Study to Determine Optimal Dose and Evaluate Safety, Tolerability, and Pharmacokinetics of Progerinin in Patients with Hutchinson-Gilford Progeria Syndrome (HGPS)

Researchers will compare treatment with progerinin plus lonafarnib vs lonafarnib alone to assess optimal dosing, safety, tolerability, and pharmacokinetics in patients with Hutchinson-Gilford Progeria Syndrome (HGPS). Subjects in the randomized study arms will continue to take the standard of care (SOC), lonafarnib, and will be randomized to either take SOC alone or in combination with progerinin.

During this trial, a total of 10 subjects will be randomized in a 4:1 ratio to receive treatment with progerinin plus lonafarnib vs lonafarnib alone. Dose escalation will occur through intra-subject dose titration. Two ascending doses of progerinin will be assessed. The dose levels proposed in this study were determined using body weight based on adult doses assessed in previously completed studies, and on a simulated population pharmacokinetic (PK) model. If systemic exposures of Progerinin in pediatric patients are lower than those in adults, a dose escalation may be added at the end of the study.

Progerinin will be administered, with food. The study treatment is available in sachets of 250 mg or 350 mg and the doses in the study range from 500 to 1500 mg daily, dosed BID (twice a day).

Lonafarnib is considered as the standard of care (SOC) and all subjects in the randomized study arms will continue taking lonafarnib for the duration of the study. Subjects who are not already taking lonafarnib will also have the opportunity to initiate lonafarnib on this study as part of the lonafarnib naïve arm (separate from the randomized study arms).

Eligibility Criteria:
Inclusion Criteria:

Subjects will be eligible for enrollment in the study only if they meet ALL the following criteria at time of Screening:

1. Subjects ≥ 1 year of age and weight ≥ 17.6 lb (8 kg).
2. Subject must have confirmatory mutational analysis showing the classic Hutchinson-Gilford Progeria Syndrome (HGPS) mutation (c. 1824 C\>T), nonclassic HGPS, Zmpset24 gene mutation, or other LMNA mutation (all subjects will have documentation of genetic testing prior to enrollment). \*Only subjects with progerin producing mutations will be eligible for randomization. Other PL are eligible to enroll as naïve subjects (see note for criterion #5).
3. Subject must display clinical signs of Progeria as per the clinical trial team.
4. Subject must be willing and able to come to Boston for appropriate assessments and examinations.
5. Subject must be taking lonafarnib for at least 4 months prior to enrollment and have no history of grade 3 or 4 side effects that can be probably or possibly attributed to lonafarnib for at least 2 months prior to enrollment.

   Note: Subjects with no prior treatment (i.e., no commercial or managed access program source) with lonafarnib may be enrolled to initiate treatment with lonafarnib monotherapy. These subjects will initiate lonafarnib therapy in preparation for an upcoming phase of the study following the completion of phase 2a. These subjects will be excluded from the analysis of this phase 2a study. These subjects must be at least 12 months of age per lonafarnib package insert.
6. Subjects must have had no recent fractures or major surgery (within four weeks).
7. Subject must have adequate organ and marrow function as defined by the following parameters:

   1. Blood: absolute phagocyte count (APC) (absolute neutrophil count \[ANC\] + bands + monocytes) \>1,000/μL, platelets \>75,000/μL (transfusion independent); hemoglobin \>9 g/dL.
   2. Renal: creatinine ≤ 1.5 times normal for age or Glomerular Filtration Rate (GFR) \>70 mL/min/1.73m2.
   3. Hepatic: bilirubin ≤1.5x upper limit of normal for age; Serum Glutamic Pyruvic Transaminase (SGPT) (Alanine Transaminase, \[ALT\]) \< and Serum Glutamic-Oxaloacetic Transaminase (SGOT) (Aspartate Aminotransferase, \[AST\]) ≤ 2.5x normal range for age.
8. The subject is willing to provide written informed assent form, when possible, to participate in the study after reading the informed assent form and the information provided and has had the opportunity to discuss the study with the investigator or designee. Additionally, the subject's legally authorized guardian (LAR) is willing to provide written informed consent.
9. The subject is able to communicate satisfactorily with the investigator and to participate in, and comply with, the requirements of the study.
10. The subject (or LAR) is able to understand the nature of the study and any potential hazards associated with participating in it.
11. Negative pregnancy test for female subjects of childbearing potential and those who have not been surgically sterilized or who do not have verbal or laboratory confirmation of two years postmenopausal status. Women of childbearing potential (WOCBP) and Women of non-childbearing potential are eligible to participate. Women of childbearing potential should use an acceptable method of birth control and agree to continue to use this method for the duration of the study and for 90 days after taking the last dose of Progerinin.

Acceptable methods of contraception include abstinence, female subject/partner's use of hormonal contraceptive (oral, implanted, or injected) in conjunction with a barrier method (WOCBP only) (e.g., diaphragm, cervical cap, male condom, and female condom and spermicidal foam, sponges, and film), female subject/partner's use of an intrauterine device (IUD), or if the female subject/partner is surgically sterile (e.g., bilateral tubal ligation, hysterectomy) or two years postmenopausal at time of screening. All male subjects/partners (excluding men who have been sterilized) must agree to consistently and correctly use a condom for the duration of the study and for 90 days after taking the study drug. In addition, subjects may not donate sperm for the duration of the study and for 90 days after taking study drug.

Exclusion Criteria:

Subjects meeting ANY of the following criteria at time of Screening will be excluded from enrollment:

1. Other than the drugs used in this protocol, other drugs targeted to treat Progeria are excluded. Drugs to treat symptoms of Progeria are permitted.
2. Subjects are taking medications that significantly affect the metabolism of Progerinin.
3. Subjects with an active bleeding diathesis or on oral anti-vitamin K medication (except low dose coumadin).
4. Subjects who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

   1. known severely impaired lung function
   2. active (acute or chronic) or uncontrolled severe infections.
   3. liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis.
   4. history of hepatitis B or hepatitis C documented by history and confirmed by serology if positive for history.
5. Other concurrent severe and/or uncontrolled medical disease that could compromise participation in the study (i.e., uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration).
6. A known history of Human Immunodeficiency Virus (HIV) seropositivity or known immunodeficiency.
7. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Progerinin (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A nasogastric tube (NG tube) or gastric tube (G tube) is allowed.
8. Subjects who have known or suspected hypersensitivity to any of the excipients included in the formulation should not be treated.
9. Subjects who have used marijuana or other (Tetrahydrocannabinol) THC containing products either recreationally or for medical purposes within three months prior to entering the study.