of how the interplay among oligonucleotide sequence, chemistry and backbone 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 to rapidly develop and manufacture clinical candidates that meet pre-defined product profiles.
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, the anticipated therapeutic benefit of WVE-004 as an investigational therapy for C9-ALS and C9-FTD; the anticipated timing of data to enable decision-making on next steps for WVE-004; the predicted pharmacology of WVE-004 and the associated trial protocol, design and endpoints; our beliefs related to the cause of C9-ALS and C9-FTD and our understandings of the effects of G4C2 expansion; the anticipated therapeutic benefits of our potential therapies, including our compounds containing PN chemistry, compared to others; and the potential benefits of PRISM, including our novel PN backbone chemistry modifications, and our stereopure oligonucleotides compared with stereorandom oligonucleotides. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release and actual results may differ materially from those indicated by these forward-looking statements as a result of these risks, uncertainties and important factors, including, without limitation, the risks and uncertainties described in the section entitled “Risk Factors” in Wave’s most recent Annual Report on Form 10-K filed with the
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Source: Wave Life Sciences USA, Inc.