Obesity stems from many factors, but it is usually the product of an energy imbalance. As the body absorbs more energy than it expends, the excess is stored as fat. Dietary changes and exercise offer the lowest payoff for adjusting balance, but these measures don’t work for everyone, and for those who lose weight, it can be difficult to maintain weight loss.
Drug stalkers have pursued various pharmacological approaches to eliminate fat, With more or less success. Companies selling obesity drugs struggled to turn them into big sellers. Rivus Pharmaceuticals aims for a better outcome with a new class of therapies that harnesses the body’s built-in metabolic mechanism.
“We have a differentiated approach to this fat-selective weight loss that we can achieve by increasing energy expenditure rather than decreasing energy intake,” CEO Allen Cunningham said.
Rivus, based in Charlottesville, Va., has generated encouraging clinical data for its diet pill. Now it has racked up $135 million to pursue clinical trials of this drug candidate. The Series B Funding Round announced Thursday was led by RA Capital Management.
Rivus is developing a drug that targets mitochondria, the components of cells that produce energy. 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 drug-controlled metabolic accelerators, or CMAs. These small molecules target the 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 to target this mechanism with small molecules in a safe and well-tolerated way. In other words, the goal is a drug that causes the breakdown of fat without causing toxic effects, such as fever. By controlling the concentration of the drug and keeping it at effective levels, Khan said Rivus’ lead drug candidate, HU6, can safely lead to fat loss.
“This pharmacology is robust and we are the first to leverage it in a well-controlled randomized clinical trial using modern drug development techniques,” Khan said.
Last November, Rivus announced results from a phase 1 dose-escalation study showing increased energy expenditure as well as dose-dependent weight loss with no apparent safety signals. The company conducted a placebo-controlled Phase 2a study recruiting 80 obese participants with fatty liver disease. In February, Rivus posted results showing that after eight weeks, patients treated with HU6 showed statistically significant reductions in fat at all three doses tested. Moreover, this weight loss came almost entirely from fat. That’s important because not all weight loss is good, Khan said. Some weight loss drugs cause muscle loss 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 usually entirely fat.”
With the new capital, Rivus plans to continue the clinical development of HU6. A Phase 2a study is currently underway in heart failure with preserved ejection fraction (HFpEF), Cunningham said. A phase 2b obesity study is expected to start next year. The company is also exploring other cardiometabolic disorders. Type 2 diabetes and nonalcoholic steatohepatitis are driven by obesity and have the potential to be treated with a drug that focuses on energy expenditure, Cunningham said.
Expanding 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 tissue types, Khan explained. Cunningham said the Series B money will fund the completion of mid-term testing of HU6 in obesity and HFpEF. In addition to the continued development of HU6, he said the capital would support the advancement of an additional drug candidate into the clinic. The silver is expected to last until 2024.
Rivus formed in 2019, based on intellectual property originally developed at Gencia, a Charlottesville biotech researching mitochondria-targeting drugs. Cunningham, who was CEO of Gencia, said the mitochondrial uncoupling assets were transferred to Rivus, where they were developed and advanced into preclinical and clinical development. Cunningham said he took on a managerial role at Gencia; Gencia is a shareholder of Rivus.
Rivus officially launched last year with a Series A funding of $35 million co-led by Longitude Capital and Medicxi, as well as Rx Capital. These investors also participated in the startup’s latest financing, which added new investors Bain Capital Life Sciences and BB Biotech.
Photo by Rivus Pharmaceuticals