Proteostasis On Track to Develop Organoids for Personalized Medicine Strategy for CF Patients with Rare Mutations

A project aimed at personalized medicine based on the use of organoids, or “mini-organs,” from cystic fibrosis (CF) patients with rare mutations is on track to collect samples from 500 people with CF by the end of April, Proteostasis Therapeutics announced.

The organoids will be used as a platform for developing personalized medications, and are expected to help determine patient responses to Proteostasis’ CFTR modulators. The responses will then be confirmed in a Phase 3 trial called CHOICES, the researchers said.

The trial update was shared in a poster, titled “Intestinal Organoid Models as a Path for Personalized Therapy Development in Cystic Fibrosis,” at the Keystone Symposia on Tissue Organoids, held Jan. 19-23 in Vancouver, Canada.

CF is caused by mutations in the CFTR gene, and more than 2,000 alterations have been identified. F508del is CF’s most common causative mutation, with nearly 90% of CF patients carrying at least one CFTR copy with this alteration. Every person has two copies of this gene, one inherited from each parent.

Therapies for CF are tailored to the type of mutation a person carries, but the ones currently available — all by Vertex Pharmaceuticals — only cover a limited set of mutations. The treatments now available include Orkambi (ivacaftor/lumacaftor), prescribed to people with the F508del mutation in both copies of the CFTR gene; Kalydeco (ivacaftor), approved for the treatment of 38 different mutations; Symdeko (ivacaftor/tezacaftor, marketed in Europe as Symkevi), used for patients with the F508del mutation in both copies the CFTR gene or at least one of 26 specific mutations; and Trikafta (elexacaftor, tezacaftor, and ivacaftor), given to people with at least one F508del mutation.

However, this leaves at least 10% of CF patients — those carrying other mutations in the CFTR gene, called ultra-rare mutations — without an approved therapy. According to Proteostasis, in Europe alone this patient population comprises approximately 2,300 adults.

Proteostasis is part of an EU initiative called HIT-CF (Human Individualized Therapy of CF). This consortium of academic, clinical, and industry partners is using CF patient-derived organoids with rare mutations with an aim of developing new treatments for individuals who are ineligible for the current standard-of-care CFTR modulator therapies.

Organoids are stem cell-derived human “mini-organs.” In this case, the organoids are grown from rectal biopsies of CF patients who have ultra-rare mutations. These so-called mini-organs faithfully mimic the genetic and phenotypic profiles of diseased tissues, and are thus a great tool to test patients’ responsiveness to investigational CFTR modulators — compounds that act directly on the faulty protein that causes CF.

“Access to CFTR modulators in Europe is challenged by either the ineligibility of patients for approved drugs due to their genotype, or by the lack of reimbursement for approved drugs due to their high cost,” Cornelis K. van der Ent, professor at the Wilhelmina Children’s Hospital at the University Medical Center Utrecht, in the Netherlands, and HIT-CF project coordinator, said in a press release.

“An organoid-assay-based personalized medicine approach offers the potential of a new decision-supporting technology to inform clinical decisions, and provide each patient with CFTR modulators that lead to their highest possible benefit,” van der Ent said.

Proteostasis’ CFTR modulators include dirocaftor, previously known as PTI-808, the CFTR corrector posenacaftor (PTI-801), and the CFTR amplifier nesolicaftor (PTI-428).

According to data presented in the poster, 329 biopsies have been collected so far within the HIT-CF project, and the rate of success in the establishment of organoids is approximately 95%.

Importantly, researchers are on track to complete tissue collection — for a total of 500 samples — by April. Patients with mutations that lead to the absence of CFTR protein are excluded from the study.

Identifying CF patient-derived organoids that respond favorably to the therapeutic agents is a first step in establishing whether these mini-organs can be used to personalize treatment for people with CF.

Based on the organoids’ responses, the researchers will select a group of patients to enroll in a confirmatory Phase 3 clinical study, Crossover trial based on Human Organoid Individual response in CF – Efficacy Study. This CHOICES trial will assess Proteostasis’ CFTR modulators and their combinations.

Results from the CHOICES trial may help identify potential personalized therapies for CF patients with rare mutations.

“With advancements in models such as organoid testing used to predict the effectiveness of CFTR modulator treatments, the transition from precision to personalized medicine in this disease is an inevitability,” said Geoffrey Gilmartin, MD, chief medical officer of Proteostasis Therapeutics. “Essential to this transition is the introduction of more therapeutic options that expand the treatment choices for patients and physicians.”

Data from a previous Phase 2 trial testing the triple combo in CF patients carrying the F508del mutation showed the therapy led to significant improvements in lung function.

Now, preliminary results from a dirocaftor and posenacaftor combination used in organoids with ultra-rare mutations showed that 31% of the assessable organoids were responsive to treatment. The data also showed that these results were superior to the response reported in literature with Orkambi in organoids with the F508del mutation in both CFTR copies.

Proteostasis plans to also test the triple combination of Proteostasis’ CFTR modulators in the future, and to launch the CHOICES trial in mid-2020.

“As the only company in the HIT-CF consortium with a proprietary combination of novel CFTR modulators that have demonstrated positive Phase 2 data, we remain very enthusiastic about its progress and the translation of these results to the clinic in the CHOICES trial,” Gilmartin said.