Lilly’s oral interleukin exit hints at a dicey future

Liver toxicity with the group’s oral IL-17 inhibitor could raise doubts about projects from Dice, Leo and Sanofi.

Injectable antibodies against interleukin-17, such as Novartis’s Cosentyx, have proven big hits in autoimmune disease. This has led to various groups attempting to inhibit this cytokine with oral projects in an attempt to improve compliance and push use into mild disease.

However, efforts to develop an oral IL-17 inhibitor took a blow earlier this year when Lilly discontinued LY3509754. And last week it emerged that liver toxicity had been seen in a phase 1 study of the project, setting up a nervous time for the few remaining players in the space, which include Dice Therapeutics, Leo Pharma and Sanofi.

Dice is more exposed than Sanofi. The phase 1 oral IL-17 blocker DC-806 is the former’s lead asset, while Sanofi gained its preclinical project via a €7m ($8.4m) up-front licensing deal with C4X Discovery last year (C4X shows being early to the party can bring success, April 14, 2021).

Leerink analysts, who spotted the Lilly liver tox disclosure on clinicaltrials.gov, said the issue was likely specific to LY3509754, adding: “There is no intrinsic reason to believe that IL-17 inhibition should have liver-associated risk.” They added that Lilly’s discontinuation could in fact be good news for Dice, giving the young group one less competitor to worry about.

Still, this might not provide much comfort to investors in Dice, who have seen the company’s valuation halve since it floated last September. The group’s mission is to develop oral therapies against validated targets; as well as IL-17 inhibitors these include integrins and PD-1 inhibitors that, until recently, were being developed alongside Sanofi.

A big test is approaching, with topline data from a phase 1 study of DC-806 in healthy volunteers and psoriasis patients due in mid-2022.

Dice has an earlier-stage, potentially more potent oral IL-17 blocker, but other oral projects with this mechanism are few and far between.

Mymd Pharmaceuticals claims that its synthetic plant alkaloid MYMD-1 modulates several pro-inflammatory cytokines, including IL-17A, TNF-α and IL-6, while Immunic calls its asset IMU-935 both an IL-17 inhibitor and RORγt inverse agonist. Counterintuitively, that project is being tested in psoriasis as well as prostate cancer.

There are various other oral RORγt-targeting projects in development, such as Abbvie’s ABBV-157 and Dr Reddy's AUR-101, both in phase 2 for psoriasis. And other oral autoimmune mechanisms include Tyk2 inhibition, although there are questions about this approach after toxicity concerns with the rest of the Jak family.

This just shows that, even if Lilly’s exit is in Dice’s favour, the group has plenty more oral rivals to contend with.

Selected oral IL-17 inhibitors
Project Company Status
MYMD-1 Mymd Pharmaceuticals Ph2 in chronic inflammation associated with sarcopenia/frailty
DC-806 (S011806) Dice Therapeutics  Ph1 in healthy volunteers & psoriasis pts, topline data due mid-2022
LEO 153339 Leo Pharma Ph1 in healthy volunteers completes Nov 2022
DC-853 (Dice Novel Scaffold Immunology Program-1) Dice Therapeutics  Preclinical
Oral IL-17A inhibitor programme C4X/Sanofi Preclinical
LY3509754 Lilly Abandoned in ph1 (NCT04152382 & NCT04586920)
Source: Evaluate Pharma & clinicaltrials.gov.

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