Pull up the RISE UP trial protocol and look at what Agios Pharmaceuticals chose as their primary endpoint. No vaso-occlusive crisis rate. No hospitalization count. Instead: a hemoglobin response threshold tied directly to the drug’s proposed biological mechanism. That choice, made years before a single patient was dosed, explains why this week’s Lancet publication reads like more than a positive Phase 3 readout. It reads like a regulatory argument that was built from the glycolytic pathway up.
The topline number Agios released on November 19, 2025 was 40.6%: the proportion of mitapivat-treated patients who met the hemoglobin response criterion. In a disease where the biological machinery responsible for red cell destruction has resisted modification for decades, getting four out of ten patients across a mechanistically defined response threshold in a global, double-blind, randomized trial is not a modest achievement. The question worth asking now is how the trial got there, and what that path reveals about a highly productive strategy in rare disease drug development.
The Glycolytic Trap Inside Every Sickle Cell
Understanding why mitapivat works requires spending a moment inside the red blood cell’s energy economy. Normal red blood cells have no mitochondria. They cannot run oxidative phosphorylation. Every unit of ATP they generate comes from glycolysis, and at the pivot point of that pathway sits pyruvate kinase R, the erythrocyte-specific isoform encoded by the PKLR gene. In sickle cell disease, chronic hemolysis imposes extraordinary metabolic demand on circulating red cells, and the glycolytic pathway buckles under it.
When pyruvate kinase activity runs below its optimum, two things happen simultaneously, and each one accelerates sickling through a different channel. First, ATP production drops. ATP fuels the ion pumps that keep intracellular potassium and water in balance. Lose ATP and the red cell dehydrates. Concentrated intracellular hemoglobin S is far more likely to polymerize under hypoxic conditions, and polymerization is the molecular event that distorts the cell into its pathological crescent shape. Second, the metabolic intermediate 2,3-diphosphoglycerate accumulates. As detailed in the pharmacological characterization of AG-348 published in PMC, elevated 2,3-DPG shifts hemoglobin’s oxygen dissociation curve rightward, reducing oxygen affinity and increasing the probability that hemoglobin S releases oxygen prematurely, exactly the condition that triggers polymerization in the microvasculature.
Mitapivat attacks both problems at the source. As an allosteric activator of pyruvate kinase R, it binds outside the enzyme’s active site and stabilizes a high-activity conformation. The result: ATP rises, 2,3-DPG falls, red cells stay better hydrated, hemoglobin S holds oxygen longer in transit. Call this the glycolytic rescue principle: instead of targeting the downstream consequences of sickling, the drug repairs the metabolic precondition that makes sickling probable in the first place.
That mechanism is what made a hemoglobin-based primary endpoint scientifically defensible. If mitapivat genuinely reduces hemolysis by improving red cell survival, hemoglobin concentration should rise. The endpoint is not a surrogate chosen for convenience. It is a direct readout of whether the proposed mechanism operated in vivo at therapeutic doses. A 40.6% responder rate in the treatment arm, against the placebo arm’s rate, signals that the glycolytic rescue worked in a meaningful fraction of a genetically and phenotypically heterogeneous patient population.
What the FDA’s Own Rare Disease Guidance Says About This Approach
The FDA finalized its guidance document “Rare Diseases: Considerations for the Development of Drugs and Biological Products” on December 26, 2023. Read section by section, that document is a quiet authorization of exactly the development strategy Agios executed. The guidance explicitly encourages early development work on biomarkers as surrogate endpoints and directs sponsors to engage the agency early to establish whether those surrogates fit the biology of the disease. According to the RAPS analysis of that guidance, the FDA’s stated position is that rare disease populations make powering traditional clinical outcome trials statistically and ethically difficult, and that mechanistically grounded surrogates can carry the evidentiary weight when the biological plausibility is airtight.
The RISE UP design treated that guidance as operational instructions. Agios did not wait for FDA pressure to justify hemoglobin response as a primary endpoint. They built the biological rationale during Phase 1 and 2 work, pre-specified the response threshold, and entered Phase 3 with an endpoint architecture that a reviewer could trace back to the enzyme kinetics. That is the development sequence the guidance describes, and it is the sequence most sponsors still do not follow because it requires committing to a mechanistic argument three to four years before the pivotal readout.
The regulatory cost of waiting is visible across the graveyard of sickle cell programs that targeted vaso-occlusive crisis rates as their primary endpoint. VOC trials require enormous sample sizes to detect modest reductions in an event that is patient-reported, variably defined across sites, and heavily confounded by concomitant hydroxyurea use. The signal-to-noise ratio is punishing. Mechanistic endpoints anchored in hematology, by contrast, can generate clean separation with smaller, shorter trials, provided the biological premise is solid enough to survive FDA scrutiny.
The Dissent Worth Taking Seriously
Not every observer reads the RISE UP data through an optimistic lens. Commentary published in PubMed-indexed analysis of the trial results raises a pointed concern: a 40.6% hemoglobin responder rate means that nearly 60% of treated patients did not meet the response criterion, and the dataset does not yet resolve whether the patients who respond hematologically also experience fewer pain crises, fewer hospitalizations, and better functional capacity over the long term. A drug that raises hemoglobin without proportionately reducing clinical events would fit the glycolytic rescue mechanism and still leave the burden of disease largely intact. That gap between hematological response and clinical benefit is the unfinished chapter of this story, and sponsors who design subsequent sickle cell programs around hemoglobin endpoints alone, without embedding patient-reported outcome instruments and VOC adjudication into their protocols from day one, will find that gap waiting for them at the label negotiation stage.
The FDA’s December 2023 rare disease guidance anticipated exactly this tension. It does not grant surrogate endpoints unconditional approval standing; it conditions their use on a reasoned evidentiary chain running from mechanism to surrogate to clinical outcome. The chain Agios built is stronger than most. Whether it is strong enough to support the label language that makes mitapivat commercially viable for the full sickle cell population will be settled in the review, not in the trial.
The systemic insight here cuts across every rare disease program in development: the endpoint you choose in Year One of your development plan is not a statistical decision. It is a regulatory strategy, a biological argument, and a commercial bet compressed into a single line of protocol text. RISE UP demonstrates that when the mechanism is genuinely novel and the surrogate is genuinely tied to that mechanism, the FDA’s 2023 rare disease framework creates a viable path through a disease space that has frustrated sponsors for a generation. Any sponsor that applies that logic to the next intractable hemoglobinopathy will help set the evidentiary standard that subsequent programs get measured against.
References
- The Lancet, “Efficacy and safety of mitapivat in patients with sickle cell disease (RISE UP): a phase 3, double-blind, global, randomised, placebo-controlled trial”
- PMC, “Pyruvate kinase activator mechanism: ATP production, 2,3-DPG reduction, and RBC dehydration prevention in sickle cell disease”
- RAPS, “FDA Issues Final Guidance on Rare Disease Drug Development” (December 26, 2023)
- PubMed, Commentary on pyruvate kinase activators and vaso-occlusive crisis outcomes in sickle cell disease
Moe Alsumidaie, MBA, MSF, is founder and Chief Editor of Vanguard Publications, which publishes Clinical Trial Vanguard, Pharma Vanguard and BullScope, and Head of Research at CliniBiz. He has two decades in clinical trial operations and data science, with earlier roles at Genentech, Abbott Vascular and Stanford University Medical Center, and is a guest lecturer in clinical trial sciences at Rutgers University.
