ACTIVATE: IN PATIENTS WHO WERE NOT REGULARLY TRANSFUSED

PYRUKYND® (mitapivat) delivered a significant, clinically meaningful increase in Hb1

40% (n=16) of patients receiving PYRUKYND achieved a clinically meaningful Hb response (compared to baseline) vs 0% on placebo1

graph illustrating a 40% increase in Hb on PYRUKYND versus 0% increase on placebo graph illustrating a 40% increase in Hb on PYRUKYND versus 0% increase on placebo
  • Clinically meaningful Hb response (≥1.5 g/dL increase from baseline) in ≥2 assessments over the 12-week fixed-dose period (weeks 16, 20, and 24 without transfusions)1
  • The majority of patients on PYRUKYND saw an increase in Hb, while the majority on placebo saw a decrease in Hb (weeks 16, 20, and 24)1*

*Approximately 99% of all randomized patients completed 24 weeks of treatment.

Robust average Hb increases in
patients who responded to PYRUKYND2

Average change from baseline Hb levels in all patients studied1,2:

3.1 g/dL average increase in those who had Hb response (P<0.0001) 3.1 g/dL average increase in those who had Hb response (P<0.0001)

Patients on PYRUKYND experienced improvements in tiredness and shortness of breath, which are symptoms of pyruvate kinase (PK) deficiency1†

Difference in LS Mean of PYRUKYND minus placebo (scale 0–10): -1.1, SE 0.4 for tiredness and -0.3, SE 0.3 for shortness of breath, as collected in the daily Pyruvate Kinase Deficiency Diary where lower scores represent a lower disease burden.1

PYRUKYND showed improvement in key markers of hemolysis through 24 weeks1

Improvements seen in indirect bilirubin, haptoglobin, reticulocytes, and LDH at weeks 16, 20, and 242

Indirect Bilirubin

graph illustrating a decrease in bilirubin for patients on PYRUKYND versus placebo

Haptoglobin

graph illustrating an increase in haptoglobin for patients on PYRUKYND versus placebo

Reticulocytes

graph illustrating a decrease in reticulocytes for patients on PYRUKYND versus placebo

LDH

graph illustrating decrease in LDH for patients on PYRUKYND versus placebo

THE PK DEFICIENCY DIARY (PKDD) TRACKED CHANGES IN SIGNS AND SYMPTOMS OF HEMOLYSIS AND ANEMIA

Patients taking PYRUKYND measured changes in major signs and symptoms of PK deficiency, such as:

  • Lower Score=Less Severe

JAUNDICE

Scale: 1-4

TIREDNESS

Scale: 1-10

SHORTNESS OF BREATH

Scale: 1-10

Patients on PYRUKYND saw improvements in jaundice, a sign of hemolysis

Baseline was defined as the average of all screening assessments within 45 (42 + 3) days before randomization for subjects randomized and not dosed or before start of study treatment for subjects randomized and dosed.2

§For jaundice symptom change, the difference in LSM of PYRUKYND minus placebo (scale 0–4): -0.4, SE: 0.1 as collected in the daily Pyruvate Kinase Deficiency Diary where lower scores represent a lower disease burden.1

Average Hb increases were maintained in the long-term
extension (LTE)1-3

graph illustrating patients on placebo who crossed over to PYRUKYND during the LTE saw Hb improvements similar to those in ACTIVATE clinical trial graph illustrating patients on placebo who crossed over to PYRUKYND during the LTE saw Hb improvements similar to those in ACTIVATE clinical trial

This is an ongoing study, and individual patients started the trial at different times. Only 11 patients have been in the study for ≥72 weeks.

86.7% of patients (13 out of 15 evaluable patients that had a Hb response) maintained an increase in Hb ≥1.5 g/dL3||

||15 of the 16 patients with an Hb response in ACTIVATE continued in a long-term extension study and were evaluable for maintenance of response. The median duration of response for the 16 patients with Hb response was 6.9 months (range: 3.3, 18.4+).

ACTIVATE CLINICAL STUDY DETAILS

In patients who were not regularly transfused

A 24-week, randomized, placebo-controlled clinical study1

PYRUKYND has been studied for up to 5 years in multiple clinical studies in 155 participants1,4

STUDY DESIGN1-3

chart illustrating the ACTIVATE study design, from screening, to individualized dose optimization period, to fixed-dose period, ending with long-term extension chart illustrating the ACTIVATE study design, from screening, to individualized dose optimization period, to fixed-dose period, ending with long-term extension

KEY ELIGIBILITY CRITERIA

  • Presence of at least 2 variant alleles in the PKLR gene, of which at least 1 was a missense variant1
  • ≤4 transfusions in the 52-week period prior to treatment and 0 transfusions in the 3-month period prior to study1
  • Patients who were homozygous for the c.1436G>A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded1

KEY EFFICACY ENDPOINTS

  • Clinically meaningful Hb response (≥1.5 g/dL increase from baseline) in ≥2 assessments over the 12-week fixed-dose period (weeks 16, 20, and 24)2
  • The ACTIVATE trial also evaluated the average change from baseline (weeks 16, 20, and 24) for Hb, indirect bilirubin, reticulocytes, LDH, haptoglobin, and changes in major symptoms of hemolysis and anemia2

LONG-TERM EXTENSION STUDY

  • The long-term extension study is ongoing with Hb response data currently out to 19.5 months3

Baseline characteristics reflect a broad range of patients with PK deficiency1

PATIENT DEMOGRAPHICS

  • The median patient age was 33 years (range: 18-78 years)
  • 55 patients (69%) had the missense/missense PKLR gene variant, and 25 patients (31%) had the missense/non-missense PKLR gene variant
  • 58 patients (73%) had a history of splenectomy

HEMOGLOBIN (g/dL)

  • The median baseline Hb was 8.5 g/dL (range: 6.4-10.2 g/dL)

EVIDENCE OF COMPLICATIONS & COMORBIDITIES ASSOCIATED WITH PK DEFICIENCY

  • Iron overload (median baseline ferritin was 479 ng/mL [range: 21-5890 ng/mL])
  • Chelation therapy use in the year before the first dose of study treatment in 15 patients (19%)
  • Decreased bone mineral density in 64 patients (80%) who had a baseline femoral neck or lumbar spine T-score <-1.0
  • History of cholecystectomy in 58 patients (73%)

In ACTIVATE, the presence of iron overload and low bone density reflects a high disease burden1,5,6

BL=baseline; Hb=hemoglobin; LDH (U/L)=lactate dehydrogenase units per liter; LSM=least squares mean; SE=standard error.

References: 1. PYRUKYND. Prescribing information. Agios Pharmaceuticals, Inc.; 2022. 2. Data on file. Agios Pharmaceuticals, Inc. 3. Grace RF, Glenthøj A, Barcellini W, et al. Durability of hemoglobin response and reduction in transfusion burden is maintained over time in patients with pyruvate kinase deficiency treated with mitapivat in a long-term extension study. Presented at: American Society of Hematology Annual Meeting; December 11-14, 2021; Atlanta, GA. https://ash.confex.com/ash/2021/webprogram/Paper147711.html. Accessed January 9, 2022. 4. Al-Samkari H, Grace RF, Glenthoej A, et al. Bone mineral density remains stable in pyruvate kinase deficiency patients receiving long-term treatment with mitapivat. Presented at: American Society of Hematology Annual Meeting; December 11-14, 2021; Atlanta, GA. 5. Grace RF, Bianchi P, van Beers EJ, et al. Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study. Blood. 2018;131(20):2183-2192. 6. Bianchi P, Fermo E, Glader B, et al. Addressing the diagnostic gaps in pyruvate kinase deficiency: consensus recommendations on the diagnosis of pyruvate kinase deficiency. Am J Hematol. 2019;94(1):149-161 [supplementary online material].

Indication

PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.

Important Safety Information

Acute Hemolysis: Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath.

Adverse Reactions: Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, each of which occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.

Drug Interactions:

  • Strong CYP3A Inhibitors and Inducers: Avoid concomitant use.
  • Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily.
  • Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage.
  • Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index.
  • UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.
  • P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.

Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment.

Please see full Prescribing Information for PYRUKYND.

Indication

PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.

Important Safety Information

Acute Hemolysis: Acute hemolysis with subsequent anemia has been observed
following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath.

Indication

PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.

Important Safety Information

Acute Hemolysis: Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath.

Adverse Reactions: Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, each of which occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.

Drug Interactions:

  • Strong CYP3A Inhibitors and Inducers: Avoid concomitant use.
  • Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily.
  • Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage.
  • Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index.
  • UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.
  • P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.

Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment.

Please see full Prescribing Information for PYRUKYND.

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