Developing Bespoke Antisense Oligonucleotides To Treat Rare Diseases

By Tyler Menichiello, contributing editor

Therapeutic development is typically approached in a population-based way. Even in rare diseases (which by definition affect less than 200,000 people in the U.S.), clinical trials are built around a given patient population. However, when a disease only affects a handful of individuals (if that), “You don’t have the benefit of being able to conduct a traditional, randomized clinical trial,” says Kent Rogers, CEO of EveryONE Medicines. “So, you’ve got to find another pathway to address what regulators need for approval.”

That’s exactly what EveryONE Medicines is aiming to do by developing individualized antisense oligonucleotide (ASO) therapies for pediatric patients with rare neurodegenerative diseases (in many cases, diseases with an n = 1). Rogers calls it precision medicine at the most granular level.

While individual patients may not be part of a bigger patient population, he says, they collectively represent an enormous unmet need in the market. The company’s mission is to create a scalable business model to address this unmet need, one patient at a time.

Pioneering A New Regulatory Pathway

As Rogers explains it, EveryONE Medicines’ operational model is set up like this:

• A patient presents with neurologic symptoms, and a physician performs whole genome sequencing to identify the patient’s disease state as well as any specific, pathogenic mutation that may be causing their disease.
• If the mutation is amenable to an ASO (i.e., a single mutation that can be addressed with a single strand of RNA), then the company designs and develops an ASO to treat the patient’s specific mutation.
• Treatment, in this case, is delivered to the patient through an intrathecal injection, which he describes as a “highway straight to the brain”.

However, to effectively treat patients at scale and help as many children with these diseases as possible, the company needs to work with regulators to create a pathway and make this solution sustainable.

“That pathway doesn’t exist today,” says Rogers. “What we need to do is provide regulatory authorities with the rationale and clinical evidence to approve the chemistry of these ASOs," he tells me, which will likely require an investment in the development of several ASOs up front. Rogers anticipates that the company will begin this process outside of the U.S. and build clinical evidence for regulators in Europe.

“The more patients we treat, the more experience we have, and the more data we provide, the better our chances are of convincing regulators that a new pathway for these diseases is warranted,” he says. “It’s not going to be easy, but we are fully committed to achieving this goal.”

Several years ago, this type of regulatory lift may have been too heavy, says Rogers, “But the support for developing individualized medicines is palpable today.” This support is marked by the recently announced Rare Disease Innovation Hub, an FDA cross-center program designed to foster collaboration between CBER and CDER to address the rarest of diseases.

“The good thing is that regulators are taking it seriously,” Rogers says. “They’re not only thinking about it, but they’re arguably trying to find ways to address it. It is going to be an iterative process.”

There will of course need to be conversations between regulators and EveryONE Medicines about what is expected from a safety and efficacy perspective in lieu of breaking the traditional clinical trial approach. “We contend that you just need a regulatory environment that creates a proportionate pathway, knowing that the population could be just one or a few individuals, where the time and cost of approval is streamlined to do it,” Rogers says. “Because time is not just of the essence for these children, it’s the enemy.”

The Other Piece Of The Puzzle: Finding Patients

Aside from establishing a regulatory pathway, finding patients is EveryONE Medicine’s biggest barrier to scaling, says Rogers. However, he’s hopeful this will improve with time. “Whole genome sequencing is becoming much more affordable and therefore more accessible, which will likely increase the number of rare genetic mutations being diagnosed,” he says.

Rogers isn’t the only one advocating for increased genomic testing. It’s a sentiment I’ve heard before from leaders in the gene therapy space (most recently from the folks at Regeneron). Unfortunately, the U.S. is somewhat behind in terms of the push for broader genetic testing.

“In the U.K. and other parts of the world, whole-genome sequencing is being done on a much broader scale,” he says, pointing to the advent of the Rare Therapies Launch Pad that EveryONE Medicines is a part of. “We are honored to have a seat at that table to strategize how we can create a system where patients are more readily identified through whole genome sequencing and connected with treatments for their individual diseases.”

Despite the regulatory hurdles and lack of access to genetic testing, Rogers is positive that EveryONE Medicines can realize its mission with enough time and investment. “We know the model is scalable and that it can be sustainable,” he says confidently. “We just have to get a regulatory pathway that makes approval more timely and efficient.”

While the current clinical trial-to-commercial-approval pathway doesn’t quite lend itself to a business like EveryONE Medicines, rare diseases demand rare exceptions. From what Rogers tells me, it seems like regulators are coming around to this realization and taking meaningful steps towards progress. As an industry, we owe it to patients who are the one of ones to do whatever is possible to treat their diseases. In time, I think (and hope) we will see this reflected in the company’s success.