Argenx’s efforts to Advance fall flat

Argenx’s filing strategy for its FcRN antagonist Vyvgart in the new use of primary immune thrombocytopenia (ITP) had already raised eyebrows. Now the group has received a blow to its hopes here after flunking the pivotal Advance-SC trial, which tested a subcutaneous formulation.

The failure looks comprehensive, with placebo numerically outperforming Vyvgart on the primary endpoint, sustained platelet count response, and the study also falling short on secondary endpoints. Argenx blamed a high – and variable – placebo response, but a conference call today did not shed much light on its future filing plans in ITP. The group’s stock fell as much as 12% this morning.

Intravenous and subcutaneous

Vyvgart is already approved for generalised myasthenia gravis, as both an intravenous and subcutaneous formulation. But if it is to become a mega-blockbuster, as hoped, it will need to expand beyond this use.

ITP is just one area that Argenx is trying to move Vyvgart into. At last year’s ASH meeting the company presented a win – albeit it a marginal one – with the intravenous formulation in the Advance study. 

The company has already filed Vyvgart for ITP in Japan, where only one pivotal trial is needed. The US FDA and the EU’s EMA, meanwhile, have asked for two trials to support approval. Argenx had intended to include Advance and Advance-SC in the same filing package – a plan that had already looked controversial after the company admitted that the formulations were seen as different products by regulators.

Now that plan is in tatters. It is unclear whether Argenx will need to run another phase 3 study, or if it would even want to. During a conference call today, the group’s chief executive officer, Tim Van Hauwermeiren, said Argenx will be “responsible stewards of capital” and make “data-based decisions” once it has digested the Advance-SC results.

Advance-SC 

He noted that the company still doesn’t fully understand why Advance-SC failed where Advance succeeded, but there are various theories.

The two studies had a similar design, with both enrolling previously-treated ITP patients, and both with the primary endpoint of the proportion of patients achieving a sustained platelet count response, defined as platelet counts of ≥50x10⁹/l on at least four of the six visits between week 19 and week 24 of the trial. 

In Advance-SC, 14% of Vyvgart-treated patients met the endpoint, versus 16% in the placebo group. In the earlier Advance trial, 22% of Vyvgart-treated patients achieved this outcome, versus 5% on placebo.

Argenx execs said today that the driving force behind the different trial outcomes was the much higher placebo response in Advance-SC. They added there were regional differences in placebo response, including in geographies that were not included in Advance. 

They also noted that responders in Advance-SC were typically earlier in the course of their disease and not receiving concomitant medications. This pattern could be relevant because Advance-SC had a high proportion of highly refractory patients: 75% patients had received three or more prior ITP therapies, versus 68% in Advance. However, the company’s chief medical officer, Luc Truyen, said he didn’t think that would fully explain the findings.

One thing Argenx seemed to rule out was a difference between the intravenous and subcutaneous formulations, saying the pharmacodynamic data in Advance-SC were in line with the intravenous study and other prior trials.

The company also played down any risk to ongoing studies in other indications, several of which are set to yield data soon. Argenx will have to hope that Advance-SC is just a blip, rather than a sign of things to come. 

Current indications and upcoming readouts for Vyvgart

CIDP: chronic inflammatory demyelinating polyneuropathy; gMG: generalised myasthenia gravis; ITP: immune thrombocytopenia; POTS: postural orthostatic tachycardia syndrome. Source: OncologyPipeline, clinicaltrials.gov and company presentation.