The failure of Inflarx’s IFX-1 had already sown doubts about Chemocentryx’s similarly acting lead project, avacopan, in the skin disease hidradenitis suppurativa. Now it seems Chemocentryx is going to ignore a new red flag: despite the phase II Aurora study of avacopan being a bust, the company is pushing into phase III.
The group will no doubt point to the fact that it saw a signal in more severe patients as a reason for continuing development in this population. Chemocentryx has plenty of cash to fund another trial, but maybe its money would be more wisely spent running another small phase II study in severe patients, or indeed advancing other pipeline projects.
Aurora fails to shine
Chemocentryx attempted to spin the Aurora trial as a success, with its press release heralding “positive” topline data. But in fact this failed to meet its primary endpoint, the proportion of patients achieving hidradenitis suppurativa clinical response (HiSCR) at week 12. This was true of both twice-daily doses studied, 10mg and 30mg, with placebo subjects doing numerically better than those on the lower dose.
But the company claimed a statistically "significant improvement" with the higher dose in the more severe patients enrolled, those with Hurley Stage III disease. However, even if this subgroup was prespecified, as Chemocentryx asserted, such a finding can still only be considered exploratory given the failure of the primary endpoint.
And the result came in a fairly small number of patients. Around 35% of those in Aurora were classed as Hurley stage III, while around 65% had less severe Hurley stage II disease.
|Proportion of patients achieving HiSCR in Aurora|
|Placebo||Avacopan 10mg BID||Avacopan 30mg BID|
|Hurley Stage II||35%||21%||31%|
|Hurley Stage III||22%||24%||43%*|
|*Nominal p value of 0.0349. HiSCR response is defined as a ≥50% reduction in inflammatory lesion count and no increase in abscesses or draining fistulas. Source: company release.|
This has not deterred Chemocentryx – the company will now focus on Hurley stage III patients. But the market was unimpressed, with the group’s stock opening down 12% today.
Leerink analysts were inexplicably positive about the data: while they acknowledged that “some investors may be disappointed”, they added that the “results seem to be pointing in the right direction”. They increased their probability of success for avacopan in hidradenitis suppurativa from 40% to 50%.
This seems like misplaced optimism – pushing into pivotal trials after a phase II flop rarely ends well, as demonstrated by Catabasis earlier this week.
And it is not like Chemocentryx does not have other irons in the fire. Avacopan is awaiting US approval in another indication, ANCA-associated vasculitis, after positive phase III data last year (Chemocentryx soars on superior avacopan, November 26, 2019).
And more results with the project are coming soon, from the Accolade trial in C3 glomerulopathy.
Still, hidradenitis suppurativa would be a lucrative prize. The only approved therapy is Abbvie’s Humira, which has only moderate efficacy yet still brings in over $1bn per year in the disorder, according to Chemocentryx.
But even if it gets a win in phase III, the company will only be able to target the 35,000-50,000 US patients with severe disease, rather than the overall population of around 200,000. Victory is far from assured.
|Selected mid to late-stage industry-sponsored trials in hidradenitis suppurativa|
|Project||Company||Mechanism of action||Trial details|
|Cosentyx||Novartis||IL-17 antibody||Sunshine (NCT03713619), ends Jul 2021|
|Bimekizumab||UCB||IL-17A & IL-17F antibody||Be Heard I (NCT04242446), Be Heard II (NCT04242498), both end May 2022|
|IFX-1||Inflarx||Complement factor C5a antibody||Shine (NCT03487276), failed 2019, company continues discussions with regulators|
|Xilonix||Johnson & Johnson||IL-1A antibody||NCT04019041, completed May 2020|
|Avacopan||Chemocentryx||Complement factor C5a inhibitor||Aurora (NCT03852472), failed Oct 2020|
|Skyrizi||Abbvie||IL-23 antibody||Determined 1 (NCT03926169), ends Feb 2021|
|Rinvoq||Abbvie||Jak1 inhibitor||NCT04430855, ends Jun 2021|
|LY3041658||Lilly||CXCR1 & CXCR2 antibody||NCT04493502, ends Dec 2021|
|INCB54707||Incyte||Jak1 inhibitor||NCT04476043, ends Dec 2021|
|PF-06650833||Pfizer||Irak4 inhibitor||NCT04092452, ends Jan 2022|
|PF-06700841||Pfizer||Tyk2 inhibitor; Jak1 inhibitor||NCT04092452, ends Jan 2022|
|PF-06826647||Pfizer||Tyk2 inhibitor||NCT04092452, ends Jan 2022|
|Iscalimab (CFZ533)||Novartis||CD40 antibody||NCT03827798, ends Sep 2022|
|LYS006||Novartis||Unknown||NCT03827798, ends Sep 2022|
|Source: EvaluatePharma, clinicaltrials.gov.|