Leveraging recently proposed regulatory flexibilities, the gene-editing sector is working to cut R&D costs and unlock indications that were previously economically unviable, according to a new playbook published by the Alliance for Regenerative Medicine.
The gene-editing space has a new playbook aimed at radically reducing the work needed to bring these therapies to the clinic.
Building on the FDA’s draft guidance published this summer, the advocacy organization Alliance for Regenerative Medicine (ARM) has set out how developers can reuse data to eliminate redundant studies and drive down costs. ARM argues that by reusing data, developing genetic medicines for ultrarare diseases can be viable even though these indications affect too few patients to generate a return on typical R&D budgets.
“If we can leverage the platform and make the cost of the incremental effort to treat a mutation very minimal, rare disease patients suddenly get this kind of therapy where they wouldn’t have otherwise,” John Evans, CEO of Beam Therapeutics, which was involved in creating the playbook, told BioSpace.
Implementing the platform approach
ARM’s playbook, published late last month, provides a guide for developers seeking to reuse data to streamline drug development. Josephine Lembong, ARM’s associate director for scientific affairs, outlined the first steps for developers that want to implement the proposed plan.
“First, developers should decide on their main objective,” Lembong told BioSpace via email. “Especially for rare diseases, that goal may be rapid clinical proof of concept, full licensure or long-term commercial viability, and the choice should factor in population size, unmet need and the availability of alternative treatments.”
Whatever the objective, Lembong recommended preparing for a regulatory filing from the outset, designing and building programs for a potential submission. That approach aligns with how Beam operates under Evans, who said that the biotech designs Phase 1 trials to be registrational. In doing so, Beam aims to go from first-in-human trials to FDA approval in four to five years, compared to eight to 10 years in the traditional clinical pathway.
In parallel with discussions of their main objectives, Lembong said developers should shape their regulatory strategy by mapping their programs to existing FDA frameworks and guidance. At the same time, she added, companies should “define the platform’s scientific boundaries, distinguishing its fixed components from its variable ones.”
Fixed and variable components “depend on the target disease and its known mutations,” Lembong explained. The delivery vehicle, route and formulation may be fixed, allowing developers to reuse data. In contrast, guide-specific biology cannot be assumed from the first product and should be evaluated directly.
Reusing data
Acute toxicity studies offer the biggest opportunity to reuse data under the platform model, Evans said. A lipid nanoparticle will trigger “the exact same acute toxicity outcome” when the payload is adapted to a new target mutation, he continued, making repeat studies redundant.
Chemistry, manufacturing and controls tasks provide further opportunities to reuse data. Such tasks are “a huge amount of the overhead in genetic medicine,” Evans said, reflecting the complexity of the drugs. Under the platform approach, he said, Beam can “use the same assays every time and we know exactly what we’re going to get.”
Those opportunities apply to a range of genetic medicines, but Evans sees further streamlining opportunities that are “somewhat more unique” to Beam’s base-editing method. Companies could use the plausible mechanism pathway, which the FDA unveiled last year, to stop generating animal data in each genetic driver of a disease that may have many such drivers, Evans said. He highlighted phenylketonuria (PKU), for which Beam is actively pursuing a treatment, as being caused by hundreds of variants.
After reusing safety, efficacy and manufacturing data, developers will have short lists of product-specific tasks that they need to perform every time. Beam will need to show every new editor is potent enough, which can often be done in cells, Evans said. Beyond that, companies will continue to run on- and off-target editing studies.
“That might be 10% of the work of a full package. Everything else is cross-referenced to studies we’ve already run,” Evans said. Investigational new drug (IND) applications “are now effectively platform INDs where multiple edits can live together, all trying to deliver the same functional outcome on the gene and on the patient. That’s the really novel part of this.”
Further enhancements
The platform model alone “may not be sufficient to fully address the cost and access challenges facing the field,” ARM said in its playbook. This concern led ARM to conclude its report with a call for “a broader discussion of whether certain traditional development expectations should be modified, abbreviated or, in carefully justified cases, removed altogether”—when risks are low and potential benefits are high.
ARM argued that existing accelerated clinical development pathways are “untenable” for many sponsors in the rare and ultrarare disease space. Developing drugs for diseases that affect very small numbers of patients or are especially severe or urgent will “require a higher appetite for risk,” ARM said.
The group proposed a bifurcated regulatory framework allowing higher-risk, streamlined development of treatments for severe rare diseases that have no standard of care. ARM’s push to further streamline development is part of a broader focus on maximizing genetic medicine’s impact.
“We don’t want to look up in five or 10 years and see that we’ve done this once or twice. We want to have done this 10, 20, 100 times,” Evans said. “There’s a direct line from the efficiency with which we can move these products through the regulatory process . . . and how many diseases we can tackle.”
