FDA Office

A new field of precision medicine, pioneered by a study to design a treatment for one young girl with Batten’s disease, is growing—one patient at a time. More and more patients with rare genetic disorders are looking to the future of hyper-personalized treatments for hope. These treatments, consisting of custom antisense oligonucleotides (ASO), are vastly different from traditional medicines designed with the goal of benefiting large groups of patients. The biggest difference? The number of people who could benefit from a hyper-personalized treatment is exceptionally low—as low as one. As such, they demand a newly designed process for regulation.

Drafting new guidance on a brand-new class of drug in a field that is in its infancy is not a small task. “I think,” notes Art Krieg, M.D., founder and CEO of Checkmate Pharmaceuticals and past president of the Oligonucleotide Therapeutics Society (OTS), “that the FDA feels pressure from patient groups to simplify the normal drug development process in the case of these unique or nearly unique mutations. But they also have to be thoughtful that the precedents set in these cases do not have unintended consequences.”

Recently, FDA published a draft guidance for regulating these drugs entitled, “Nonclinical Testing of Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases.” The response from those in the field has been positive.

“I’m thrilled,” says Stanley Crooke, M.D., co-founder of n-Lorem, a non-profit dedicated to providing experimental ASO treatments to help desperate patients with ultra-rare mutations. “It’s a very significant step forward.”

There are three big reasons, Crooke explains, for his positivity. The first is timing. What this field is doing, he explains, “stresses every element of the legislation, policy, regulation that you can imagine.” As a result, the pace of producing a relatively definitive and specific set of guidelines, as rapidly as they have, is “truly remarkable.”

Krieg agrees with Crooke. He told Clinical OMICs that the FDA has been “quite proactive” in considering this work since the first case was performed in 2019. That year, Tim Yu, M.D., associate professor in pediatrics at Boston Children’s Hospital, led the team that designed and administered a drug named Milasen to a young girl with Batten’s disease named Mila Makovec. The drug, and the case (which garnered international attention), were landmarks for the field despite their failure to provide a cure—Mila died earlier this year.

Crooke, the founder and executive chairman of Ionis Pharmaceuticals, where he served as CEO for more than 30 years, cites two other reasons why he is pleased with the guidance: 1) it is focused on ASOs and 2) it reflects a good understanding of the technology. It also provides guidance to less mature technologies regarding what they need to have in place should they want to try to help these patients.

Lastly, Crooke is pleased because n-Lorem had submitted extensive proposals and they “essentially got everything we asked for.” He adds that there were a couple of extra items that they didn’t ask for that will help—especially in patients who are progressing rapidly toward death or a permanent disability.

No wasted time

Having FDA guidance in place will speed up the process of drug development, which is a top priority. With the new guidance, patients can begin treatment sooner—potentially even three months sooner—than they could before. One aspect that hastens the process is streamlining of the toxicology studies. The new guidance allows patients to receive drugs before the toxicology studies have been completed. In addition, the studies can be performed in a single animal species. This change, Crooke thinks, will enable them to help patients that they might otherwise lose.

Many of the other details outlined in the guidance are consistent with n-Lorem’s current process. But Crooke says that the importance lies in knowing the rules. Before the guidance, he says, investigators were “operating in a vacuum of rules.”

Long road ahead

“The guidance is a great first step,” notes Krieg, who has spent decades working in the oligonucleotide field. But he says it does not address all of the issues. As more is learned, Krieg notes, it is possible the guidance may evolve to reflect new learnings.

One thing that Crooke would like to see—and has submitted a substantial proposal to address—are specifics on how to guarantee that quality systems are in place. How will the field ensure that they have good treatment plans for each patient and that the patients are treated with the best ASO possible? That is not a trivial undertaking, he asserts. For Crooke, this is of the utmost importance because, “we cannot add any unnecessary risks to these patients.”

Krieg adds that there are many different platforms, designs, and chemistries for developing RNA therapeutics. “It’s not easy to develop a policy that can be generally applicable,” he says. The questions he thinks that will need to be addressed in the future include: what measure of efficacy is used to define success? How can treatment be monitored? And can a customized oligo be approved so that insurance companies will reimburse for the treatment?

The key question now for Krieg is how the FDA and the investigators and academic centers developing these new therapies will implement this guidance in the most responsible way possible. “We all want to move quickly,” he notes, “but we also don’t want to create unrealistic expectations on the part of patients or their families that an individualized oligo is going to be a miracle drug for their condition.” Beyond the work of the OTS and others to advance this work, he adds, “society as a whole needs to address the questions of how to ensure equitable access to these drugs for patients with amenable mutations, while working to continue to reduce the cost of development and streamlining the process further.”

Ultimately, says Crooke, FDA guidance allows investigators to know that they are on the right path from day one, which is an important step for the patients and their families. A common feature of drug development, he explains, is that you think you’re doing what is required but then you find out that you have to go back and do something else. As Crooke says, “we simply can’t afford that with these patients.”

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