Although analysts urged a more moderate stance, investors sheared Wave Life Sciences Ltd.'s stock, apparently displeased with final results from the phase I trial with suvodirsen, or WVE-210201, in Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping.

Shares of the Cambridge, Mass.-based company (NASDAQ:WVE) closed Tuesday at $24.47, down $9.55, or 28.1 percent after Wave made known data from its experiment with the stereopure oligonucleotide, presented at the Muscular Dystrophy Association Clinical and Scientific Conference in Orlando, Fla.

Jefferies analyst Eun Yang called the stock haircut an overreaction and said the important outcomes lie ahead in findings from the open-label extension (OLE) study, due in the second half of the year. "On the heels of an unexpected recent delay in the Huntington's disease [HD] efficacy data, there seems biased skepticism on Wave, which might not resolve" until the OLE findings are in hand, she wrote in a report. "From our discussion with Wave, no maximum tolerated dose was hit in phase I," she added, and "with expected much higher suvodirsen active drug concentration" as compared to Exondys 51 (eteplirsen, Sarepta Therapeutics Inc.), Wave "seems confident" about the OLE trial.

Exondys 51 was approved in September 2016. (See BioWorld Today, Sept. 29, 2016.)

Wave designed its global, multicenter, double-blind, placebo-controlled phase I experiment to test the safety, tolerability and plasma concentrations of single ascending doses of suvodirsen given intravenously (I.V.). Thirty-six patients were given doses of 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 7 mg/kg or 10 mg/kg of suvodirsen (n=26) or placebo (n=10) in five ascending dose cohorts. They were followed for 85 days. No serious adverse events (AEs), deaths or discontinuations due to AEs turned up in any patients treated with suvodirsen.

Near the end of last year, Wave chose an initial dose for the upcoming Dystance 51 phase II/III effort based on results from the first four phase I cohorts (0.5 mg/kg-5 mg/kg). Results in those (n=24) and in all placebo patients (n=10) found that suvodirsen was generally safe and well-tolerated, with 67% of patients given the drug (16/24) and 80% of patients on placebo (8/10) experiencing one or more AEs. The most common AEs in two or more patients were pyrexia, headache, vomiting and tachycardia, consistent with infusion-associated reactions, but they were mild to moderate in intensity and resolved spontaneously or with symptomatic treatment.

Researchers detected no clinically relevant changes in renal or hepatic parameters or platelet levels and, in patients given 5 mg/kg of suvodirsen, the AEs surfacing within 24 hours of infusion were associated with transient increases in high-sensitivity C-reactive protein and complement factor Bb levels, both of which were resolved within a week. No changes appeared in complement C3 levels. Based on results of the first four ascending-dose cohorts, the independent safety monitoring committee endorsed continued dose exploration, allowing Wave to proceed to the last planned cohort. Here, doses of 7 mg/kg or 10 mg/kg of suvodirsen were given to two patients in the fifth cohort and were associated with similar AEs as those observed at lower doses but were more severe in intensity.

DMD success 'key'

Dystance 51, the phase II/III project due to start in July, will sign up boys between 5 and 12 years of age with a genetically confirmed diagnosis of DMD amenable to exon 51 skipping treatment. Patients will be randomized for 4.5 mg/kg or 3 mg/kg of I.V. suvodirsen or placebo once weekly for 48 weeks. The 4.5-mg/kg dose provides about the same amount of active ingredient as the 5-mg/kg dose in the phase I study, Wave said. Dystance 51's primary efficacy endpoints will measure change in dystrophin protein level and change in the North Star Ambulatory Assessment score, with functional outcome measures as secondary endpoints. Results of Dystance 51 will be used to seek regulatory approvals globally, the company said.

During a conference call with investors Tuesday, Stifel analyst Paul Matteis questioned safety. "What gives you confidence that AE events rates or severity won't accrue more significantly upon repeat dosing, given that most patients had pyrexia after just one dose?" he asked. Chief Medical Officer Michael Panzara said that "if you look at the literature on different types of immune activation, it is not uncommon for immune activation to decrease with continued dosing," and added that it would be "counterintuitive to say that the doses that we would see with repeat dosing would lead, certainly, to a worsening. I think that would be highly unusual." What's more, events "that we did see lasted just for a few hours and sometimes didn't require treatment."

Even on the label for Exondys 51, "it's not unusual to see elevations in temperature and things like vomiting. We're pretty comfortable where we are and not worried about some sort of amplification that's going to happen," he said.

A week ago, Wave pushed back the top-line data readout from its ongoing Precision-HD program, which consists of two global phase Ib/IIa trials evaluating WVE-120101 and WVE-120102 for patients with HD. Saying the results, originally expected in the first half of the year, will be available by the end of the year instead, Wave gave the reason as operational, caused by slower than anticipated patient enrollment because of the logistics of screening and scheduling. The update, the firm was quick to point out, was not due to a preclinical or clinical safety finding and the program remains blinded.

The delay served to pique investor interest still more in the DMD data, as well as outcomes in the HD indication from Carlsbad, Calif.-based Ionis Pharmaceuticals Inc. and partner Roche Holding AG, of Basel, Switzerland. The pair is developing IONIS-HTTrx (RG-6042) for HD in a phase III experiment. It's an antisense drug designed to reduce the production of the huntingtin (HTT) protein, the genetic cause of HD, propelled by expansion of the CAG trinucleotide sequence in the HTT gene, which produces a toxic protein that progressively destroys neurons in the brain. European regulators have granted orphan drug status to IONIS-HTTrx.

Wave's WVE-120101 and WVE-120102 stereopure antisense oligonucleotides are designed to selectively target the mutant HTT mRNA transcript of single-nucleotide polymorphism (SNP) rs362307 and SNP rs362331, respectively. In vitro studies in patient-derived cell lines have shown that WVE-120101 and WVE-120102 can knock down levels of mutant HTT mRNA transcript and protein while leaving wild-types relatively intact. Wave's allele-specific approach may enable the company to address the pre-manifest, or asymptomatic, HD patient population in the future, the company said.

The slowed enrolling of Precision-HD "adds half a year of breathing room by delaying a potentially negative catalyst in Wave's competitor data," SVB Leerink analyst Mani Foroohar pointed out, adding in a report that "investors bearish on Wave argue this delay suggests missteps in clinical execution on the part of Wave in a program that is key to the credibility" of the platform, which means "successful execution in the DMD program [is] key to addressing any emerging concerns," in his view.

Could boost enrollment

About 30,000 people in the U.S. have symptomatic HD and more than 200,000 others are at risk for inheriting it and, although the genetic cause has been known for 26 years, no approved disease-modifying therapies exist. That may be about to change, and sooner than hoped.

Foroohar consulted with SVB Leerink's Medacorp key opinion leaders and gained "feedback supporting more rapid uptake of oligonucleotide therapies in HD and higher peak market penetration, driven by patient receptivity and awareness. The potential market for oligonucleotide-based treatments in HD is considerably larger than the market in spinal muscular atrophy [SMA]," and he projected about 55% of U.S. and EU symptomatic HD patients could be treated with drugs in the works by Wave and Ionis/Roche, encompassing more than 34,000 patients with greater than $6.8 billion in estimated peak sales, unadjusted for probability of success.

On its recent earnings call, Roche informed Wall Street of its aim to file for approval of IONIS-HTTrx within the next 12 months, so the company likely wants to include in the submission functional clinical data from its OLE study of IONIS-HTTrx, interim biomarker data from the phase III Generation-HD study, and data from Roche's natural history study of HD as a comparator for the single-arm OLE. A filing in January 2020 would put U.S. approval around the middle of the year, with a launch in the second half – "more than a year ahead" of the timeline first assumed by Foroohar. "Though Wave's oligonucleotides could potentially have safety and efficacy advantages in SNP-eligible patients, we expect widespread use of both products," he said.

Jefferies' Yang didn't seem bothered by Wave's HD holdup. "Typically patient enrollment accelerates near the end of trial recruitment as clinical sites are running more efficiently," she said in a report. "Wave's prior timeline was based on its anticipated uptick in enrollment." The stall "could be due to various reasons, including patient recruitment to trial sites [and] patient selection/genotyping," as well as Ionis/Roche taking patient share for its effort, which is enrolling 660 patients and was briefly paused for an amendment. Wave "has steps in place to increase the enrollment rate, but [made] no specific comment for competitive reasons," nor has the firm made known how many patients have come aboard thus far for the Precision-HD trials, which bear a target enrollment of 50 for the first and 50 for the second, with a 3-to-1 ratio between therapy and placebo.