Dose-Escalation and Dose-Finding Study of (S)-4,5-Dihydro-2-[2-Hydroxy-4-(3,6-Dioxaheptyloxy)phenyl]-4-Methyl-4-Thiazolecarboxylic Acid in Transfusion-Dependent α- or β-Thalassemia

Trial ID: 2023-507396-21-00
Protocol: P-SP420-THAL-01
Sponsor: Pharmacosmos A/S

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Diseases & Conditions

Thalassaemia beta Thalassaemia alpha Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome

Objectives

The primary objective of this study is to establish the **dose-response relationship** of SP-420 over a 24-week period in the treatment of subjects with transfusion-dependent α- or β-thalassemia. This objective is clinically relevant as it aims to determine the optimal dosing regimen of SP-420, which is crucial for maximizing therapeutic efficacy while minimizing potential adverse effects in this patient population.

Secondary objectives include:

Assessing the efficacy of SP-420 in clearing iron from the liver after 12, 24, and 48 weeks of treatment in subjects with transfusion-dependent α- or β-thalassemia.
Evaluating the efficacy of SP-420 in total body iron removal after 12 and 48 weeks of treatment.
Assessing the efficacy of SP-420 on serum ferritin levels.
Evaluating the safety and tolerability of ascending doses of SP-420.

Participants

The clinical trial involves a total of **60 participants** diagnosed with **transfusion-dependent α- or β-thalassemia**, including HbE/β-thalassemia, who require iron chelation therapy. The study population comprises both **male and female** subjects aged **18 years and older**. Participants were selected based on their stable health status, specifically those on a consistent dose of iron chelation for at least four weeks prior to screening. All participants have a weight of at least 35 kg and exhibit transfusion iron overload, as defined by a liver iron concentration (LIC) between 5 and 35 mg/g dw, confirmed by R2-MRI within two weeks before the baseline. The trial includes individuals who have been under treatment and follow-up for at least six months at a specialized center with comprehensive medical records. Participants are required to discontinue their current iron chelation therapy shortly before and during the trial period. The study population is characterized by a willingness to participate, as evidenced by signing the informed consent form.

Plans and Procedures

The clinical trial is designed as an **open-label**, dose-escalation, dose-finding, and proof-of-concept study to evaluate the efficacy and safety of SP-420 in subjects with transfusion-dependent **α- or β-thalassemia**. The primary objective is to establish the dose-response relationship of SP-420 over a 24-week period. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on May 11, 2023. Participants will be administered SP-420 in **capsule** form, taken orally, with a maximum daily dose of 84 mg/kg and a total dose not exceeding 12096 mg/kg over the course of the study.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, weight, and medical history, including a stable dose of iron chelation therapy. The trial includes multiple follow-up visits to monitor changes in liver iron concentration (LIC) and total body iron, as well as to assess safety through the incidence of adverse events. Key secondary endpoints include changes in LIC measured by R2-MRI at weeks 12, 24, and 48, and changes in s-ferritin levels at specified intervals throughout the study.

The expected duration of participant involvement is up to 48 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The end-of-study visit will evaluate the primary efficacy endpoint, which is the total body iron removed by SP-420 from baseline to week 24. The trial is conducted in compliance with regulatory standards, ensuring the collection of robust data to support the therapeutic potential of SP-420 in managing iron overload in thalassemia patients.

Treatment

The clinical trial involves the administration of the experimental medication **SP-420**, which is formulated as **capsules**. The active substance in SP-420 is **(S)-4,5-dihydro-2-[2-hydroxy-4-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid**, a chemical compound. The medication is intended for **oral use**. The dosing regimen for SP-420 is based on body weight, with a maximum daily dose of 84 mg/kg and a total maximum dose of 12096 mg/kg over the course of the treatment period. The maximum treatment duration is 48 weeks. The trial is designed to establish the dose-response relationship of SP-420 in subjects with transfusion-dependent **α- or β-thalassemia**.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as deemed necessary by the study protocol. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is open-label, allowing for direct observation of the effects of SP-420 on the study participants.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the total body iron removed by SP-420 from baseline to week 24. This will be measured to determine the effectiveness of the treatment in reducing iron overload in subjects with transfusion-dependent **α- or β-thalassemia**.

Secondary efficacy endpoints include changes in liver iron concentration (LIC) measured by R2-magnetic resonance imaging (MRI) from baseline to week 24, as well as at weeks 12 and 48. Additionally, the total body iron removed by SP-420 will be evaluated from baseline to week 12 and week 48, and from week 24 to week 48. Changes in serum ferritin (s-ferritin) levels will also be monitored at multiple timepoints: baseline, weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48.

The efficacy parameters will be collected and analyzed using validated methods, including R2-MRI for LIC and laboratory tests for s-ferritin levels. These assessments will provide comprehensive data on the efficacy of SP-420 in managing iron overload in the specified patient population over the course of the trial.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Thalassemia cohorts: 1. Women and men aged ≥18 years
Thalassemia cohorts: 2. Transfusion-dependent α-thalassemia or transfusion-dependent β-thalassemia including HbE/β-thalassemia requiring iron chelation therapy (β-thalassemia with mutation and/or multiplication of α-globin is allowed)
Thalassemia cohorts: 3. On a stable dose of iron chelation for at least 4 weeks prior to screening
Thalassemia cohorts: 4. Weight ≥35 kg at screening
Thalassemia cohorts: 5. Willing to discontinue current iron chelation therapy 7 days (± 3 days) prior to the first dose of SP-420 and for the duration of the trial
Thalassemia cohorts: 6. Transfusion iron overload defined as LIC ≥5 and ≤35mg/g dw on the R2-MRI obtained within 2 weeks prior to baseline
Thalassemia cohorts: 7. Subject has been treated and followed for at least the past 6 months in a specialised centre that maintained detailed medical records, including transfusion and iron chelation histories
Thalassemia cohorts:8. Willingness to participate and signing the informed consent form (ICF)
MDS cohort: 1. Women and men aged ≥18 years at screening
MDS cohort: 2. Very low, low, or intermediate risk MDS according to IPSS-R, with an IPSS-R score of ≤3.5 at screening. An IPSS-R based on an assessment conducted within 6 months prior to screening can be used if the subject is haematologically stable according to the Investigator. An IPSS-R score ≤2.5 based on an assessment conducted within 12 months prior to screening can be used if the subject is haematologically stable according to the Investigator
MDS cohort: 3. Required RBC transfusions of ≥2 units of RBCs due to MDS related anaemia within 16 weeks prior to screening
MDS cohort: 4. Anticipated to be transfused with at least 6 units of RBCs within the 48 weeks of the trial
MDS cohort: 5. Weight ≥35 kg at screening
MDS cohort: 6. Willing to discontinue any current iron chelation therapy 7 days (± 3 days) prior to the first dose of SP-420 and for the duration of the trial
MDS cohort: 7. Transfusion iron overload defined as either: a) If no cardiac T2*-MRI is available within the past 6 months prior to screening: S-ferritin >800 ng/mL 2-4 weeks before the screening visit (in medical records) which is confirmed with a second measurement at screening†, and a history of transfusion of 10 to 100 units of RBCs or b) If a cardiac T2*-MRI is available within the past 6 months prior to screening: S-ferritin >800 ng/mL 2-4 weeks before the screening visit (in medical records) which is confirmed with a second measurement at screening†, a history of transfusion of ≥10 units of RBCs, and a cardiac T2*-MRI score of ≥25 msec
MDS cohort: 8. Subject has been treated and followed for at least the past 6 months at medical facilities experienced in MDS, with detailed medical records maintained, including transfusion and iron chelation histories
MDS cohort: 9. Willingness to participate and signing the ICF †If the Investigator suspects an acute reaction as the cause of the s-ferritin being >800 ng/ml at screening and no suitable data are available from the medical records, a second blood sample may be taken after at least 7 days for re-assessment of eligibility. This will not be considered a re-screening. If the second sample fulfils the enrolment criterion, the subject may be enrolled. The results should be available at the baseline visit at the latest, i.e., max 5 weeks after the screening visit.

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Exclusion Criteria

Thalassemia cohorts: 1. α- or β-thalassemia with the structural Hb variants HbS and HbC
Thalassemia cohorts: 25. Men who do not agree to practice effective barrier contraception during the entire trial period, or do not agree to completely abstain from heterosexual intercourse
Thalassemia cohorts: 26. Any other laboratory abnormality, medical condition, or psychiatric disorder which, in the opinion of the Investigator, will put the subject's disease management at risk or may result in the subject being unable to comply with the trial requirements.
Thalassemia cohorts: 10. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2
Thalassemia cohorts: 3. S-ferritin <500 ng/mL
Thalassemia cohorts: 4. Current malignancy with the exceptions of localised basal cell or squamous cell skin cancer or localised prostate cancer or is receiving immunotherapy, chemotherapy, or radiation therapy for a malignancy
Thalassemia cohorts: 5. Current MDS
Thalassemia cohorts: 6. Current biliary disorder
Thalassemia cohorts: 7. ALAT >4 times the upper limit of normal, decompensated cirrhosis, or ascites at screening
Thalassemia cohorts: 8. Historic or ongoing clinically significant kidney disease
Thalassemia cohorts: 9. Creatinine greater than the upper limit of normal at screening
Thalassemia cohorts: 18. History of hypersensitivity to an iron chelator (investigational or marketed)
MDS cohorts: 1. Therapy-related MDS or MDS with a known bone marrow fibrosis
Thalassemia cohorts: 11. Urine protein to creatinine ratio >0.5 (>56.50 mg/mmol) mg/mg at screening
Thalassemia cohorts: 12. Heart failure grade II, III or IV by NYHA
Thalassemia cohorts: 13. LVEF on MRI <56 % (echocardiography allowed if MRI not available)
Thalassemia cohorts: 14. A QTcF >450 ms, 2nd or 3rd degree atrioventricular block, complete left bundle branch block, or the presence of clinically significant abnormalities as determined by the Investigator at screening
Thalassemia cohorts: 15. Hypertransfused defined as more than 6 units/month on average for the last 6 months prior to screening
Thalassemia cohorts: 16. Ongoing symptoms of neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, or paraesthesia at screening
Thalassemia cohorts: 17. Platelet count <100×109/L at screening
MDS cohorts: 2. Any other clinically significant malignancy not remitted or in remission <5 years, prior to screening. Exceptions are the following diagnoses, which are allowed: localized basal cell skin cancer, squamous cell skin cancer, localized prostate cancer, cervical carcinoma in situ, ductal carcinoma in situ, or completely resected colonic polyps with carcinoma in situ
MDS cohorts: 3. Prior hematopoietic stem cell transplantation (HSCT) or organ transplantation at any time, or planned HSCT or organ transplantation during the trial
Thalassemia cohorts: 19. Documented history of non-compliance to chelation therapy within past 2 years
MDS cohorts: 4. Platelet count <50×109/L at screening
MDS cohorts: 5. Absolute neutrophil count <0.8×109/L at screening
MDS cohorts: 6. Hypertransfused defined as more than 6 units/month on average for the last 6 months prior to screening
MDS cohorts: 7. Total bilirubin >2.5 times the upper limit of normal (subjects with Gilbert syndrome are exempt from this limit)
MDS cohorts: 8. ALAT or aspartate aminotransferase (ASAT) >3.5 times the upper limit of normal
MDS cohorts: 9. Diagnosis of decompensated liver cirrhosis (either established diagnosis or diagnosis by liver biopsy or appropriate imaging if liver cirrhosis is suspected due to medical history [e.g., hepatitis C virus (HCV) infection] and/or liver function tests)
MDS cohorts: 10. Clinically significant kidney disease, either historic or ongoing
MDS cohorts: 11. eGFR <60 mL/min/1.73 m2 at screening
MDS cohorts: 12. Heart failure grade III or IV by NYHA
Κοόρτεις θαλασσαιμίας: 2. Cardiac T2*-MRI score <10 msec obtained within 2 weeks prior to baseline
Thalassemia cohorts: 20. Received an investigational drug within 30 days or investigational drug within 30 days or 5 half-lives, whichever is longer, or investigational antibody within 90 days or 5 half-lives, whichever is longer, before baseline
Thalassemia cohorts: 21. Treatment with prohibited medication: a) iron, aluminium containing antacid therapies, systemic corticosteroids (systemic low dose [≤5 mg/day prednisone equivalent dose], topical, and pulmonary corticosteroids are allowed), chronic use of high dose NSAIDs (as needed and low dose acetylsalicylic acid are allowed), drugs with known renal toxicity, drugs with known QTc prolongation, potent (UGT) enzyme inducers (e.g. rifampicin, phenytoin, phenobarbital, ritonavir) drugs with a narrow therapeutic index (such as methotrexate or coumarin anticoagulants [e.g., warfarin]) which are majorly metabolized by CYP2C8 and/or CYP2C9, and/or are primarily dependent on OAT1/3 or OATP1B1/3 for their renal excretion and/or liver uptake, respectively, within 7 days prior to baseline; b) Initiation of treatment with any bisphosphonate within 12 weeks prior to baseline. A bisphosphonate is allowed if initiated ≥12 weeks prior to baseline and if no gastrointestinal or kidney AE have been observed (new or ongoing) in the 12 weeks prior to baseline, and if subject on oral bisphosphonates has been on stable dose for ≥12 weeks prior to baseline
Thalassemia cohorts: 22. Initiation of treatment with luspatercept within 6 months prior to screening (luspatercept is allowed if initiated and dose is stable at least 6 months prior to screening)
Thalassemia cohorts: 23. Subject unable to undergo trial assessments including MRI, e.g. who are claustrophobic to MRI, have a cardiac pacemaker, ferromagnetic metal implants other than those approved as safe for use in MR scanners (e.g. some types of aneurysm clips, and shrapnel), and subjects who are obese (exceeding the equipment limits)
Thalassemia cohorts: 24. Pregnant or nursing women. In order to avoid pregnancy, women of childbearing potential (i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) have to use highly efficient contraception (e.g., combined [estrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation [oral, intravaginal, or transdermal], progestogen-only hormonal contraception associated with inhibition of ovulation [oral, injectable, or implantable], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, or vasectomised partner) during the whole trial period and 4 weeks post-dosing. A sterile sole partner (i.e., permanently sterile by bilateral orchidectomy) or abstinence from heterosexual intercourse is also considered acceptable provided it reflects the usual and preferred lifestyle of the participant. Postmenopausal woman, defined as a woman who has experienced 12 consecutive months without menstruation without any alternative medical cause, do not need to use contraception
MDS cohorts: 13. LVEF <50 %, assessed by an appropriate method (e.g., echocardiography, MRI, or multigated acquisition [MUGA] scan)
MDS cohorts: 14. Uncontrolled ischemic heart disease or uncontrolled arrhythmia (e.g., uncontrolled atrial fibrillation), within 6 months prior to screening as determined by the Investigator
MDS cohorts: 15. Uncontrolled hypertension (defined as repeated elevations of diastolic blood pressure ≥100 mmHg despite adequate treatment) at screening
MDS cohorts: 16. Uncontrolled dyslipidaemia (defined as low-density lipoprotein (LDL) cholesterol >190 mg/dL (4.9 mmol/L), or triglycerides >500 mg/dL (5.65 mmol/L), or total cholesterol/high-density lipoprotein (HDL) cholesterol ratio >5.0) at screening
MDS cohorts: 17. Uncontrolled diabetes (glucose >200 mg/dL (11.1 mmol/L) in presence of typical symptoms of the disease [polyuria, polydipsia, weight loss], or fasting glucose >126 mg/dL (7.0 mmol/L), or recent history of severe hyperglycaemia requiring hospitalisation or emergency medical intervention) at screening
MDS cohorts: 18. A QTcF >450 ms, 2nd or 3rd degree atrioventricular block, complete left bundle branch block, or the presence of clinically significant abnormalities as per Investigator’s judgement at screening
MDS cohorts: 19. Eastern Cooperative Oncology Group (ECOG) performance status >2
MDS cohorts: 20. Life expectancy <1 year as per Investigator’s judgement
MDS cohorts: 21. Major surgery within 8 weeks prior to screening. Subjects must have completely recovered from any previous surgery prior to screening
MDS cohorts: 22. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment), uncontrolled human immunodeficiency virus (HIV) infection (defined as CD4+ lymphocytes <200/µL or detectable viral load >40 copies/mL), uncontrolled hepatitis B virus (HBV) infection (defined by HBV DNA ≥2000 IU/mL), and uncontrolled HCV infection (defined by HCV ribonucleic acid (RNA) >15 IU/mL)
MDS cohorts: 23. Ongoing symptoms of clinically significant neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, or paraesthesia at screening
MDS cohorts: 24. History of hypersensitivity (immunologically based) to an iron chelator (investigational or marketed)
MDS cohorts: 25. Received an investigational drug within 30 days or 5 half-lives, whichever is longer, or investigational antibody within 90 days or 5 half-lives, whichever is longer, before baseline
MDS cohorts: 26. Treatment with prohibited medication or procedures: a) Disease modifying treatments for MDS (e.g. hypomethylating agents), or granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], or thrombopoietin mimetics, or immunotherapy, chemotherapy, or radiation therapy for any malignancy within 30 days prior to baseline; b) Iron, aluminium-containing antacid therapies, systemic corticosteroids (systemic low dose [≤5 mg/day prednisone equivalent dose], topical, and pulmonary corticosteroids are allowed), chronic use of high dose NSAIDs (as needed and low dose acetylsalicylic acid are allowed), imetelstat, drugs with known renal toxicity, drugs with known QTc prolongation, potent UGT enzyme inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir), drugs with a narrow therapeutic index (such as methotrexate or coumarin anticoagulants [e.g., warfarin]) which are majorly metabolized by CYP2C8 and/or CYP2C9, and/or are primarily dependent on OAT1/3 or OATP1B1/3 for their renal excretion and/or liver uptake, respectively, within 7 days prior to baseline; c) Initiation of treatment with any bisphosphonate within 12 weeks prior to baseline. A bisphosphonate is allowed if initiated ≥12 weeks prior to baseline and if no gastrointestinal or kidney AE have been observed (new or ongoing) in the 12 weeks prior to baseline, and if subject on oral bisphosphonates has been on stable dose for ≥12 weeks prior to baseline
MDS cohorts: 27. Initiation of treatment with an erythropoiesis stimulating agents (ESAs) or luspatercept within 3 months prior to screening (both are allowed if initiated and the dose is stable ≥3 months prior to screening)
MDS cohorts: 28. Subject who is considered potentially unreliable or non-cooperative
MDS cohorts: 29. Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of SP-420
MDS cohorts: 30. Subject unable to undergo trial assessments
MDS cohorts: 31. Pregnant or nursing women. To avoid pregnancy, women of childbearing potential (i.e., fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) have to use highly efficient contraception (e.g., combined [estrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation [oral, intravaginal, or transdermal], progestogen-only hormonal contraception associated with inhibition of ovulation [oral, injectable, or implantable], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, or vasectomised partner) during the whole trial period and 4 weeks post-dosing. A sterile sole partner (i.e., permanently sterile by bilateral orchidectomy) or abstinence from heterosexual intercourse is also considered acceptable provided it reflects the usual and preferred lifestyle of the participant. Postmenopausal woman, defined as a woman who has experienced 12 consecutive months without menstruation without any alternative medical cause, do not need to use contraception
MDS cohorts: 32. Men who do not agree to practice effective barrier contraception during the entire trial period, or do not agree to completely abstain from heterosexual intercourse
MDS cohorts: 33. Any other laboratory abnormality, medical condition, or psychiatric disorder which, in the opinion of the Investigator, will put the subject’s disease management at risk or may result in the subject being unable to comply with the trial requirements