When a Clinical Trial Fails and It Was Your Family's Trial

On September 2nd, Ultragenyx announced that apazunersen, the antisense therapy that had carried the hopes of the Angelman syndrome community for 7 years, failed its Phase 3 trial. Six days later, Novartis announced that del-desiran, the centerpiece of its $12 billion acquisition of Avidity Biosciences, failed its Phase 3 trial in myotonic dystrophy type 1. Neither disease has an approved treatment. Both communities had let themselves believe that was about to change.

The headlines that followed were about cratering stock prices and strategic reviews, written for investors. Families got the same news framed as a portfolio event. This piece is for the other audience: the more than 200 Angelman families who lived through the Aspire trial, the 159 people with DM1 who enrolled in HARBOR across 9 countries, and everyone in both communities now sitting with the question of what happens next. There are real answers, and some of them hold more hope than the headlines suggest.

What Happened in the Aspire Trial for Angelman Syndrome

Apazunersen, formerly called GTX-102, is delivered by spinal injection and designed to switch on a silenced backup copy of the UBE3A gene, the gene whose loss causes Angelman syndrome. The approach had every advantage the system can grant: Breakthrough Therapy, Orphan Drug, Rare Pediatric Disease, and Fast Track designations from the FDA, and Phase 1/2 results striking enough that families and clinicians described visible changes in children. The Phase 3 Aspire study was the test that mattered, comparing treated children against a sham-procedure group on a cognitive measure called the Bayley-4 and a bundle of secondary measures. On both, there was no difference between the groups that could support efficacy.

“Based on everything we observed in the robust Phase 1/2 clinical development program and long-term extension study, we are disappointed by the Aspire result. Even more, we are disappointed for the global patient community who has invested so much in early-stage research, working to bring a first-ever treatment to their children.”

Emil Kakkis, M.D., Ph.D., CEO of Ultragenyx

Ultragenyx says it will evaluate the program and decide its fate, alongside significant cost cuts across the company. The word that matters in that sentence is evaluate. A decision about whether apazunersen continues in any form has not been announced as of this writing.

Del-desiran took aim at the root cause of myotonic dystrophy type 1, the most common adult-onset form of muscular dystrophy, in which a genetic repeat produces toxic RNA that jams the machinery of muscle cells. The Phase 3 HARBOR study measured something deceptively simple: video hand opening time, the seconds it takes a person to open a clenched hand, which captures the grip-lock symptom called myotonia that shapes daily life with DM1. Treated patients did not improve on that measure significantly more than patients on placebo. Novartis noted that some secondary and exploratory measures showed evidence of clinical activity, which is genuinely worth knowing and also is not the same as a positive trial.

“Developing therapies for a complex disease like DM1 remains challenging, and setbacks are part of scientific progress. As we continue to evaluate the full HARBOR dataset, we remain committed to identifying the most appropriate development path for the del-desiran program and advancing innovative approaches for people living with DM1 and other serious neuromuscular diseases.”

Shreeram Aradhye, M.D., President of Development and Chief Medical Officer, Novartis

Novartis paid roughly $12 billion for Avidity Biosciences largely on the strength of this program, a fact worth naming because it answers a question families sometimes ask quietly: did the company believe in this drug? Twelve billion dollars says yes. Belief, money, and designations do not decide trials. Data does.

Why Promising Drugs Fail in Phase 3

The hardest part of both announcements is the same detail: the early data looked real. Families saw changes. Clinicians saw changes. The Foundation for Angelman Syndrome Therapeutics (FAST) published a remarkable letter from its chief science officer, Allyson Berent, that refuses to wave any of that away while being equally honest about the result.

“We can believe deeply in what many people saw in their loved ones, and also that the Phase 3 study did not demonstrate wide benefit. Both can be true. None of it makes anyone's experience less real.”

Allyson Berent, DVM, DACVIM, Chief Science Officer, FAST

The FAST letter walks through the honest list of explanations, and it applies to almost any Phase 3 failure. The dose or dosing schedule may not have been enough, even when the biology is right. The placebo response may have been large, because hope itself changes how children perform and how caregivers score them, and a sham-controlled trial subtracts that effect in a way that early open-label studies never can. The measurement tools may have missed a real effect, since a cognitive assessment is hard to complete for a child with apraxia and anxiety, whether or not a drug is working. One year may simply be too short to see separation in a neurodevelopmental disease where all learning takes time. Most likely, several of these combined.

It helps to know the base rates. Across all of drug development, industry analyses have found that roughly 4 in 10 drugs entering Phase 3 fail to advance, and that is at the final stage, after a decade of winnowing (BIO, Informa Pharma Intelligence, and QLS Advisors, 2021). Rare disease trials carry extra difficulty on top: tiny populations, measurement tools borrowed from other fields, and diseases so variable that signal and noise wear the same clothes. A Phase 3 failure is devastating. It is not evidence that anyone was foolish to hope.

What Happens to the Families Who Were in the Trials

This is the question the investor coverage never answers. For Aspire families, FAST says many parents who believe their children responded are asking whether expanded access or another mechanism could keep the drug available. The honest status: no path has been announced, and FAST reports it is working directly with Ultragenyx and study investigators on next steps, with full results to be presented to the community at the FAST Global Science Summit in November. For HARBOR families, Novartis issued a letter to the DM community alongside its announcement and continues to analyze the complete dataset, and the Myotonic Dystrophy Foundation says it will push for clear and timely communication of what that full dataset shows.

“There are no words that can erase the disappointment our community is feeling today. We are thinking especially of the people who took the courageous step of joining this trial. Their contribution matters. Their voices matter. And their hope for a better future matters.”

Dr. Tanya Stevenson, CEO, Myotonic Dystrophy Foundation

If your family was in either trial, 3 practical things. Your site coordinator remains your channel for anything about your child's status, ongoing visits, and any future access programs, so keep that line open. The trial data your family contributed stays in the scientific record permanently and is already shaping the next generation of studies, which is not a consolation prize; it is how the successful trial eventually gets designed. Support exists for the emotional part too: MDF runs a one-on-one Warmline for the DM community, and FAST, the Angelman Syndrome Foundation, and their local chapters are staffed by people, many of them parents, who have absorbed this exact news alongside you.

Neither Pipeline Is Empty

Here is what the stock-price coverage leaves out entirely. Angelman syndrome has two other antisense programs in Phase 3 right now: obudanersen from Ionis, which completed enrollment of its pivotal cohort this summer, and rugonersen from Oak Hill Bio, which dosed its first Phase 3 participant in July. Both companies published letters to the Angelman community this week explaining how their molecules, doses, and trial designs differ from apazunersen's and why their programs continue. Different is not a guarantee of better. It does mean the Aspire result is one drug's answer, not the field's.

The DM1 pipeline also runs deeper than one program, with multiple companies advancing RNA-targeted approaches through clinical trials, and the HARBOR secondary endpoints that showed activity will inform all of them. The MDF drug development pipeline tracks the full picture, and our myotonic dystrophy page lists every trial currently recruiting. The same is true for Angelman syndrome.

September has now delivered both faces of rare disease research in a single month: these 2 failures, and a run of 8 FDA decisions through the 30th that could give 4 diseases their first-ever treatment, a stretch we covered in our September decisions guide. Progress and heartbreak are not taking turns. They arrive together, sometimes in the same week, and communities like these have learned to hold both.

“I know this is hard. I know there is disappointment, uncertainty, and a lot of unanswered questions. As a parent, I deeply feel this too. But I also know that questions are where progress begins.”

Allyson Berent, DVM, DACVIM, Chief Science Officer, FAST