Health

Investigational Drug Promising in Obese Patients With Diabetes

LAS VEGAS — An investigational agent, bimagrumab (Novartis) — which was originally being tested to see if it would increase lean muscle mass in people with sarcopenia — is effective and safe for weight loss, according to preliminary results from a study in patients with obesity and type 2 diabetes.

Laura A. Coleman, PhD, RD, a researcher at Novartis in Cambridge, Massachusetts, presented intriguing phase 2 trial findings with this activin receptor antagonist here in a late-breaking research forum before the start of Obesity Week 2019.

The investigators randomly assigned 75 patients with obesity and type 2 diabetes to receive monthly injections of the drug, or placebo, plus twice monthly visits with a registered dietitian.

“Neither group really changed their diet” or met their goal of a 500 calorie/day deficit, Coleman reported.

However, at 48 weeks, on average, patients in the treated group had a 21% drop in body fat mass (-7.5 kg, or -16.5 lb), a 6.5% reduction (-5.9 kg) in body weight, and a 3.6% increase (1.7 kg) in lean body mass.  

In the placebo group, patients had a 0.5% drop in body fat mass (-0.2 kg), a 0.8% fall in body weight (-0.8 kg), and a loss of lean body mass of 0.8% (-0.4 kg).

Invited to comment, session chair Lee M. Kaplan, MD, PhD, president of the Obesity Society, pointed out that by gaining lean muscle mass, the participants receiving bimagrumab were also losing more fat mass, with the resulting net weight loss of 6.5%, which is similar to that seen with other anti-obesity medications that suppress appetite.

“What it suggests,” Kaplan told Medscape Medical News, “is that there may be a completely new mechanism at play here, because in this situation, patients weren’t eating less but [those taking bimagrumab]…were losing the same amount of weight as [those taking] other drugs that work by causing  patients to eat less.”

“Is this going to be the kind of complementary drug with a different mechanism that’s going to augment the effects of other drugs?” wondered Kaplan, the director of the Obesity, Metabolism & Nutrition Institute at Massachusetts General Hospital in Boston. He was not involved in the current study but has previously served as a scientific consultant to Novartis.

Research is suggesting that there are “multiple subtypes of obesity, like cancer,” he added, saying he believes what will eventually be required are  “multiple drugs with multiple mechanisms, for multiple subtypes of obesity.”

Coleman told Medscape Medical News: “It’s exciting that we were able to achieve this profound weight loss with an increase in lean mass in our subjects, along with metabolic benefits.”

Muscle Increase, Fat Decrease in Humans, Not Mice

Coleman explained to delegates that data from a prior phase 2 trial of patients with sarcopenia showed that bimagrumab increased lean muscle mass, but this did not translate into an improvement in function — which had been the primary efficacy endpoint of the study — so Novartis stopped work on that indication.  

Researchers had observed, however, that the drug decreased fat mass in humans, an effect which had not been seen in animal studies.

To further investigate this, researchers first performed a study in 16 patients with prediabetes, which showed that bimagrumab reduced body fat.  

Building on this, the current phase 2 study aimed to determine the safety and efficacy of bimagrumab on body composition and glycemic control in adults with obesity and type 2 diabetes.

The investigators enrolled 75 patients who had a BMI of 28 to 40 kg/m2, and an A1c of 6.5% to 10% at 8 sites in the UK and 1 site in the US.

Most patients were were receiving metformin (85%), some metformin plus a DPP-4 inhibitor (4%), while 11% were not on any antidiabetic medication.

Patients in both the bimagrumab and placebo groups had a mean age of about 60 and a mean A1c of about 8%.

However, there were more women in the bimagrumab group than in the placebo group (62% vs 32%) and they had a lower mean weight (90.1 kg vs 98.9 kg) and BMI (32.7 vs 33.1), both of which were adjusted for in the subsequent calculations.

In addition to the frequent visits with a dietitian, all patients were advised to follow a walking program as recommended by the American Diabetes Association.

The patients received subcutaneous injections of 10 mg/kg bimagrumab or placebo every 4 weeks, for 48 weeks, with the last dose at week 44.

Adverse events were primarily mild (such as diarrhea) and transient, and most occurred with the early doses.

At 48 weeks, 96% of the patients receiving bimagrumab had lost at least 5% of their total body fat, and 77% had lost at least 15% of their total body fat.

In terms of weight loss, 66% of those on the active drug had lost at least 5% of their total body weight and 12% had lost at least 15% of their body weight.

A1c was decreased by 0.76% in the bimagrumab group vs 0.04% in the placebo group.

And this despite the fact that those “in the placebo group received more than standard of care,” Coleman stressed.

“Nobody’s insurance pays for a dietitian every 2 weeks for a year,” she said, “and the weight loss diet didn’t work.”

36th ASMBS Annual Meeting at Obesity Week 2019: Presented November 4, 2019.

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