Trial of WVE-004 in Patients With C9orf72 Mutations Begins Dosing

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by Forest Ray PhD |

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Dosing has begun in a clinical trial of WVE-004, Wave Life Sciences‘ investigational therapy for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with C9orf72 gene mutations.

“ALS and FTD are devastating illnesses where therapeutic progress has been extremely limited. Advancing discovery and development of new treatments … is an urgent need,” Michael Panzara, MD, MPH, chief medical officer of Wave Life Sciences, said in a press release.

The Phase 1b/2a trial, called FOCUS-C9 (NCT04931862), is evaluating the safety and tolerability of single- and multiple-ascending doses of WVE-004 against a placebo in about 50 adults, ages 18 to 80, for six months (24 weeks). Recruitment is underway at a site in Utrecht, Netherlands, with a second site expected to soon open in Quebec, Canada.

Four dose levels are planned, and dosing will be adaptable. An independent committee will guide decisions concerning dose strength and frequency, based on trial data as they emerge.

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Additional study goals include measuring how the compound moves through and affects the body (its pharmacokinetics and pharmacodynamics), and how it affects changes in the levels of abnormal proteins generated by C9orf72 gene mutations, known as dipeptide repeat proteins (DPR). These aberrant molecules can form toxic clumps within cells.

DPRs occur when certain sequences of nucleotides — the building blocks of DNA and RNA — are repeated within the C9orf72 messenger RNA (mRNA), which is essentially the molecule carrying the instructions for C9orf72 protein production.

C9orf72 normally makes three mRNA variants called V1, V2, and V3. Repeat expansions in V1 and V3 lead to the disease-causing DPRs and lower amounts of healthy C9orf72 proteins, which play vital roles in neural and immune system function.

WVE-004 is an antisense oligonucleotide, meaning that it is a short strand of nucleotides that can specifically target other RNA molecules — in this case, the mRNA molecules corresponding to V1 and V3. By attaching itself to those mRNA molecules, WVE-004 is designed to mark them for destruction, leaving only the healthy V2 protein to carry out its work within cells.

The medication’s specificity to V1 and V3 was validated in preclinical studies performed in mice altered to carry the mutated human C9orf72 gene. The candidate therapy successfully removed over 90% of the DPRs in the spinal cord, and over 80% of DPRs around the brain, of these mice. This effect lasted for at least six months.

Wave designed WVE-004 with chemical modifications known as PN chemistry, meant to increase the molecule’s strength, exposure, and durability.

“The predicted pharmacology of WVE-004, afforded by PN chemistry and based upon in vivo models, allowed us to design FOCUS-C9 to be adaptive, enabling data-driven decisions regarding dose level and frequency as the trial proceeds and potentially accelerating time to proof-of-concept,” Panzara said.

“Opening the FOCUS-C9 trial to those diagnosed with C9orf72-associated ALS or FTD may also facilitate the ability to pursue both indications in the future,” he added. “We anticipate generating clinical data in 2022 that will enable decision-making on next steps for the program.”

In the U.S., C9orf72 mutations are reported to be found in 40% of people with familial ALS, and 8% to 10% of those with sporadic ALS.