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Spectrum: Autism Research News

Going on Trial: Trofinetide approval for Rett; n-of-1 ASO therapies; cord-blood deals

by  /  30 March 2023
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Illustration by Laurène Boglio

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Welcome to the March issue of Going on Trial, a monthly newsletter that rounds up the latest in clinical trials and drug development for autism and related conditions. This edition spotlights n-of-1 trials for rare conditions, the newly approved drug for Rett syndrome and some changes to a deal between Duke University and a cord-blood bank around a controversial and unproven stem-cell treatment for autism.

Thank you to everyone who has subscribed to the newsletter so far. And if you’re not already signed up, you can subscribe here to receive Going on Trial in your inbox every month. As always, please email me at [email protected] with feedback about how this newsletter can best support the research community and any tips about the latest trends and happenings in clinical trials that you’d like to see covered in a future issue.


N of 1:

What happens when a condition is so rare that it’s impossible to recruit enough participants for a rigorous clinical trial? And what if the condition is so profound that assigning participants to a placebo group would be downright unethical? Some scientists who face these challenges have turned to n-of-1 trials, which involve a single participant. Multiple readers have told me to keep an eye on these small trials, especially those that evaluate antisense oligonucleotides (ASOs) designed to correct protein production issues caused by rare gene variants.

So I spoke to Joseph Gleeson, professor of neuroscience at the University of California, San Diego, and chief medical officer at the n-Lorem Foundation, a nonprofit that develops personalized ASO treatments for people with rare neurodevelopmental conditions. As of this newsletter’s publication, n-Lorem has launched three n-of-1 trials, Gleeson says, and it aims to start seven more by the end of 2023.

Earlier this month, the foundation published a list of more than 100 candidate genes that clinicians have nominated for n-of-1 trials, including many genes linked to autism and other neurodevelopmental conditions. Gleeson spoke to Spectrum about how these trials differ from conventional ones, as well as the lessons they can teach us.

This interview has been edited for length and clarity.

Spectrum: How do you design a study for just one participant?

Joseph Gleeson: Designing a trial for an n of 1 is a huge challenge. You have no control arm; you only have that one person. And so how can you convince yourself and convince skeptics that that drug had an effect? It literally isn’t possible. But you can make sure you have really good information about the patient up to the point that drug is used, to compare it with. And ideally, some of the aspects of what’s being measured should be measured by an unbiased observer, a machine ideally. Even then, it’s possible that you will be biased.

S: How does the regulatory process for an n-of-1 trial differ from your usual placebo-controlled trial?

JG: It is totally different. The U.S. Food and Drug Administration (FDA) has issued special guidelines for antisense drugs. They allow these drugs to be used on a compassionate basis. Normally, if you’re using a drug on a compassionate basis, you’re using a drug that has already been in people, so you know the side effects. The FDA considers antisense drugs to be similar to each other because they have the same backbone. The only difference is the actual DNA bases that they’re composed of, so it considers the class to be de-risked to the point where, if it’s for a severe debilitating or life-threatening condition, we can get approval from the FDA within a couple of weeks. That has been a game changer.

S: How do the goals of an n-of-1 trial differ from those of conventional clinical trials?

JG: In a standard FDA trial, the goal is to see if patients benefit from the drug. But with these n-of-1 trials, we have a dual purpose: We’re trying to improve someone’s life, and we’re also trying to measure objectively some aspect of improvement that could guide future treatments. We must put outcome measures in place that we think are going to be meaningful, not just for that one patient, but if another patient comes along who could benefit from that same drug.

We could use what we learn from the first patient to help design even better trials for the second patient. Or maybe we want to use those same outcome measures in multiple locations, if we’ve got 10 or 15 patients treated with the same antisense drug and we’re doing the same measurements. In that case, we’re starting to get pretty close to a clinical trial, we just still don’t have a placebo arm. But what we do have is the natural history of that condition when it’s untreated, for comparison.

Read the full interview.


Daybue’s debut:

“There had never been a medication approved specifically to treat Rett syndrome, so when Deanna Adair heard about a clinical trial of a drug called trofinetide that could potentially help her daughter’s symptoms, she signed up,” my colleague Shaena Montanari writes in Spectrum this month.

“The drug was approved by the U.S. Food and Drug Administration (FDA) last week, making it the first-ever treatment for Rett syndrome, a rare genetic neurodevelopmental condition that shares some traits with autism. Trofinetide, a synthetic analog of insulin-like growth factor 1 (IGF-1) peptide, now branded as Daybue, was developed by Australia’s Neuren Pharmaceuticals before being licensed in North America to Acadia Pharmaceuticals in 2018.

“Yet Daybue might be just the first in a raft of treatments for Rett syndrome. Kathie Bishop, Acadia’s senior vice president and head of rare disease and external innovation, agrees that the approval will likely accelerate drug development for the condition. Daybue’s approval, she says, will show others what’s possible.”

Read more in “FDA approval of trofinetide may spur further drug development for Rett.”


Drug samples:

  • Upping the dose of the experimental ASO drug STK-001 — from 20 milligrams to 30 or 45 milligrams — did not meaningfully ease seizures in people with Dravet syndrome in a phase 1/2 trial, STAT reported in November. The FDA has once again OK’d Massachusetts-based drug company Stoke Therapeutics to give trial participants an even higher dose: 70 milligrams. STK-001 significantly improved survival in Dravet model mice, Spectrum reported in 2020.
  • “Several randomized, placebo-controlled trials on the effectiveness of (add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, NAC [N-acetylcysteine], SFN [sulforaphane], and/or omega-3 fatty acids on core and related symptoms of [autism] have been performed, with promising findings,” according to a review published this month in CNS Drugs.
  • Only about 13 percent of pediatric clinical trials funded by the U.S. National Institutes of Health (NIH) and completed from 2017 to 2019 had submitted results to within a year of completion — as required by the NIH — according to a February research letter in JAMA. And nearly half of all trials hadn’t published results after four years.
  • Autistic children who received the cannabis-based drug NTI164 showed significant improvement in social communication and adaptive behavior, according to results of a year-long phase 1/2 trial released this month by Australian biopharmaceutical company Neurotech International. NTI164 contains cannabidiolic acid (CBDA), which is minimally psychoactive, plus a small amount of the psychoactive cannabinoid THC and an assortment of other cannabinoids.
  • Trials of cord-blood stem cell therapies for autism appear to continue apace, despite research showing no benefit over placebo. Duke University and Florida-based company Cryo-Cell have been charging families for this treatment, and now Cryo-Cell plans to fund Duke’s ongoing phase 2 trial and open a manufacturing facility in anticipation of a phase 3 clinical trial, according to a 9 March filing with the U.S. Securities and Exchange Commission.
  • Designing clinical trials with three arms — treatment, placebo and no treatment — could help autism researchers discern a drug’s effects, according to a March review in Developmental Medicine & Child Neurology.
  • The anti-seizure drug perampanel reduces seizure frequency more in people with rare genetic conditions that disrupt the brain’s signaling balance, including GNAO1 and SYNGAP1, than in people with genetic variants affecting the mammalian target of rapamycin (mTOR) pathway, such as TSC1 mutations, according to a February study in Epilepsia.

And that’s it for the March issue of Going on Trial! Be sure to subscribe so you can receive this newsletter in your inbox every month.

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