8:39 PM
Apr 21, 2017
 |  BioCentury  |  Product Development

Playing JAKs

How cytokine-level thinking is guiding Pfizer’s clinical immunology plans

A desire to improve upon marketed autoimmune drug Xeljanz tofacitinib, coupled with interesting biological findings, led Pfizer Inc. to develop a portfolio of selective Janus kinase inhibitors that are taking the target into new disease areas.

A broad Phase II program is designed to study each molecule in one or a couple of lead indications that could give hints about how it will perform in several others. Data emerging in the 2018-19 time frame will help the pharma find the most likely indications for monotherapy and combination regimens.

Xeljanz is an oral pan-JAK inhibitor approved to treat rheumatoid arthritis. Collectively, JAK kinases mediate the effects of cytokine signaling. There are four members of the JAK family: JAK-1, -2 and -3, and tyrosine kinase 2 (TYK2).

In RA, pan-JAK inhibition broadly suppresses the activity of TNF, growth factors and hormones, giving oral Xeljanz efficacy that has been shown to be comparable to marketed TNF inhibitors that must be injected. But in other indications like psoriasis, the mechanism has not been as effective as other classes of drugs, including IL-17 inhibitors now flocking to the market.

In addition, as is the case with most autoimmune therapies, pan-JAK inhibition has immunosuppressive effects that increase risk of opportunistic infections.

Michael Vincent, SVP and CSO of Pfizer’s inflammation and immunology unit, told BioCentury Xeljanz’s immunosuppressive side effects may be more strongly dose-dependent than its efficacy, and Pfizer hoped molecules that selectively inhibited different members of the JAK family might help separate out therapeutic activity from risk.

The pharma also hypothesized that molecules with differential inhibition profiles might boost efficacy in different indications.

For instance, Vincent said clinical data from biologics that inhibit IL-17 suggest that pathway is important in psoriasis. Inhibiting TYK2 reduces the activity of IL-12 and IL-23, which in turn reduces production of...

Read the full 1527 word article

User Sign in

Trial Subscription

Get a 4-week free trial subscription to BioCentury

Article Purchase

$150 USD
More Info >