Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Siremadlin · 2 trials · 2 indications
Maximum Observed Blood Concentrations (Cmax) for siremadlin. Blood samples will be collected to measure Cmax at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Area Under Plasma Concentration-time Curve from time zero to the last measurable concentration sampling time (AUClast) for siremadlin. Blood samples will be collected to measure AUClast at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Area Under Plasma Concentration from time zero to time "t" (AUC0-t). The definition of "t" may be data driven post-hoc to mitigate bias in the exposure comparision due to between-group differences in Tlast for siremadlin. Blood samples will be collected to measure AUC0-t at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Area Under Plasma Concentration from time zero to 24-hour post-dose sampling time (AUC0-24h) for siremadlin. Blood samples will be collected to measure AUC0-24h at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Last measurable plasma concentration (Tlast) for siremadlin. Blood samples will be collected to measure Tlast at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Time to Reach Maximum Blood Concentrations (Tmax) for siremadlin. Blood samples will be collected to measure Tmax at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Apparent total body clearance of siremadlin from plasma (CL/F). Blood samples will be collected to measure CL/F at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Apparent volume of distribution during terminal elimination phase (Vz/F) of siremadlin. Blood samples will be collected to estimate Vz/F at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Terminal Elimination Half-life (T1/2) for siremadlin. Blood samples will be collected to measure T1/2 at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
Area Under Plasma Concentration from time zero to infinity (AUCinf). Blood samples will be collected to measure AUCinf at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.
A dose-limiting toxicity (DLT) is defined as an adverse event (AE) or abnormal laboratory value considered by the Investigator to be at least possibly related to siremadlin as a single contributor or in combination with other component(s) of study treatment that occurs beginning the first day of siremadlin dosing in the study until end of cycle 1.
Assessed by CR rate. CR rate is defined as the percentage of participants with best overall response of complete remission (CR) as per investigator assessment.
| Arm | Type | Description |
|---|---|---|
| Group 1: Healthy Control | EXPERIMENTAL | Each healthy participant will receive a single dose of HDM201 |
| Group 2: Mild; Child-Pugh A | EXPERIMENTAL | Each participant with mild Child-Pugh will receive a single dose of HDM201 |
| Group 3: Moderate; Child-Pugh B | EXPERIMENTAL | Each participant with moderate Child-Pugh will receive a single dose of HDM201 |
| Group 4: Severe; Child-Pugh C | EXPERIMENTAL | Each participant with severe Child-Pugh will receive a single dose of HDM201 |
| Arm 1: Adult participants with unfit AML who responded sub-optimally to standard of care | EXPERIMENTAL | Unfit adult participants with unfit AML who responded sub-optimally to at least 2 and not more than 4 cycles of first-line venetoclax plus azacitidine therapy. Siremadlin was adminstered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m\^2. |
| Arm 2: Adult participants with newly diagnosed unfit AML with high risk clinical features | EXPERIMENTAL | Adult participants with unfit AML who were newly diagnosed and presenting with high-risk clinical features (which related to factors conferring to a low likelihood of response to venetoclax plus azacitidine) and with adverse genetic risk stratification (according to ELN 2022) (Except TP53 mutation positive participants). Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m\^2. |
| Name | Type | Description |
|---|---|---|
| Siremadlin | DRUG | HDM201 capsule |
| venetoclax | DRUG | Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths. |
| azacitidine | DRUG | Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously comes in 100 mg but was administered according to standard local clinical practice. |
Key Inclusion Criteria: All participants: * Male and non-child-bearing potential females between 18 and 75 years of age, inclusive, at Screening. * Participant must have been a non-smoker or moderate smoker (up to 10 cigarettes or equivalent nicotine containing products per day) at Screening. Part...
Siremadlin is an investigational small molecule being studied for Acute Myeloid Leukemia (AML) and Hepatic Impairment. In AML, it is being evaluated in combination with venetoclax plus azacitidine for adult patients ineligible for chemotherapy. It is also being studied to assess its pharmacokinetics and safety in patients with mild, moderate, and severe hepatic impairment.
Siremadlin is being developed by Novartis AG, which trades on the New York Stock Exchange under the ticker NVS. The company is conducting clinical trials to evaluate the drug's safety and efficacy in the studied indications.
Siremadlin is in Phase 1 clinical development. It is an investigational drug and has not been approved by regulatory authorities. Two Phase 1 trials have been completed, one in Acute Myeloid Leukemia and one in Hepatic Impairment, with no active trials currently listed.
Siremadlin has been studied in two completed Phase 1 trials. NCT05155709 evaluated Siremadlin in combination with venetoclax plus azacitidine in adults with Acute Myeloid Leukemia who are ineligible for chemotherapy, enrolling 14 participants across multiple countries. NCT05599932 assessed its pharmacokinetics and safety in participants with hepatic impairment, enrolling 38 participants in the United States.
Siremadlin is a small molecule that targets MDM2, a protein that regulates the tumor suppressor p53. By inhibiting MDM2, Siremadlin aims to reactivate p53 function, which can promote cell cycle arrest and apoptosis in cancer cells. This mechanism is being explored in the context of Acute Myeloid Leukemia.