A positive phase II readout for Bristol-Myers Squibb Co.'s lead oral tyrosine kinase 2 (Tyk2) inhibitor in plaque psoriasis has shone a new light on signaling pathways explored by few drugmakers to date. Despite the pathway's implication in multiple immune-mediated diseases, the phase III program BMS is actively enrolling for patients with moderate to severe plaque psoriasis puts it at the head of a cohort that includes just two other clinical-stage drugs of the class – both Pfizer Inc.'s – and only four discovery-stage assets, according to Cortellis.
The class has been explored for years, with animal research starting at least as far back as 2003, when work out of Brown University identified a natural mutation in Tyk2 as underlying altered susceptibility of mice to infection and autoimmunity. Since then, however, only 11 programs have progressed far enough to gain much notice, including the four in discovery, another four with no reported development and one discontinued program.
This week, BMS established itself as the leader of the two-company clinical race with Pfizer, at least for the moment, with the revelation of phase II data from its randomized double-blind, placebo-controlled study of BMS-986165 in 267 adults with moderate to severe plaque psoriasis.
Data from the IM011-011 study, published in The New England Journal of Medicine, showed a 75 percent reduction in Psoriasis Area and Severity Index (PASI 75) in 7 percent of patients receiving placebo, 9 percent of those receiving 3 mg every other day (p=0.49 vs. placebo), 39 percent for 3 mg every day (p<0.001), 69 percent for 3 mg twice daily (p<0.001), 67 percent for 6 mg twice daily (p<0.001) and 75 percent for 12 mg every day (p<0.001). The PASI 90 response rates were 2 percent, 7 percent, 16 percent, 44 percent, 44 percent and 43 percent, respectively. Complete clearance of lesions, or PASI 100 response rates, were 0 percent, 2 percent, 0 percent, 9 percent, 18 percent and 25 percent, respectively.
Based on those results, BMS is proceeding with enrollment of a pair of phase III studies of its oral selective Tyk2 inhibitor, BMS-986165. The program is called POETYK, for "PrOgram to Evaluate the efficacy and safety of BMS-986165, a selective Tyk2 inhibitor." In addition to evaluating '165 itself, the studies — POETYK-PSO-1 and POETYK-PSO-2 — will also compare its performance to Celgene Corp.'s blockbuster psoriasis and psoriatic arthritis drug, Otezla (apremilast), a PDE4 inhibitor.
Mary Beth Harler, BMS's head of innovative medicines development, identified '165 as having "a distinct mechanism of action."
Chrissy Trank, a spokeswoman for the Princeton, N.J.-based company, described Tyk2, an intracellular signaling kinase, as having the capability of mediating cytokine-driven immune and pro-inflammatory signaling pathways that are critical in the cycle of chronic inflammation central to immune-mediated diseases. "Tyk2 inhibition selectively blocks IL-23, IL-12 and type I IFN-driven responses, but not cytokine responses mediated by other kinases, such as IL-6, hematopoietic growth factors and the IL-2 family," she said.
Cortellis records indicate that '165 is already being tested in a double-blind, placebo-controlled phase II study among patients with moderate to severe Crohn's disease slated for completion in September 2021. Another study, investigating it in patients with systemic lupus erythematosus, is also listed as currently recruiting. That trial, conducted in collaboration with the Lupus Research Alliance and its affiliate, Lupus Therapeutics LLC, is estimated to be complete in July 2020.
New York-based Pfizer has also taken a serious interest in Tyk2 with its development of PF-06700841, a dual JAK1/Tyk2 inhibitor, for the potential oral treatment of plaque psoriasis, alopecia areata, ulcerative colitis and Crohn's disease. Results of a randomized phase IIa study of the drug and another candidate, PF-06651600, in 142 participants with moderate to severe alopecia areata are expected in August 2019. Results of a randomized phase II study of both drugs in a separate trial of 250 participants with severe Crohn's are expected in February 2021.
Pfizer is also developing PF-06826647, a Tyk2 inhibitor, for the potential oral treatment of psoriasis and inflammatory bowel disease. That program, currently in phase I, entered the clinic in July 2017 and is expected to be complete in January 2019.
Not to be left behind, Summit, N.J.-based Celgene is also exploring the nascent class though a strategic immunology alliance with Cambridge, Mass.-based Nimbus Therapeutics Inc. Although the financials of their partnership have not been disclosed, in October 2017 the big biotech took an option to acquire two programs, up through an undisclosed clinical inflection point, that include a preclinical effort targeting Tyk2. In describing the class, Nimbus has pointed to its "potential to replicate efficacy of Th17 biologics (anti-IL23, anti-IL17) with a small-molecule drug" and its ability to avoid being inhibited by 'Jakinibs' (e.g. tofacitinib and others) at clinical doses." (See BioWorld, June 6, 2018.)
Beyond Nimbus and Celgene, the organizations listing Tyk2 inhibitors in discovery include Cambridge, U.K.-based Sareum Holdings plc, which is working with Menlo Park, Calif.-based SRI International on both autoimmune and oncology applications, and Osaka, Japan-based Takeda Pharmaceutical Co. Ltd., which has said little about the class publicly to date. The University of North Carolina is also thought to be investigating inhibitors of the Src pathway, including the Src activator Tyk2, for the potential treatment of renal cell carcinoma.
The safety profile of the class is still coming into focus. In its phase II study of '165, BMS investigators reported that nasopharyngitis, headache, diarrhea, nausea and upper respiratory tract infection were the most common adverse events (AEs). There were three serious AEs reported in the active groups and two in the placebo group.
In the years ahead, the safety, efficacy and the commercial potential for the class are likely to become clearer as further trial readouts appear. Meanwhile, optimism seems to reign among those actively involved in testing the pathway's potential to make a meaningful impact for patients.