A phase 1/2 study of SLN124 in patients with Polycythemia Vera

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Silence Therapeutics PLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Nov 2023 → ongoing

Decision date (initial)

2023-07-24

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Silence Therapeutics, plc

External identifiers

EU CT number

2023-503544-13-00

ClinicalTrials.gov

NCT05499013

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Efficacy, Others, Pharmacokinetic

Phase 1:
• To assess the safety and tolerability of single and multiple subcutaneous (s.c.) doses of SLN124 in patients with PV.
• To evaluate the effect of multiple doses of SLN124 on phlebotomy requirements in patients with PV.
Phase 2:
• To assess the proportion of patients who achieve a response receiving SLN124 or placebo between 18 and 36 weeks. A responder is defined as a patient with (Hct) remaining < 45% in the absence of phlebotomies during this time period.

Secondary objectives 6

1. Phase 1: To determine the pharmacokinetic (PK) parameters of SLN124 after single and multiple s.c. doses
2. Phase 1: To assess the pharmacodynamic (PD) effect of SLN124 on hematological parameters and biomarkers of iron metabolism after single and multiple s.c. doses.
3. Phase 1: To assess quality of life (QoL) changes after multiple doses of SLN124 using MPN-SAF-TSS and PGI-C
4. Phase 2: In the placebo-controlled double-blind period, compare the effect of SLN124 vs placebo over 36 weeks on the following: • number of phlebotomies required. • proportion of patients who achieve a response. • safety and tolerability. • hematology parameters and biomarkers of iron metabolism. • QoL changes using the MPN-SAF-TSS, PGI-C, the Patient-Reported Outcome Measurement Information System Short Form (PROMIS SF) Fatigue 10a and MF-SAF version 4 assessment forms.
5. Phase 2: In the double-blind extension period and in the OLE period: • assess long-term effects of SLN124 on QoL assessments (MPN-SAF-TSS, the PGI-C, and the PROMIS SF Fatigue 10a and MF-SAF version 4).
6. Phase 2: To determine SLN124 PK parameters during the placebo-controlled double-blind period and up to Week 85 of the double-blind extension period.

Conditions and MedDRA coding

Polycythemia Vera

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, Medicines And Healthcare Products Regulatory Agency, Federal Institute For Drugs And Medical Devices

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. Male and female patients aged 18 years or older
2. Records of phlebotomies and associated Hct performed at least 6 months or, if available, for up to 12 months, prior to screening and any of the following associated data (soluble transferrin receptor 1 [sTfR1], ferritin or transferrin saturation [TSAT], if available)
3. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and a negative urine pregnancy test at predose on Day 1
4. Must agree to adhere to appropriate contraception requirements, as follows: a. Female patients of childbearing potential (who are heterosexually active) must agree to use 1 highly effective method of contraception, from the beginning of the screening period until 3 months after the last administration of trial drug. b. Male patients must use a male condom (with or without spermicide) if sexually active with a WOCBP from the beginning of the screening period until 3 months after the last administration of trial drug.
5. Women of childbearing potential must agree to not donate ova, from the beginning of the screening period until 3 months after the last administration of trial drug.
6. Male patients must agree to not donate sperm from the beginning of the screening period until 3 months after the last administration of trial drug.
7. Patients must have Hct < 45% prior to dosing. Hct test can be repeated during the screening period.
8. Phase 2 for Patients who completed Phase 1: Records of phlebotomies and Hct and, if available, associated hematological test data, between the end of Phase 1 and the entry into Phase 2 .
9. New Patients in Phase 2: Prior to dosing, patients must have had ≥ 3 phlebotomies in the last 28 weeks, or 5 or more phlebotomies in the last 12 months, with documented raised Hct.
10. New Patients in Phase 2: Records of phlebotomies and associated Hct performed for at least 28 weeks, or if available, for up to 12 months, prior to dosing, and any of the following associated data; soluble transferrin receptor 1 [sTfR1], ferritin or transferrin saturation [TSAT], if available
11. Patients who are not receiving cytoreductive therapy must have been discontinued from any prior cytoreductive therapy for at least 24 weeks before dosing and have recovered from any adverse events due to cytoreductive therapy.
12. Patients receiving cytoreductive therapy with hydroxyurea, interferon, busulfan or ruxolitinib must have received a stable dose of cytoreductive therapy for at least 12 weeks before dosing with no planned change in cytoreductive dose.
13. Phase 1: Patients must have had a dermatological examination within 6 months prior to screening or during screening.
14. Must have an Eastern Cooperative Oncology Group score of 0, 1, or 2
15. Must be able and willing to comply with all protocol requirements.
16. A confirmed diagnosis of PV according to the revised 2016 World Health Organization criteria: 1. Hb/Hct level above 16.5 g/dL/49% in men and 16 g/dL/48% in women or red cell mass > 25% above mean normal predicted value 2. Consistent bone marrow morphology 3. Presence of a JAK2V617F or JAK2 exon 12 mutation 4. Subnormal serum erythropoietin (Epo) level
17. Willing and able to provide written informed consent before any screening procedures and in accordance with national, local, and institutional guidelines
18. Prior to screening patients must have had ≥ 3 phlebotomies in the last 6 months or 5 or more phlebotomies in the last 12 months, with documented raised hct and/or documented presentation of symptoms of PV
19. Phase 2: Patients must have had a dermatological examination within 28 weeks prior to dosing.
20. Phase 2 for Patients who completed Phase 1: Patients must have completed Phase 1 at least 6 months prior to entry to Phase 2 and have had ≥3 phlebotomies in the 28 weeks prior to dosing in Phase 2.

Exclusion criteria 12

1. Drug intolerance: a. History of intolerance to oligonucleotides, or GalNAc, or any component of SLN124. b. History of intolerance to s.c. injections
2. Co-morbidity: a. Any serious medical or surgical condition, laboratory abnormality, or active psychiatric disorder that, in the opinion of the Investigator, places the patient at significant or unacceptable risk if he/she were to participate in the trial. b. Any known underlying disease that, in the opinion of the Investigator, might confound the ability to interpret data from the trial. c. Infection requiring hospitalization or intravenous antimicrobial therapy, or opportunistic infection within 12 weeks prior to the start of dosing. d. Any infection requiring systemic antimicrobial therapy within 4 weeks prior to first dose. Prophylactic antibiotics are allowed. e. For Phase 1, history of malignancies. Exceptions are resolved local basal cell carcinoma [BCC] and non-melanoma skin tumors that have been resolved no less than 6 months from screening, carcinoma in situ of the cervix, carcinoma in situ of the breast, incidental histological finding of prostate cancer [T1a or T1b using the Tumor, Node, Metastasis staging classification system]. f. For Phase 2, history of malignancies in the last 3 years including those that are currently undergoing active investigations for suspected or recurrence of malignancies before screening. Exceptions are (i) local BCC and non-melanoma skin tumors that have been resolved no less than 6 months from screening, (ii) treated carcinoma in situ of the cervix, (iii) treated carcinoma in situ of the breast, (iv) incidental histological finding of localized prostate cancer [T1a or T1b using the Tumor, Node, Metastasis staging classification system] requiring active surveillance only. g. For Phase 1, significant renal impairment, defined as estimated glomerular filtration rate (using the Chronic Kidney Disease Epidemiology Collaboration equation) < 45 mL/min/1.73m2 at screening. h. h. For Phase 2, significant renal impairment, defined as estimated glomerular filtration rate <30mL/min/1.73m2 at screening (using the Chronic Kidney Disease Epidemiology Collaboration equation) < 30 mL/min/1.73m2 at screening. i. History and/or clinical evidence of cirrhosis. j. Active infectious hepatitis A, B, or C virus. k. Known history or clinical evidence of alcohol and/or drug misuse within 2 years prior to screening. l. Clinically significant or symptomatic cardiac disease including cardiac arrhythmias. m. Clinically significant pulmonary disease.
3. For Phase 1, Biochemical and hematological parameters: a. Biochemical evidence of significant liver disease during screening, defined as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 1.5 × upper limit of normal (ULN); total bilirubin to ≥ ULN; prothrombin time or International Normalized Ratio (INR) ≥ ULN (Isolated INR ≤ 1.3 is acceptable in the absence of other changes in liver function). b. Hematological parameters at screening as follows: platelets > 1,000,000/L; or white blood cell (WBC) count >25,000/L; or peripheral blasts > 1%.
4. Pregnancy and reproduction: a. Femal patients who: are pregnant, or plan to be pregnant during the trial, or are lactating
5. Clinically significant thrombosis (e.g., deep vein thrombosis or splenic vein thrombosis) within 12 weeks prior to screening
6. History of major bleeding events and/or a requirement for blood transfusion therapy owing to bleeding in the last 6 months prior to screening
7. Meets the criteria for post-PV myelofibrosis as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment [Arber et al, 2022].
8. Known primary or secondary immunodeficiency.
9. Any major invasive surgical procedure requiring general anesthesia within 4 weeks prior to screening or planned elective surgery during the trial.
10. Use of any investigational drug less than 6 weeks prior to the first dose of trial drug or not recovered from effects of any prior investigational agent (excludes patients with PV who have previously participated and completed Phase 1 of this protocol).
11. Use of any investigational or marketed GalNAc targeting product less than 48 weeks prior to the first dose of trial drug or not recovered from effects of prior administration of any investigational or marketed GalNAc targeting product taken more than 48 weeks before the first dose of the trial drug (excludes patients with PV who have previously participated and completed Phase 1 of this protocol).
12. For Phase 2, biochemical and hematological parameters: a. Biochemical evidence of significant liver disease during screening, defined as ALT and/or AST ≥ 3 × ULN; or total bilirubin ≥ 2 × ULN. b. Hematological parameters at screening as follows: platelets > 1,000,000/L; or WBC count > 30,000/L; or peripheral blasts > 1%.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Phase 1: Assessment of the following safety parameters: i. Adverse events. ii. Safety laboratories iii. Evaluation of sTfR1, serum ferritin, MCV, and MCHC. iv. Vital signs measurements. v. Twelve-lead ECG parameters. vi. Physical examination findings.
2. Phase 1: Tolerability: all AEs including injection site reactions
3. Phase 1: Efficacy: Assessment of the number of phlebotomies at 3 intervals: i. From 6 months prior to dosing to Day 1 predose. ii. From Day 1 to Day 169. iii. From Day 169 to end of follow-up Day 239
4. Phase 2: Efficacy: Proportion of patients who achieve a response receiving SLN124 compared to placebo between 18 and 36 weeks. A responder is defined as a patient with Hct remaining < 45% in the absence of phlebotomies during this time period.

Secondary endpoints 16

1. Phase 1: Pharmacokinetics: i. Duration at which drug is at maximum concentration in plasma (tmax), maximum observed plasma concentration (Cmax), plasma terminal elimination half-life (t1/2), area under the plasma concentration-time curve (AUC) from time zero to 48 h postdose (AUC0–48h), AUC extrapolated to infinity (AUC0–∞), AUC from time zero to the last quantifiable concentration (AUC0–last), apparent total plasma clearance (CL/F), apparent volume distribution (Vz/F), and Λ
2. Phase 1: Pharmacodynamic:- Hematocrit (Hct), Hb levels, and biomarkers of erythropoiesis including complete blood count (CBC), red blood cells (RBC) count, WBC count, platelet count, erythrocyte count, reticulocyte count, (MCV and mean corpuscular hemoglobin content (MCHC). - Hepcidin and other biomarkers of iron metabolism and erythroid function including TSAT, serum ferritin, serum iron, TIBC, GDF-15, and erythroferrone.
3. Phase 1: Assessment of the changes in QoL from baseline to Day 239 using the with MPN SAF TSS and PGI-C assessment forms
4. Phase 2: Comparison of number and frequency of phlebotomies in patients treated with SLN124 and placebo for 36 weeks.
5. Phase 2: Proportion of patients who achieve response receiving SLN124 and placebo between Week 1 and 36. Response is defined as a patient with Hct remaining < 45% in the absence of phlebotomies.
6. Phase 2: Safety and tolerability for 36 weeks
7. Phase 2: Comparison of all AEs reported in patients treated with SLN124 and placebo arms for 36 weeks.
8. Phase 2: Assessment of SLN124 Cmax at Day 1 and Day 169 of the trial.
9. Phase 2: Assessment of SLN124 PD: i) Changes from baseline for Hct, Hb, and biomarkers of erythropoiesis ii)Changes from baseline for Hepcidin and other biomarkers of iron metabolism
10. Phase 2: Assessment of the changes in QoL (MPN-SAF-TSS, PGI-C PROMIS SF Fatigue 10a and MF-SAF version 4 assessments) from baseline to Week 12, 24 and 36 or end of the placebo-controlled double-blind period.
11. Phase 2 Double-blind extension period and OLE period: Safety and tolerability.
12. Phase 2 Double-blind extension period and OLE period: Assessment of PK trough levels of SLN124 prior to dosing at Week 43, 49, 55, 61, 73 and 85.
13. Phase 2 Double-blind extension period and OLE period: Proportion of patients who achieve response receiving SLN124 at Week 61, 85, 109, 133, 157 and 181. A responder is defined as a patient with Hct remaining < 45% in the absence of phlebotomies.
14. Phase 2 Double-blind extension period and OLE period:Assessment of SLN124 PD: i) Changes from baseline for Hct, Hb, and biomarkers of erythropoiesis ii) Changes from baseline for Hepcidin and other biomarkers of iron metabolism
15. Phase 2 Double-blind extension period and OLE period: Assessment of changes in QoL (MPN-SAF-TSS, PGI-C, PROMIS SF Fatigue 10a and MF-SAF version 4 assessments) from baseline to 61, 85, 109, 133, 157 and 181 weeks of treatment.
16. Phase 2: Proportion of patients who achieve response receiving SLN124 and placebo between Week 12 and 36. A responder is defined as a patient with Hct remaining < 45% in the absence of phlebotomies. Proportion of patients who achieve response receiving SLN124 and placebo during Week 1-12, Week1-24 and Week1-36, week 12 - 24 and week 24 - 36.

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Silence Therapeutics PLC

Sponsor organisation

Silence Therapeutics PLC

Address

Office 205, 12 Hammersmith Grove 12 Hammersmith Grove

City

London

Postcode

W6 7AP

Country

United Kingdom

Scientific contact point

Organisation

Silence Therapeutics PLC

Contact name

Alberto Martinez

Public contact point

Organisation

Silence Therapeutics PLC

Contact name

Alberto Martinez

Third parties 6

Locations

5 EU/EEA countries · 20 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 160 files

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

Application history

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