Pharmacokinetics and Safety Study of Siremadlin (HDM201) in Participants With Mild, Moderate and Severe Hepatic Impairment

Key Inclusion Criteria:

All participants:

• Male and non-child-bearing potential females * between 18 and 75 years of age,inclusive, at Screening.

• Participant must be a non-smoker or moderate smoker (up to 10 cigarettes orequivalent nicotine containing products per day) at Screening. Participant mustagree to maintain the same smoking status (i.e., smoker or non-smoker) fromScreening until after Study Completion evaluations.

Additional key inclusion criteria for healthy participants (Group 1):

• Participants must weigh at least 50.0 kg and must have a BMI within the range of 18.0 to 38.0 kg/m2, inclusive at Screening.

• Participants with no clinically significant abnormalities as determined by pastmedical history, physical examination, ECG and clinical laboratory test atScreening.

Additional inclusion criteria for mild, moderate and severe HI participants (Groups 2-4):

• Participants must weigh at least 50.0 kg and must have a BMI within the range of 18.0 to 38.0 kg/m2, inclusive at Screening. For participants without overt ascites,the BMI must be within the range of 18.0 to 40.0 kg/m2, inclusive. For participantswith overt ascites, the BMI must be within the range of 18.0 to 45.0 kg/m2,inclusive.

• Participant must satisfy the criteria for HI as evidenced by a Child-Pugh class ofA, B, or C at Screening and Baseline (see Table 8-2 Child-Pugh classificationcriteria):

• Group 2: Class A; Mild; Child-Pugh score 5-6, inclusive

• Group 3: Class B; Moderate; Child-Pugh score 7-9, inclusive

• Group 4: Class C; Severe; Child-Pugh score 10-15, inclusive. If the results ofthe assessments at Screening and Baseline indicate different Child-Pugh class,a third assessment must be conducted. If the results of the 2 most recentassessments (the second and third) are in agreement with regard to theparticipant's Child-Pugh class, the participant may be enrolled at theChild-Pugh class determined by the most recent assessment. If the second andthird measurements differ, the participant will not be eligible for the studyon the basis that their liver function is not stable.

• Participants with impaired hepatic function and other stable medical disorders suchas diabetes, hypertension, hyperlipidemia, hypothyroidism etc., may be eligible, aslong as they are considered appropriate for enrollment, as determined by pastmedical history, physical examination, vital signs, ECG, and clinical laboratorytests at Screening.

Key Exclusion Criteria:

All participants (Groups 1-4):

• Contraindication or hypersensitivity to the investigational compound/compound classor excipients being used in this study.

• History or presence of clinically significant ECG abnormalities or a family historyor presence of prolonged QT-interval syndrome.

• History of malignancy of any organ system, treated or untreated, within 3 yearsprior to Screening, regardless of whether there is recurrence or metastases. Thosewith localized basal cell carcinoma of the skin, in-situ cervical cancer, orhepatocellular cancer treated with local ablative therapy more than 6 months priorto Screening may be enrolled.

• Use of investigational drugs, other than siremadlin (i.e., participation in anyclinical investigation) within 4 weeks prior to dosing or longer if required bylocal regulation, or within 5 half-lives of the investigational agent taken prior todosing (whichever is longer).

• Clinically significant illness within 2 weeks prior to dosing that may jeopardizesafety of the study participant and/or alter the study results as judged by theInvestigator.

Additional key exclusion criteria for healthy participants (Group 1):

• Any single parameter of ALT, AST, GGT, or ALP exceeding 1.2 x ULN or ≥ 1.5 x ULN TBLor any elevation above ULN of more than one parameter of ALT, AST, GGT, ALP, orserum TBL at Screening.

• Participants known to have Gilbert's syndrome.

• Participants with abnormal laboratory values for the following parameters atScreening:

• Hemoglobin levels < 12.0 g/dL (males) or < 11.0 g/dL (females).

• WBC count outside the range of 3.5 x 109-10.7 x 109 /L (unless deemed notclinically significant by the Investigator).

• Platelet count < 100 x 109 /L (unless deemed not clinically significant by theInvestigator).

• Presence of impaired renal function as indicated by serum creatinine > ULN orabnormal urinary constituents at Screening.

Additional key exclusion criteria for mild and moderate HI participants (Groups 2-3):

• Participants with abnormal laboratory values for the following parameters atScreening:

• Hemoglobin < 9 g/dL.

• Platelet count < 30 x 109/L.

• WBC count < 2.5 x 109/L.

• TBL > 8 mg/dL.

• Serum amylase > 5 x ULN with no abdominal symptoms (> 2 x ULN with abdominalsymptoms)

• INR > 2.5.

• Corrected serum calcium < 8.6 or > 10.2 mg/dL.

• Presence of moderate to severe impaired renal function as indicated by creatinineclearance < 50 mL/min as calculated using the Cockcroft-Gault formula.

• Severe complications of liver disease within the preceding 3 months prior todosing..

• Trans-jugular intrahepatic portosystemic shunt and/or have undergone portacavalshunting.

Additional key exclusion criteria for severe HI participants (Group 4):

• Participants with abnormal laboratory values for the following parameters atScreening:

• Hemoglobin < 8.5 g/dL.

• Platelet count < 30 x 109/L.

• WBC count < 2.5 x 109/L.

• TBL > 8 mg/dL.

• Serum amylase > 5 x ULN with no abdominal symptoms (> 2 x ULN with abdominalsymptoms).

• INR > 2.5.

• Presence of moderate to severe impaired renal function as indicated by creatinineclearance < 50 mL/min as calculated using the Cockcroft-Gault formula.

• Severe complications of liver disease within the preceding 3 months prior to dosing.

• Trans-jugular intrahepatic portosystemic shunt and/or have undergone portacavalshunting.

Other protocol-defined Inclusion/Exclusion criteria may apply.