WAVE Life Sciences (NASDAQ:WVE) outlined progress across its obesity-focused siRNA program and RNA editing pipeline during a Chardan discussion, with President and CEO Paul Bolno emphasizing the company’s chemistry platform, upcoming clinical studies and regulatory alignment for its alpha-1 antitrypsin deficiency program.
Bolno said the company entered the year with two principal objectives: generating Phase I data for WVE-007, an INHBE-targeting treatment being developed for obesity and cardiometabolic disease, and advancing what he described as the first RNA editing medicine to enter clinical testing for alpha-1 antitrypsin deficiency, or AATD.
WVE-007 Data Highlight Body Composition
According to Bolno, WVE-007 produced reductions in fat while preserving lean muscle mass in a Phase I healthy-volunteer study. He said the findings supported the potential for once-yearly dosing and showed a safety and tolerability profile that could support further development.
The company reported that a single dose resulted in nearly a 15% reduction in visceral fat, along with reductions in subcutaneous fat, a 3.3% reduction in waist circumference and a 1% change in body weight. Bolno stressed that the study enrolled healthy volunteers without comorbidities, a population he said generally has substantially less visceral and subcutaneous fat than patients in conventional obesity trials.
“We did not just see a strong reduction in visceral fat,” Bolno said. “We saw a strong reduction in subcutaneous fat, which is what ultimately drives weight loss.”
He contrasted the results with other INHBE programs, saying Wave’s preclinical and clinical findings differentiated the company’s construct through deeper and more durable target suppression. Bolno attributed that potential differentiation to the company’s oligonucleotide chemistry and its ability to improve loading into the AGO2 component of the RNA-induced silencing complex, or RISC.
Bolno said Wave’s chemistry work produced nearly a 15-fold improvement in AGO2 loading in research described in a paper published several years ago. In the company’s view, that improvement may support potent knockdown and annual administration.
Phase II-A Studies to Assess Obesity and Cardiometabolic Outcomes
Wave has begun dosing patients in its INLIGHT Phase II-A monotherapy study of WVE-007. The trial includes patients with body mass indexes ranging from 35 to 50 and permits participants with diabetes and other comorbidities, Bolno said.
The study includes two dose groups and separate diabetic and non-diabetic cohorts. In addition to measuring body weight and body composition, Wave plans to assess liver fat through MRI-PDFF, insulin sensitivity and lipid profiles. Bolno said the design could help the company evaluate potential applications beyond obesity, including metabolic dysfunction-associated steatohepatitis, or MASH, and diabetes.
Wave has also initiated a combination study of WVE-007 with tirzepatide. Bolno said the company sees potential use cases for the therapy as monotherapy in people with sarcopenic obesity, in combination with incretin therapies, and as a maintenance option following incretin treatment.
The company has not committed to a data-release date for the Phase II-A programs. Bolno said Wave may decide to unblind data at either three or six months, noting that the longer interval could provide a clearer view of weight change after lean mass stabilizes and fat reduction continues.
Alpha-1 Antitrypsin Program Moves Toward Registrational Study
Bolno also discussed Wave’s RNA editing program for AATD, a genetic condition associated with lung and liver disease. He said early clinical data showed consistent editing across patients, with conversion of the disease-associated Z form to the normal M form of alpha-1 antitrypsin. The company also reported that treatment was safe and well tolerated in the data discussed.
Wave recently aligned with the FDA on what Bolno characterized as an innovative trial design that could shorten the path to approval. The company plans a two-year clinical trial intended to support registration, with a potential interim analysis at one year that could support accelerated approval.
Bolno said the company has observed acute-phase responses in more than one patient, including protein production above 20 micromolar during an inflammatory event in one case. He said the observations support the premise that RNA editing could enable patients to produce functional protein when it is needed during periods of inflammation.
While declining to disclose specific FDA discussions around thresholds for total alpha-1 antitrypsin or M-form protein, Bolno said Wave believes achieving an MZ-like phenotype could be an important component of an approval path.
Looking ahead, Bolno said Wave plans to discuss next-generation chemistry at its November research day, including bifunctional and multifunctional oligonucleotides. The company also expects to provide further information on its PNPLA3 RNA editing program, which targets liver-related diseases in patients homozygous for PNPLA3 variants.
About WAVE Life Sciences (NASDAQ:WVE)
WAVE Life Sciences Ltd. (NASDAQ: WVE) is a biotechnology company focused on developing medicines that act on RNA, a molecule involved in translating genetic information into proteins. The company uses its proprietary chemistry and drug-design technologies to create oligonucleotide therapeutics intended to selectively modify RNA and address the underlying causes of genetic diseases.
Its research programs have included RNA editing and RNA-targeting approaches for conditions such as alpha-1 antitrypsin deficiency, Duchenne muscular dystrophy and other serious genetic disorders.
