Improvements in Patient-Reported Outcomes in Mitapivat-treated Patients With Pyruvate Kinase Deficiency: A Descriptive Analysis From the Phase 3 ACTIVATE Trial

Improvements in patient-reported outcomes in mitapivat-treated patients with pyruvate kinase deficiency: A descriptive analysis from the phase 3 ACTIVATE trial

Kevin H M Kuo, MD,1 Rachael F Grace, MD,2 Eduard J van Beers, MD,3 Wilma Barcellini, MD,4 Andreas Glenthøj, MD,5 Susanne Holzhauer, MD,6 Parija Patel, PharmD, MBA,7 Vanessa Beynon, MD,7 Junlong Li, PhD,7 Erin Zagadailov, PharmD, MS,7 Hanny Al-Samkari, MD8

1Division of Hematology, University of Toronto, Toronto, ON, Canada; 2Dana-Farber/Boston Children's Cancer and Blood Disorder Center, Harvard Medical School, Boston, MA, USA; 3Benign Hematology Center, Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands; 4Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; 5Department of Hematology, Rigshospitalet, Copenhagen, Denmark; 6Department of Pediatric Hematology and Oncology, Charité University Medicine, Berlin, Germany; 7Agios Pharmaceuticals, Inc., Cambridge, MA, USA;

8Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

P1735

BACKGROUND

• Pyruvate kinase (PK) deficiency is a rare, congenital hemolytic anemia characterized by mutations in PKLR encoding the red blood cell (RBC)-specific form of PK (PKR)1-4
• PK deficiency is associated with acute and long-term complications, as well as a spectrum of signs and symptoms including jaundice, fatigue, and dyspnea, resulting in a profound, wide- ranging impact on health-related quality of life (HRQoL; Figure 1)3,5

Figure 1. Conceptual model of the burden and impact of PK deficiency on HRQoL, based on the signs, symptoms, and impacts reporteda by 21 adult patients with PK deficiencyb,5

Symptoms of anemia
	Physical		Appearance		Activities of		Social		Emotional
• Fatigue		limitations				daily living		impacts		impacts
• Tiredness		• Need for		• Negative impact		• Difficulty with		• Negative impact		• Concern about
• Lack of/low energy
additional rest		on appearance		household		on social		the future
• Exhaustion	• Difficulty with				activities		activities
• Weakness	exercise/sports				• Lack of		• Negative impact
• Dizziness/lightheadedness	• Difficulty climbing				motivation		on relationships
• Shortness of breath	stairs/walking				• Less productive		with family/
• Decreased stamina	uphill						friends
Appearance-related signs	• Susceptibility to						• Receiving
illness						unwanted
• Jaundice (yellow eyes								attention
and/or skin)
• Pale skin
Other signs and symptoms
• Cognitive impairment		Proximal to PK
• Bone pain					Distal to PK deficiency
	deficiency
• Joint pain

a1-hour interviews were conducted to better understand the burden of PK deficiency in terms of signs, symptoms, and impact of the disease on participants' HRQoL; bParticipants were primarily recruited through the Pyruvate Kinase Natural History Study (NHS; NCT02053480) via a recruitment flyer distributed by NHS investigators. Participants were also recruited through a patient advisory board, a PK deficiency patient advocacy/support website, and a Facebook support page; HRQoL, health-related quality of life; NHS, Natural History Study; PK, pyruvate kinase

• Mitapivat is an oral PK activator that has been approved by the US FDA for the treatment of hemolytic anemia in adults with PK deficiency; it targets the underlying enzymatic defect that causes hemolysis in PK deficiency by restoring PKR activity (Figure 2)6-8
• Mitapivat was shown to improve hemoglobin (Hb), hemolysis, and hematopoiesis in a phase 3, randomized, placebo-controlled trial evaluating mitapivat in adults with PK deficiency who were not regularly transfused (ACTIVATE; NCT03548220)9
• In addition, significant improvements in patient-reported outcomes (PROs) (measured by validated, disease-specific PRO instruments: the PK deficiency diary [PKDD] and the PK deficiency impact assessment [PKDIA]; Figure 3) were demonstrated in patients receiving mitapivat compared with placebo9-11

Figure 2. Mitapivat mechanism of action in PK deficiency

ATP, adenosine triphosphate; mPKR, mutant PKR; PK, pyruvate kinase; PKR, RBC-specific form of PK; RBC, red blood cell

Figure 3. The PKDD and PKDIA were developed as self-administered tools to assess and capture changes in symptom burden and HRQoL impact in patients with PK deficiency

e D

e

Daily sum score

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Scoring algorithm

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7-item

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3. Jaundice

In-trial validation

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1. Tiredness at its worst

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PKDD

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2. Tired after finishing daily activities

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evening diary

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4. Bone pain

y

r

a

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Signs and

y

5. Shortness of breath

T-score

High internal

6. Energy level at beginning of day

Mean 50, SD 10

consistency

symptoms

7. Energy level at end of day

Min 25, Max 76

MCICa is a reduction of 4.2

Excellent retest

reliability

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ien

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Sum score

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y

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1. Finishing things you wanted to get done

Lower score =

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2. Household activities

Scoring algorithm

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lower disease burden

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p

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PKDIA

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3. Negative impact on social activities

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4. Negative impact on leisure activities

8-itemb

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weekly measure

s

5. Relationships with friends or family negatively

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s

affected

a

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t

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T-score

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Disease impacts

6. Difficulty concentrating

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Mean 50, SD 10

7. Difficulty performing moderate physical activity

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Min 30, Max 76

y

n

8. Needing additional rest or sleep

P

t

MCICa is a reduction of 5.5

aMCIC is estimated using the median change for patients achieving an anchor-based1-point improvement in PGIS in the ACTIVATE study; bBaseline IRT modeling revealed that 4 of the original 12 items were less relevant to the ACTIVATE trial population or did not contribute unique information due to skewness or redundancy and were removed; HRQoL, health-related quality of life; IRT, item response theory; MCIC, minimal clinically important change; PGIS, Patient Global Impression of Severity; PK, pyruvate kinase; PKDD, PK deficiency diary; PKDIA, PK deficiency impact assessment; SD, standard deviation

Figure 4. ACTIVATE study design

Screening	Individualized dose			Fixed-dose period
	escalation period
						50 mg BID
			20 mg BID					Optimized mitapivat dose
		5 mg BID								Open-label
Mitapivat					50 mg BID				extension
							period
	Ra
	1:1		20 mg BID					Mock optimized placebo dose
Placebo

5 mg BID

6 weeks

12 weeks

12 weeks

Key eligibility criteria:	Key exclusion criteria:
• ≥18 yrs of age	• Homozygous for R479H mutation or have
• Documented ≥2 mutant alleles in PKLR	2 non-missense mutations, without another
(≥1 missense mutation)	missense mutation, in PKLR
• Not regularly transfused	• Splenectomy during study, or within
(≤4 transfusion episodes in previous year)	12 months of enrollment
• Baseline Hb ≤10 g/dL	• Prior bone marrow or stem cell transplant
• Adequate organ function

aStratified by average of screening Hb values (<8.5 g/dL vs ≥8.5 g/dL) and PKLR gene mutation category (missense/missense vs missense/ non-missense); BID, twice daily; Hb, hemoglobin; PK, pyruvate kinase; R, randomized; wks, weeks; yrs, years

OBJECTIVE

• To describe PKDD and PKDIA outcomes for the subset of patients in the ACTIVATE trial who achieved the primary endpoint of Hb response

METHODS

• ACTIVATE was a phase 3, randomized, double-blind,placebo-controlled study that evaluated the efficacy and safety of mitapivat in adult patients with PK deficiency who were not regularly transfused (Figure 4)
• • Primary endpoint: Hb response, defined as ≥1.5 g/dL increase in Hb concentration from baseline (BL) sustained at ≥2 scheduled assessments at Weeks (Wks) 16, 20, and 24 during fixed-dose period
  • Changes from BL at Wk 24 in PKDD and PKDIA scores were prespecified secondary endpoints
• In this post hoc analysis:
• • Changes from BL in PKDD weekly mean score and PKDIA score measured at scheduled visits (Wks 4, 8, 12, 16, 20, and 24) were summarized descriptively for patients in ACTIVATE who:
  • • Achieved the primary endpoint of Hb response and
    • Were randomized to receive either mitapivat or placebo and dosed
  • Numbers of patients who achieved minimal clinically important change (MCIC) at Wk 24 in terms of PKDD and PKDIA assessments were also summarized
  • • MCIC is considered as a reduction of 4.2 in PKDD score, and 5.5 in PKDIA score from BL; those threshold values were estimated via an anchor-based method using Patient Global Impression of Severity (PGIS) as the anchor

RESULTS

Population

• 80 patients were randomized 1:1 to receive mitapivat (N=40) (5/20/50 mg twice daily) or PBO (N=40) in the ACTIVATE trial
• • Baseline characteristics were well-balanced across mitapivat and placebo arms, and reflective of high disease burden; these data have been previously reported9
• 16 (40%) mitapivat-treated patients met the primary endpoint of Hb response in the core study period, compared with 0 placebo-treated patients
• These 16 mitapivat-treated patients who met this endpoint of Hb response were the focus population for this post hoc analysis

ACTIVATE study primary analyses

• Results from primary analyses of the ACTIVATE trial have previously been reported9

Post hoc analysis

• Greater improvements across both disease-specific PRO instruments were observed in the 16 mitapivat-treated patients who achieved the primary endpoint of Hb response (Tables 1 and 2)
• The majority of mitapivat-treated patients who achieved Hb response also achieved meaningful improvements in both PKDD and PKDIA scores above the MCIC threshold at Wk 24 (Tables 1 and 2)
• Mean change from baseline in PKDD weekly mean score was greatest in mitapivat-treated patients who achieved Hb response, indicating the most improved signs/symptoms in this group (Table 1)

Table 1. Summary of PKDD weekly mean score and change from baseline at Wk 24 for patients who achieved Hb response and overall

	Mitapivat
	Patients who achieved	All patients	Placebo all patients
Visit	Hb response
N=40	N=40
	n=16
Baseline
n	15	37	36
Mean (SD)	50.08 (6.274)	50.47 (7.315)	47.04 (8.103)
Median (Q1, Q3)	48.86 (45.67, 52.14)	50.57 (48.00, 52.86)	48.77 (44.58, 51.46)
Min, Max	42.2, 61.0	27.0, 65.1	27.0, 58.1
Wk 24
n	16	39	34
Mean (SD)	42.27 (6.985)	44.41 (7.587)	45.81 (7.669)
Median (Q1, Q3)	43.00 (38.29, 46.77)	45.00 (40.00, 49.67)	47.29 (42.86, 49.33)
Min, Max	29.4, 55.4	27.0, 61.0	27.0, 64.3
Wk 24
Change from baseline
n	15	36	31
Mean (SD)	-7.12 (6.959)	-5.43 (6.009)	-1.86 (5.945)
Median (Q1, Q3)	-9.14(-12.74,-0.30)	-6.36(-9.62,-0.15)	-1.29(-4.21, 1.14)
Min, Max	-16.0, 4.8	-16.0, 5.6	-17.6, 12.5
% of patients with reduction in	60.0	55.6	29.0
score ≥MCIC threshold

Baseline of weekly mean score is defined as the average of daily scores collected within 7 days before randomization for patients randomized and not dosed or before start of study treatment for patients randomized and dosed. Patient-level weekly mean score at week is NA if there are less than 4 daily scores in that week. MCIC threshold estimation is calculated using the median change score in ∆PGIS = -1 group; Hb, hemoglobin; MCIC, minimal clinically important change; NA, not available; PGIS, Patient Global Impression of Severity; PKDD, pyruvate kinase deficiency diary; SD, standard deviation; Wk, Week

• Mean change from baseline in PKDIA score was greatest in mitapivat-treated patients who achieved Hb response, indicating the most benefit on disease impact in this population (Table 2)

Table 2. Summary of PKDIA score and change from baseline at Wk 24 for patients who achieved Hb response and overall

	Mitapivat
	Patients who achieved	All patients	Placebo all patients
Visit	Hb response
N=40	N=40
	n=16
Baseline
n	15	39	39
Mean (SD)	49.9 (6.85)	49.2 (9.00)	48.5 (9.15)
Median (Q1, Q3)	51.0 (43.0, 56.0)	51.0 (43.0, 56.0)	51.0 (39.0, 54.0)
Min, Max	39, 60	30, 66	30, 66
Wk 24
n	16	40	34
Mean (SD)	41.7 (7.24)	44.3 (8.68)	47.5 (9.65)
Median (Q1, Q3)	39.5 (36.0, 44.5)	42.5 (37.0, 50.5)	48.0 (39.0, 55.0)
Min, Max	35, 59	30, 64	30, 62
Wk 24
Change from baseline
n	15	39	34
Mean (SD)	-8.1 (5.39)	-4.8 (7.27)	-1.1 (7.58)
Median (Q1, Q3)	-9.0(-12.0,-4.0)	-4.0(-11.0, 0.0)	0.0 (-6.0, 3.0)
Min, Max	-16, 0	-21, 9	-18, 14
% of patients with reduction in	60.0	43.6	26.5
score ≥MCIC threshold

Baseline is defined as the last complete assessment (with no missing item in response) before randomization for patients randomized and not dosed or before start of study treatment for patients randomized and dosed. MCIC threshold estimation is calculated using the median change score in ∆PGIS = -1 group; Hb, hemoglobin; MCIC, minimal clinically important change; PGIS, Patient Global Impression of Severity; PKDIA, pyruvate kinase deficiency impact assessment; SD, standard deviation; Wk, Week

• Mitapivat led to early and sustained improvements in PKDD weekly mean score; improvements were even more pronounced in the 16 mitapivat-treated patients who achieved the primary endpoint of Hb response (Figure 5)
• Mitapivat led to early and sustained improvements in PKDIA score; improvements were even more pronounced in the 16 mitapivat-treated patients who achieved the primary endpoint of Hb response (Figure 6)

Figure 5. Mean (95% CI) change from baseline in PKDD weekly mean score for patients who achieved Hb response and overall

	0
Mean (95% CI) change from BL in PKDD weekly mean score	-3
-6
-9
	-12
Mitapivat Hb responder (n=16)	15	14	14	14	14	15	14	15	15	15	15	15	14	15	15	15	14	14	13	12	13	15	13	14	15
Mitapivat (N=40)	37	36	35	36 36	37	35	36	37	36	35	35	35	35	36 36	35	35 34	32	34	37	35	35	36
Placebo (N=40)	36 36	35	35 34 34 35	35 34 34 35 34 35 34	32	33	31	32	34 33	33	32	32	31	31
		BL	1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19 20 21	22 23 24
														Week
Mitapivat achieved Hb response (n=16)			Placebo (N=40)			Mitapivat (N=40)		MCIC threshold

Analyses performed on the Full Analysis Set, defined as all patients who were randomized. Achieved Hb response defined as ≥1.5 g/dL increase in Hb from BL, sustained at ≥2 scheduled assessments at Wks 16, 20, and 24; BL, baseline; CI, confidence interval; Hb, hemoglobin; MCIC, minimal clinically important change; PKDD, pyruvate kinase deficiency diary; Wk, Week

Figure 6. Mean (95% CI) change from baseline in PKDIA score for patients who achieved Hb response and overall

Mean (95% CI) changefrom BL in PKDIA score	0
-3
-6
-9
	-12
Mitapivat Hb responder (n=16)	15	15	15	15	15	15	15
Mitapivat (N=40)	39	39	38	39	38	38	39
Placebo (N=40)	39	38	38	38	35	37	34
		BL	4	8	12	16	20	24
					Week
Mitapivat achieved Hb response (n=16)		Placebo (N=40)		Mitapivat (N=40)		MCIC threshold

Analyses performed on the Full Analysis Set, defined as all patients who were randomized. Achieved Hb response defined as ≥1.5 g/dL increase in Hb from BL, sustained at ≥2 scheduled assessments at Wks 16, 20, and 24; BL, baseline; CI, confidence interval; Hb, hemoglobin; MCIC, minimal clinically important change; PKDIA, pyruvate kinase deficiency impact assessment; Wk, Week

CONCLUSIONS

• In the ACTIVATE trial, mitapivat-treated patients demonstrated significant improvements in signs, symptoms, and impacts based on PK deficiency-specific PRO instruments, compared with placebo
• This post hoc analysis further suggests that across both PRO instruments (the PKDD and PKDIA), improvements in HRQoL were even greater and were clinically meaningful in the subset of mitapivat-treated patients who achieved the protocol-defined primary endpoint of Hb response

Mitapivat, a disease-modifying pharmacotherapy for patients with PK deficiency, improved HRQoL, indicating a potential for beneficial real-world impacts in patients with this condition

Acknowledgments: We would like to thank the patients and study investigators for taking part in this study. Editorial assistance was provided by Kate Collins, Adelphi Communications, Macclesfield, UK, and supported by Agios Pharmaceuticals, Inc.

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

KHM Kuo: Agios, Alexion, Apellis, bluebird bio, Celgene, Forma, Novartis, Pfizer - consultancy; Alexion, Novartis - honoraria; Bioverativ - membership on an entity's Board of Directors or advisory committees; Agios, Pfizer - research funding; RF Grace: Agios, Dova (Sobi), Novartis - research funding; Principia (Sanofi) - consultancy; EJ van Beers: Agios, Forma - advisory board member; Agios, Novartis, Pfizer, RR Mechatronics - research funding; Imara - data safety monitoring board; W Barcellini: Agios - consultancy; A Glenthøj: Agios, bluebird bio, Celgene, Novartis, Novo Nordisk

• consultancy; Alexion, Saniona, Sanofi - research funding; S Holzhauer: There are no relationships to disclose; H Al- Samkari: Agios, Argenx, Dova, Forma, Moderna, Novartis, Rigel, Sobi - consultancy; Agios, Amgen, Dova - research funding; P Patel, V Beynon, J Li, E Zagadailov: Employee of Agios Pharmaceuticals, Inc.

References: 1. Grace RF et al. Am J Hematol 2015;90:825-30. 2. Zanella A et al. Br J Haematol 2005;130:11-25.

3. Grace RF et al. Blood 2018;131:2183-92. 4. van Beers EJ et al. Haematologica 2019;104:e51-3. 5. Grace RF et al. Eur J Haematol 2018;101:758-65. 6. Kung C et al. Blood 2017;130:1347-56. 7. Yang H et al. Clin Pharmacol Drug Dev 2019;8:246-59. 8. PYRUKYND (mitapivat). Prescribing information. Agios Pharmaceuticals, Inc. https://www. accessdata.fda.gov/drugsatfda_docs/label/2022/216196s000lbl.pdf. Accessed May 22, 2022. 9. Al-Samkari H et al. N Engl J Med 2022;386:1432-42. 10. Egan S et al. Blood 2021;138:4144. 11. Egan S et al. Blood 2021;138:4145.

Presented at the 2022 European Hematology Association (EHA) Hybrid Congress, June 9-12, 2022, Vienna, Austria, and Virtual