Things did not go well for Agios Pharmaceuticals today because it noted that it would no longer develop its next-generation pyruvate kinase [PK] activator tebapivat for the treatment of patients with sickle cell disease [SCD]. The reason why this was the case was because of the clinical data that it had obtained as part of evaluating this phase 2 program.

Specifically, the goal was to see if this next-generation candidate could somehow differentiate itself from other PK activators. The reason why is because PK activation indeed does work in being able to treat these SCD patients. Agios just needed to see that it could have some kind of edge over prior therapies of the same class.

It announced topline results from a phase 2 study using tebapivat as a next-generation oral PK activator to treat patients ages 16 and older with SCD. This company kind of went all out, because it didn’t just test only one dose of this drug. It randomized a total of 59 patients to receive one of three once-daily [QD] doses of 2.5 mg, 5.0 mg, 7.5 mg, or placebo.

The primary endpoint was hemoglobin response, which was defined as ≥1.0 g/dL increase in average hemoglobin concentration from Weeks 10 through 12 compared with baseline. First, it is important to state that this is just a standard measure used in clinical studies to measure improvement for hemoglobinopathies.

With that said, the main problem with SCD patients is the formation of sickle-shaped red blood cells [RBCs]. This leads these patients to experience anemia [low hemoglobin to carry oxygen to tissues in the body], inability for blood to flow freely, and pain crises. This last one is known as a vaso-occlusive crisis [VOC] and occurs when these mis-shaped RBCs block blood flow in small blood vessels. This results in a sharp pain for the patient that can occur in certain parts of the body.

The point here is that if hemoglobin concentration can be increased, then this could have an impact on reducing fatigue [anemia], preventing pain crisis events, and improving oxygen levels for tissues. It was revealed that the primary endpoint of hemoglobin response of 43.8%, 47.1%, and 29.4% was achieved in patients who took 2.5 mg, 5.0 mg, and 7.5 mg of therapy, respectively. For the patients who took the placebo, this efficacy endpoint was achieved in 33.3% of the patients.

As you can see, the drug didn’t really do well to separate itself immensely from the placebo. Plus, it is not all that much different in what this drug achieved compared to other PK activators. Therefore, Agios has concluded that it is best to just stop development of tebapivat for these SCD patients.

This wasn’t the first program to be terminated for tebapivat, though. A few months ago, in May of 2026, it had decided to discontinue development of a 24-week phase 2b study using this drug to treat patients with lower-risk myelodysplastic syndrome [LR-MDS]. Upon completion of this study, it was mentioned that a certain proportion of patients didn’t meet the threshold necessary to continue development of tebapivat for these pateints.

Not all is lost for Agios because it still has its other first-in-class PK activator mitapivat, which is being put up for FDA review. Just several weeks ago, the FDA accepted the supplemental New Drug Application [sNDA] of this drug for review for the treatment of patients with SCD. This regulatory application was accepted by this U.S. agency based on an accelerated approval pathway.

This is important because drugs accepted for review on this pathway have a shorter review time period, down 6 months from 12 months. Having said that, the FDA has set a Prescription Drug User Fee Act [PDUFA] date of November 1, 2026. This is the date that the FDA can decide on, or before, whether or not mitapivat should be approved to treat SCD patients.

It is important to state that the phase 3 RISE UP study, which is one of the few studies being used for this approval, had only one of the co-primary endpoints achieved in a statistically significant manner. The primary endpoint met was hemoglobin response in this phase 3 RISE UP trial. Unfortunately, the other primary endpoint of annualized rate of SCPCs [pain crises] was not met with statistical significance.

The hope is that the company can at least achieve FDA accelerated approval for mitapivat in SCD. If it does, it would be huge, because it would be the first ever PK activator approved to treat this specific group of patients.