Conference Coverage

Novel oral orphan drug tames pemphigus

 

Key clinical point: A novel oral noncorticosteroid specifically targeting B-cell function showed promising safety and efficacy in a phase 2 study for pemphigus.

Major finding: Five of 12 pemphigus vulgaris patients achieved control of disease activity within the first 4 weeks on the investigational oral Bruton tyrosine kinase inhibitor PRN1008.

Data source: An interim analysis of the first 12 patients with pemphigus vulgaris in an ongoing multicenter, international open-label, phase 2 clinical trial.

Disclosures: The study presenter reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008 and sponsored the Believe-PV trial.


 

AT THE EADV CONGRESS

– An oral reversible Bruton tyrosine kinase inhibitor known as PRN1008 showed promising efficacy and safety for the treatment of pemphigus vulgaris in an interim analysis of an ongoing small-to-date, open-label phase 2 study, according to DeDee Murrell, MD.

PRN1008 is a designer drug intended as an alternative to the long-standing standard therapy for pemphigus, months to years of moderate- or high-dose systemic corticosteroids, with all the debilitating side effects that sledgehammer approach often brings, she said at the annual congress of the European Academy of Dermatology and Venereology.

Dr. DeDee Murrellprofessor of dermatology at the University of New South Wales Medical School in Sydney, Australia Bruce Jancin/Frontline Medical News
Dr. DeDee Murrell
The novel agent, which has been granted orphan drug status by the Food and Drug Administration, was designed to revamp B-cell function without reducing B-cell numbers. PRN1008 is a highly potent and selective inhibitor of Bruton tyrosine kinase (BTK), an enzyme that plays a major role in the signaling pathway running downstream from B cells to the B-cell receptors found on most white blood cells with the exception of T cells and plasma cells.

Thus, PRN1008 inhibits a range of inflammatory cellular activities in mast cells, neutrophils, and other cells activated in autoimmune diseases, without killing those cells or directly affecting T cells. And – like corticosteroids – it works quickly, according to Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.

“The development of an oral, fast-acting treatment that could safely and effectively modulate B-cell function without depleting B cells would be a major advance in treating autoimmune diseases like pemphigus, vasculitis, immune thrombocytopenic purpura, multiple sclerosis, and rheumatoid arthritis,” she said.

Also, PRN1008 was designed to provide durable inhibition of BTK, coupled with rapid systemic clearance of the drug in order to minimize side effects.

The ongoing phase 2 multicenter international study, known as Believe-PV, to date includes 12 patients with biopsy-proven mild to moderate pemphigus vulgaris. Five patients were newly diagnosed and treatment naive, while seven had relapsing disease. All were placed on fixed-dose PRN1008 at 400 mg b.i.d. for 12 weeks with low-dose prednisone as needed, then followed for an additional 12 weeks off PRN1008 to evaluate the durability of responses.

The primary study endpoint was control of disease activity by week 4 on a background of little or no prednisone, which 5 of 12 patients achieved. The secondary endpoint of complete clinical remission at 12 weeks was achieved in half of patients. Total pemphigus disease activity index (PDAI) scores dropped throughout the study period, reaching a mean 70% reduction at 12 weeks from a baseline of 20 points. Scores on the autoimmune bullous quality of life metric improved by 43%.

Eight of the 11 individuals who completed the study had control of disease activity by week 4 and/or complete clinical remission at 12 weeks. Those results are comparable with those typically seen with high-dose steroids at 12 weeks, the dermatologist noted.

Levels of anti–desmoglein-1 and/or -3 autoantibodies, which were elevated at baseline in 10 of 12 subjects, decreased during treatment with PRN1008.

Seventy-five percent of Bruton tyrosine kinase receptors were occupied by PRN1008 by day 2 of the study, confirming earlier studies in canine models of pemphigus. It turns out that pemphigus foliaceus is as common in dogs as atopic dermatitis is in humans, according to Dr. Murrell.

Side effects were limited to mild headache in two patients. One patient developed serious grade 3 cellulitis. She was taken off the study medication, although it was deemed unlikely that the infection was treatment related because she had had a recent history of multiple episodes of cellulitis.

During the second 12-week phase of the trial, after discontinuation of PRN1008, most patients retained their on-treatment reduction in total PDAI scores.

Dr. Murrell noted that the gradient of improvement in PDAI scores seen with PRN1008 in the Believe-PV study was quite similar to that seen in a recent 90-patient French randomized trial of rituximab (Rituxan) for the treatment of pemphigus. That’s of considerable interest, she said, because rituximab is a much more powerful drug, which drastically depletes the B-cell population. Moreover, the gradient of improvement in the rituximab-treated patients in the French trial was achieved with the aid of moderate-dose prednisone at 1 or 1.5 mg/kg per day, while PRN1008-treated patients in Believe-PV were taking on average only 0.2 mg/kg per day.

Asked if she thinks PRN1008 has a future as a stand-alone treatment for pemphigus or is better suited as an adjunct to systemic corticosteroids, Dr. Murrell said she believes the drug can be used effectively without steroids. However, since it’s recommended that patients be screened for tuberculosis before going on rituximab, and PRN1008 also targets B cells, she and her coinvestigators followed the same practice in Believe-PV. And because it takes a couple of weeks for the results of the Quantiferon-TB Gold In-Tube test to come back, it would be unethical for patients newly diagnosed with pemphigus to go untreated and in pain during that period, they get corticosteroids, at least initially.

Dr. Murrell reported serving as a paid consultant to Principia Biopharma, which is developing PRN1008.

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