Just a day after Sanofi bought Kadmon, the French group got a reminder of the risks involved in acquisitions. Rilzabrutinib, one of the oral BTK inhibitors that Sanofi gained through its $3.7bn purchase of Principia, failed a phase 3 study in its lead indication, the skin disorder pemphigus.
Sanofi’s swoop for Principia always looked risky, and today’s news raises doubts about whether rilza will work in the various other indications that Sanofi is eyeing. The main focus of the buyout was the multiple sclerosis candidate tolebrutinib, however, which is still very much in play.
It will be a while before it becomes apparent whether Sanofi’s faith in tolebrutinib was justified, with the first of four pivotal MS studies set to yield data in 2023.
It should be remembered that mid-stage data from tolebrutinib were not clear cut, with questions about the use of a surrogate endpoint, the complex trial design and small patient numbers (Multiple sclerosis “win” makes the Principia shorts squirm, February 6, 2020).
|What Sanofi got from Principia|
|Project||Indication(s)||Trial details||2026e sales ($m)|
|Tolebrutinib (SAR442168)||Relapsing MS||Ph3 Gemini 1 & Gemini 2 vs Aubagio, end Aug 2023||648|
|Primary progressive MS||Ph3 Perseus vs placebo, ends Aug 2024|
|Secondary progressive MS||Ph3 Hercules vs placebo, ends Aug 2024|
|Rilzabrutinib (PRN1008)||Pemphigus||Ph3 Pegasus failed Sep 2021||422|
|Immune thrombocytopenia||Ph3 Luna3 ends Oct 2023|
|IG4-related diseases||Ph2 ends Dec 2021|
|Atopic dermatitis||Ph2 not yet recruiting|
|Warm autoimmune haemolytic anaemia||Ph2 not yet recruiting|
|Chronic spontaneous urticaria||Ph2 planned|
|SAR444727 (PRN473)||Atopic dermatitis||Ph2 ends Aug 2022||-|
|Source: Evaluate Pharma & clinicaltrials.gov.|
As for rilza, its failure in pemphigus seems pretty definite. Sanofi did not give detailed data, but said the Pegasus trial did not show a difference between rilza and placebo on its primary endpoint, complete remission from week 29 to week 37. Patients were on “minimal doses” of corticosteroids, 10mg/day or less.
This outcome is not entirely surprising: when phase 2 data in pemphigus were released Evaluate Vantage flagged the lack of placebo arm and the possibility that background steroids could have been responsible for the responses seen.
There were also reasons to be cautious about phase 1/2 results in immune thrombocytopenia, where rilza is currently in a pivotal trial. Hopes cannot be high now in ITP, and the latest flop also does not bode well for Sanofi’s plan to evaluate rilza for a raft of other uses.
The rilza setback could also be bad news for others developing BTK inhibitors for autoimmune diseases, banking on the theory that B cells have a major role in such disorders. MS is a big focus, and here Biogen recently licensed Innocare’s orelabrutinib to add to its own phase 1 asset, BIIB091.
Many MS BTK hopefuls have made much of their projects’ ability to cross the blood-brain barrier. But the more immediate question, underlined by rilza’s failure, is whether this mechanism is effective in autoimmune disease full stop.
|BTK inhibitors in mid-to-late-stage development for autoimmune diseases|
|Rilzabrutinib (PRN1008)||Sanofi (ex Principia)||See table above|
|Tolebrutinib (SAR442168)||Sanofi (ex Principia)||See table above|
|Fenebrutinib (RG7845)||Roche||Relapsing (vs Aubagio, Fenhance) and primary progressive (vs Ocrevus, Fentrepid) MS|
|Evobrutinib||Merck KGaA||Relapsing MS vs Aubagio (EvolutionRMS 1 & EvolutionRMS 2)|
|Remibrutinib (LOU064)||Novartis||Ph3 urticaria (Remix-1), ph2 Sjögren's (Louisse)|
|Branebrutinib (BMS-986195)||Bristol Myers Squibb||RA, SLE, Sjögren's (NCT04186871); atopic dermatitis (NCT05014438)|
|Elsubrutinib (ABBV-105)||Abbvie||SLE +/- Rinvoq (NCT03978520)|
|SHR1459||Reistone Biopharma||Neuromyelitis optica (NCT04670770)|
|Orelabrutinib (ICP-022)||Biogen//Innocare||Relapsing-remitting MS (NCT04711148); SLE (NCT04305197)|
|MS=multiple sclerosis; RA=rheumatoid arthritis; SLE=systemic lupus erythematosus. Source: Evaluate Pharma & clinicaltrials/gov.|