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TYK2 INHIBITOR: Novel oral agent shows unprecedented efficacy in psoriasis.


PARIS -- A novel oral small molecule that selectively targets tyrosine kinase 2 signaling pathways critical in the pathogenesis of psoriasis performed impressively in a phase 2 clinical trial including 267 adults with moderate to severe disease, James G. Krueger, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

"I would say the clinical response here is almost dead-on as a copy for ustekinumab, which is an [injectable interleukin] IL-23/IL-12 blocker. And we're only at 12 weeks here; some of the curves look like they're on a trajectory to go up further in terms of improvement. So I'm getting a performance with an oral drug that is just so much better than the approved alternatives that we have," said Dr. Krueger, head of the laboratory of investigative dermatology and professor in clinical investigation at Rockefeller University in New York.

Oral apremilast (Otezla), for example, can't touch those PASI 75 response rates in patients with moderate to severe psoriasis. Indeed, many psoriasis experts favor reserving apremilast for patients with moderate disease.

The 12-week, double-blind, placebo-controlled study was conducted at 82 sites in the United States and seven other countries. In this dose-ranging study, participants were randomized to the oral selective tyrosine kinase 2 (TYK2) inhibitor, known for the time being as BMS986165, at 3 mg every other day, 3 mg daily, 3 mg twice a day, or 6 mg twice a day, 12 mg daily, or to placebo.

The primary outcome was a 75% or greater reduction from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 12. The TYK2 inhibitor outperformed placebo in dose-dependent fashion starting at the 3-mg/day dose. The PASI 75 rate was 7% with placebo, 9% with 3 mg of BMS-986165 every other day, 39% with 3 mg daily, 69% with 3 mg BID, 67% with 6 mg BID, and 75% with 12 mg/day. All secondary endpoints followed suit (see table).

A striking finding in the phase 2 study was that, when the drug was stopped for a month at the end of the 12-week treatment period, for the most part, the PASI 75 response and other clinical benefits were retained.

"I would contrast this to experiments that I have personally done with cyclosporine, where I have cleared people with cyclosporine, stopped it, and a month later every single patient has rip-roaring disease back. So I think this TYK2 inhibitor has some different performance features than just blocking a downstream T-cell transduction molecule," observed the dermatologist, who is credited as the discoverer of the importance of the T cell in psoriasis pathogenesis.

The strong multidimensional evidence of clinical efficacy in the phase 2 study was supported mechanistically by analysis of skin biopsies obtained on study days 1, 15, and 85. The laboratory studies showed that the oral drug improved molecular, cellular, and clinical biomarkers associated with treatment efficacy. For example, at doses of 3 mg twice a day or higher, the TYK2 inhibitor reduced expression of IL-19 and IL-36A, which are key drivers of keratinocyte activation and epidermal hyperplasia.

The drug also markedly decreased expression of genes in the Th17 pathway and essentially normalized expression of the proinflammatory genes beta-defensin and S100A9.

In contrast to the Janus kinase (JAK) 1/3 and JAK 2 inhibitors in development for treatment of psoriasis, which paint with a much broader brush, the TYK2 inhibitor is highly selective for IL-23, IL-12, and interferon-alpha.

"Previous studies have shown pan-JAK inhibition can be very effective in remitting psoriasis. The problem is that, if one inhibits JAK1 and JAK 3, one blocks the transduction of effector cytokines that are essentially there for protective immunity. That could lead to undesirable levels of immuno-suppression," Dr. Krueger explained.

The most important cytokine in the pathogenesis of psoriasis is clearly IL-23, he continued. In cell-based assays, the TYK2 inhibitor has been shown to be 100 times more selective in inhibiting IL-23, IL-12, and interferon-alpha than JAK 1/3 inhibitors and 3,000 times more selective than JAK 2 inhibitors. This high degree of selectivity makes for fewer off-target effects and for a favorable safety profile.

"There were no major safety signals that would lead you to be concerned," Dr. Krueger said. Indeed, based upon the encouraging safety and efficacy demonstrated in this phase 2 study, a phase 3 pro gram known as POETYK-PSO is underway (POETYK-PSO-1 and POETYK-PSO-2).

The phase 2 clinical trial results were published online in conjunction with the EADV congress.

The TYK2 inhibitor is being developed by Bristol-Myers Squibb. Dr. Krueger reported receiving personal fees as well as research grants paid directly to Rockefeller University from that pharmaceutical company and numerous others.

Please Note: Illustration(s) are not available due to copyright restrictions.


SOURCE: Papp K et al. N Engl J Med. 2018 Sep 11. doi: 10.1056/NEJMoa1806382.

Caption: Dr. James G. Krueger
12-week outcomes with oral TYK2 inhibitor in moderate to severe

Endpoint              Placebo      3 mg every    3 mg
                                   other day     daily

PASI 75                   7%           9%         39%
Static Physician's        7%           20%        39%
Global Assessment
score of 0 or 1
PASI 50                  31%           43%        68%
PASI 90                   2%           7%         16%
PASI 100                  0            2%          0
Dermatology Life          4%           16%        16%
Quality Index
score of 0 or 1

Endpoint              3 mg twice   6 mg twice    12 mg
                      a day        a day         daily

PASI 75                  69%           67%        75%
Static Physician's       76%           64%        75%
Global Assessment
score of 0 or 1
PASI 50                  91%           78%        89%
PASI 90                  44%           44%        43%
PASI 100                  9%           18%        25%
Dermatology Life         42%           60%        64%
Quality Index
score of 0 or 1

Note: The randomized, double-blind, placebo-controlled phase 2 study
included 267 patients.

Source: N Engl J Med. 2018 Sep 11. doi: 10.1056/NEJMoa1806382
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Author:Jancin, Bruce
Publication:Dermatology News
Date:Nov 1, 2018
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