Antisense therapies pose a regulatory conundrum

This is the second article in Nature Medicine’s three-part series on personalized antisense oligonucleotides and the future of regulating them. Read the first story in the series here.

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By age six, Mila Makovec had already lost her eyesight, and her body was weakening. Doctors finally diagnosed her in 2016 with a rare, inherited neurodegenerative condition called Batten disease. The prognosis was dire: the doctors predicted that in just a few years, the disease would take her life, and there was no drug to halt its progression. But when Timothy Yu, a neurologist at Boston Children’s Hospital, heard about Mila’s case, he thought he might be able to change Mila’s future.

Yu turned to a new type of therapeutic called an antisense oligonucleotide (ASO), a customizable sequence of 20 nucleotides designed to alter how the body makes certain proteins. He created an ASO, which he dubbed milasen in Mila’s honor, customized to target the specific Batten-disease-linked mutation she carried in her DNA. He managed to design the drug and administer it to Mila in less than a year. Although the ASO didn’t reverse the brain damage Mila had already experienced, it halted the progression of her disease. Yu’s reporting of these early results at the American Society for Human Genetics meeting in October made international headlines.

News of Mila’s treatment broke just as 25-year-old Jaci Hermstad of Spencer, Iowa, began showing the first signs of amyotrophic lateral sclerosis (ALS). Jaci faced a disease with few therapies and no cures. Just as a custom-made ASO saved Mila, Jaci and her family hope that the same approach will help her. Together with Ionis Pharmaceuticals, neuroscientist Neil Shneider, director of the Eleanor and Lou Gehrig ALS Center at Columbia Medical Center, developed an ASO to target the FUS^P525L mutation that Jaci carries.

In late May, the US House of Representatives passed Jaci’s Bill. The legislation, which was sponsored by embattled Congressman Steven King of Iowa and House Speaker Nancy Pelosi of California, urged the country’s Food and Drug Administration (FDA) to allow Shneider to administer the ASO to Jaci before the completion of toxicology testing in rodents. It was an unusual bill in that it focused very narrowly on Jaci’s access to the ASO. This week, the FDA formally signed off on the request.

Make way for personalized ASOs

The path to ASOs began in 1978, when Mary Stephenson and Paul Zamecnik of Harvard University first showed that a 13-nucleotide sequence of DNA — the antisense sequence to a piece of Rous sarcoma virus RNA — could block the production of viral protein by binding to its corresponding RNA. This work inspired scientists like Stanley Crooke to use ASOs to explore how the technology could be harnessed to prevent the production of harmful proteins in the body. In 1989, Crooke left his job at a large pharmaceutical company to start Ionis Pharmaceuticals and devote all his attention to ASOs.

Ionis Pharmaceuticals started by designing ASOs to act as antivirals. In August 1998, the FDA approved the company’s — and the world’s — first antisense drug, fomivirsen, to treat cytomegalovirus retinitis in immunocompromised patients. The drug blocked the production of a protein made by a type of herpes virus. But Crooke didn’t want to be limited to only viral proteins. He set his sights on developing treatments for neurodegenerative diseases.

Crooke quickly found that getting ASOs to alter or block the production of mutated human proteins was both a chemical and biological challenge. Early experiments revealed that very little of the ASO survived long enough to bind to the corresponding RNA. Decades of refinement finally homed in on a chemical backbone for the ASO that would allow the drug to resist being broken down in the bloodstream or degraded in cells in lysozymes and other cellular compartments.

ASOs targeting the production of human proteins have made recent headway. In 2016, the FDA approved Ionis’s nusinersen to treat a degenerative motor neuron disease called spinal muscular atrophy, and other approvals have followed. These successes have inspired smaller startups focused on ASOs, such as Wave Life Sciences, Stoke Therapeutics, and GeneTx. At least 28 ASOs are in clinical trials that have started or are slated to begin.

The appeal is obvious, according to Richard Smith, a neuroscientist at the University of California, San Diego. “They have a huge amount of versatility, which lets you develop drugs for low-incidence diseases. It goes on and on, the things this might be useful for,” Smith says.

The customizability of ASOs makes it possible to tailor them for ultra-rare diseases. “ASOs are the only technology that even has a hope of addressing some of these n-of-one to n-of-ten diseases,” Crooke says.

A unique approach

The same rare disease can be caused by different DNA mutations. P. J. Brooks, a neuroscientist at the National Institutes of Health’s Office of Rare Diseases Research, says the challenge will be recruiting enough patients to test the ASOs that target these relatively unique mutations.

“The only way to do this now is to have a new trial for each drug and each disease. But who’s going to open a clinical trial for those 11 people?” Brooks says. “The limiting factor is not scientific, it’s operational.”

The FDA may need to adapt its requirements for the approval of each drug, including the biomarkers and clinical endpoints it requires — all while juggling the needs and political pressures from patient advocacy groups. And this balancing act isn’t without controversy. When the FDA approved eteplirsen in September 2016, some researchers worried that the agency caved to patient pressure and that the drug wouldn’t make a meaningful difference to patients. Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA, stands by the Administration’s decision, but the argument raises a valid question: when patient numbers are so small — when you have an n-of-1 — what kind of proof is enough?

The FDA is actively trying to plan for future requests for personalized ASOs like Jaci’s. Woodcock and other officials invited Yu and patient advocates, including Mila’s mother, to a closed meeting at the FDA on May 6 to discuss how to adapt the agency’s historical reliance on large, randomized control trials for drug approval to niche drugs for illnesses like Batten disease and ALS. Although both Woodcock and Yu declined to mention specifics, saying the meeting was off the record to give all sides a chance to share concerns freely, they said they were confident in their ability to work together.

Even scientists themselves don’t necessarily see case-by-case legislation by Congress as a prudent way to address the coming wave of personalized therapies for rare diseases. But they note that regulatory pathways need to be prepared for tailored ASOs. “This is personalized, precision medicine. We need to find a way to vet these therapies in a way that meets patient timelines,” Shneider says. “We all feel an obligation to do whatever we can.”