Mitochondria are the batteries that power all our cells
At first glance, primary mitochondrial diseases are an incredibly hard target for biopharma companies to pursue.
There are literally hundreds of different subtypes, caused by mutations in either nucleic DNA (nDNA) or mitochondrial DNA (mDNA). Even within that, patients that carry the same mutations (genotypes) often have variable symptoms and disease characteristics (phenotypes).
Perhaps that’s why there are no targeted therapies currently approved for primary forms of the disease and thus, a huge unmet need.
But it doesn’t stop there. Secondary mitochondrial dysfunction is implicated in some of the greatest public health burdens facing us to do, from Parkinson’s and Huntington’s disease to heart failure.
In this light, there’s a dire need to better understand and develop therapies for the cellular battery packs we call mitochondria.
Boston, Massachusetts-based Stealth Biotherapeutics has a good shot at making in-roads. Its lead program seeks to address a common denominator across all primary subtypes — skeletal muscle weakness (myopathy).
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
“Based on epidemiology, our best guess is that approximately 40,000 patients in the U.S. have what we would consider primary mitochondrial myopathy,” said Jim Carr, Stealth’s chief clinical development officer, by phone.
According to Carr, myopathy, “seems to be a primary feature and you could say, chief complaint of patients with primary mitochondrial diseases.”
Skeletal muscle requires huge amounts of energy when the individual exerts him or herself, which is why patients with these conditions fatigue very easily.
In Stealth’s first trial, dubbed MMPOWER, participants were given the experimental drug elamipretide intravenously every day, for five days. A six-minute walk test was then conducted at the end of treatment, which registered clinically meaningful gains in the patient endurance.
The major aim, however, was to determine the optimal dose. Stealth was also able to gather additional safety data, which Carr said gave the team confidence to progress.
In a subsequent trial, MMPOWER-2, the same participants were invited back to build on those results. Thirty out of 36 patients signed up for a second round.
“The primary objective of MMPower-2 was to find identify additional endpoints to take into Phase 3,” Carr explained.
Stealth went to great lengths to understand what symptoms really impact the patients and what metrics would correlate with actual improvements in quality of life — an approach FDA encourages with rare conditions.
The results from MMPOWER-2 were presented this week at the United Mitochondrial Disease Foundation (UMDF) Symposium in Washington D.C.
“We were very gratified with what we saw,” Carr said. “We found additional endpoints that seemed to be very sensitive to the changes that occurred in response to the molecule.”
Stealth’s drug elamipretide is a four-amino acid peptide with an affinity for cardiolipin, found in the membrane of the many mitochondria functioning within our cells.
Elamipretide’s mechanism of action has not been fully elucidated, but Carr believes it has to do with the stabilization of the mitochondrial membrane.
“When there’s disease, the membrane tends to lose some of it integrity and those complexes drift apart,” he explained, which comprises the mitochondria’s electronic transfer chain. “So what we think happens is that the molecule associates with cardiolipin and helps to pull the complexes together and restore normal electronic flow.”
Carr said the company has also demonstrated with repeat dosing in different animal models that the drug can improve the morphology of the mitochondria, “making very sick-looking mitochondria look normal again.”
With its affinity for cardiolipin, elamipretide is readily absorbed by cells. However, it doesn’t appear to impact healthy mitochondria.
“It associates with mitochondria whether there is disease or not, but the drug really only has activity if the mitochondria are dysfunctional. So it’s a built-in safety mechanism,” Carr noted.
The toxicity profile has been favorable thus far. In the second study, which moved from IV dosing to subcutaneous injections, a majority (80%) of patients suffered localized effects (itching, redness) at the site of administration. According to Carr, there were no serious events.
“We don’t view that as a safety concern. If anything, it may affect compliance and adherence going on, so we’re very conscious of that.”
It’s manageable, but one major question remains: How much of an impact will the therapy really have? It’s a very relevant question in this day and age, following the approval of some rare disease drugs that barely move the needle. In some cases, insurers are reluctant to cover them.
“Of course we have to prove this definitively, but we think it’s going to make a fairly significant difference, a fairly meaningful difference to patients,” Carr said. “In fact, that’s one of the reasons we wanted to develop the patient reported outcomes; because the patients need to tell us that. To me, that’s the most important deliverable for patients with this molecule, to help them feel better and live a more normal life.”
In the MMPOWER-2 study, patients improved on the six-minute walk test — albeit less emphatically than in the first trial. But they also reported less overall fatigue, less fatigue associated with activity, less muscle pain, and less muscle weakness, with “persuasive P-valuations” as Carr put it.
The average age of patients in the study was 40. Imagine living for 40 years with extreme fatigue and severe physical limitations. There’s no promise of a miracle gene therapy-like effect, but a five or 10 percent improvement in energy could make a profound difference to their lives.
Those patients are now rolling over into an open-label extension, Carr said, to gauge the effects of longer-term treatment.
“Our hope is, certainly when we give the drug for even longer, the effects will be intensified.”
The continuation is a testament to the relationship Stealth has built with U.S. and international mitochondrial patient advocacy groups.
They’re all on the front line of a pivotal battle in the wider war against disease, given how important our tiny cellular energy packs are.
To that end, planning for a Phase 3 trial of elamipretide is well underway.
Photo: wir0man, Getty Images
