FNIH Enhances Rare Disease Research by Adding 8 Diseases to BGTC

May 23, 2023 - On May 16, 2023, the Foundation for the National Institutes of Health (FNIH) announced eight rare diseases to be explored by the Accelerating Medicines Partnership Bespoke Gene Therapy Consortium (AMP BGTC). As one of the newest additions to AMP, this consortium hopes to enhance and propel gene therapies for rare diseases.

Although roughly 25–30 million people in the United States are struggling with over 7,000 rare diseases, there have only been two FDA-approved gene therapy products for rare diseases, with a painfully slow drug development process. As a result, millions of rare disease patients have unmet medical needs.  

According to the National Center for Advancing Translational Science (NCATS), individuals with rare diseases spend 3–5 times more on healthcare than those without a rare disease. The limitations in rare disease research and available gene therapy treatments have driven pricing through the roof, contributing to an exorbitant amount of healthcare spending.

In an attempt to further the development of gene therapies for rare disorders, the BGTC has chosen a group of rare diseases with a small number of patients to advance research.

An Overview of the Accelerating Medicines Partnership

According to the FNIH website, the Accelerating Medicines Partnership is a collaborative effort between the NIH, non-profit organizations, pharmaceutical companies, and other private sector members to advance disease understanding, develop improved treatment targets, and deliver speedy and accessible treatment options to patients.

The partnership comprises 31 industry partners, 16 NIH Institutes and cross-Institute programs, and 36 nonprofits. The United States Food and Drug Association (FDA) and the European Medicines Agency (EMA) have also provided some regulatory input. Some notable partners include but are not limited to the following:

• AbbVie
• The American Psychiatric Association
• Pfizer
• Sanofi
• Biogen
• The National Alliance on Mental Illness

Ten programs have developed over the lifetime of this partnership, accounting for $820 million in investments. Since its launch in 2014, the program has had projects focused on neurological disorders, autoimmune and immune-mediated diseases, heart failure, rheumatoid arthritis and lupus, type 2 diabetes, and schizophrenia.

Bespoke Gene Therapy Consortium

As part of the AMP program, the BGTC enhances and accelerates treatment options, focusing on rare genetic diseases and therapies. According to the consortium overview, BGTC’s primary focus is on rare diseases that affect such a limited patient population that major commercial development companies are not incentivized to focus on them as with other conditions that impact public health.

“A lot of pharmaceutical development is more on the large market,” explained Courtney Silverthorn, PhD, Associate Vice President of Science Partnerships at the FNIH, in an interview with PharmaNewsIntelligence. “While some rare diseases, at the very high end of the prevalence scale, could fall into something that might be of commercial interest, for the diseases with a very low prevalence, there is no viable path forward.”

Although efforts have been made by academic medical institutions, parents, and non-profit organizations, they have been siloed because they can’t scale.

“While there has been limited success, it proves how challenging and convoluted the pathway is for parents to advocate for their kids,” noted Silverthorn.

To accelerate the development of treatment options, BGTC focuses on adeno-associated viruses (AAV), a single gene delivery technology that has already proven safe.

According to an article published in Molecular Therapy, “AAV is a non-enveloped, single-stranded DNA virus, with a genome size of 4.7 kb and a small icosahedral capsid of ∼25 nm, that was discovered in the 1960s as a contaminant in a simian adenovirus preparation.”

Clinical trials have proven that AAV vectors have been explored for treating hemophilia, inherited blindness, spinal muscular atrophy, and muscular dystrophy. However, a study in Synthetic Biology notes that AAV gene therapy still needs to be fully understood.

Beyond developing a robust understanding of AAV life cycle biology, the consortium hopes to standardize the regulatory route for this kind of gene therapy concerning rare or bespoke diseases.

“We're trying to create the baseline process rather than push the boundaries of technology — using wild-type AAVs wherever possible or plasmids that had already been developed for that particular indication — because we're trying to keep the development timeline very short,” she expanded. “Wherever we can reuse technology that's already been established and proven, that helps us get a little bit faster in the process.”

Goals for Choosing Rare Diseases

Silverthorn explained that there were two primary goals when compiling specific diseases to work on for the consortium. The first goal was to choose research directions or illnesses close to the first-in-human clinical trial phases.

“We had several criteria that we were evaluating directed to that,” added Silverthorn. “Was there an animal model for the disease? Has there been a proof of concept or a natural history study? Is there any information about toxicology studies or dose-finding studies that would make the pathway to that IND in that first-in-human clinical trial as rapid as possible for the consortium?”

The second goal when choosing the rare diseases the consortium would focus on was building diversity by selecting diverse conditions representing an equally diverse patient population.

“We managed to achieve that goal with the selection of the diseases,” revealed Silverthorn. “We have diseases that cover multiple routes of administration and target tissues. We have three different serotypes that we'll be using across the portfolio. Also, the diseases reflect pretty good patient diversity within the patient populations that they affect.”

She explained that they looked beyond one diversity component, attempting to establish a portfolio with gender, racial, geographic, and economic diversity, asking each clinical protocol to develop a diversity plan to address those factors when applicable. Beyond that, the consortium is leveraging the contact registry and affiliated patient advocacy group to recruit patients from the disease population.

“We tried to take a comprehensive view of what diversity in the portfolio would mean. It didn't necessarily mean that every single trial had to have a diverse patient population, but that across the entire portfolio that we were achieving diversity because, for some of these monogenetic diseases, the patient populations can look very homogenous,” she added.

Selection Process

Turning toward the patient, parent, research, and clinical communities for insight and nominations on disease focuses, the consortium received 62 recommendations based on a general form.

“It was about three pages of information in total that asked the submitter for information about the disease, the clinical presentation, some information about the patient population it affects, and if there was any preclinical or clinical history research, a natural history study, a contact registry, and so forth,” explained Silverthorn.

Reviewing each of the 62 submissions, the team at the consortium evaluated, reviewed, discussed, and scored each application using the criteria mentioned above. That process allowed them to narrow it down to 14 trials. After opening up those diseases to clinical trial protocol submissions, the team landed on the eight rare diseases they will focus on.

“We want to create the most replicable processes we can,” emphasized Silverthorn. “In practice now, that means leveraging more tried and true technologies.”

With that in mind, the consortium leaders steered clear of any novel technologies or administration routes that have not been used or approved for an IND before.

After a rigorous selection process, the consortium landed on the following eight rare diseases:

• Charcot–Marie–Tooth disease type 4J
• Congenital hereditary endothelial dystrophy
• Morquio A syndrome
• Multiple sulfatase deficiency
• NPHP5 retinal degeneration
• Propionic acidemia (PCCB)
• Retinitis pigmentosa 45
• Spastic paraplegia 50

Goals and Metrics

As the procedural goal for this initiative, the consortium hoped to use clinical trials on these eight rare diseases as test cases for regulatory approval by the FDA, streamlining preclinical testing, drug manufacturing, and investigational new drug (IND) submissions.

“BGTC hopes to give a better roadmap to these organizations, small companies, clinician–researchers, and family foundations on how to get through the process to an IND and into that first-in-human clinical trial that may provide life-changing therapy for their children,” noted Silverthorn.

Silverthorn also discussed the benchmarks and success measurements that the consortium hopes to use to track the outcomes of this project. The primary measure of success would be eight successful clinical trials across the portfolio, representing 60–70 patients in total.  

“However, if we only had eight successful clinical trials and accomplished nothing else, I'm not sure that we would consider the consortium a success because it's really about using those clinical trials to demonstrate processes that other organizations can then use for other indications,” she countered.

“When we put all this information out into the public — the consensus protocols for manufacturing, critical quality attributes for the preclinical testing, different routes of administration, and the regulatory templates — we would want to get a sense of how those are being used, how many organizations can pick that up, and use that in their journey toward an IND approval,” added Silverthorn.

Although the consortium is currently only equipped to help push trials into first-in-human phase one clinical trials, Silverthorn notes that measuring their success and progress could be another metric of success.

“While we only have eight indications in the consortium for the clinical portfolio, we strive to make the outputs of the consortium able to help other patients and other indications on their journey. That's what we would consider success,” concluded Silverthorn.

Editor's Note: This article has been edited to correct quotes.