Interest in Tyk2 might soon tick up

Pfizer is still the only big pharma to have followed Bristol's lead in going all-in on the mechanism.

Spotlight

Bristol Myers Squibb is clearly a big believer in Tyk2 inhibition. The group has involvement in three clinical projects using this mechanism, including deucravacitinib, which scored in its first phase III trial in psoriasis last week.

A lot will depend on the detailed data, but Bristol has long maintained that deucravacitinib has similar efficacy to biologicals, with oral convenience. Perhaps it is a wonder, then, that there appears to be so little interest in Tyk2 from other big pharmas – with the exception of Pfizer.

Like Bristol, Pfizer has a pure Tyk2 inhibitor, PF-06826647. And a key test of this asset is coming up, with data due early next year from a phase II study in psoriasis – the same setting in which deucravacitinib triumphed.

But unlike Bristol, which has a raft of studies ongoing with deucravacitinib in various indications, Pfizer is carrying out a much less extensive programme with PF-06826647.

Safety first

A big focus for upcoming readouts will be safety, given that Tyk2 is part of the Jak family and some Jak inhibitors have seen issues with infections and blood clots.   

In deucravacitinib's phase II psoriasis study higher rates of adverse events were seen with higher doses of the project, 6mg twice daily and 12mg once-daily, explaining why Bristol went for a 6mg daily dose in Poetyk-PSO-1.

And safety was obviously a focus during Bristol’s earnings call last week, with several analysts asking for more details on deucravacitinib’s adverse-event profile. All the company said when it reported the topline win in Poetyk-PSO-1, a pivotal study in psoriasis, was that that side effects were consistent with earlier trials.

The group did not give much away on the call either, with Samit Hirawat, Bristol’s chief medical officer, saying these data were being reserved for a future medical meeting. He added: “We’re very happy with where we are.”

Still, fresh phase II data in psoriatic arthritis might reassure investors. A late-breaking abstract released last week by the American College of Rheumatology conference concluded that there were no deucravacitinib-related serious adverse events, with no serious infections or thrombotic events.

The 6mg daily dose also performed well versus placebo in terms of efficacy, as the chart below shows.

Phase II data with deucravacitinib in psoriatic arthritis. Source: American College of Rheumatology.

The toxicity issues with Jaks are thought to thought to be due to these drugs’ broad activity across various Jak subtypes. By not hitting Jak2 and 3 it is thought that Tyk2 inhibitors could also sidestep these adverse events.

Pfizer also has a Tyk2/Jak1 inhibitor in development, brepocitinib (PF-06700841), that could in theory also avoid these problems. Topical and oral versions of this project are in a huge number of phase II trials, summarised below.

However, mixed data on topical brepocitinib in atopic dermatitis were recently presented at the European Academy of Dermatology and Venereology (EADV) meeting. There was an apparent lack of dose response, with a 3% daily dose not meeting the primary endpoint, change in Easi score versus placebo, although the 1% daily and 1% twice-daily doses did show an effect.

And two cases of rhabdomyolysis in a phase II trial of oral brepocitinib in alopecia areata were likely behind Pfizer’s decision to focus on its Jak3 inhibitor ritlecitinib (PF-06651600) here.

Other projects, including one being developed by Theravance and Johnson & Johnson, act more broadly across the Jak family, raising questions about toxicity.

However, Theravance/J&J’s TD-1473 is thought to act locally in the gut with minimal systemic absorption, which could reduce potential for side-effects. This project is only being investigated in inflammatory bowel diseases, but Theravance also has two wholly owned inhaled pan-Jak inhibitors, TD-8236 and TD-0903, being tested in asthma and Covid-19 respectively.

Oncostellae is also taking a targeted approach with its gut-restricted contender, OST-122.

Still, others have not fared so well with Tyk2/Jak combos: Galapagos recently stopped a phase I of its Jak1/Tyk2 inhibitor, GLPG3121, owing to an undesirable pharmacokinetic profile. The asset is still listed on Galapagos's pipeline as an “optionable partner programme”.

Bristol, meanwhile, has another Tyk2 inhibitor in phase I, and the option on another being developed by Nimbus Therapeutics. However, for now, all eyes are on deucravacitinib.

Selected clinical-stage projects targeting Tyk2
Project Company Status Trial details
Deucravacitinib (BMS-986165) Bristol Myers Squibb Psoriasis (ph3) Poetyk-PSO-1 (NCT03624127) succeeded, Poetyx-PSO-2 (NCT03611751) data due Q1 2021
Psoriatic arthritis (ph2) NCT03881059, due at ACR Nov 2020
Ulcerative colitis (ph2) NCT03934216, ends 2021
Crohn's disease (ph2) NCT03599622, ends 2023
Lupus nephritis (ph2) NCT03943147, ends 2023
Systemic lupus erythematosus (ph2) NCT03920267, ends 2023
PF-06826647 Pfizer Psoriasis (ph2) NCT03895372, data due H2 2020
Hidradenitis suppurativa (ph2) NCT04092452, ends 2022 (also includes brepocitinib & PF-06650833 arms)
Ulcerative colitis (p2) NCT04209556, ends 2023
Topical brepocitinib (PF-06700841)* Pfizer Atopic dermatitis (ph2) NCT03903822, data reported at EADV
Psoriasis (ph2) NCT03850483, ends 2021
Oral brepocitinib (PF-06700841)* Pfizer Psoriatic arthritis (ph2) NCT03963401, primary completion Apr 2020 but remains ongoing
Systemic lupus erythematosus (ph2) NCT03845517, ends 2022
Hidradenitis suppurativa (ph2) NCT04092452, ends 2022 (also includes PF-06826647 & PF-06650833 arms)
Ulcerative colitis (ph2) NCT02958865, ended Oct 2020 (also includes ritlecitinib (PF-06651600) arm)
Vitiligo (ph2) NCT03715829, ends 2021 (also includes ritlecitinib (PF-06651600) arm)
Crohn's disease (ph2) NCT03395184, ends 2022 (also includes ritlecitinib (PF-06651600) arm)
TD-1473** Theravance Biopharma/ Johnson & Johnson Ulcerative colitis (ph2/3) Rhea (NCT03758443), data due 2021
Crohn's disease (ph2) Dione (NCT03635112), data due 2021
OST-122*** Oncostellae Ulcerative colitis (ph1/2) NCT04353791, ends 2021

BMS-986322

Bristol Myers Squibb Ph1 in healthy volunteers NCT04175925, ended Oct 2020 
Tyk2 Allosteric Inhibitor Research Program Nimbus^ Ph1 N/A

Notes: *also hits Jak1; **also hits Jak1-3; ***also hits Jak3 & ARK5; ^Bristol Myers Squibb has option. Sources: EvaluatePharma, clinicaltrials.gov.

This story has been updated to clarify the ownership of Nimbus's Tyk2 inhibitor.

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