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Results aren’t usually publicly shared, but behind the scenes, real-world data (RWD) and evidence (RWE) are having a big effect on rare disease drug development and clinical management.

That impact is particularly evident in Duchenne Muscular Dystrophy (DMD) right now.

Sarepta Therapeutics, for example, has three commercial DMD products already. That’s a nice slice of the estimated $1.3 billion global DMD market, which is anticipated to grow to $2.1 billion by 2031 thanks to almost 5% compounded growth from 2022 to 2031.

Katherine Gooch
Katherine Gooch, PhD, vice president and head, Global Market Access, HEOR and RWE at Sarepta

“We gather both real-world data and generate real-world evidence plans for our treatments and have been doing so for many years,” says Katherine Gooch, PhD, Vice President and Head, Global Market Access, HEOR and RWE at Sarepta, via email.

“We have been working to generate RWD and RWE for all our approved products (EXONDYS 51, VYONDYS 53, and AMONDYS 45) in addition to planning for future treatments,” she adds.

FDA has accepted Sarepta’s application for a gene therapy called SRP-9001 under the Accelerated Approval pathway. Since all three of its previous drugs followed the same path, post marketing is a particularly important way RWD is currently used at the company.

Sarepta building
Credit: Sarepta

You won’t find many news releases about Sarepta’s efforts in this area, but they are sharing some data with peers.

A recent conference poster presented at the World Muscle Congress in October 2022 (Iff, J. et al), featured RWE for EXONDYS 51 (eteplirsen)—which addresses a genetic mutation in the dystrophin gene treatable by skipping exon 51. That study found a 5.4 year survival benefit for patients taking eteplirsen compared to a matched natural history group.

Gooch says “Real-world evidence is an important way to better understand the use and benefit-risk profile for any treatment outside of the clinical trial setting. RWE is derived from real-world data such as claims data, electronic health records and registries as examples.”

She adds that, “In rare disease, existing RWE describing the natural history of disease and the unmet need typically is very limited, often requiring substantial RWE generation to close important evidence gaps.”

An Organized Push

Susan J. Ward, PhD, has long been at the forefront of using RWD in muscular dystrophy. She is executive director and co-founder of cTAP, the Collaborative Trajectory Analysis Program, in 2015 with James Signorovitch, PhD, a managing partner at Analysis Group.

Susan J. Ward
Susan J. Ward, executive director and co-founder of cTAP

“I was working with a patient foundation doing strategic planning, and so many clinical trials were failing at that time, we needed something beyond existing trial design to make real progress,” Ward says.

The biggest problem they saw was that different children would progress at markedly different rates, making it especially difficult to conduct the types of small clinical trials typical of rare diseases.

DMD is mainly seen in boys, and there are over 200 mutations that can underlie the disease. The DMD gene consists of almost 80 exons, intragenic deletions, and duplications that together account for over two thirds of the mutations leading to the condition. That opens up a lot of room for variation, and yet most studies were grouping subjects according to age.

After years of trials, with only a handful of successes for patients with certain mutations, the outstanding question was: “How can we design smarter clinicals trials that can overcome the variability caused by different patients progressing at different rates?” Ward says.

To answer that question, cTAP set out to advance statistical methods that would allow the type of smaller clinical trials typical of a rare disease like DMD, but with higher probability of success.

Fortunately, pharmas, biotechs, and patient advocacy groups were also on board, including CureDuchenne, which provided seed funding, and Parent Project Muscular Dystrophy (PPMD), the largest non-profit in the U.S. for Duchenne muscular dystrophy.

Pat Furlong
Pat Furlong founding president and CEO, of Parent Project Muscular Dystrophy (PPMD)

PPMD founder Pat Furlong knew first-hand that children progressed at different rates. She watched her two sons, who were born two years apart in the early 1980s, succumb to the disease. “When Chris was diagnosed, he was riding a two-wheeler,” she says. Her other son, Patrick, was never able to ride a bike. Both boys died about the same age—seventeen and fifteen respectively.

Since then, PPMD, cTAP, and the whole field of DMD research have made huge strides. cTAP now has about more than 20 members, including leading developers of DMD treatments, such as Entrada Therapeutics, Pfizer, Sarepta, and Roche.

In 2020 cTAP announced results from the largest ever multi-national, multi-collaboration study in DMD. Their study showed that disease progression in both RWD and natural history data (NHD) data are highly comparable to that from patients treated with placebo in multiple recent clinical trials.

“One of the biggest concerns about RWD is the risk of bias – that patients may ‘try harder” during assessments when they are in a clinical trial because they know they might be receiving a drug,” says Ward. So, rather than speculate about how big that risk is, what cTAP has done is measure directly how RWD compares to placebo.

She adds that, “We found that once we had adjusted baseline function to allow an ‘apples to apples’ comparison, it was not possible to detect any difference between RWD and placebo.”

In their most recent report, the cTAP team looked further at the use of external controls based on RWD and natural history. They conducted a multi-institution study comparing mean 48-week changes in North Star Ambulatory Assessment (NSAA) total score between trial placebo arms and RWD/NHD sources, with and without adjustment for baseline prognostic factors (Muntoni et al. Feb. 2022). The NSAA is a standard means of evaluating patients in DMD trials.

The authors of that study (Muntoni et al. 2022) wrote that this work “provides a well-validated framework for baseline adjustment of prognostic factors, and supports the suitability of RWD/NHD external controls for drug evaluations in ambulatory DMD.”

Overall, Ward says, cTAP has established the foundations for using RWD and natural history as well as developed and published tools for the wider rare disease community. The team, she says, hopes it will ultimately “create a new paradigm that delivers on the sweet spot that triangulates drug developers’ needs, academics’ responsibilities for patient data, and high-end science to bring new therapeutics to patients sooner.”

Beyond Muscular Dystrophy

Other groups are on a similar track.

Genetic Alliance (GA), for example, inked a deal with LunaPBC in 2019 to merge GA’s patient outreach Platform for Engaging Everyone Responsibly (PEER) with LunaDNA, which helps individuals share their health data for medical research. As a press release announced at that time, the goal of the deal was to “provide individuals and communities with more resources to support health management while maximizing research opportunities.”

Genetic Alliance includes more than 2,000 disease-specific advocacy organizations, as well as thousands of universities, private companies, government agencies, and public policy organizations.

But Terry is also the parent of two now adult children with the rare disease pseudoxanthoma elasticum (PXE), a progressive disorder characterized by the accumulation of deposits of calcium and other minerals in elastic fibers.  In 1995, she and her former husband, Patrick Terry, founded PXE International to find a cure for the disease and support individuals with this condition.

Sharon Terry
Sharon Terry, CEO, Genetic Alliance

The issue of RWD became top of mind because, “In FDA meetings they are always asking us to collect real-world data from trials of our PXE drugs, because we don’t have good biomarkers yet,” says Sharon F. Terry, chief executive officer, the Genetic Alliance. PXE International has two drugs currently in Phase II trials.

The GA/Luna team has taken the use of RWD to the next level. The pair worked with Biogen to design a drug discovery program for KCNT-1 Epilepsy. Biogen aimed to study the cause of the disease and develop treatments.

“Biogen will eventually develop their drug,” says Terry, “But we’ve learned a lot about these patients in the meantime.”

And others are now using the LunaDNA platform to generate more RWD and RWE. Terry says that that “dozens” of advocacy groups are using it to “build cohorts or registries, to track natural histories, find biomarkers, or design and conduct phase I or II trials.”

What patients actually want, is a key question. “For example, during the Biogen project, we discovered that while parents wanted their children, who were experiencing hundreds of seizures a day, to have less seizures, stopping drooling was also a high priority,” Terry says.  They also discovered that some parents were using Botox to stop this, and the result was better quality of life for their children, including more crawling and other milestones.

Others are also using RWD to just make life better for rare disease patients. Researchers at University of South Wales in Australia, for example, determined that newborn screening for spinal muscular atrophy (SMA), when combined with early treatment, results in better movement ability in affected children, including the ability to walk, when compared to children who are diagnosed only once symptoms develop.

SMA is a rare, genetic neuromuscular condition that usually develops in childhood and features problems with muscles and movement that often lead to significant disability and sometimes death.

Didu Kariyawasam
Didu Kariyawasam, pediatric neurologist at Sydney Children’s Hospital

Didu Kariyawasam, lead author of the paper and a pediatric neurologist at Sydney Children’s Hospital, points out that without newborn screening, parents of children with SMA don’t realize that something is wrong until, “their child’s movements become weaker, slower and they stop gaining gross motor milestones.”

There have been several international clinical trials, Kariyawasam says, that suggest that new therapies plus early intervention, especially before symptoms start, leads to better outcomes in terms of survival, motor function, and reduction in comorbidities (e.g., need for feeding and breathing support).

“Our study, however, is only one of a handful that shows that newborn screening, as a pathway to diagnosis and access to early treatment can change outcomes in real-world practice for children outside the strict inclusion/exclusion criteria of the trials,” she adds.

Rachel Sobel
Rachel Sobel, executive director & head of Pharmacoepidemiology Regeneron Pharmaceuticals

Rachel E. Sobel of Regeneron Pharmaceuticals, says registries are another important way to collect RWD and derive RWE. The problem, she says, is that these are often started up “Without enough funding to go through as long as is needed to get all the answers.” Sobel is DrPH, FISPE, executive director & head, pharmacoepidemiology.

“As useful as they are, registries tend to be few and scattered,” she adds. “In many cases, they would be more powerful if they were connected.”

Regeneron has drugs in development for several rare diseases including fibrodysplasia ossificans progressiva (FOP), myasthenia gravis, and lipodystrophy. These each involve small, heterogeneous groups of patients with extremely severe diseases.

“RWE gives us valuable insights on who to recruit, how to design trials, an understanding of the natural history of these diseases, and how to best follow these patients,” says Sobel.

So, without knowing how much of it to attribute to real-world data or evidence, PPMD celebrated this year by announcing that among other things, 10 years have been added to average lifespan of DMD patients.

“I think real-world data is having an impact,” says Furlong. “We were recently having a discussion with the FDA and we were talking about one of the measures and how much of a difference what may seem like a small amount of ambulatory ability actually made.”

The regulator expressed skepticism and, Furlong adds, “I told him, I would send him some videos. Because it is so much more convincing when you see how big an impact on quality of life it is to just be able to hold your head up off the bed.”


Malorye Branca is a freelance science writer based in Acton, MA.

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