20-year look at CF orphan drugs shows shift in therapy approaches

Of 107 possible treatments given designation in 2000-21, 10 approved

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Note: This story has been updated Aug. 11, 2023, to correct the definition of a rare disease, which is defined as one affecting fewer than 200,000 people in the U.S., and to reflect that researchers estimate cystic fibrosis may affect about 160,000 people worldwide.

Of the more than 100 investigational therapies given orphan drug designation for cystic fibrosis (CF) in the last two decades, 10 went on to secure regulatory approval in the U.S. or European Union, becoming treatments.

That’s according to a recent analysis of orphan drug trends, which also identified a substantial shift toward work into therapies that directly target disease mechanisms, such as CFTR modulators. These targeted CF treatments also were more likely to be approved than were those treating specific symptoms.

“Successful drug development is a long journey,” the scientists wrote. “Its success requires the convergence of several factors: the biological rationale confirmed in the clinical setting, financial strength to overcome [research and development] hurdles, and an attractive regulatory ecosystem.”

The analytical report, “Traits, trends and hits of orphan drug designations in cystic fibrosis,” was published in the Journal of Cystic Fibrosis.

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According to researchers, CF may affect more than 160,000 people worldwide, with most residing in the U.S. or Europe. It’s a rare disease, defined as affecting fewer than 200,000 people in the U.S. or fewer than 5 in 10,000 people in Europe.

As such, investigational therapies with significant potential in CF are eligible for an orphan drug designation from the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA).

Intended to incentivize the development of therapies for rare and serious diseases, this designation comes with regulatory support and financial benefits that can include tax credits for clinical trials, waived fees, and a period of post-approval market exclusivity should a product earn regulatory clearance.

Scientists, led by those in the Netherlands, examined the pool of therapies given orphan drug status for CF between January 2000 and December 2021, looking for therapeutic trends and to identify factors that inform successful therapy development.

A total of 107 potential treatments collectively were designated orphan drugs for CF by the FDA and EMA over those years. The scientists followed their development through the close of 2022.

Of these 107 therapies, 26 (24.3%) were designed to target underlying deficits in the CFTR protein that cause CF, whereas the remaining 81 (75.7%) addressed CF symptoms. The latter included therapies for infections (35.5%), inflammation (16.8%), mucus clearance (20.6%), and gastrointestinal complications (2.8%).

CF treatment shift from easing given symptoms to targeting the CFTR protein

While the overall number of orphan designations remained relatively stable from year to year, the types of CF treatments being developed changed over time.

Particularly, CFTR-targeting treatments increasingly earned this designation, while the proportion of symptomatic treatments fell. Mechanism-targeted therapies comprised 11.1% of orphan drugs in the first half of the study period, rising to 37.7% in the second half.

“The identification of the CFTR gene in 1989 represented the watershed in the R&D [research and development] approach to CF,” the scientists noted.

Conversely, symptomatic treatments declined from 88.9% to 62.3% over this time, with a particular reduction in therapies targeting mucus clearance and a “near disappearance” of gastrointestinal therapies.

That trend “is likely explained by the decreased interest of sponsors to develop symptom-based therapies for those on CFTR-based products that may obviate the need for symptom-based therapies,” the researchers noted.

As of December 2022, 19 therapies with orphan drug status (17.8%) were still in development, 78 (72.9%) had been discontinued, and 10 earned marketing approval in the U.S. and/or Europe.

Of 10 approvals over 20 years, four were for Vertex’s CFTR modulators

Among the 10 approvals were four CFTR modulators — Kalydeco (ivacaftor), Orkambi (ivacaftor/lumacaftor), Symdeko (ivacaftor/tezacaftor; sold as Symveki in Europe), and Trikafta (elexacaftor/tezacaftor/ivacaftor; sold as Kaftrio in Europe) — all of which are marketed by Vertex Pharmaceuticals in the U.S. and Europe.

One mucus reduction agent and two antibiotics also were cleared by both regulatory agencies, while three other antibiotics were approved only in Europe.

Overall, CFTR protein-targeted orphan drugs had a higher rate of approval than symptomatic treatments — 21.1% versus 9%.

Most orphan drug designated treatments (83.8%) entered clinical trials, but far fewer (38.2%) transitioned from Phase 2 to Phase 3 testing. The most common reason for discontinuation was a failure in the research and development process (57.9%).

“Although an agent may show safety in Phase 1, lack of safety or early signs of efficacy during Phase 2 evaluation precludes the agent from conclusive efficacy evaluation in a Phase 3 study,” the scientists wrote.

Still, for other rare diseases, “even early phase clinical trials of orphan drugs are less feasible based on potential participant recruitment,” the team added. “The CF community benefits from a well-established network of specialized centers that ensures clinical research infrastructure as well as patient access to diagnosis and relevant treatment.”

While no specific variables emerged as statistically significant factors influencing the likelihood of an approval, certain factors were considered possible drivers of success. These included mechanism-targeted therapeutics and medications developed by large companies with experience in orphan drug development.

Financial instability was the factor seen to most hamper such development in small or medium-sized companies.

“At present, one large company owns the entire CFTR modulators market,” the scientists noted. “Whether this will drive or hamper access for [people with CF] to new beneficial products is relevant to future study.”

“Nonetheless, the future therapeutic horizon for [people with CF] as measured by current [orphan drug designations] looks promising,” they concluded.