07 Jan Mixed results from Precision HD 2 trial likely to impact the prospects of Wave Life Sciences
Wave Life Sciences (NASDAQ: WVE), a clinical-stage Company developing novel stereopure oligonucleotides to treat genetic defects, announced topline data from an ongoing Phase 1b/2a PRECISION-HD2 trial evaluating the safety and efficacy of WVE-120102, a first-in-class allele-selective approach to treat Huntington’s disease (HD). The study shows that patients treated with multiple intrathecal doses of WVE-120102, when compared to a placebo, demonstrated a statistically significant reduction of 12.4% in mutant huntingtin (mHTT) protein in cerebrospinal fluid (CSF). However, there was no statistically significant reduction in mutant huntingtin (mHTT) in those treated with WVE-120102 as compared to a placebo.
WVE-120102, is an allele-selective molecule, which targets two disease-associated single nucleotide polymorphisms (“SNPs”) within the huntingtin gene, namely rs362307 (“mHTT SNP-1”) and rs362331 (“mHTT SNP-2”), to reduce the production of the disease causing protein, while leaving the wild-type (healthy) HTT protein unaffected. Wave will now initiate a 32 mg cohort in January 2020. The Company is using an assay developed by the CHDI Foundation, a not-for-profit biomedical research organization, to measure total HTT (tHTT) protein and its affect on wtHTT.
Michael Panzara, MD, MPH, Chief Medical Officer of Wave Life Sciences commented,
“This topline analysis has given us the opportunity to evaluate early data from our ongoing dose finding study. The data demonstrate a reduction in mutant HTT and a safety and tolerability profile that supports exploration of higher doses of WVE-120102, with the goal of maximizing mutant HTT reduction and avoiding a negative impact on the healthy huntingtin protein.”
Wave is currently engaged in a Phase 1b/2a trial named PRECISION-HD1, which is evaluating the safety and efficacy of WVE-120101 in early manifest HD patients who carry SNP rs362307 (SNP1). The Company will now initiate a 32 mg cohort for this trial based on the above results.
In December 2019, the Company announced the decision to discontinue the development of suvodirsen for patients with Duchenne muscular dystrophy (DMD), who have mutations amenable to exon 51 skipping, based on the interim results from a phase 1 open-label extension (OLE) study.
Wave Life Sciences (NASDAQ: WVE)
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Huntington’s disease is a progressive degeneration of the neurons in the brain resulting in loss of cognition, motor ability, uncontrolled movements and emotional distress. The disease can be categorized into adult onset, which manifests in the form of depression, irritability, lack of coordination and poor decision making skills. The disease is characterized by chorea, involuntary jerking or twitching movements, which become progressively worse, with patients having a life span of around 15-20 years after onset.
The Juvenile form of the disease is less common, and develops usually in childhood or adolescence, marked by symptoms such as frequent falling, slurred speech, and rigidity in movements and drooling. In addition, cognitive decline hampers academic and social performance. This form of the disease progresses more quickly with a life span of just 10-15 years from the onset of symptoms.
According to an estimate by the NIH the disease affects an estimated 3 to 7 per 100,000 people of European ancestry and is primarily caused by a mutation in the HTT gene that is responsible for providing clear instructions for making the huntingtin protein. The malfunctioning of the gene involves a DNA segment known as CAG trinucleotide repeat, the increase in the size of which leads to production of abnormally long version of the huntingtin protein. The abnormal binding and accumulation of the protein results in the dysfunction and death of neurons in the brain.
The disease is inherited in an autosomal dominant pattern, which makes one copy of the altered gene in either parent, sufficient for the child to inherit this disorder. The disease is diagnosed through genetic testing and has no cure at present. The treatment options aim at alleviating the symptoms. Teva pharmaceuticals (NYSE: TEVA) Austedo and Bausch Health’s (NYSE: BHC) Xenazine are the only two marketed drugs for the treatment of Huntington’s.
There are numerous candidates under clinical development which are using novel approaches such as lysosomal cysteine transporter, Huntington, SIRT1, vasopressin receptors, semaphorin 4D/CD100, aryl hydrocarbon receptor, phosphodiesterase 10a, PPAR delta, and PPAR gamma according to a report by ResearchandMarkets. According to a report by Grand View Research Inc, the global Huntington’s disease market is expected to be worth over USD 1.5 billion by 2023, growing at a CAGR of 38.2% during the forecast period
Wave Life Sciences is taking the oligonucleotide approach to creating nucleic acid based therapeutics, for the treatment of rare genetic diseases, such as Huntington’s disease, amyotrophic lateral sclerosis and frontotemporal dementia. The Company’s proprietary platform can chemically modify short-length RNA or DNA strands to alter the production of disease-causing proteins and inhibit degradation of oligonucleotides by changing their natural phosphate backbone to phosphorothioates, by replacing a non-bridging oxygen atom with a sulphur atom. Its chemistry platform allows for the design, manufacturing and optimization of stereopure oligonucleotides.
The technology enables the company to create medicines with improved safety profiles, stability and far greater pharmacological properties, which have a wide applicability across platforms such as Antisense, Exon Skipping, Splice Correction, RNAi and MicroRNA. The company has a scalable in-house cGMP manufacturing unit in Lexington, Massachusetts, which helps it regulate the development and supply of its products.
The development of the company’s lead candidate for DMD suvodirsen (WVE-210201), which used exon skipping to create truncated functional dystrophin protein to target restoration of the mRNA reading frame, was discontinued in December 2019. The Drugs Phase 2/3 efficacy and safety trial for Duchenne muscular dystrophy (DMD) was selected for the complex innovative trial designs (CID) by the U.S. Food and Drug Administration (FDA) pilot program.
Wave has global 50:50 co-development and co-commercialization profit share collaboration with Takeda Pharmaceuticals for developing therapies for the treatment of central nervous system (CNS) disorders. It has partnered with Pfizer for developing therapeutics for debilitating metabolic diseases by combining its stereopure platform, across antisense and RNAi modalities, with GalNAc and Pfizer’s hepatic targeting technology. In addition it has a tie-up with ReadCoor for developing stereochemistry in optimizing silencing and splicing therapies in the brain.
It has multiple research collaborations such as with the University of Oxford for the study of its proprietary isomers to improve the pharmacology of oligonucleotides for the treatment of DMD and with University of Dundee for developing treatment for common and rare skin diseases using antisense oligonucleotides.
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