Trial of WVE-007 for obesity aims to inform decisions about drug for MASH
Injection medication being assessed for possible use in severe liver disease
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An upcoming portion of an ongoing clinical trial that will test Wave Life Sciences’ WVE-007 in adults with obesity and related health problems will inform the drug’s potential development in metabolic-associated steatohepatitis (MASH), a severe form of steatotic liver disease.
That’s according to the drug developer, which noted in a company press release that the Phase 2a portion of the Phase 1/2a INLIGHT trial (NCT06842186) is expected to start in the coming months. This new part will assess changes in several measures, such as body weight, blood levels of sugars and fats, and liver fat content, among trial participants.
Interim results from the study’s ongoing Phase 1 portion, involving adults who are clinically overweight, showed that WVE-007 treatment was associated with reductions in body weight, visceral fat — fat around organs in the chest and abdomen — and fat mass, as well as increases in lean mass.
“Our analysis suggests there will be even greater improvement in individuals with higher BMI [body mass index] in the Phase 2a portion of INLIGHT, including more pronounced visceral and total fat loss with similar lean mass preservation, thus inducing greater weight loss,” said Christopher Wright, MD, PhD, Wave’s chief medical officer. BMI is a ratio of height and weight that is used as a proxy of excess body fat.
“Beyond obesity, by significantly lowering visceral fat and retaining skeletal muscle, [Phase 1 trial] data also suggest WVE-007’s powerful, differentiated cardiometabolic profile could address additional indications such as MASH, type 2 diabetes, and cardiovascular disease,” Wright said. “The Phase 2a portion of INLIGHT is designed to inform these additional opportunities.”
An approved obesity drug, Novo Nordisk’s Wegovy (semaglutide), has also received conditional approval in Canada as a treatment for MASH. Wegovy’s approval for the same indication is now under review in the European Union and Japan.
MASH is a severe form of SLD in which excess fat in the liver results in inflammation and scarring, or fibrosis, which can set the stage for life-threatening liver damage. The disease is typically associated with cardiometabolic risk factors such as obesity, diabetes, and high blood levels of fatty molecules.
Trial’s earlier part tested WVE-007 in overweight adults
WVE-007, administered through subcutaneous, or under-the-skin, injections, is designed to reduce the activity of INHBE, a gene that codes for the activin E protein. That protein helps to control how the body stores fat.
According to Wave, people with naturally-occurring genetic variations that lead to lower INHBE activity have lower visceral fat, liver inflammation or fibrosis, and liver damage, as well as improved control of blood sugar and a lower risk of type 2 diabetes. High visceral fat levels are associated with health issues such as MASH, diabetes, and heart disease, per the developer.
In clinical use, if approved as a weight loss drug, WVE-007 is expected to drive fat breakdown without appetite suppression and associated muscle loss — side effects that typically occur with standard of care for obesity. It also shows potential for once or twice dosing per year.
INLIGHT’s Phase 1 portion of the study enrolled adults with a BMI of 28 to 35 kilograms per square meter (kg/m2), which classifies as overweight and is lower than the typical BMI range for obesity trials, according to Wave. The study is being conducted at sites sites in the U.S., the U.K., Moldova, and Romania.
Participants were randomly assigned to receive one injection of either one of four WVE-007 doses (75, 240, 400, and 600 mg) or a placebo, and are followed for at least six months.
Early data show fat key reductions in fat around organs
Recently announced six-month data from 24 patients given the 240 mg dose showed significant reductions in visceral fat, by an average of 14.3% relative to the placebo group. The therapy was also associated with trends toward reduced body weight, waist circumference, and fat mass, as well as improvements in body composition and increases in lean mass.
“Even in this early Phase 1 trial, we are seeing our differentiated chemistry translate into clinically meaningful levels of fat loss, particularly harmful visceral fat, with muscle preservation,” Wright said, noting that the therapy “continues to be safe and well tolerated.”
“What’s remarkable is that these results were observed in participants who have a substantially lower BMI and less fat than those typically enrolled in later-stage obesity studies, six months after only a single dose,” Wright said.
Three-month data from participants treated with the 400 mg dose demonstrated results consistent with those seen in the 240 mg group, and data from the 600 mg group are expected later this year, per the developer.
Additional analyses in the 400 mg group showed that larger, significant reductions in visceral fat were observed in participants with higher visceral fat and higher BMI at study’s start.
“These results emphasize the impact of [initial] body composition on therapeutic effect and support expectations that evaluating individuals with higher BMI and visceral fat at [the study’s start] will lead to greater improvements in body composition and weight loss,” the release stated.
New trial part to see if obesity drug might help in severe liver disease
The trial’s Phase 2a portion is meant to test if this is true. The study will enroll adults with a BMI of 35-50 kg/m2, classified as obesity, who have obesity-related conditions such as type 2 diabetes.
Participants will be randomly assigned to take either multiple doses of WVE-007 or a placebo over the course of a year. The researchers will evaluate whether the therapy is superior to the placebo at reducing body weight, liver fat, and blood levels of sugar and fatty molecules, as well as improving body composition and muscle function.
The results will help to inform potential development in MASH and other obesity-related conditions.
“It is exciting to see WVE-007’s unique effect on fat loss with muscle preservation,” said Angela Fitch, MD, cofounder and chief medical officer at Knownwell and former president of the Obesity Medicine Association. “These data are highly encouraging especially given the profound impact on visceral fat and impressive reduction in waist circumference — both of which are tied to meaningful clinical outcomes — following just a single dose.”
