Clozel's CHF1bn Actelion Spin-Out Idorsia Awaits Janssen Buy-In
Executive Summary
Upon completion of Johnson & Johnson's $30bn acquisition of Actelion, Jean-Paul Clozel, the latter's outgoing CEO, aims to build a new European biopharma big-hitter – Idorsia – with the earlier-stage assets Actelion leaves behind. He's hoping that J&J's Janssen will soon opt in to rights to its lead candidate. Idorsia is preparing to launch onto the Swiss Stock Exchange with CHF1bn in cash at inception.
New company Idorsia's moment of truth will come soon after its inception: will Janssen Biotech Inc. exercise an option on its lead product? The opt-in on ACT-132577, an orally active dual endothelin receptor antagonist for which a Phase III trial design is in the works, would entail a milestone payment of $230m from Janssen.
That's on top of the CHF1bn that Idorsia has been given as launch cash following its formation as a spin-out from Actelion Pharmaceuticals Ltd., after the latter's $30bn acquisition by Janssen Biotech's parent, Johnson & Johnson. Jean-Paul Clozel – who built Actelion from scratch over the past 20 years – has new ambitions to make "one of Europe's leading biopharmaceutical companies" out of Idorsia, which was formed to take forward Actelion's earlier clinical pipeline and discovery assets. Clozel will head Idorsia, which is on track to be launched on the Swiss stock exchange by the end of the second quarter.
Clozel and Actelion's head of global clinical development, Guy Braunstein, in an update on the launch plans for Idorsia and on its pipeline assets, reported that ACT-132577 would progress to Phase III in resistant hypertension (i.e. in patients who have failed three different classes of prior drug treatment at optimal doses including a diuretic), following a positive Phase II dose-finding study in 490 patients with essential hypertension randomized to receive one of four doses of the candidate, placebo or lisinopril once daily.
The study established that it was well tolerated across four doses (5, 10, 25 and 50mg). "We have all the information we need to design the Phase III confirmatory program in resistant hypertension," said Braunstein. "The need for another mechanism of action in treating resistant hypertension has long been stressed by the medical community."
Braunstein noted that there are no other endothelin receptor antagonists developed for hypertension.
ACT-132577 Ph II Results
Resistant hypertension is a small subset of the hypertensive population, but it represents a high unmet need because patients with resistant hypertension are at greater risk of cardiovascular events. In the Phase II trial, the primary endpoint was change from baseline diastolic blood pressure after eight weeks, and ACT-132577 showed a statistically significant reduction in a dose-dependent manner.
In terms of safety, there were low discontinuation rates due to adverse events in all treatment groups. There were two cases of increased liver enzymes, one in placebo and one in the lowest dose ACT-132577 group: "that's something we always look at with endothelin receptor antagonists, but this time we were extremely satisfied by the results," said Braunstein.
There were four cases of peripheral edema (two in the 25mg group and two in the 50mg group). There was no weight gain associated with ACT-132577 observed. Clozel was upbeat about these two indicators: "In the past, selective A [ERAs] have been tested in hypertension and they have had some serious issues with edema and weight gain… We are very encouraged by the results that we have seen, plus other studies that we are not discussing today… and we have …a strong rationale to believe that with the mixed antagonist [ACT-312577 targets both ETA and ETB) you will not have the type of issue that you can see with the selective endothelin receptor antagonist."
Braunstein concurred, saying the cases of edema would be "no obstacle to development" and describing the adverse event profile of the compound as "pretty minimal".
There was a slight decrease in hemoglobin in patients on the ERA.
"It is of course anticipated that the results can be extrapolated to resistant hypertension," stated Braunstein.
He said a Phase III clinical development program would be discussed in the next few months with health authorities, with a current proposal for two pivotal studies evaluating ACT-132577's effect on systolic and diastolic blood pressure in patients with "true" resistant hypertension (as opposed to those who have secondary hypertension or hypertension not controlled because of reasons like poor compliance).
Janssen Milestone
The real validation of Idorsia will be whether Janssen opts in to that program, triggering the $230m milestone and a joint development collaboration (with Janssen holding commercial rights). That cannot come before the J&J/Actelion deal has completed – expected in the second quarter – but it should be soon after. Janssen's option stands until 30 days after the presentation of the Phase II data to Janssen and the end of Phase II meeting with the US FDA.
"We view the potential royalties on sales to be impressive, at 20% up to $500m, 30% from $500m to $2bn, and then 35$ >$2bn," wrote Jefferies analyst Peter Welford in a May 22 note, in which he described the Phase II study findings as "encouraging".
Idorsia Pipeline
Behind the lead program, the Actelion executives outlined plans for a number of earlier stage assets being taken on by Idorsia, including Phase II candidates ACT-541468 (a dual orexin receptor antagonist for insomnia) and endothelin receptor antagonist clazosentan in vasospasm associated with aneurysmal subarachnoid hemorrhage.
A pivotal Phase III study expected to start in 2018 is meanwhile being designed for lucerastat in Fabry disease (the glucosylceramide synthase inhibitor targets all patients regardless of mutation).
Selective sphingosine-1-phosphate receptor 1 modulator cenerimod is ready to move into an exploratory Phase II dose-finding study to provide information needed to design a Phase III study in systemic lupus erythematosus. It has completed a Phase II safety study which showed it to be well tolerated and to induce a dose-dependent reduction in lymphocyte count in SLE patients.
A further four compounds are in Phase I development for a range of indications.