Planned CHOICES Trial in Rare CF Mutations Given Regulatory Support

Planned CHOICES Trial in Rare CF Mutations Given Regulatory Support
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Proteostasis Therapeutics reported receiving scientific advice for its CHOICES clinical trial program, which is to test its personalized triple combination for cystic fibrosis (CF) patients without available treatment options, from the Dutch Medicines Evaluation Board.

Regulatory officials outlined necessary steps in this planned, pivotal trial that would support approval of the company’s CFTR modulators — dirocaftor, posenacaftor, and nesolicaftor — if results are favorable.

They expressed support for the company’s goal of helping patients which the rarest forms of CF, Proteostasis reported in a press release. But they also voiced interest in expanding this personalized treatment approach to include people with more common mutations, such as the F508del mutation.

The CHOICES’ protocol was also review by medical experts in CF, as well as by statisticians, study coordinators, and patient reviewers from the European Cystic Fibrosis Society‘s Clinical Trial Network.

It received a high strategic priority score, meaning that Proteostasis may have access to the 58 clinical sites across 17 countries represented in this network.

“We are thrilled with the outcome of our meeting with the Dutch regulators who provided us with scientific advice as we move forward with clinical development of our proprietary triple combination in patients with rare genotypes,” Meenu Chhabra, president and CEO of Proteostasis, said in the release.

“This meeting marks an important step toward securing a clear path for the development and regulatory approval of the dirocaftor, posenacaftor, and nesolicaftor combination throughout Europe,” Chhabra added.

CHOICES, expected to begin getting underway this year, is designed for the 10% of CF patients who carry ultra-rare mutations in the CFTR gene. These people are not eligible for such approved CF therapies as Orkambi (ivacaftor/lumacaftor) or Kalydeco (ivacaftor), which work only on the most common mutations.

CHOICES will be a placebo-controlled, double-blind trial testing a combination of dirocaftor (a CTFR potentiator formerly known as PTI-808), posenacaftor (PTI-801, a CFTR corrector), and nesolicaftor (PTI-428, a CFTR amplifier).

Before testing the combination directly in patients, researchers will first examine its effectiveness in organoids, or ‘mini-organs,’ grown using stem cells. In this case, intestinal organoids are being grown from cells collected through rectal biopsies of patients who are candidates for the trial.

Only if the ‘mini-intestines’ of a given candidate respond favorably to the triple combo will that patient be enrolled in CHOICES and eligible for treatment. Participants will receive the triple combination, or a placebo, for eight weeks, followed by six months of constant dosing.

According to Proteostasis, this will be the first trial based on personalized treatment in CF.

The approach builds on prior positive results from a European Union initiative, called HIT-CF (Human Individualized Therapy of CF), that is testing investigational CF treatments — including Proteostasis’ triple combo — in organoids from patients with rare disease-causing mutations.

Inês Martins holds a BSc in Cell and Molecular Biology from Universidade Nova de Lisboa and is currently finishing her PhD in Biomedical Sciences at Universidade de Lisboa. Her work has been focused on blood vessels and their role in both hematopoiesis and cancer development.

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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.

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Inês Martins holds a BSc in Cell and Molecular Biology from Universidade Nova de Lisboa and is currently finishing her PhD in Biomedical Sciences at Universidade de Lisboa. Her work has been focused on blood vessels and their role in both hematopoiesis and cancer development.

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