Agios Pharmaceuticals (NASDAQ:AGIO) has taken a step closer to getting its pyruvate kinase deficiency candidate AG-348 approved after presenting positive results in a phase II proof-of-concept study that spurred Leerink analysts to increase the project's probability of success from 50% to 75%.
But, in an indicator of the state of the market, a case of thrombocytopenia with the company’s earlier-stage PKD asset, AG-519, sent Agios's stock down 20% last week, while news of ’348's success only boosted the share price by 3% yesterday. Investors are jittery about the group’s chances.
Both of Agios’s candidates are pyruvate kinase R activators, and it is hoped that they can combat the underlying cause of PKD, a rare genetic disease resulting from mutations in the PKLR gene that lead to the breakdown of red blood cells.
But until last week ’519 had been seen as the more promising candidate amid worries that ’348 could be limited by off-target effects, specifically the inhibition of aromatase.
Now, somewhat unexpectedly, it is the earlier-stage project that has been hit by safety concerns. A phase I dose-finding study presented at the European Hematology Association meeting reported a case of thrombocytopenia that seems likely to be drug-related – several days after dosing with ’519 was stopped, platelet levels returned to normal.
Agios will continue to explore dose-ranging studies in healthy volunteers with ’519, which it said led to a dose-dependent increase in PKR activity.
But ’348 now looks like the better candidate to take into phase III. Fortunately for Agios, it performed well in the first patients enrolled in the open-label Drive-PK trial, according to data also presented at the EHA congress.
Nine of the 18 transfusion-independent patients treated so far had haemoglobin increases of over 2g/dl, with a mean maximum haemoglobin rise of 3.4g/dl – results that the Leerink analysts described as impressive.
As well as upping the chance of success for Agios’ PKD franchise, the analysts have increased their 2026 sales forecast to $755m, from $531m previously. Presumably most of this figure comes from ’348, which is expected to go into phase III next year.
In spite of this optimism, the impact on sex hormones remains a valid concern for ’348. The Drive-PK data also suggest that this project might be most effective in those with missense mutations, as these were present in all nine patients who saw haemoglobin increases.
Missense mutations affect 75-80% of PKD patients, but these can be associated with less severe disease, meaning that it could be difficult for Agios to justify high orphan drug prices if ’348 is approved. Future trials might be needed in the more severely affected transfusion-dependent patients if the product is to command a premium.
But for now Agios has reasons to be cheerful. Its most advanced PKD candidate is the one that should go into phase III, reducing the likelihood of delays. And it could be the first specific treatment for the disorder, providing an alternative to blood transfusions or splenectomy. Now it just has to navigate phase III without any safety mishaps.