Agios Pharmaceuticals : The launch of a global, phase 2, open label, multicenter, single arm study of mitapivat in patients with sickle cell disease and nephropathy

The launch of a global, phase 2, open-label, multicenter, single-arm study of mitapivat
in patients with sickle cell disease and nephropathy	P2194

Fuad El-Rassi, MD1,2, Kenneth I Ataga, MD3, Jeffrey Lebensburger, DO, MSPH4, Santosh Saraf, MD5, James Xiao, PhDa,6, Katrin Uhlig, MD, MS6, Kareem Osman, MD6, Ahmar U Zaidi, MD6, Michael U Callaghan, MD6, Miguel R Abboud, MD7

1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 2Georgia Comprehensive Sickle Cell Center at Grady Health System, Grady Memorial Hospital, Atlanta, GA, USA; 3Center for Sickle Cell Disease, University of Tennessee Health Sciences Center, Memphis, TN, USA; 4Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA; 5Division of Hematology & Oncology, University of Illinois Chicago, Chicago, IL, USA; 6Agios Pharmaceuticals, Inc., Cambridge, MA, USA; 7Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

aEmployee of Agios Pharmaceuticals, Inc. at time of research

BACKGROUND

• Furthermore, PKM2 is highly expressed in kidney tubules,10-12

Key inclusion criteria

≥

≥

Table 2. Key secondary objectives and endpoints

• Sickle cell nephropathy (SCN) causes significant mortality,1

with approximately 10% of all sickle cell disease (SCD)-related

deaths associated with kidney disease2

• It is estimated that approximately 30% of adults with SCD

develop chronic kidney disease secondary to SCN3

• Albuminuria is a marker of kidney damage and predicts

progressive decline in kidney function in children and adults

with SCD1

• SCD treatment guidelines recommend screening for potential

SCN in patients with SCD using urinary albumin-creatinine

and improved ATP production in the hypoxic, acidotic, and

hyperosmolar environment of the tubules is a proposed

mechanism by which mitapivat may benefit patients with

renal disease in SCN4,13,14

• Studies are ongoing to investigate the role of PKM2 activation

in improving renal fibrosis by reprogramming metabolism and

decreasing collagen synthesis15

• There continue to be significant unmet needs for patients with

SCN, and therapies that target end-organ damage in SCD,

such as SCN, are needed

• Aged 16 years ( 18 years in France) at the time of providing

informed consent/assent

• Documented SCD diagnosis (homozygous for sickle cell Hb

or HbS/ß0-thalassemia)

• Hb level 5.5-10.5 g/dL during the screening period

• 2 urine ACR resultsa of ≥100 and <2000 mg/g collected during

the screening period

• 1 ACR result >100 mg/g within 24 weeks before providing

informed consent/assent

• If receiving hydroxyurea (HU), the dose must be stable for

≥90 days before starting mitapivat

• If taking angiotensin-converting enzyme inhibitor or

angiotensin receptor blocker therapy, the dose must be stable

Key secondary objectives To determine the effect of mitapivat on:

Cystatin C and creatinine-based eGFR (eGFRcr-cys)

ACR

Efficacy measures related to nephropathy

To evaluate the safety of mitapivat

Key secondary endpoints

Measured by:

Change from baseline in eGFRcr-cys

• eGFRcr-cys will be calculated according to the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin equation17

Change from baseline in ACR

Stable ACR, defined as Month 6 ACR within ±20% of baseline ACR

Annualized rate of visits to emergency room Annualized rate of days of hospitalizations

Type, frequency, and severity of adverse events (AEs) and serious AEs and relationship to study drug

ratio (ACR),4,5 a widely acceptable biomarker of kidney

disease

• Mitapivat, a first-in-class, oral, small-molecule allosteric

activator of pyruvate kinase (PK), including red blood cell-

specific PK (PKR) and PK muscle isoenzyme 2 (PKM2)

isoforms, is under investigation for the treatment of SCD6-8

(Figure 1)

• In patients with SCD, mitapivat has demonstrated statistically

significant and clinically meaningful improvement in

hemoglobin (Hb) response compared with placebo, in

addition to observed improvements in markers of hemolysis

and erythropoiesis and reductions in annualized rates of

sickle cell pain crises (SCPCs) (phase 2 portion of RISE UP

[NCT05031780])8

- Mitapivat was well tolerated, with an observed safety profile

consistent with previously reported data on mitapivat in

SCD and other hemolytic anemias8

Figure 1. PK activation in SCD may improve anemia and reduce sickling9​

Glucose

GLYCOLYSIS

OBJECTIVE

•To report the design of the phase 2, open-label, multicenter, global, single-arm study evaluating the efficacy and safety of mitapivat in patients with SCD and nephropathy (NCT06286046)16

METHODS

Study design

• This phase 2 study is designed to evaluate the efficacy and safety of mitapivat in patients with SCD and nephropathy, with the primary and key secondary objectives and endpoints displayed in Tables 1 and 2
• Patients with SCD and nephropathy will receive oral mitapivat 100 mg twice daily for up to 24 months (Figure 2)
• Treatment continuation past Month 6 will be at the discretion of the investigator and patient
• Duration of participation in the study is up to 2.2 years

Populations for analysis

• All patients who received at least 1 dose of mitapivat will be

for ≥90 days before providing informed consent/assent

• Women of childbearing potential must be abstinent of activities

that may induce pregnancy, or agree to use

2 forms of contraception, 1 of which must be considered highly

effective

a1 result can be from an untimed urine sample; the other must be from the first (or second) morning void on a different day

Key exclusion criteria

• Pregnant, breastfeeding, or parturient

• Receiving regularly scheduled blood transfusions

- Episodic transfusion in response to worsened anemia or vaso-

occlusive crisis is permitted

• Received blood transfusion within 60 days of providing informed

consent/assent or during the screening period

• Hospitalizationa due to SCPCs or other vaso-occlusive event

within 14 days of providing informed consent/assent or during

the screening period

• >10 SCPCs in the 52 weeks prior to providing informed consent/

assent

• Renal dysfunction (defined as estimated glomerular filtration

rate [eGFR] <45 mL/min/1.73 m2), renal disease due to another

disorder unrelated to SCD, or evidence of acute kidney injury

• History of stroke, hepatobiliary disorders, or kidney

ACR, albumin-creatinine ratio; AE, adverse event; eGFR, estimated glomerular filtration rate; eGFRcr-cys, cystatin C and creatinine-based estimated glomerular filtration rate

RESULTS

• Approximately 40 patients with SCD and nephropathy will be enrolled in this study
• 35 sites across 7 countries are planned for recruitment (Figure 3)

Figure 3. Study geographic distribution

Ireland

France Lebanon

USA	Saudi Arabia
	Oman

Brazil

CONCLUSION

FBP

1,3-DPG

3-PG

PEP

PK

2,3-DPG

ADP

Decreasing 2,3-DPG reduces HbS polymerization by increasing Hb oxygenation and may inhibit

the sickling process

included in efficacy and safety analyses

Figure 2. Phase 2 study design

Primary endpoint: ACR response, defined as

a ≥30% decrease in ACR from baseline to Month 6

transplantation at any time

• Currently undergoing renal replacement therapy (hemodialysis,

peritoneal dialysis, hemofiltration, kidney transplantation)

• Individuals receiving treatment with disease-modifying SCD

therapies other than HU, or hematopoietic stimulating agents

(last dose of such therapies must have been administered ≥90

days prior to randomization)

•This phase 2 study is designed to evaluate the efficacy and safety of mitapivat in patients with SCD and nephropathy

Further trial information is available at www.clinicaltrials.gov (NCT06286046)

Mitapivat

ATP		Increasing ATP enhances
		RBC energy metabolism and
		may improve membrane integrity

period weeks)		-up lastdose)	study

• Poorly controlled hypertensionb refractory to medical

management

and from [e-mail]

Pyruvate

ADP, adenosine diphosphate; DPG, diphosphoglycerate; FBP, fructose bisphosphate; Hb, hemoglobin; HbS, hemoglobin S; PEP, phosphoenolpyruvate; PG, phosphoglycerate; PK, pyruvate kinase; RBC, red blood cell; SCD, sickle cell disease

• In patients with SCN, improvement in anemia and reduction in sickling and hemolysis may reduce damage to the kidneys by improving blood perfusion, reducing sickling-related ischemia, and decreasing the toxicity caused by free heme in the kidneys

				Mitapivat
				(100 mg BID)
Screening (up to 6	Enrollment N=40			Endof
				Safetyfollow weeksafter
							(4
				Treatment period: up to 24 months
				(with up to 1 additional week of dose taper)a

aPrimary endpoint is assessed at 6 months; it is at the discretion of the Investigator and the patient whether to continue mitapivat treatment for up to 24 months

ACR, albumin-creatinine ratio; BID, twice daily

aDefined as an in-patient admission to a hospital that may or may not be preceded by an emergency room or outpatient clinic visit; bDefined as systolic blood pressure (BP) >150 mm Hg or diastolic BP >90 mm Hg

Table 1. Study primary objective and endpoint

Primary objective	Primary endpoint
To determine the effect of	Measured by:
mitapivat on:
ACR response in patients with SCD	≥30% decrease in ACRa from baseline
and nephropathy	to Month 6

aDerived as the mean of the ACR results from 2 urine samples (1 untimed and 1 from a first or second morning void) ACR, albumin-creatinine ratio; SCD, sickle cell disease

Acknowledgments: We would like to thank all the patients and study investigators for taking part in this trial, and the study investigators for contributing to the design of this study. Medical writing assistance was provided by Colette Szarka, MPhil, of Adelphi Group, Macclesfield, UK, funded by Agios Pharmaceuticals, Inc.

Disclosures: This study was funded by Agios Pharmaceuticals, Inc.

FE-R: Afimmune, Agios, Novartis, Novo Nordisk - research funding. KIA: Novartis, Novo Nordisk - research funding; Agios, Biomarin, Fulcrum Therapeutics, Hillhurst Biopharmaceutics, Novartis, Novo Nordisk, Pfizer, Sanofi - advisory board member. JL: Agios, BPL, Novartis - consultant. SS: Novartis, Novo Nordisk, Pfizer - research funding; Agios, BEAM Therapeutics, Novartis, Novo Nordisk, ORIC Pharmaceuticals, Pfizer - advisory board member. JX: Agios - employee and shareholder, at the time of research.

KU, KO, AUZ, and MUC: Agios - employee and shareholder. MRA: Agios - advisory board member; Novartis - research funding; Vertex - data monitoring committee; Pfizer - research funding; Roche - travel grant; Novo Nordisk - research funding.

References and

supplemental materials are available via the QR code

This study was funded by Agios Pharmaceuticals, Inc. Presented at the 2024 European Hematology Association (EHA) Hybrid Congress, June 13-16, 2024, Madrid, Spain, and Virtual