Over the past couple of years Tyk2 inhibition has emerged as the most important novel mechanism to watch in autoimmune diseases. And the company that has made the biggest bet on it, Bristol-Myers Squibb, will this year deliver the first pivotal data with the most advanced Tyk2 inhibitor, BMS-986165.
A measure of Bristol’s confidence is that BMS-986165’s clinical programme aims to enrol over 6,000 subjects into phase I-III studies across several indications. The most advanced use, psoriasis, is the subject of two pivotal trials ending this year, and Bristol promises “initial results” from the first of these in late 2020.
Underpinning the confidence is basically one dataset: the results of a phase II psoriasis trial released in late 2018. These suggested that BMS-986165 could have the convenience and relatively clean safety profile of the PDE-4 inhibitor Otezla, but with higher efficacy.
Otezla, of course, was Celgene’s psoriasis blockbuster, but Bristol divested it to Amgen to satisfy US regulatory conditions of its Celgene acquisition. The concern was that Otezla and BMS-986165 together could constitute a monopoly, and the fact Bristol sold off the former and not the latter was a huge vote of confidence in Tyk2.
|% of market cap||4%|
|Event||Initial pivotal data in psoriasis|
The idea behind BMS-986165 is that it has efficacy in line with biologicals like Abbvie’s Humira and Novartis’s Cosentyx, with oral convenience. Otezla and Pfizer’s Xeljanz, a Jak inhibitor, are oral, but the former suffers from relatively lower efficacy, while broad Jak inhibition is associated with side effects including infections.
At this year’s JP Morgan conference Bristol said that in BMS-986165 it had potentially the best-in-class oral drug, with potential for biological-like efficacy with convenient administration. It is putting its money where its mouth is: the phase III Poetyk-PSO-1 and 2 studies test BMS-986165 head to head against Otezla.
Both measure as co-primary endpoints the numbers of patients achieving a PASI 75 score, and those with sPGA scores of 0 or 1, each at 16 weeks. With enrolment complete and no apparent delay due to Covid-19, Bristol expects data to be reported by the end of this year for the first study, it said on its second-quarter call.
In phase II the highest BMS-986165 dose saw 75% of patients score a PASI 75 at 12 weeks, and on a cross-study basis this looked strikingly better than Otezla’s 33%. The controlled head-to-head setting of a blinded, multicentre phase III trial means that the same margin of superiority is unlikely, but expectations will have been set nevertheless.
Bristol will also report phase II results with BMS-986165 in psoriatic arthritis, at a medical meeting; these data have been received, it says, and support beginning phase III. Mid-stage study results in lupus and ulcerative colitis are what it terms 2021+ events.
|Selected BMS-986165 trials|
|Poetyk-PSO-1 ('046)||Psoriasis||600||Vs placebo & vs Otezla||Aug 2020 (data late 2020)|
|Poetyk-PSO-2 ('047)||Psoriasis||1,000||Vs placebo & vs Otezla||Dec 2020 (data Q1 2021)|
|IM011-084||Psoriatic arthritis||180||Vs Stelara||Jan 2021 (data in house)|
|Lattice-UC||Ulcerative colitis||120||Vs placebo||Aug 2021|
|Paisley||Systemic lupus erythematosus||360||Vs placebo||Dec 2021|
What is still not clear is whether specific Tyk2 inhibition will deliver optimal efficacy and safety, or whether the mechanism should be combined with Jak, to which it is related. Bristol’s nearest competitor is Theravance/J&J’s Tyk2/Jak1-3 inhibitor TD-1473, though its phase II/III trials are in ulcerative colitis.
The biggest threat, meanwhile, probably comes from Pfizer, which has brepocitinib, a Tyk2/Jak1 inhibitor, and PF-06826647, a pure anti-Tyk2, in phase II. The latter also faces a key catalyst: a psoriasis study is due to read out in the second half.
Clearly Pfizer will not give up its Xeljanz franchise without a long fight. The size of the threat from Bristol will become apparent soon enough.