Investigational Compound Induces Significant Drop in Mutant Huntingtin Protein, Ongoing Trial Data Show

Huntington’s patients who were treated with the compound WVE-120102 showed a statistically significant drop in mutant huntingtin protein (HTT) in their cerebrospinal fluid, according to a recent Phase 1b/2a clinical trial.

The compound was also found to be safe and well-tolerated. These data support the testing of higher dosages in ongoing studies, said Michael Panzara, MD, chief medical officer of Wave Life Sciences, which developed the compound.

“This topline analysis has given us the opportunity to evaluate early data from our ongoing dose finding study,” he said in a press release. “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.”

Huntington’s disease is caused by a repeating set of nucleotides, called a CAG repeat, in the HTT gene. If the genetic code reads like a sentence, the CAG repeat is like a stutter. This genetic stutter results in a progressive loss of neurons in the brain, causing involuntary movements and cognitive decline.

WVE-120102 targets the messenger RNA (mRNA) of a specific single nucleotide polymorphism (SNP) rs362331, called SNP2, that codes for the mutant huntingtin protein. An SNP is a change of one single nucleotide, or a letter of the genetic code, in a given gene; mRNA is essentially an instruction manual for making a protein.

By binding directly to that mRNA, WVE-120102 prevents the instructions from being read, while leaving the wild-type (healthy) version relatively untouched. Wild-type HTT plays an important role in normal neuronal function.

The ongoing Phase 1b/2a trial, called PRECISION-HD2 (NCT03225846), is comparing the effects of WVE-120102 versus a placebo in Huntington’s patients who carry SNP2.

The trial was designed in two parts: in the first part, patients received a single dose and underwent a washout period of at least eight weeks; and in the second part, the patients entered a multidose portion that included three monthly doses.

Thirty-one patients received WVE-120102 and 13 received a placebo in the multidose portion of the trial. Data from 39 patients (27 WVE-120102 and 12 placebo) were available to be assessed for the topline analysis.

Participants received doses of 2, 4, 8 or 16 mg. WVE-120102 was given via intrathecal injection, meaning directly into the spinal canal.

WVE-120102 proved to be safe and well-tolerated up to the maximum dosage. No serious adverse side effects were experienced, although 72% of those who received WVE-120102 did experience a mild to moderate adverse effect, compared with 83% of those on placebo. The most common side effects were headaches, procedural pain (that of being injected), falls, and viral upper respiratory infection.

Wave measured a significant drop in the levels of mutant huntingtin within the cerebrospinal fluid (CSF) — the liquid that surrounds the brain and spinal cord — in those given the treatment compared with those given a placebo. The amount of total huntingtin in CSF did not change, suggesting that WVE-120102 acts specifically on the mutant version, as intended.

Last October, Wave initiated an open-label extension study for patients outside of the U.S. who participated in the PRECISION-HD2 trial.

Wave is also conducting another trial, PRECISION-HD1 (NCT03225833), of a similar therapy, called WVE-120101. Given the PRECISION-HD2 results, Wave expects to add a higher (32 mg) dosage to both studies and to report topline results in the second half of 2020.

Both studies are still actively recruiting. Those interested in enrolling will be screened for either of the mutations targeted by the two therapies, and, if eligible, directed to the relevant study.