A Novel Approach to MASH Obesity Treatment: Weight Loss with Mitochondrial Science

Obesity has long been framed as a condition of excess intake, excess weight, excess risk.

But for Dr. Shaharyar Khan, Co-Founder and Chief Scientific Officer of Rivus Pharmaceuticals, the real opportunity lies in addressing the other half of the energy equation: expenditure.

In this Xtalks Clinical Edge interview, Dr. Khan discusses Rivus’ development of investigational Controlled Metabolic Accelerators (CMAs) — drugs that boost the body’s energy use by modulating how mitochondria produce heat and burn calories.

By tapping into the body’s ability to burn energy, Rivus is aiming to provide new options for patients with conditions where disrupted energy balance contributes to disease progression, including heart failure, type 2 diabetes and metabolic dysfunction-associated steatohepatitis (MASH).

Often underdiagnosed, MASH is a progressive liver disease tightly linked to metabolic dysfunction and obesity. In the US alone, an estimated 6.5 million adults had MASH in 2022, according to a modeled analysis published in JAMA Network Open. The majority were undiagnosed, with disease often progressing silently alongside obesity, diabetes and other metabolic conditions.

From First Principles to Therapeutic Strategy

Dr. Khan’s path to mitochondrial biology began with a fundamental fact: “All activity, life, how we navigate the world, how life happens, is dependent on energy.”

That focus on energy — particularly how it’s generated and expended at the cellular level — eventually led him to co-found Rivus, following earlier work at Gencia Biotech.

“And so we created a new company — which became Rivus — that was essentially focused on leveraging this important biology of modulating your metabolic rate by inducing mitochondrial uncoupling in a safe and controlled fashion, hence Controlled Metabolic Accelerators.”

At the crux of Rivus’ scientific philosophy is a reframing of obesity, not as a static condition but as a spectrum of metabolic decline that can span decades — from high BMI to insulin resistance, then diabetes, liver disease and cardiac dysfunction.

Rivus’ goal is to intervene along that trajectory, not simply manage its late-stage consequences.

Addressing the Other Side of the Equation

Most metabolic therapies target energy intake — such as appetite suppression or nutrient absorption. Rivus is taking a different route.

“We’ve got all these drugs that are being developed on the energy intake side of the equation, but there’s this lack of approach that leverages the energy expenditure side of the equation.”

The company’s lead compound leverages mitochondrial uncoupling to safely increase metabolic rate and reduce fat stores, particularly visceral adiposity, which is harder to lose through diet alone.

“Especially as you get older, it’s harder and harder to lose weight. More and more of that fat, and that weight is visceral adiposity.”

That fat, Dr. Khan explained, is not inert — it secretes inflammatory and fibrotic signals that damage organs. By enhancing energy expenditure, their lead candidate appears to preferentially mobilize these “bad” fat depots.

Visceral fat tends to be more energetically active, with a higher density of mitochondria, making it more responsive to the mechanism Rivus targets.

This insight is central to Rivus’ approach: not all weight is equal, and not all weight loss is helpful.

In fact, in aging or frail patients, preserving muscle mass may be as critical as reducing fat.

He added that preserving skeletal muscle mass — often depleted with age — plays a critical role in how cardiometabolic disease progresses.

At the cellular level, Dr. Khan notes that mitochondrial uncoupling — the process Rivus targets — may have deeper biological relevance: “Why do we generate heat? Why are we endotherms and why do we have a body temperature?”