Mass General program shows feasibility of expanded access model

An expanded access program (EAP) at Massachusetts General Hospital (MGH) shows that such programs can work, a study found.

The program enabled 11 people with SOD1-associated amyotrophic lateral sclerosis (ALS) who could not participate in clinical trials to receive Qalsody (tofersen) before its U.S. approval. In addition, it “generated clinically meaningful insights into safe implementation of gene-directed therapies while providing timely treatment for trial-ineligible patients without disrupting ongoing drug development or regulatory review,” the researchers wrote.

The patients received the then-investigational treatment over two years. It was generally well tolerated and caused no treatment-related serious side effects. Running the program cost about $337,000 and relied on philanthropic support, insurance reimbursement, waived institutional fees, and donated clinician time.

“This experience demonstrates the feasibility of implementing a resource-intensive expanded access protocol within an academic medical center using a mixed funding model to facilitate early access to emerging ALS therapies,” the researchers wrote.

The study, “Optimizing Research Operations and Resource Utilization in ALS Care: Insights From the Tofersen Antisense Oligonucleotide Expanded Access Protocol,” was published in Muscle & Nerve.

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Promising results from trial data

Qalsody, developed by Biogen, is conditionally approved in the U.S. to treat adults with ALS caused by mutations in the SOD1 gene. The RNA-targeting therapy received accelerated approval in 2023 based on data from the Phase 1/2/3 VALOR clinical trial (NCT02623699) and its open-label extension study (NCT03070119).

While data showed that early treatment with Qalsody led to slower disease progression and improved survival, these effects were delayed, with no benefits observed in the randomized part of the VALOR trial. But Qalsody also reduced blood levels of neurofilament light chain (NfL), a marker of nerve cell damage, which the U.S. Food and Drug Administration (FDA) used for the first time as a surrogate biomarker of ALS disease progression and survival to support the conditional approval.

After the VALOR trial readout and before the approval, some patients could receive Qalsody through FDA-regulated EAPs. These programs allow people with serious diseases who are unable to enroll in clinical trials to receive experimental treatments.

Participants in the MGH program had a median age of 52 at symptom onset. Most were women (90.9%), and nearly half had a family history of ALS. Four patients carried SOD1 mutations expected to cause rapidly progressing disease. The median time from symptom onset to diagnosis was about 18 months, and the time from symptom onset to receiving Qalsody was about 28 months. Three of the patients were initially enrolled in single-patient EAPs before transitioning to a larger program.

The patients received their first dose an average of 35.6 days after referral for an EAP.

FDA approval of the single-patient programs took two to 10 days, while MGH’s institutional review board took 11-21 days to approve a single-patient program and 42 days to approve the intermediate-sized program.

Participants received 100 mg of Qalsody by intrathecal injection, or an injection directly into the spinal canal by a procedure called lumbar puncture. In total, 120 doses were administered, with nearly all delivered via routine bedside lumbar punctures. Only one participant with morbid obesity, for whom the standard procedure was more difficult, required imaging to guide the needle during injections.

Qalsody and the repeated lumbar punctures were generally well tolerated. Soreness at the injection site was the most common side effect and was reported by all participants, while six experienced mild headaches that resolved within 24 hours.

Three participants died during follow-up, but none of the deaths were considered treatment-related.

Operating the program cost $336,620 over two years. Philanthropic donations covered most operational and patient-related expenses, while insurance reimbursed routine laboratory testing. Biogen supplied Qalsody at no cost, the hospital waived administrative and pharmacy fees, and clinicians volunteered their time. Researchers also coordinated treatment with multidisciplinary ALS clinic visits, reducing the number of separate appointments participants needed.

The scientists noted that performing lumbar punctures at the bedside, rather than using imaging guidance, helped reduce costs.

They also acknowledged that expanded access programs remain difficult for smaller centers lacking the necessary infrastructure and resources, and cautioned that their single-center experience may not apply to other healthcare settings.  Travel may also pose challenges for participants, they said.

“Developing sustainable funding mechanisms, such as the mixed-model approach we presented, may help expand equitable access to EAPs for patients who may otherwise face substantial financial and travel barriers to care,” the researchers wrote.