Eidos was always going to have a hard task going up against Pfizer, its much bigger amyloidosis rival. The design of the smaller group’s pivotal trial of its candidate AG10, revealed today, demonstrates the extent to which Eidos is stuck between a rock and a hard place.
The group has long claimed that AG10 could be better than Pfizer’s tafamidis in treating transthyretin (TTR) amyloid cardiomyopathy. But, instead of waiting for tafamidis to be approved so it could put this to the test, Eidos has opted to push into a placebo-controlled pivotal study now.
The smaller company probably did not have much choice. Delaying the trial would have made it even more difficult for Eidos to claw back ground from Pfizer, which expects US approval of tafamidis by July in cardiomyopathy; meanwhile, a new free acid formulation of tafamidis is due a decision by November.
But once Pfizer’s project does get the nod, which is widely expected following positive data last year, Eidos could have problems finding the targeted 510 patients for its pivotal Attribute-CM trial. Potential recruits might not want to run the risk of receiving placebo once tafamidis is an option.
Eidos’s chief medical officer, Jonathan Fox, conceded that this was a possibility, but told Vantage: “That’s why this is going to be a multinational study. We’re going to geographies [where] product launches have been rather slow.”
The inference here is that tafamidis will not be available in these countries while Eidos is enrolling into its trial. The company estimates that this will take around 12 months, although this might be an unrealistic goal.
And Attribute-CM will also include US sites. While Mr Fox said the exact number was still being finalised, he forecast a 40:60 split between US and ex-US centres.
Even in the US he maintained that tafamidis, once approved, might not be as big a threat to the Eidos study as feared. He cited a potentially high price for the Pfizer drug and financial constraints that could make it difficult for some patients to get treatment. “Enrolling in our trial may represent the best option for them.”
Still, he admitted that any worries about tafamidis’s price were theoretical – Pfizer has not said how much it will cost in cardiomyopathy. A clue could come from Europe, where a lower, 20mg, dose is approved for polyneuropathy and reportedly comes in at around $13,000 per month.
These concerns notwithstanding, Eidos has a chance for a quick approval of AG10. Attribute-CM has two sections, with part A measuring change in six-minute walk distance at 12 months versus placebo.
Part B, meanwhile, will look at mortality and cardiovascular hospitalisations at 30 months, the same endpoint that the Attr-act trial of tafamidis met last year (ESC 2018 – Pfizer impresses with tafamidis, but amyloidosis battle goes on, August 27, 2018).
The FDA has agreed that the six-minute walk endpoint could support registration of AG10, Mr Fox said during a conference call today. He also stressed to Vantage that this was an endpoint for full approval rather than a surrogate outcome that would later need to be confirmed by mortality data, an approach often taken in cancer.
If the 30-month endpoint is also hit, this could lead to an updated label with a cardiovascular and mortality benefit later, he added.
Interestingly, Eidos's statistical analysis plan gives unequal weighting to the co-primary outcomes: the six-minute walk endpoint has to achieve a p value of less than 0.01 to be deemed significant, while the mortality/CV hospitalisation endpoint needs to hit 0.04. If all goes to plan, data on the six-minute walk test should be available in the first half of 2021, with a regulatory filing to follow later that year, Mr Fox said.
In total, the trial will cost around $60m, Eidos’s chief financial officer, Christine Siu, said on the call today. She added that getting to topline data with the group’s current funding should be “very manageable”.
Both AG10 and tafamidis are oral small molecules designed to stabilise transthyretin, the protein that in amyloidosis is broken down into insoluble amyloid fibrils, which build up in the patient’s organs. AG10 produces “near-complete” stabilisation, while tafamidis is a partial stabiliser; this is why Eidos believes that its molecule could be best in class.
Investors took Eidos’s attempt at a quick approval for AG10 at face value, sending its stock up 10% this morning. However, any delay in trial recruitment could hint at problems to come.