Agios reports sustained mitapivat haemoglobin responses in sickle cell disease and early AG-236 findings supporting further development in polycythaemia vera.
Written By: Saniya Katakdhond, PharmD
Reviewed By: Pharmacally Editorial Team
Agios Pharmaceuticals will present new clinical findings from its rare haematology portfolio at the 68th American Society of Hematology (ASH) Annual Meeting and Exposition, scheduled for December 12–15, 2026, in New Orleans, Louisiana. The programme includes 14 accepted abstracts, including three oral presentations, highlighting long-term mitapivat findings across sickle cell disease (SCD) and thalassemia, alongside first-in-human data for AG-236 in polycythaemia vera (PV).
The findings particularly highlight sustained haemoglobin responses with mitapivat in the Phase 3 RISE UP trial and prolonged biological activity with AG-236, an investigational small interfering RNA (siRNA) targeting TMPRSS6.
Mitapivat Demonstrates Sustained Haemoglobin Improvements in RISE UP
Long-term findings from the open-label extension (OLE) of the Phase 3 RISE UP trial (NCT05031780) showed sustained haemoglobin improvements among patients with SCD receiving mitapivat for up to 115 weeks.
Of the 176 patients who completed the double-blind period, 174 entered the OLE, including 118 who continued mitapivat and 56 who switched from placebo. Among patients continuing treatment, 62.7% (74/118) achieved a haemoglobin improvement, defined as an increase of at least 1.0 g/dL from baseline in average haemoglobin across any two consecutive study visits.
Notably, 39.7% (25/63) of patients who had not responded during the double-blind period achieved this improvement during the extension. Among patients crossing over from placebo, 51.8% (29/56) achieved a haemoglobin improvement. The safety profile remained consistent with that observed during the double-blind period.
These findings indicate that some patients may achieve haemoglobin improvements with continued treatment despite not responding initially, although the open-label design limits comparative conclusions regarding long-term efficacy.
Kidney Analysis Identifies Reductions in Hyperfiltration
A separate post hoc analysis of the double-blind period evaluated estimated glomerular filtration rate (eGFR) among patients with baseline kidney hyperfiltration, defined as eGFR above 135 mL/min/1.73 m².
Among 132 patients meeting this criterion, mitapivat-treated patients (n=92) experienced a 14.7 mL/min/1.73 m² reduction in eGFR at Week 52, compared with a 4.9 mL/min/1.73 m² reduction among placebo recipients (n=40).
The reduction occurred regardless of haemoglobin response. Agios suggested that the findings may involve both PKR, expressed in red blood cells, and PKM2, expressed in organ tissues. However, these exploratory results do not establish long-term protection against kidney complications.
Cardiac Analysis Suggests Favourable Remodelling
Another post hoc analysis assessed cardiac structure using left ventricular mass index (LVMI) and left atrial volume index (LAVI).
At Week 52, patients achieving a haemoglobin response with mitapivat experienced a 5.9 g/m² reduction in LVMI (n=40). In comparison, LVMI increased by 5.8 g/m² among mitapivat-treated non-responders (n=45) and 4.6 g/m² in the placebo group (n=27).
LAVI decreased by 4.7 mL/m² among haemoglobin responders (n=35), compared with reductions of 1.7 mL/m² among non-responders (n=41) and 0.2 mL/m² in the placebo group (n=27).
These findings suggest an association between haemoglobin response and favourable cardiac remodelling. The company indicated that reduced haemolysis may contribute to these changes, potentially alongside PKM2-mediated effects. Nevertheless, further studies are needed to determine whether these structural changes translate into meaningful cardiovascular benefits.
AG-236 Shows Sustained Iron-Regulatory Activity in Phase 1 Study
Agios also reported first-in-human findings from a Phase 1 single-ascending-dose study of AG-236 involving 24 healthy volunteers.
AG-236 is designed to silence TMPRSS6, a gene that normally suppresses hepcidin, a hormone regulating iron availability. By reducing TMPRSS6 expression, the investigational therapy aims to increase hepcidin levels and restrict circulating iron availability, potentially reducing excessive red blood cell production in PV.
Across the evaluated doses of 1.0, 3.0 and 9.0 mg/kg, AG-236 produced sustained increases in hepcidin and reductions in serum iron and transferrin saturation through Month 6 after dosing. Reductions in erythropoiesis-related biomarkers, haemoglobin and haematocrit were also observed over this period.
The treatment was well tolerated, with no serious adverse events or dose-limiting toxicities reported. These findings support further investigation of prolonged biological activity and a potential once-every-six-month dosing schedule.
Agios plans to advance AG-236 into a Phase 2/3 development programme in PV (NCT07859423), with initiation of the Phase 2 portion expected in the second half of 2026. Importantly, the Phase 1 findings were obtained in healthy volunteers, and clinical efficacy in patients with PV remains to be established.
Broader Mitapivat Development Across Thalassemia
Beyond SCD, the ASH programme includes an oral presentation of long-term changes in iron overload, iron regulation and erythropoiesis from the Phase 3 ENERGIZE open-label extension in non-transfusion-dependent thalassemia. A separate poster will examine the clinical and patient-centred implications of reduced transfusion burden in transfusion-dependent thalassemia from the ENERGIZE-T study.
Clinical Interpretation
The ASH 2026 findings highlight two distinct development approaches within Agios’ rare haematology portfolio. Mitapivat’s extended RISE UP results demonstrate sustained haemoglobin improvements, while exploratory kidney and cardiac analyses suggest potential effects beyond red blood cell function. However, these post hoc findings do not establish prevention of long-term organ complications.
For AG-236, sustained changes in hepcidin and iron-related biomarkers provide an early pharmacological rationale for further development in PV. The potential for an extended dosing interval could also differentiate its future clinical profile, provided these findings translate into patients with the disease.
The upcoming ASH presentations will provide further insight into the clinical relevance of these findings and the continued development of both programmes.
Reference
November 4, 2026. Agios to Highlight Strength and Differentiation of Rare Hematology Portfolio with New Clinical Data for Mitapivat in Sickle Cell Disease and AG-236 in Polycythemia Vera at ASH 2026, Agios Pharmaceuticals, 04 November 2026
A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants with Sickle Cell Disease (RISE UP), ClinicalTrials.gov ID NCT05031780
About the Writer
Saniya Sanjay Katakdhond (Linkedin) is a Doctor of Pharmacy professional with hands-on experience in patient case review, clinical documentation, medical record analysis, and patient care.
Her hospital experience has strengthened her understanding of clinical conditions, treatment approaches, and multidisciplinary healthcare practices.
With ICH-GCP certification and a research-oriented approach, she brings clinical insight and attention to detail to healthcare content development.
As a healthcare writer, Saniya focuses on translating clinical knowledge and patient-care experience into clear, accurate, and evidence-informed medical content.