An open-label, dose-escalation, dose-finding, and proof-of-concept trial of SP-420 in subjects with transfusion-dependent α- or β-thalassemia or low-risk myelodysplastic syndromes

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pharmacosmos A/S

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

16 Mar 2023 → ongoing

Decision date (initial)

2024-06-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pharmacosmos A/S

External identifiers

EU CT number

2023-507396-21-00

EudraCT number

2022-002395-36

WHO UTN

U1111-1277-5903

ClinicalTrials.gov

NCT05693909

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Safety, Dose response, Therapy, Pharmacokinetic, Efficacy

1. Primary efficacy objective Thalassemia cohorts: 1. To establish dose-response relationship of SP-420 for 24 weeks in the treatment of subjects with transfusion-dependent α- or β-thalassemia 2. Primary safety objective MDS cohorts: 1. To assess the safety and tolerability of ascending doses of SP-420 after 12 weeks treatment

Secondary objectives 7

1. Thalassemia cohorts 1. Key-secondary efficacy objective 1: To assess the efficacy of SP-420 in total body iron removal after 24 weeks treatment of subjects with transfusion-dependent α- or β-thalassemia
2. 2. Secondary efficacy objective 1: To assess the efficacy of SP-420 in clearing iron from the liver after 12, 24 and 48 weeks treatment of subjects with transfusion-dependent α- or β-thalassemia
3. 3. Secondary efficacy objective 2: To assess the efficacy of SP-420 in total body iron removal after 12 and 48 weeks treatment of subjects with transfusion-dependent α- or β-thalassemia
4. 4. Secondary efficacy objective 3: To assess the efficacy of SP-420 on serum (s-) ferritin
5. 5. Secondary safety objective 1: To assess the safety and tolerability of ascending doses of SP-420
6. MDS cohorts 1. Secondary safety objective: 1. To assess the safety and tolerability of ascending doses of SP-420
7. 2.Secondary efficacy objective 1: To assess the efficacy of SP-420 on s-ferritin

Conditions and MedDRA coding

transfusion-dependent α- or β-thalassemia or low-risk myelodysplastic syndromes

Study design 6 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 1. Thalassemia cohorts: 1. Women and men aged ≥18 years
2. 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)
3. 1. Thalassemia cohorts: 3. On a stable dose of iron chelation for at least 4 weeks prior to screening
4. 1. Thalassemia cohorts: 4. Weight ≥35 kg at screening
5. 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
6. 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
7. 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
8. 1. Thalassemia cohorts:8. Willingness to participate and signing the informed consent form (ICF)
9. 2. MDS cohort: 1. Women and men aged ≥18 years at screening
10. 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
11. 2. MDS cohort: 3. Required RBC transfusions of ≥2 units of RBCs due to MDS related anaemia within 16 weeks prior to screening
12. 2. MDS cohort: 4. Anticipated to be transfused with at least 6 units of RBCs within the 48 weeks of the trial
13. 2. MDS cohort: 5. Weight ≥35 kg at screening
14. 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
15. 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
16. 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
17. 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.

Exclusion criteria 59

1. 1. Thalassemia cohorts: 1. α- or β-thalassemia with the structural Hb variants HbS and HbC
2. 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
3. 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.
4. 1. Thalassemia cohorts: 10. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2
5. 1. Thalassemia cohorts: 3. S-ferritin <500 ng/mL
6. 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
7. 1. Thalassemia cohorts: 5. Current MDS
8. 1. Thalassemia cohorts: 6. Current biliary disorder
9. 1. Thalassemia cohorts: 7. ALAT >4 times the upper limit of normal, decompensated cirrhosis, or ascites at screening
10. 1. Thalassemia cohorts: 8. Historic or ongoing clinically significant kidney disease
11. 1. Thalassemia cohorts: 9. Creatinine greater than the upper limit of normal at screening
12. 1. Thalassemia cohorts: 18. History of hypersensitivity to an iron chelator (investigational or marketed)
13. 2. MDS cohorts: 1. Therapy-related MDS or MDS with a known bone marrow fibrosis
14. 1. Thalassemia cohorts: 11. Urine protein to creatinine ratio >0.5 (>56.50 mg/mmol) mg/mg at screening
15. 1. Thalassemia cohorts: 12. Heart failure grade II, III or IV by NYHA
16. 1. Thalassemia cohorts: 13. LVEF on MRI <56 % (echocardiography allowed if MRI not available)
17. 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
18. 1. Thalassemia cohorts: 15. Hypertransfused defined as more than 6 units/month on average for the last 6 months prior to screening
19. 1. Thalassemia cohorts: 16. Ongoing symptoms of neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, or paraesthesia at screening
20. 1. Thalassemia cohorts: 17. Platelet count <100×109/L at screening
21. 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
22. 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
23. 1. Thalassemia cohorts: 19. Documented history of non-compliance to chelation therapy within past 2 years
24. 2. MDS cohorts: 4. Platelet count <50×109/L at screening
25. 2. MDS cohorts: 5. Absolute neutrophil count <0.8×109/L at screening
26. 2. MDS cohorts: 6. Hypertransfused defined as more than 6 units/month on average for the last 6 months prior to screening
27. 2. MDS cohorts: 7. Total bilirubin >2.5 times the upper limit of normal (subjects with Gilbert syndrome are exempt from this limit)
28. 2. MDS cohorts: 8. ALAT or aspartate aminotransferase (ASAT) >3.5 times the upper limit of normal
29. 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)
30. 2. MDS cohorts: 10. Clinically significant kidney disease, either historic or ongoing
31. 2. MDS cohorts: 11. eGFR <40 mL/min/1.73 m2 at screening
32. 2. MDS cohorts: 12. Heart failure grade III or IV by NYHA
33. 1. Κοόρτεις θαλασσαιμίας: 2. Cardiac T2*-MRI score <10 msec obtained within 2 weeks prior to baseline
34. 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
35. 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
36. 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)
37. 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)
38. 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
39. 2. MDS cohorts: 13. LVEF <50 %, assessed by an appropriate method (e.g., echocardiography, MRI, or multigated acquisition [MUGA] scan)
40. 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
41. 2. MDS cohorts: 15. Uncontrolled hypertension (defined as repeated elevations of diastolic blood pressure ≥100 mmHg despite adequate treatment) at screening
42. 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
43. 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
44. 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
45. 2. MDS cohorts: 19. Eastern Cooperative Oncology Group (ECOG) performance status >2
46. 2. MDS cohorts: 20. Life expectancy <1 year as per Investigator’s judgement
47. 2. MDS cohorts: 21. Major surgery within 8 weeks prior to screening. Subjects must have completely recovered from any previous surgery prior to screening
48. 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)
49. 2. MDS cohorts: 23. Ongoing symptoms of clinically significant neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, or paraesthesia at screening
50. 2. MDS cohorts: 24. History of hypersensitivity (immunologically based) to an iron chelator (investigational or marketed)
51. 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
52. 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) 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
53. 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)
54. 2. MDS cohorts: 28. Subject who is considered potentially unreliable or non-cooperative
55. 2. MDS cohorts: 29. Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of SP-420
56. 2. MDS cohorts: 30. Subject unable to undergo trial assessments
57. 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
58. 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
59. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 1. Thalassemia cohorts - 1. Primary efficacy endpoint: Total body iron removed by SP-420 from baseline to week 24
2. 2. MDS cohorts - 1. Primary safety endpoint: Type and incidence of AEs after 12 weeks of treatment

Secondary endpoints 7

1. 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)
2. 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
3. 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
4. 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
5. 1. Thalassemia cohorts 5. Secondary safety endpoints 1: Type and incidence of adverse events (AEs)
6. 2. MDS cohorts - 1. Secondary safety endpoints: Type and incidence of AEs; Left ventricular ejection fraction (LVEF) at weeks 24 and 48
7. 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

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pharmacosmos A/S

Sponsor organisation

Pharmacosmos A/S

Address

Roervangsvej 30

City

Holbaek

Postcode

4300

Country

Denmark

Scientific contact point

Organisation

Pharmacosmos A/S

Contact name

Janus Houe Magnussen

Public contact point

Organisation

Pharmacosmos A/S

Contact name

Janus Houe Magnussen

Third parties 12

Locations

4 EU/EEA countries · 28 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

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

Documents 44 files

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

Application history

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