(S)-4,5-DIHYDRO-2-[2-HYDROXY-4-(3,6-DIOXAHEPTYLOXY)PHENYL]-4-METHYL-4-THIAZOLECARBOXYLIC ACID for Transfusion-dependent alpha thalassemia | Transfusion-dependent beta thalassemia | Low-risk myelodysplastic syndromes

Inclusion criteria

• {"criterion_text":"- 1. Thalassemia cohorts: 1. Women and men aged ≥18 years\n- 2. 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\n- 2. MDS cohort: 3. Required RBC transfusions of ≥2 units of RBCs due to MDS related anaemia within 16 weeks prior to screening\n- 2. MDS cohort: 4. Anticipated to be transfused with at least 6 units of RBCs within the 48 weeks of the trial\n- 2. MDS cohort: 5. Weight ≥35 kg at screening\n- 2. 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\n- 2. 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\n- 2. 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\n- 2. 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.\n- 1. 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)\n- 1. Thalassemia cohorts: 3. On a stable dose of iron chelation for at least 4 weeks prior to screening\n- 1. Thalassemia cohorts: 4. Weight ≥35 kg at screening\n- 1. 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\n- 1. 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\n- 1. 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\n- 1. Thalassemia cohorts:8. Willingness to participate and signing the informed consent form (ICF)\n- 2. MDS cohort: 1. Women and men aged ≥18 years at screening"}

Exclusion criteria

• {"criterion_text":"- 1. Thalassemia cohorts: 1. α- or β-thalassemia with the structural Hb variants HbS and HbC\n- 1. Thalassemia cohorts: 8. Historic or ongoing clinically significant kidney disease\n- 1. Thalassemia cohorts: 9. Creatinine greater than the upper limit of normal at screening\n- 1. Thalassemia cohorts: 18. History of hypersensitivity to an iron chelator (investigational or marketed)\n- 2. MDS cohorts: 1. Therapy-related MDS or MDS with a known bone marrow fibrosis\n- 1. Thalassemia cohorts: 11. Urine protein to creatinine ratio >0.5 (>56.50 mg/mmol) mg/mg at screening\n- 1. Thalassemia cohorts: 12. Heart failure grade II, III or IV by NYHA\n- 1. Thalassemia cohorts: 13. LVEF on MRI <56 % (echocardiography allowed if MRI not available)\n- 1. 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\n- 1. Thalassemia cohorts: 15. Hypertransfused defined as more than 6 units/month on average for the last 6 months prior to screening\n- 1. Thalassemia cohorts: 16. Ongoing symptoms of neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, or paraesthesia at screening\n- 1. 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\n- 1. Thalassemia cohorts: 17. Platelet count <100×109/L at screening\n- 2. 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\n- 2. MDS cohorts: 3. Prior hematopoietic stem cell transplantation (HSCT) or organ transplantation at any time, or planned HSCT or organ transplantation during the trial\n- 1. Thalassemia cohorts: 19. Documented history of non-compliance to chelation therapy within past 2 years\n- 2. MDS cohorts: 4. Platelet count <50×109/L at screening\n- 2. MDS cohorts: 5. Absolute neutrophil count <0.8×109/L at screening\n- 2. MDS cohorts: 6. Hypertransfused defined as more than 6 units/month on average for the last 6 months prior to screening\n- 2. MDS cohorts: 7. Total bilirubin >2.5 times the upper limit of normal (subjects with Gilbert syndrome are exempt from this limit)\n- 2. MDS cohorts: 8. ALAT or aspartate aminotransferase (ASAT) >3.5 times the upper limit of normal\n- 2. 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)\n- 1. 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.\n- 2. MDS cohorts: 10. Clinically significant kidney disease, either historic or ongoing\n- 2. MDS cohorts: 11. eGFR <40 mL/min/1.73 m2 at screening\n- 2. MDS cohorts: 12. Heart failure grade III or IV by NYHA\n- 1. Κοόρτεις θαλασσαιμίας: 2. Cardiac T2*-MRI score <10 msec obtained within 2 weeks prior to baseline\n- 1. 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\n- 1. 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\n- 1. 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)\n- 1. 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)\n- 1. 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\n- 2. MDS cohorts: 13. LVEF <50 %, assessed by an appropriate method (e.g., echocardiography, MRI, or multigated acquisition [MUGA] scan)\n- 1. Thalassemia cohorts: 10. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2\n- 2. 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\n- 2. MDS cohorts: 15. Uncontrolled hypertension (defined as repeated elevations of diastolic blood pressure ≥100 mmHg despite adequate treatment) at screening\n- 2. 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\n- 2. 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\n- 2. 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\n- 2. MDS cohorts: 19. Eastern Cooperative Oncology Group (ECOG) performance status >2\n- 2. MDS cohorts: 20. Life expectancy <1 year as per Investigator’s judgement\n- 2. MDS cohorts: 21. Major surgery within 8 weeks prior to screening. Subjects must have completely recovered from any previous surgery prior to screening\n- 2. 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)\n- 2. MDS cohorts: 23. Ongoing symptoms of clinically significant neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, or paraesthesia at screening\n- 1. Thalassemia cohorts: 3. S-ferritin <500 ng/mL\n- 2. MDS cohorts: 24. History of hypersensitivity (immunologically based) to an iron chelator (investigational or marketed)\n- 2. 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\n- 2. 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)\tIron, 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\n- 2. 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)\n- 2. MDS cohorts: 28. Subject who is considered potentially unreliable or non-cooperative\n- 2. MDS cohorts: 29. Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of SP-420\n- 2. MDS cohorts: 30. Subject unable to undergo trial assessments\n- 2. 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\n- 2. 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\n- 2. 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\n- 1. 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\n- 1. Thalassemia cohorts: 5. Current MDS\n- 1. Thalassemia cohorts: 6. Current biliary disorder\n- 1. Thalassemia cohorts: 7. ALAT >4 times the upper limit of normal, decompensated cirrhosis, or ascites at screening"}

Primary endpoints

• {"endpoint_text":"- 1. Thalassemia cohorts - 1. Primary efficacy endpoint: Total body iron removed by SP-420 from baseline to week 24\n- 2. MDS cohorts - 1. Primary safety endpoint: Type and incidence of AEs after 12 weeks of treatment","definition_or_measurement_approach":"Thalassemia primary: total body iron removed measured from baseline to week 24 (timeframe specified). MDS primary: type and incidence of adverse events recorded after 12 weeks of treatment (safety AE reporting)."}

Secondary endpoints

• {"endpoint_text":"- 1. Thalassemia cohorts 1. Key-secondary efficacy endpoints 1: Total body iron removed by SP-420 from baseline to week 24 (pairwise treatment group comparison)\n- 1. Thalassemia cohorts 2. Secondary efficacy endpoints 1: Change in liver iron concentration (LIC) measured by R2- magnetic resonance imaging (MRI) from baseline to weeks 12, 24 and 48\n- 1. Thalassemia cohorts 3. Secondary efficacy endpoints 2: Total body iron removed by SP-420 from baseline to week 12 and week 48, and from week 24 to week 48\n- 1. Thalassemia cohorts 4. Secondary efficacy endpoints 3: Change in s-ferritin from baseline to weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48\n- 1. Thalassemia cohorts 5. Secondary safety endpoints 1: Type and incidence of adverse events (AEs)\n- 2. MDS cohorts - 1. Secondary safety endpoints: Type and incidence of AEs; Left ventricular ejection fraction (LVEF) at weeks 24 and 48\n- 2. MDS cohorts - 2. Secondary efficacy endpoints: Change in s-ferritin from baseline to weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, 24, 32, 40, and 48","definition_or_measurement_approach":"Endpoints specify measurement timepoints: LIC measured by R2-MRI at weeks 12/24/48; s-ferritin change measured at listed weeks; total body iron removed assessed at specified weeks; safety endpoints recorded as AE type and incidence; LVEF measured at weeks 24 and 48."}

Methods

• Site-based recruitment through haematology clinics and specialised centres (country-specific recruitment procedures documented: Denmark K1/K2, Poland K1/K2, Italy K1/K2, Greece K1/K2).
• Printed recruitment materials: posters and participant brochures in local languages (Danish, Polish, Italian, Greek) used at sites.
• Study visit guides and bilingual participant brochures (country-specific K2 materials) distributed to potential participants.
• Recruitment procedures (K1 documents) for each participating country describing site workflow and consenting process.

Denmark

Earliest CTIS Part Ii Submission Date

03-06-2024

Latest Decision Or Authorization Date

19-09-2025

Processing Time Days

473

Number Of Sites

3

Number Of Participants

12

Poland

Earliest CTIS Part Ii Submission Date

03-02-2026

Latest Decision Or Authorization Date

07-03-2026

Processing Time Days

32

Number Of Sites

6

Number Of Participants

21

Italy

Earliest CTIS Part Ii Submission Date

03-06-2024

Latest Decision Or Authorization Date

22-01-2026

Processing Time Days

598

Number Of Sites

10

Number Of Participants

27

Greece

Earliest CTIS Part Ii Submission Date

02-08-2024

Latest Decision Or Authorization Date

09-03-2026

Processing Time Days

584

Number Of Sites

9

Number Of Participants

42

Primary sponsor

Full Name

Pharmacosmos A/S

Organisation Type

Pharmaceutical company

Country Of Registered Address

Denmark

Contract research organisations

Name

PRA Hellas CRO A.E.

Responsibilities

Operational CRO functions; sponsor duties codes: 1,12,13,2,4,5,8 (as listed in CTIS third-party duties)

Name

Icon Clinical Research Limited

Responsibilities

Multiple trial support functions including medical image analysis/review and other sponsor duties (codes listed).

Name

Icon Development Solutions LLC

Responsibilities

MDS analysis and other operational support

Name

Clario

Responsibilities

ECG analysis/review

Third parties

• {"country":"France","full_name":"Charles River Laboratories Saint-Nazaire","duties_or_roles":"PK","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Bloodgenetics S.L.","duties_or_roles":"LPI","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Greece","full_name":"PRA Hellas CRO A.E.","duties_or_roles":"codes: 1,12,13,2,4,5,8","organisation_type":"Pharmaceutical company (CRO)"}
• {"country":"United States","full_name":"Icon Development Solutions LLC","duties_or_roles":"MDS analysis; code 4","organisation_type":"Pharmaceutical company / CRO"}
• {"country":"Denmark","full_name":"Pharmacosmos A/S (third-party entry)","duties_or_roles":"QP release","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Medical image analysis/ review; code 4","organisation_type":"Pharmaceutical company / CRO"}
• {"country":"Netherlands","full_name":"Charles River Laboratories Den Bosch B.V.","duties_or_roles":"urine analysis for iron, zinc and copper","organisation_type":"Pharmaceutical company / laboratory"}
• {"country":"Australia","full_name":"Resonance Health Analysis Services Pty Limited","duties_or_roles":"Medical image analysis/ review","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Sweden","full_name":"Metasafe Sweden AB","duties_or_roles":"metabolite identification in plasma and urine","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Signant Health Management Limited","duties_or_roles":"eCOA and ePRO","organisation_type":"Pharmaceutical company / eClinical vendor"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited (second entry)","duties_or_roles":"multiple sponsor duties codes: 1,10,12,13,14,2,3,4,5,6,7,8","organisation_type":"Pharmaceutical company / CRO"}
• {"country":"United States","full_name":"Clario","duties_or_roles":"ECG analysis/ review","organisation_type":"Health care / vendor"}