One-Year Safety and Efficacy of Mitapivat in Sickle Cell Disease: Follow-Up Results of a Phase 2, Open-Label Study

One-Year Safety and Efficacy of Mitapivat in Sickle Cell Disease: Follow-Up Results of a Phase 2, Open-Label Study

Myrthe J. van Dijk1,2,*, Minke A.E. Rab2,3, Brigitte A. van Oirschot2, Jennifer Bos2, Cleo Derichs1, Anita W. Rijneveld3, Marjon H. Cnossen4, Erfan Nur5,6, Bart J. Biemond5, Marije Bartels1, Judith J.M. Jans7, Wouter W. van Solinge2,

Roger E.G. Schutgens1, Richard van Wijk2, and Eduard J. van Beers1

1Center for Benign Hematology, Thrombosis and Hemostasis - Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 2Department of Central Diagnostic Laboratory - Research, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 3Department of Hematology, Erasmus MC, University Medical Center, Rotterdam, Rotterdam, The Netherlands; 4Department of Pediatric Hematology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands; 5Department of Hematology, Amsterdam University Medical Center, Amsterdam, The Netherlands;

6Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands; 7Section Metabolic Diagnostics, Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

Aim

To report on safety and efficacy results of the 1-yearfixed-dose extension period (FDEP) of treatment with mitapivat in subjects with sickle cell disease (SCD) enrolled in the ESTIMATE study (www.clinicaltrialsregister.eu NL8517; EudraCT 2019-003438-18)

Introduction

• Targeting the primary pathogenic event of SCD, namely the polymerization of deoxygenated sickle hemoglobin (HbS) molecules, may prevent downstream clinical events.
• Mitapivat, an oral allosteric activator of pyruvate kinase (PK), has therapeutic potential by increasing adenosine triphosphate (ATP) and decreasing 2,3-diphosphoglycerate(2,3-DPG), a glycolytic red blood cell (RBC) intermediate which promotes deoxygenation by lowering the oxygen affinity of hemoglobin (Hb) (Figure 1).
• In the previously reported 8-weekdose-finding period (DFP) of this study, mitapivat was well tolerated and showed efficacy in SCD.1

Figure 1

References:

1. van Dijk MJ, Rab MAE, van Oirschot BA, et al. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in sickle cell disease: A phase 2, open-label study. Am J Hematol. 2022;97(7):E226- E229.

Methods

The ESTIMATE study is a phase 2, investigator initiated, open-label study with the following major eligibility criteria:

• Subjects ≥16 years with SCD (HbSS, HbS/β0, HbS/β+)
• 1-10vaso-occlusive episodes (VOEs) in the prior year and/or prior SCD- related complications;
• Hb level >4.0 g/dL and ≤11.1 g/dL;
• Stable dose of hydroxyurea (≥3 months), if applicable;
• No chronic transfusion (not >4 RBC units within the 12 months and/or ≥1 within the 3 months prior to the first day of study drug).

After the 8-week DFP in which subjects were dosed mitapivat 20 mg, 50 mg or 100 mg twice daily depending on safety,1 subjects continued in the 1-year FDEP

• Safety analysis included all subjects who received ≥1 dose of mitapivat;
• Efficacy analysis of the FDEP was based on the intention-to-treat principle.

Results

• Baseline characteristics (n=10): median (range) age was 26 years (16-59); 6/10 (60%) were female; 6/10 (60%) used hydroxyurea;
  8/10 (80%) HbSS, 1/10 (10%) HbS/β0, and 1/10 (10%) HbS/β+
• Safety analysis showed mostly mild treatment-emergent adverse events, most commonly (n>2 subjects): transaminase increase (all grade 1), and headache (grade 1-2).
• Apart from the non-treatment-related serious adverse event (SAE) of a urinary tract infection in the DFP (lost to follow-up),1 one non-treatment- related SAE occurred in the FDEP in a subject who died of massive pulmonary embolism due to COVID-19.
• Importantly, sustained improvement in Hb level was seen (mean increase: 1.1 ± 0.7 g/dL; p=0.0014), which was accompanied by decreases in markers of hemolysis in the nine subjects who continued treatment with mitapivat 50 mg twice daily (n=2) or 100 mg twice daily (n=7) in the FDEP (Table 1).
• The ATP/2,3-DPG ratio and Hb-oxygen affinity significantly increased, and RBC sickling (Point of Sickling) non-significantly reduced (Table 1).
• In addition, the annualized rate of VOEs reduced significantly from a historic baseline of 1.33 ± 1.32 to 0.64 ± 0.87 (p=0.0489) when combining the DFP and FDEP (Table 1 and Figure 2).

Table 1	Baseline	End of the DFP	Mean of the FDEP	p-value (baseline vs
	(n=9)	(n=9)	(n=9)	mean of the FDEP)
Hb, g/dL	8.8	(1.8)	10.3 (1.3)	9.9	(1.8)	0.0014
Reticulocytes:
ARC, 109/L	235 (88)	141 (50)	156 (50)	0.0038
% of RBCs	8.2	(2.3)	4.2	(1.4)	5.0	(1.4)	0.0003
Total bilirubin, mg/dL	2.6	(1.3)	1.2	(0.5)	1.4	(0.7)	0.0025
LDH, U/L	500	(307)	328	(113)	401	(224)	0.0217
ATP, mg/gHb	2.9	(0.7)	3.6	(0.5)	3.6	(0.5)	0.1386
2,3-DPG, mg/gHb	11.4 (1.0)	7.9	(1.1)	9.0	(1.1)	0.0004
ATP/2,3-DPG ratio	0.25	(0.05)	0.46	(0.09)	0.40	(0.06)	0.0009
Point of Sickling, mmHg	40.2	(8.8)*	33.1	(9.7)*	36.2	(6.3)*	0.0802
EImax, EI	0.450 (0.074)*	0.477 (0.059)*	0.478 (0.061)*	0.0017
EImin, EI	0.067 (0.048)*	0.116 (0.049)*	0.101 (0.066)*	0.0054
p50, mmHg	24.0 (2.4)	21.5 (1.4)	22.5 (1.8)	0.0032
Annualized VOE rate:
- DFP + FDEP	1.33	(1.32)		0.64 (0.87)		0.0489
- FDEP	1.33	(1.32)	0.72 (2.17)	0.60 (0.78)	0.0625
Annualized SCD-related	5.3	(7.0)	0.0 (0.0)	4.1 (5.6)	0.4452
hospital admission days

Data are presented as mean (standard deviation). P-values derived from paired sample t-test or Wilcoxon signed-rank test when appropriate. *Due to technical issues of the oxygen gradient ektacytometer, data is missing for n=1 subject, a week 52 visit (n=1 subject) and four visits from week 24 to week 52 in the FDEP (n=2 subjects).

Figure 2

Annualized VOE rate

	2.0	✱
VOEs/year	Baseline
	Intention-to-treat:fixed-dose extension period
	1.5	Intention-to-treat:dose-finding period +
	fixed-dose extension period
of	1.0
Number	0.5
	0.0	*p-value ≤ 0.05

Conclusion

Overall, this study demonstrated longer term safety and efficacy of treatment with mitapivat in SCD, supporting further evaluation in the ongoing phase 2/3 RISE UP study (ClinicalTrials.gov NCT05031780).

Acknowledgements: We thank all subjects who participated in this study and all members of the Dutch SCORE consortium. This study was sponsored by Julius Clinical, Zeist, The Netherlands and supported in part by research funding from Agios Pharmaceuticals Inc. Cambridge, MA, USA.

*Contact information: Myrthe van Dijk; e-mail:[e-mail]