Obesity stems from many factors, but it’s generally the product of an energy imbalance. As the body takes in more energy than it expends, the excess is stored as fat. Dietary changes and exercise offer the lowest hanging fruit for tweaking the balance, but those measures don’t work for everyone and for those who do lose weight, it can be hard to maintain the weight loss.

Drug hunters have pursued various pharmacological approaches for shedding fat, with varying degrees of success. Companies with commercialized obesity drugs have found it hard to turn them into big sellers. Rivus Pharmaceuticals is aiming for a better outcome with a new class of therapies that harnesses a built-in metabolic mechanism of the body.

“We have a differentiated approach for this fat-selective weight loss that we can achieve by increasing energy expenditure versus reducing energy input,” said CEO Allen Cunningham.

Charlottesville, Virginia-based Rivus has generated some encouraging clinical data for its fat-reducing pill. Now it has bulked up with $132 million to continue clinical testing of that drug candidate. The Series B round of financing announced Thursday was led by RA Capital Management.

Rivus is developing drugs that target mitochondria, the components of cells that produce energy. More specifically, the company aims to harness mitochondrial uncoupling, a natural metabolic process in which the body dissipates energy, said Shaharyar Khan, the company’s chief scientific officer. Rivus calls its drugs controlled metabolic accelerators, or CMAs. These small molecules target mitochondria, increasing energy expenditure and calorie consumption, which leads to fat-selective weight loss, he explained.

Scientists have known about mitochondrial uncoupling for more than a century, Khan said. The 1978 Nobel Prize in Chemistry was won by scientist Peter Mitchell for his work contributing to the understanding of biological energy transfer. But the challenge for drug developers has been targeting this mechanism with small molecules in a safe and well-tolerated manner. In other words, the goal is a drug that leads to the breakdown of fat without causing toxic effects, such as fever. By controlling the concentration of the drug and keeping it within effective levels, Khan said Rivus’s lead drug candidate, HU6, can safely lead to fat loss.

“This pharmacology is robust and we’re the first to leverage it in a well-controlled, randomized clinical trial utilizing modern drug development techniques,” Khan said.

Last November, Rivus announced results from a Phase 1 dose-ascending study showing an increase in energy expenditure as well as dose-dependent weight loss with no apparent safety signals. The company proceeded to a placebo-controlled Phase 2a study enrolling 80 obese participants with fatty livers. In February, Rivus reported results showing that after eight weeks, patients treated with HU6 showed statistically significant fat reductions at all three doses tested. Furthermore, that weight loss was almost all from fat. That’s important because not all weight loss is good, Khan said. Some weight-loss drugs lead to the loss muscle as well as fat, which is not what patients or clinicians want. Losing muscle also poses other problems.

“Once you lose that skeletal muscle mass, it’s hard to get it back,” Khan said. “The weight we gain is typically all fat.”

With the new capital, Rivus plans to continue clinical development of HU6. A Phase 2a study is now underway in heart failure with preserved ejection fraction (HFpEF), Cunningham said. A Phase 2b study in obesity is on track to start next year. The company is also exploring other cardiometabolic disorders. Type 2 diabetes and non-alcoholic steatohepatitis are driven by obesity and have the potential to be treated by a drug that focuses on energy expenditure, Cunningham said.

Expansion to additional indications could mean expanding the drug pipeline beyond HU6. For example, a particular cardiometabolic disorder might require a CMA designed to affect particular types of tissues, Khan explained. Cunningham said the Series B cash will fund the completion of mid-stage testing of HU6 in both obesity and HFpEF. In addition to the continued development of HU6, he said the capital will support the advancement of one additional drug candidate into the clinic. The cash is expected to last through 2024.

Rivus formed in 2019, based on intellectual property initially developed at Gencia, a Charlottesville biotech pursuing mitochondria-targeting drugs. Cunningham, who was CEO of Gencia, said the mitochondrial uncoupling assets were transferred to Rivus, where they were further developed and advanced into preclinical and clinical development. Cunningham said he took on a director role at Gencia; Gencia is a shareholder in Rivus.

Rivus formally launched last year with a $35 million Series A financing co-led by Longitude Capital and Medicxi, as well as Rx Capital. Those investors also participated in the startup’s latest financing, which added new investors Bain Capital Life Sciences and BB Biotech.

Photo by Rivus Pharmaceuticals