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

Prior treatment

• 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).
• 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).
• Clinically significant thrombosis (e.g., deep vein thrombosis or splenic vein thrombosis) within 12 weeks prior to screening
• History of major bleeding events and/or a requirement for blood transfusion therapy owing to bleeding in the last 6 months prior to screening
• Any major invasive surgical procedure requiring general anesthesia within 4 weeks prior to screening or planned elective surgery during the trial.

Other illness

• Drug intolerance: a. History of intolerance to oligonucleotides, or GalNAc, or any component of SLN124. b. History of intolerance to s.c. injections

Lab values

• 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%.
• 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.
• 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%.

Other

• Pregnancy and reproduction: a. Femal patients who: are pregnant, or plan to be pregnant during the trial, or are lactating
• Meets the criteria for post-PV myelofibrosis as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment [Arber et al, 2022].
• Known primary or secondary immunodeficiency.

• Male and female patients aged 18 years or older
• 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
• 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.
• 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.
• Phase 1: Patients must have had a dermatological examination within 6 months prior to screening or during screening.
• Must have an Eastern Cooperative Oncology Group score of 0, 1, or 2
• Must be able and willing to comply with all protocol requirements.
• 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
• Willing and able to provide written informed consent before any screening procedures and in accordance with national, local, and institutional guidelines
• 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
• Phase 2: Patients must have had a dermatological examination within 28 weeks prior to dosing.
• 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)
• 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.
• 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
• 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.
• 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.
• 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.
• Patients must have Hct < 45% prior to dosing. Hct test can be repeated during the screening period.
• 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 .
• 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.