Mutations of the CFTR gene cause CF. The most common is F508del, which leads to faulty CFTR protein.
Normal CFTR protein is required for transporting chloride ions through cell membranes. This helps generate the thin mucus the body needs to protect and lubricate organs and tissues. Abnormal CFTR protein leads to an accumulation of thick mucus in organs, impairing breathing and digestion.
PTI-428 increases the amount of an immature form of CFTR protein, which can then be targeted by other CFTR-based therapies.
The FDA’s designation covers PTI-428 as a treatment for patients with two copies of the F508del mutation — one from their mother and one from their father — who are receiving Vertex’s Orkambi (lumacaftor/ivacaftor).
Regulators based their decision on the results of a Phase 2 trial (NCT02718495) of PTI-428 in 24 CF patients who were taking Orkambi. Patients received either 50 mg of PTI-428 once a day or a placebo for 28 days.
PTI-428 improved patients’ lung function. The measurement was forced expiratory volume, or how much air is exhaled after a deep breath.
It also increased CFTR protein levels in nasal mucous.
“We believe the Breakthrough Therapy Designation for PTI-428 reflects the strength of the recent Phase 2 study results for our amplifier, a novel and proprietary class of CFTR modulators,” Meenu Chhabra, the president and CEO of Proteostasis, said in a press release.
“PTI-428 can potentially be added to current and future standards of care, offering the potential for improvement in pulmonary function for patients with cystic fibrosis. We look forward to working closely with the FDA as we advance our clinical [trial] programs for PTI-428,” Chhabra added.
Proteostasis is also developing PTI-428 as part of a triple combo treatment that includes PTI-808, a potentiator, and PTI-801, a corrector. A Phase 1 clinical trial of the combo is expected to start in the first half of 2018. Top CF advocacy groups in the U.S. and Europe have endorsed the idea of testing the combo.
A breakthrough therapy designation is given to potential medications that, either alone or in combination with other products, may be able to treat a serious or life-threatening disease. Before a treatment receives the designation, its developer must show in preclinical-trial studies that it is likely to be better than existing treatments.