Although the reduction in mHTT with the drug compared to placebo was statistically significant, there was no change in total huntingtin protein (tHTT) compared to placebo.
Cambridge, Massachusetts-based WAVE Life Sciences’ stock lost about half its value after reporting disappointing data from its ongoing Phase Ib/IIa PRECISION-HD2 trial in Huntington’s disease (HD).
The trial was evaluating WVE-120102 in HD. Analysis showed that all patients receiving multiple intrathecal doses of the therapeutic compared to placebo, a statistically significant reduction of mutant huntingtin (mHTT) protein was seen in cerebrospinal fluid (CSF) of 12.4%. Further analysis of a dose response across treatment groups suggested a statistically significant response in mHTT reduction at the highest doses.
WVE-120102 is an allele-selective molecule that preferentially lowers mHTT protein by targeting a point mutation called single nucleotide polymorphism (SNP) rs362331 (SNP2), which maintains the level of health HTT protein relatively intact. The wtHTT protein plays an important role in neuronal function and is potentially neuroprotective in adult brains. There is no direct measure of wtHTT in the CSF, so the company used a test developed by the CHDI Foundation, a not-for-profit biomedical research organization focused on HD.
Although the reduction in mHTT with the drug compared to placebo was statistically significant, there was no change in total huntingtin protein (tHTT) compared to placebo.
Company shares dropped about 49%. It had already plunged 55% on December 16 after the company indicated plans to abandon development of two treatments for Duchenne muscular dystrophy (DMD).
Huntington’s disease is a fatal genetic disease that results in the progressive degeneration of nerve cells in the brain. Every child of a parent with HD has a 50/50 chance of inheriting the abnormal gene. There are about 30,000 people with HD symptoms in the U.S. and more than 200,000 at-risk of inheriting it. The Huntington’s Disease Society of America describes the symptoms as like having ALS, Parkinson’s and Alzheimer’s simultaneously.
“This topline analysis has given us the opportunity to evaluate early data from our ongoing dose finding study,” said Michael Panzara, Wave’s chief medical officer. “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. We plan to initiate the 32 mg cohort imminently and look forward to sharing data in the second half of 2020.”
The topline data also evaluated the presence of neurofilament light chain (NfL) in the CSF. There was no observed difference in NfL between the treatment and placebo cohorts. NfL is a protein component of the neuronal cytoskeleton. When neurons are damaged by many neurological diseases, including HD, NfL levels in the CSF are typically elevated.
The company is also running the PRECISION-HD1 Phase Ib/IIa trial evaluating WVE-120101 in early manifest HD patients who carry SNP rs362307 (SNP1). That trial includes four dose cohorts. Based on the PRECISION-HD2 data, PRECISION-HD1 will stay blinded and add a 32 mg cohort. Topline data from PRECISION-HD1 are now expected in the second half of 2020.
Grand View Research estimates the market for Huntington’s disease therapies will bring in $1.5 billion in revenue by 2023 with a CAGR of more than 38%. The only approved therapies on the market treat the symptoms, so there’s a very large market for any therapy that modifies the disease. Currently the top drug is Teva Pharmaceutical’s Austedo, which is projected to own 45% of the market.
There are 23 drugs in the clinic for the disease, one in Phase III, 13 in Phase II, two in Phase Ib/IIa, and seven in the preclinical or discovery phase. Reportedly, the closest to market are Raptor Pharmaceutical’s RP103, (acquired by Horizon Pharma), and Prana Biotechnology’s PBT2, although it is not clear if Horizon is still developing the drug.
