With phase III trial enrollment underway and expected to enroll about 120 patients, South San Francisco-based Principia Biopharma Inc. disclosed positive preliminary data from its phase II open-label trial testing the oral Bruton tyrosine kinase inhibitor PRN-1008 against pemphigus vulgaris (PV).

Part B of the study tested six months of PRN-1008 therapy compared to three months in part A. Between the trial’s two portions, Principia has seen consistent safety and efficacy data in about 40 patients. Among the 15 in part B, six (40%) have reached a complete response (CR), with four patients on treatment who still might. “That 40% can only get better,” CEO Martin Babler pointed out during a conference call with investors. PV is a rare, blistering autoimmune disorder in which the system mistakenly attacks desmogleins, proteins that keep skin cells attached and the skin intact.

Five patients were unable to achieve a CR. So far, nine (60%) of the 15 enrolled in part B have achieved a Pemphigus Disease Area Index score (where low numbers are better) of 1 or 0. For the primary efficacy endpoint – control of disease activity – results have been similar in part A and part B. Regarding speed of onset, “we see a very similar pattern,” Babler said. “But remember, we started these patients at a lower dose, so you do see a dose-response difference between the two, but ultimately we are seeing a deepening of response over the 24 weeks.” In part B, a starting dose of 400 mg once daily was tested and found to be less effective. At the recommendation of the safety monitoring committee, all patients were escalated to twice-daily dosing.

Earlier in the year, Principia made public positive part A trial data that included 27 patients with pemphigus (including PV and pemphigus foliaceus), showing PRN-1008’s potential to induce quick responses, enable tapering and/or avoidance of corticosteroids (CS) use, and lower autoantibody levels. In part A, the CR rate was 25% for those patients who had been on therapy for 12 weeks.

The preliminary data in part B are consistent with part A and no additional serious adverse events turned up at doses as high as 600 mg twice daily, the company noted. More data from the trial will be submitted for presentation at a medical conference and, with the last patient enrolled in June, Principia expects to provide another update by the end of the year. Meanwhile, the firm’s chief medical officer, Dolca Thomas, said that, “since the trial is still ongoing, we need to finalize the total data collection to look at all the factors that may influence a response. It’s preliminary, really, to say” what might be the relationship between characteristics brought by patients to the trial and their responses. Principia presented the findings available so far at the European Academy of Dermatology and Venereology meeting in Madrid, Spain.

In the phase III effort called Pegasus, testing the drug at its twice-daily 400-mg dose, the primary efficacy endpoint is to assess whether PRN-1008 could drive durable complete remission on very low-dose CS (≤5 mg/day) after 36 weeks of treatment. Durable complete remission is reached when all lesions have healed, and no new ones have appeared for at least eight weeks. Key secondary endpoints are cumulative CS use and time to complete remission. After 36 weeks, all patients are to be treated with PRN-1008 therapy in an open-label extension period of 24 weeks. Wainwright analyst Joseph Pantginis noted in a report that “importantly, the trial size of the phase III is similar to those of two recent randomized, controlled, phase III trials investigating Rituxan [rituximab, Roche Holding AG and Biogen Inc.] and Arzerra [ofatumumab, Novartis AG] in PV.” Data are expected in the first half of 2022.

Not alone in PV

Two standards of care exist today for PV: Rituxan and CS. “By looking at historical data (six months of treatment), PRN-1008 has demonstrated a faster and deeper response than steroids,” Pantginis said. “As for Rituxan, limited data are present for six months of treatment” but “available data point to a limited CR rate. Overall, these observations along with PRN-1008’s clinical activity registered thus far reinforce the competitive advantage of PRN-1008 as opposed to standards of care, in our belief,” he added, calling the Principia candidate “a real therapeutic option for PV, which may accelerate Pegasus’ trial enrollment by offering patients a differentiated option.”

Principia has the same drug at the phase II stage for immune thrombocytopenia (ITP). “I’m not sure yet how this translates into ITP, and we’ll have to look at that once we get the ITP data,” Babler said. “Pemphigus is a great model disease for other autoimmune diseases, and basically, what we know from this data now with about 40 patients is that we are [having an anti-inflammatory effect].”

Leerink’s Geoffrey Porges liked the PV data, too, though he said in a report that “so far, Principia has not been able to answer the question of whether patients who fail prior Rituxan respond to PRN-1008, and whether PRN-1008’s responses are better than Rituxan’s on an unselected basis. Ultimately, we would like to see the company do a study [or fund an investigator-sponsored study] looking at PRN-1008 in patients with prior Rituxan experience, and in treatment-naïve patients head-to-head vs. Rituxan.”

Shares of Principia (NASDAQ:PRNB) closed Thursday at $27.74, up 95 cents.

Another player in the space is Argenx SE, of Breda, the Netherlands, which is advancing efgartigimod, described as a first-in-class antibody fragment being evaluated for the treatment of patients with severe autoimmune diseases associated with high levels of pathogenic immunoglobulin G. The drug is believed to degrade circulating disease-causing autoimmune antibodies and is being investigated for indications such as myasthenia gravis and ITP. In PV, a phase II trial is enrolling with the neonatal Fc receptor binder.

About a year ago, Philadelphia-based Cabaletta Bio Inc. raised $38 million in a series A round for its PV push. The firm signed an exclusive license agreement and executed two multiyear sponsored research deals with the University of Pennsylvania to discover and develop engineered T-cell therapy products in the space.

The lead asset, bound for clinical work, is DSG3-CAART. Cabaletta’s approach uses chimeric autoantibody receptors (CAAR) T cells to bind and destroy the disease-linked B cells, keeping normal ones safe. Specifically, DSG3-CAART is designed to eradicate the B cells that produce autoantibodies to the desmosomal glycoprotein desmoglein 3. (See BioWorld, Nov. 9, 2018.)

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