A study of mitapivat in sickle cell disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Julius Clinical Research B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

24 Sep 2020 → ongoing

Decision date (initial)

2024-08-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Agios Pharmaceuticals

External identifiers

EU CT number

2024-515569-32-00

EudraCT number

2019-003438-18

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacokinetic, Pharmacodynamic, Safety, Efficacy

- To assess (maximum) efficacy of treatment with AG-348 on sickling as evaluated by change in Point of Sickling (PoS, expressed in mmHg), as quantified by the Oxygenscan. During the Dose Finding Period the maximum fficacy is defined as the lowest PoS measured during the treatment period relative (%) to the mean PoS during the Screening Period (D-50 to D-1) and D0. During the Fixed Dose Extension Period and the Prolonged Fixed Dose Extension Period, the efficacy of treatment with AG-348 is evaluated by mean PoS during this treatment period relative (%) to the mean PoS during the Screening Period (D-50 to D-1) and D0.

- To evaluate safety of AG-348 (including the type, incidence, severity and relationship of AG-348 to AE and SAE; number of medication discontinuations due to AE; physical examination findings, vital signs and 12-lead electrocardiogram (ECG) data).

Secondary objectives 4

1. To evaluate the effect of AG-348 on changes in hemoglobin (Hb) and other hematological parameters, lactate dehydrogenase (LDH), bilirubin, carboxy hemoglobin (HbCO), red cell 2,3-DPG and ATP levels. - To evaluate the effect of AG-348 on changes of surrogate markers of mortality and organ damage in SCD (NT-proBNP, urinary albumin to creatinine ratio (ACR), CRP, LDH/HbCO).
2. To evaluate the effect of AG-348 on changes of surrogate markers of mortality and organ damage in SCD (NT-proBNP, urinary albumin to creatinine ratio (ACR), CRP, LDH/HbCO).
3. To evaluate the effect of AG-348 on RBC deformability using the Osmoscan (osmotic gradient ektacytometry)
4. To evaluate the effect of AG-348 on clinical characteristics: Health Related Quality of Life (HRQoL) (EQ-5D-5L, SF-36), movement behaviour (accelerometer Activ8), dyspnea (MRC dyspnea) and fatigue (PROMIS fatigue short form)

Conditions and MedDRA coding

Sickle cell disease

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Male or female with documented homozygous sickle cell anemia (HbSS) or HbS/beta(0 or +)-thalassemia. Documentation of genotype may be based on documented history of laboratory testing or must be confirmed by laboratory testing during screening (thin layer isoelectric focusing or high performance liquid chromatography (HPLC) with confirmation by deoxyribonucleic acid (DNA) testing if necessary).
2. Documented history of VOCs, and number of days admitted in hospital for acute sickle cell related complications during 24 months before inclusion.
3. SCD with at least one of the following conditions: I. at least 1 (but no more than 10) VOC in the past 12 months prior to the first day of study treatment; II. any sickle cell related hospital admission in the past 12 months prior to the first day of study treatment; III. any history of sickle cell related complications (such as osteonecrosis, osteoporosis, nephropathy, retinopathy, leg ulcer, acute chest syndrome, acute hemolytic crisis); IV. presence of any clinical biomarkers associated with increased mortality in SCD prior to the first day of study treatment (NT-proBNP >160 pg/mL, LDH/HbCO ratio >1,200, tricuspid regurgitant jet velocity ≥2.5 m/s).
4. Age ≥16 years, inclusive; subjects age 16 or 17 years must be documented Tanner Stage 5.
5. Hemoglobin (Hb) ≤6.9 mmol/L (approx. 11.1 g/dL) and >2.5 mmol/L (approx. 4.0 g/dL)) during screening.
6. For subjects taking hydroxyurea (HU), the dose of HU (mg/kg) must have been stable for at least 3 months prior to the first day of study treatment.
7. Subjects must start or continue taking at least the equivalent of daily 0.7 mg oral folic acid for the duration of the study.
8. Have adequate organ function, as defined by: a. Serum aspartate aminotransferase (AST) ≤2.5 × ULN (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT) ≤2.5 × ULN. b. Normal or elevated levels of serum bilirubin. In subjects with serum bilirubin > ULN, the elevation must be attributed to hemolysis with or without Gilbert’s syndrome and must not be associated with choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease. Elevated bilirubin attributed to hemolysis with or without Gilbert’s syndrome is not exclusionary. c. Serum creatinine ≤1.25 × ULN. If serum creatinine is >1.25 × ULN, then glomerular filtration rate, estimated by 24-hour measured or calculated (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) creatinine clearance, must be ≥60 mL/min/1,73 m2. d. Absolute neutrophil count ≥1.0 × 109/L during screening. e. Platelet count ≥100 × 109/L during screening. f. Activated partial thromboplastin time and international normalized ratio ≤1.25 × ULN, unless the subject is receiving therapeutic anticoagulants.
9. Be willing and able to give written informed consent and to comply to all study procedures for the duration of the study.
10. Patients with increased albumin to creatinine ratio are prioritized above patients with a normal albumin to creatinine ratio. Both are eligible.
11. For women of reproductive potential, have a negative urine and serum pregnancy test during the Screening Period (D-50 to D-1). Women of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or tubal occlusion; or who have not been naturally postmenopausal (i.e., who have not menstruated at all for at least the preceding 12 months prior to signing informed consent).
12. For (fertile men of) women of reproductive potential, agree to use double anticonception during the trial period plus 90 days (for male subjects) or 28 days (for female subjects) after the last dose of AG-348.

Exclusion criteria 16

1. More than 10 VOCs within the past 12 months.
2. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior the first day of study treatment. Subjects who may get hospitalized during the Screening Period are allowed to be rescreened 14 days after discharge.
3. Have a point of sickling (PoS) ≤24.6 mmHg as quantified by the Oxygenscan during screening to exclude subjects with no clinical relevant detectable sickling.
4. Subjects age 16 or 17 years who are documented Tanner stage 1-4.
5. Receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic or preventive transfusion), defined as more than 4 transfusion episodes in the 12-month period up to the first day of study treatment, and/or have received a transfusion within the past 3 months prior to the first day of study treatment.
6. Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound interpretation of the study data. Such significant medical conditions include, but are not limited to: a) Poorly controlled hypertension (defined as systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg) refractory to medical management. b) Any history of congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; or recent (< 6 months prior to signing informed consent) deep venous thrombosis, or pulmonary or arterial embolism. c) Cardiac dysrhythmias judged as clinically significant by the Investigator. d) Heart-rate corrected QT interval (QTc) by Fridericia's method >450 msec with the exception of subjects with right or left bundle branch block. e) Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened once the disorder has been treated and clinical symptoms have resolved. f) History of drug-induced cholestatic hepatitis. g) Iron overload sufficiently severe to result in a clinical diagnosis by the Investigator of cardiac (eg, clinically significant impaired left ventricular ejection fraction), hepatic (eg, fibrosis, cirrhosis), or pancreatic (eg, diabetes) dysfunction. h) Have a diagnosis of any other congenital or acquired blood disorder or any other hemolytic process, except mild allo-immunization, as a consequence of transfusion therapy. i) Positive test for HBsAg or HCVAb with signs of active hepatitis B or C virus infection. Subjects with hepatitis C may be rescreened after receiving ap propriate hepatitis C treatment. j) Positive test for HIV-1 or -2 antibodies. k) Active infection requiring the use of parenteral antimicrobial agents or Grade ≥3 in severity (per NCI CTCAE) within 2 months prior to the first dose of study treatment. l) Diabetes mellitus judged to be under poor control by the Investigator or requiring >3 antidiabetic agents, including insulin (all insulins are considered 1 agent); use of insulin per se is not exclusionary. m) History of any primary malignancy, with the exception of: curatively treated non-melanomatous skin cancer; curatively treated cervical or breast carcinoma in situ; or other primary tumor treated with curative intent, no known active disease present, and no treatment administered during the last 3 years. n) Unstable extramedullary hematopoiesis that could pose a risk of imminent neurologic compromise. o) Severe hepatic issues such as liver fibrosis (F3 or worse), significant cirrhosis or non-alcoholic steatohepatitis. p) Current or recent history of psychiatric disorder that, in the opinion of the Investigator, could compromise the ability of the subject to cooperate with study visits and procedures.
7. Are currently enrolled in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo. Participation in registry studies is allowed.
8. Have exposure to any investigational drug, device, or procedure within 3 months prior to the first dose of study treatment.
9. Have had any prior treatment with a pyruvate kinase activator.
10. Have a prior bone marrow or stem cell transplant.
11. Are currently pregnant or breastfeeding, or planning to become pregnant during the course of the study.
12. Have a history of major surgery within 6 months prior to signing informed consent. Note that procedures such as laparoscopic gallbladder surgery are not considered major in this context.
13. Are currently receiving medications that are strong inhibitors of CYP3A4 or strong inducers of CYP3A4 that have not been stopped for a duration of at least 5 days or a timeframe equivalent to 5 half-lives (whichever is longer) prior to the first dose of study treatment.
14. Are currently receiving hematopoietic stimulating agents (eg, erythropoietins, granulocyte colony stimulating factors, thrombopoietins) that have not been stopped for a duration of at least 28 days prior to the first dose of study treatment.
15. Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and mannitol) or history of acute allergic reaction to drugs characterized by acute hemolytic anemia, druginduced liver injury, anaphylaxis, rash of erythema multiforme type or StevensJohnson syndrome, cholestatic hepatitis, or other serious clinical manifestations.
16. For men and women of reproductive potential: unwillingness to use double anticonception during the trial period.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Safety of AG-348 including the type, incidence, severity and relationship of AG-348 to AE and SAE; number of medication discontinuations due to AE; physical examination findings, vital signs and 12-lead electrocardiogram (ECG) data.
2. Efficacy of treatment of AG-348 as evaluated by changes in sickling behaviour (Point of Sickling) as quantified by the Oxygenscan (= primary main study parameter).
3. Efficacy of treatment of AG-348 evaluated by percentage of responders defined as: o Anti-sickling response o Hematological response

Secondary endpoints 4

1. Maximum change in Hb, bilirubin, HbCO, p50 (TCS HEMOX Analyzer), 2,3-DPG and ATP levels.
2. Maximum change in RBC deformability, dehydration and cell membrane stability, ex vivo (Osmotic gradient ektacytometry (Osmoscan).
3. Changes in clinical characteristics: o Health related Quality of Life (HRQoL) (EQ-5D-5L, SF-36). o Movement behaviour (accelerometer Activ8) o Dyspnea (MRC dyspnea) o Fatigue (PROMIS fatigue short form)
4. Changes in surrogate markers of organ damage or biomarkers associated with mortality at D56 compared to baseline: o Urinary albumin to creatinine ratio o NT-proBNP o CRP o LDH/HbCO ratio o Endothelial activation: D-dimer, von Willebrand factor-antigen (VWF-Ag), soluble vascular cell adhesion molecule-1 (sVCAM-1) o Change in number of crises compared to historical rate

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Julius Clinical Research B.V.

Sponsor organisation

Julius Clinical Research B.V.

Address

Nieuweroordweg 1

City

Zeist

Postcode

3704 EC

Country

Netherlands

Scientific contact point

Organisation

Julius Clinical Research B.V.

Contact name

Dr. E. van Beers

Public contact point

Organisation

Julius Clinical Research B.V.

Contact name

Dr. E. van Beers

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications