I’m thrilled to sit down with Ivan Kairatov, a renowned biopharma expert with a wealth of experience in research and development, as well as a keen understanding of technological innovation in the industry. Today, we’re diving into the recent developments surrounding Agios Pharmaceuticals and their drug Pyrukynd (mitapivat), particularly its mixed results in a Phase 3 trial for sickle cell disease. Our conversation explores the trial outcomes, the broader implications for Agios, the evolving landscape of sickle cell treatments, and what the future might hold for this promising therapy.
Can you walk us through the key findings from the recent Phase 3 Rise Up trial for Pyrukynd in sickle cell disease?
Certainly. The Rise Up trial was a pivotal study for Agios, involving 207 participants with sickle cell disease. The trial had two primary goals: increasing hemoglobin levels and reducing the frequency of sickle cell pain crises. On the hemoglobin front, Pyrukynd performed impressively—41% of those treated saw at least a 1 gram per deciliter increase in hemoglobin, compared to just 3% in the placebo group. That’s a significant boost in oxygen-carrying capacity. However, it fell short on the second goal, as there wasn’t a statistically significant reduction in pain crises. Patients on Pyrukynd experienced about 2.6 crises per year compared to 3.1 for placebo, which wasn’t enough to meet the threshold for success in that measure.
What do you think contributed to Pyrukynd not showing a significant reduction in sickle cell pain crises?
That’s a complex issue. While Pyrukynd effectively increased hemoglobin levels, pain crises in sickle cell disease are influenced by multiple factors beyond just hemoglobin concentration. These crises often result from blood vessel blockages due to sickled cells, inflammation, and other systemic issues. It’s possible that while the drug improves red blood cell health to some extent, it may not fully address the downstream effects or variability in patient responses that drive these acute events. Interestingly, the trial did show that those who had a hemoglobin response were more likely to experience fewer pain crises, suggesting there’s a connection, but it wasn’t consistent across the entire treated group.
How do you see these mixed results impacting Agios Pharmaceuticals’ path toward FDA approval for Pyrukynd in sickle cell disease?
The mixed results create a challenging scenario for Agios. Meeting the hemoglobin endpoint is a strong point in their favor, as it demonstrates a clear biological effect that’s meaningful for patients. However, missing the pain crisis endpoint—a key clinical outcome for sickle cell patients—could raise questions with the FDA about the drug’s overall benefit. Regulators often look for therapies that address the most debilitating aspects of a disease, and pain crises are a major burden. Agios will need to present a compelling case that the hemoglobin improvement translates to real-world benefits, perhaps by highlighting secondary data like reduced fatigue or fewer hospital visits among responders. Their upcoming discussions with U.S. regulators will be critical in shaping the path forward.
Speaking of the market, can you explain the dramatic drop in Agios’ share price following the trial announcement?
Absolutely. Agios’ stock plummeted from around $45 to $24 per share almost immediately after the news broke, which reflects investor disappointment with the mixed trial outcomes. The market had high expectations for Pyrukynd in sickle cell disease, viewing it as a cornerstone of Agios’ commercial reinvention. Missing one of the two main trial goals likely fueled concerns about the drug’s approvability and market potential in this indication. Investors may also be wary of broader uncertainties, such as the FDA’s delayed decision on Pyrukynd for beta thalassemia due to safety concerns. It’s a stark reminder of how sensitive biopharma stocks are to clinical trial results, especially for companies banking on a single drug to drive growth.
Let’s talk about the current landscape for sickle cell disease treatments. How have recent changes affected options for patients?
The sickle cell treatment landscape has been quite turbulent recently. A few years ago, we saw new options emerge, like Novartis’ Adakveo and Pfizer’s Oxbryta, alongside the older standby hydroxyurea. However, both Adakveo and Oxbryta have been withdrawn from the market due to regulatory and safety issues, which has narrowed the field significantly. Meanwhile, genetic therapies from Vertex and Bluebird Bio have entered the scene, but their uptake has been slow—partly due to high costs and complex administration processes. This leaves a gap in accessible, effective treatments for many patients, creating both a challenge and an opportunity for drugs like Pyrukynd to step in with a different approach.
What sets Pyrukynd apart from other sickle cell treatments, especially the genetic therapies?
Pyrukynd offers a distinct mechanism compared to genetic therapies. It’s an oral medication that stimulates pyruvate kinase, an enzyme that helps red blood cells survive longer and function better. This contrasts with genetic treatments, which aim to fundamentally alter the patient’s blood cells through gene editing or therapy—a process that’s innovative but comes with high costs, logistical hurdles, and long-term uncertainties. Pyrukynd, being a pill, could be more accessible and easier to integrate into patients’ lives, assuming it can demonstrate consistent clinical benefits. It’s not a cure like genetic therapies aim to be, but it could serve as a complementary or interim option for many.
Given the slow uptake of genetic therapies, do you think Pyrukynd could fill a critical gap in the sickle cell market?
I believe there’s potential for Pyrukynd to address an unmet need, particularly for patients who can’t access or afford genetic therapies, or those who aren’t suitable candidates for such intensive treatments. With traditional options dwindling after recent drug withdrawals, an oral therapy that improves hemoglobin levels could be a valuable tool, even if it doesn’t fully eliminate pain crises. However, its success will depend on how regulators and payers view the mixed trial data, as well as Agios’ ability to position the drug as a practical solution for a broad patient population. Pricing and real-world effectiveness will also play a big role.
Shifting gears, can you tell us about Pyrukynd’s performance in other conditions it’s already approved for?
Pyrukynd is currently approved for a rare type of anemia called pyruvate kinase deficiency, and it’s been a modest performer so far. It’s a niche indication with a small patient population, which limits its commercial reach. Sales figures for the first nine months of the year were around $22 million, reflecting steady but not blockbuster demand. For Agios, this approval was an important first step, proving the drug’s concept and providing a foundation to build on as they pursue broader indications like sickle cell disease and beta thalassemia. It’s more about establishing credibility and gaining experience in the market at this stage.
How significant is the potential approval for beta thalassemia to Agios’ future, and what’s the latest on that front?
Approval for beta thalassemia is incredibly important for Agios, as it would expand Pyrukynd’s market significantly beyond the rare anemia it’s currently approved for. Beta thalassemia affects a larger patient population with substantial unmet needs, so it could be a major growth driver. The FDA was supposed to make a decision earlier, but they delayed it to December 7, 2025, to further evaluate safety data related to potential liver issues observed in testing. This delay adds some uncertainty, but if approved, it would validate Pyrukynd’s broader applicability in blood disorders and boost investor confidence, especially after the sickle cell setback.
Looking ahead, what is your forecast for the future of sickle cell disease treatments, including the role Pyrukynd might play?
I think the future of sickle cell treatment will be increasingly personalized, with a mix of genetic therapies, small molecules, and supportive care tailored to individual patient needs. Genetic therapies will likely dominate for those who can access them, as they offer the potential for a one-time, transformative impact. However, their slow rollout and high costs mean there’s still a huge need for accessible options like Pyrukynd. If Agios can navigate the regulatory hurdles and demonstrate real-world benefits—perhaps through additional studies or post-approval data—Pyrukynd could carve out a meaningful niche as an oral therapy for managing symptoms. I also expect we’ll see more innovation in this space, with combination approaches and novel mechanisms being explored to tackle the multifaceted nature of the disease. It’s an evolving field, and Pyrukynd has a chance to be part of that story if the data and strategy align.
