Long-term Safety and Efficacy of Mitapivat, an Oral Pyruvate Kinase Activator, in Adults with Sickle Cell Disease: Extension of a Phase 1 Dose Escalation Study

NCT04610866 Investigator-initiated trial; Principal Investigator: Swee Lay Thein

Anna Conrey1, Ingrid Frey1, Nancy Asomaning1, Ruth Pierre-Charles1, Dina Parekh1, Julia Z. Xu1, Kang Le 1, Britney Kruah1, Quan Li2, Emily Dunkelberger2, Troy Cellmer2, Amber Yates3, Megan Wind-Rotolo3, Neal Jeffries4, William A. Eaton2, and Swee Lay Thein1

1Sickle Cell Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, US; 2Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, US; 3Agios Pharmaceuticals, Inc., Cambridge, MA, US, 4Office of Biostatistics Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, US

Abstract #273

65th American Society of Hematology Annual Meeting

San Diego, 9 December 2023, 4.30 PM

Pyruvate Kinase (PK) Activation in Sickle Cell Disease (SCD)

Key factors that promote sickling

2,3-DPG (increased in patients with SCD)

  • Preferentially binds to polymerizing HbS (T) conformation
  • Stabilizes HbS fiber
  • Decreases the intra-erythrocyte pH

ATP is decreased in SCD

  • Essential for water and ion homeostasis
  • Reduced ATP leads to water and ion loss
  • RBC dehydration promotes sickling

Mitapivat :

  • Approved by FDA for treating PK deficiency
  • Also activates wild type PK in SCD
  • Generally safe and tolerable
  • Increased ATP and decreased 2,3-DPG levels in a dose- dependent manner
  • Improved Hb levels and reduced hemolytic markers

Xu et al. Blood 2022; 140: 2052.

Glucose

Glucose-

6-phosphate

Fructose-

1,6-bisphosphate

1,3-diphosphoglycerate

2,3-DPG

3-phosphoglycerate

Phosphoenolpyruvate

ADP

Pyruvate

kinase (PK)

ATP

Pyruvate

Mitapivat (PK activator)

Decreasing DPG destabilizes HbS polymers, thereby inhibiting the sickling process

2,3-DPG

ATP

Increasing ATP enhances RBC energy metabolism and RBC integrity

Study Design: Extended Treatment with Mitapivat in patients with SCD (NCT04610866)

  • Subjects who have completed previous dose escalation study +/- mitapivat naïve subjects (N=15 completing 24-week endpoints)
  • Escalate to 100 mg BID dose level as tolerated

Primary endpoints1:

• Long-term safety and

tolerability

SCREENING

DOSE

ESCALATION

50 mg BID

MAINTENANCE

100 mg BID

DOSE TAPER

FOLLOW-UP

Secondary endpoints2:

•

Hb response (Hb increase >1

g/dL above baseline) and

changes in hemolytic markers

(reticulocyte, LDH, bilirubin)

•

Sustained Hb response

4 weeks

4 weeks

Wk 2

(V2)

Up to 2 (+2+2) years*

15 days

Wk 8

Wk 24

Wk 96

Wk 288

(V4)

(V6)

(V12)

(V28)

q3 months

q6 months

4 weeks

(increase in Hb at >2

timepoints within the core 24

week period.)

•

Pharmacokinetics

•

Pharmacodynamics (2,3-DPG

Day 1

Week 4

Week 12

(V1)

(V3)

(V5)

1Evaluation of primary endpoint at 48 weeks;

2Evaluation of secondary endpoints at 24 and 48 weeks *Option of 2 +2+2 years with amendment 08-27-2022

and ATP levels)

• p50 (O2 affinity) and t50 (HbS

polymerization kinetics)

Demographics, Baseline Characteristics, and Disposition

Baseline Characteristics at

N=15

Enrollment

Age, mean (range), years

39 (25-57)

Sex, no. (%)

5 (33.3)

Female

Male

10 (66.7)

African or African-American, N (%)

15 (100)

Hydroxyurea use, N (%)

11 (73.3)

Baseline LaboratoryMeasures

N=15

Hemoglobin, mean (SD), g/dL

8.63 (1.11)

Abs reticulocyte count, mean (SD), K/µL

217.21 (88.27)

Total bilirubin, mean (SD), mg/dL

2.73 (1.43)

Lactate dehydrogenase, mean (SD), U/L

536.71 (222.16)

Hemoglobin F, mean (SD), %

15.93 (10.53)

  • #3 - withdrawn due to moving out of the country
  • #2 - pt decision to withdraw to try to conceive
  • #5 - Hb level exceeded protocol cut-off of 12.5 mg/kg at 50mg and 20mg BID. Hb stable 11.5-12.3 g/dL on 5mg BID

Total enrolled

(N=15)

Started mitapivat

(N=15)

Finished 24-week core

period (N=15)

2 withdrawals:

24 weeks*

96 weeks**

Study ongoing (N=13)

( 8 @ 100mg, 1 @ 50mg, 3 @ 50-100mg, *** 1 @ 5mg )

( Data cut : March 23, 2023)

Mitapivat Was Generally Safe and Well Tolerated

Treatment Emergent Adverse

N=15 (%)

All Grades (≥

Events (TEAEs)

Grade ≥ 3

10%)

All

15 (100%)

11 (73.3%)

Vaso-occlusive crisis (VOC)

8 (53.3%)

8 (53.3%)

Estrone decreased

7 (46.7%)

0 (0%)

Testosterone increased, total

6 (40%)

0 (0%)

Cough

5 (33.3%)

0 (0%)

ALT increased

4 (26.7%)

0 (0%)

Arthralgia

4 (26.7%)

0 (0%)

Bloating

4 (26.7%)

0 (0%)

Estradiol decreased

4 (26.7%)

0 (0%)

Serious Adverse Events(SAEs)

N=15 (%)

All

9 (60%)

VOC

8 (53.3%)

Lung infection

2 (13.3%)

Pain

1 (6.7%)

COVID-19 infection

1 (6.7%)

Vomiting

1 (6.7%)

Summary of VOCs, SAEs or Grade 3 AEs:

  • All VOCs occurred in setting of known VOC triggers.
  • 2 VOCs possibly drug related (1 during drug escalation and 1 during drug taper).
  • All other SAEs were not considered related to study drug.
  • No TEAEs requiring drug discontinuation.
  • Changes in laboratory values were not clinically significant.
  • 3 patients required dose reduction to 50 mg (pruritis, bloating, insomnia), dose subsequently increased to 100 mg in 2 patients as TEAEs resolved.
  • Total of 1080 patient-weeks of drug exposure thus far.

(Data cut : March 23, 2023)

(VOCs: vaso-occlusive crises)

Mitapivat met the Secondary endpoint of Hb Response

*Hb Response

Hemoglobin (g/dL)

100

93.3%

85.7%

% Responders

80

60

40

20

14/15

12/14

0

All

Sustained

Mean (±SD) Hb Change from Baseline

Timepoint

n

**Mean (SD)

P-value

Baseline

15

8.63 (1.11)

-

Week 4

15

1.16 (0.73)

<0.0001

Week 12

14

1.26 (0.85)

<0.0001

Week 24

15

1.38 (0.88)

<0.0001

Week 48

13

1.13 (1.2)

0.0004

Week 72

10

0.9 (1.03)

0.004

Hb

2.5

1.2 g/dL

in

2.0

1.1 g/dL

from Baseline

(±SD) change

(g/dL)

1.5

1.0

0.5

Mean

0.0

14/15

12/14

All Responders Sustained

    • Mean (SD) change from baseline
  • 14/15 (93%) of the patients met secondary endpoint at 24 wks
  • Response sustained in 12/14 patients
  • Mean Hb change from baseline:

o 1.1 g/dL in all 14 responders

o 1.2 g/dL in 12 in which response is sustained.

  • *Hb response, defined as a ≥ 1 g/dL increase in Hb at any timepoint within the core period 24 weeks compared to baseline.
  • Sustained Hb response, defined as a ≥ 1 g/dL increase in Hb at 2 or more timepoints within the core 24-week period.

Hb: hemoglobin

Improvements in Hemoglobin Were Rapid and Maintained

Through the Extension Period

Improvements Were Observed in Markers of Hemolysis and

Were Sustained

Mean(±SD) Change in LDH (U/L) from Baseline

100

0

-100

-200

-300

-400 Wk

N

Mean (±SD) Change in LDH from Baseline

Core Period

Extension Period

2 4

8

12

24

36

48

60

72

14 14

14

13

14

14

12

8

9

Mean(±SD) Change in T. Bili (mg/dL) from Baseline

Mean (±SD) Change in T. Bili from Baseline

1

Core Period

Extension Period

0

-1

-2

-3

Wk

2 4

8

12

24

36

48

60

72

N 15 15 14

14

15

13

13

9

10

Change from Baseline

Baseline

Week 4

Week 12

Week 24

Week 48

Week 72

n

Mean (SD)

n

Mean (SD)

p-value

n

Mean(SD)

p-value

n

Mean (SD)

p-

n

Mean (SD)

p-

n

Mean (SD)

p-value

value

value

LDH (U/L)

14

536.71

(222.16)

14 -147.93 (127.85) < 0.0001

13 -118.23 (113.8) < 0.0001

14 -122.86 (167.28)

0.004

12

-120.25 (178.83)

0.01

9

-158.67 (164.48)

0.002

T. Bili (mg/dL)

15

2.73

(1.43)

15

-0.91 (0.85)

< 0.0001

14

-1.03

(1.01)

< 0.0001

15

-0.94 (1.05)

0.0003

13

-0.84 (1.41)

0.03

10

-1 (1.42)

0.02

ARC (K/mcL)

15

217.21 (88.27)

15

-17.23 (68.03)

0.31

14

-23.68

(78.25)

0.24

15

-10.51 (73.37)

0.57

13

8.98 (82.26)

0.68

10

-19.72 (76.5)

0.39

AST (U/L)

15

39.67

(15.01)

15

0.13 (17.15)

0.98

14

-3.71

(8.29)

0.08

15

-2.93 (9.84)

0.23

13

-0.38 (13.1)

0.91

10

3.6 (11.7)

0.31

Abs. Retics: absolute reticulocyte count; LDH: lactate dehydrogenase; AST: Aspartate transaminase; T. Bili: Total bilirubin

Changes in Pharmacodynamics Were Consistent and Sustained

Mean (±SD) % Change in ATP and 2,3-DPG from Baseline

and

100%

Core Period

Extension Period

Changein ATP Baselinefrom

50%

(±SD)%

2,3-DPG

0%

Mean

-50%

Wk

2

4

8

12

24

36

48

60

72

N

15

15

13

14

14

13

13

9

10

ATP

2,3-DPG

At weeks 4, 12, 24, 48 and 72 (except 2,3-DPG)

  • Increases inATP, decreases in
    2,3-DPG significant and sustained

Mean (±SD) % Change in ATP/2,3-DPG from Baseline

Mean (±SD) % Change in ATP/2,3-DPG from Baseline

150%

Core Period

Extension Period

100%

50%

13

9

10

0%

Wk

2

4

8

12

24

36

48

60

72

N

15

15

13

14

14

13

13

9

10

  • Increases inATP/2,3-DPG significant and sustained

Note: % Changes in 2,3-DPG and ATP refer to intracellular concentrations, determined from whole blood concentrations divided by the hematocrit.

ATP: adenosine triphosphate; 2,3DPG: 2,3- diphosphoglycerate

Improvements in Oxygen Affinity (p50) and Sickling Kinetics (t50) Were Sustained

Mean (±SD) % Change in p50 from Baseline

10%

Core Period

Extension Period

in p50

0%

(±SD)% Change fromBaseline

-20%

10%

Mean

-30%

Wk

2

4

8

12

24

36

48

60

72

N

13

11

10

10

10

9

10

7

8

  • Decrease in p50 (indicates less HbS polymer) at Weeks 4, 12, 24, 48 and 72, from baseline, significant and sustained
  • Increase in t50 (slower HbS polymerization kinetics) at weeks 4, 12 and 24, significant

(±SD) % Change in t50 from Baseline

Mean (±SD) % Change in t50 from Baseline

Extension Period

350%

Core Period

300%

200%

100%

0%

p50: partial pressure of O2 at which 50% of hemes in Hb molecule have O2 bound.

t50: time in minutes at which 50% of RBCs are sickled in response to gradual deoxygenation with nitrogen to final O2 partial pressure of 38 torr.

Mean

-100%-150%

9

13

Note: Missing data are the result of disruptions

Wk

2

4

8

12

24

36

48

60

72

N

13

13

12

12

13

12

11

7

8

in equipment availability

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Agios Pharmaceuticals Inc. published this content on 09 December 2023 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 18 December 2023 17:12:41 UTC.