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

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 classicHutchinson-Gilford Progeria Syndrome (HGPS) mutation (c. 1824 C>T), nonclassic HGPS,Zmpset24 gene mutation, or other LMNA mutation (all subjects will have documentationof genetic testing prior to enrollment). *Only subjects with progerin producingmutations will be eligible for randomization. Other PL are eligible to enroll asnaïve 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 andexaminations.

5. Subject must be taking lonafarnib for at least 4 months prior to enrollment and haveno history of grade 3 or 4 side effects that can be probably or possibly attributedto lonafarnib for at least 2 months prior to enrollment. Note: Subjects with no prior treatment (i.e., no commercial or managed accessprogram source) with lonafarnib may be enrolled to initiate treatment withlonafarnib monotherapy. These subjects will initiate lonafarnib therapy inpreparation 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. Thesesubjects 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 followingparameters:

8. 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 PyruvicTransaminase (SGPT) (Alanine Transaminase, [ALT]) < and SerumGlutamic-Oxaloacetic Transaminase (SGOT) (Aspartate Aminotransferase, [AST]) ≤ 2.5x normal range for age.

4. The subject is willing to provide written informed assent form, when possible, toparticipate in the study after reading the informed assent form and the informationprovided and has had the opportunity to discuss the study with the investigator ordesignee. Additionally, the subject's legally authorized guardian (LAR) is willingto provide written informed consent.

5. The subject is able to communicate satisfactorily with the investigator and toparticipate in, and comply with, the requirements of the study.

6. The subject (or LAR) is able to understand the nature of the study and any potentialhazards associated with participating in it.

7. Negative pregnancy test for female subjects of childbearing potential and those whohave not been surgically sterilized or who do not have verbal or laboratoryconfirmation of two years postmenopausal status. Women of childbearing potential (WOCBP) and Women of non-childbearing potential are eligible to participate. Womenof childbearing potential should use an acceptable method of birth control and agreeto continue to use this method for the duration of the study and for 90 days aftertaking 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 Progeriaare excluded. Drugs to treat symptoms of Progeria are permitted.

2. Subjects are taking medications that significantly affect the metabolism ofProgerinin.

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 otherconditions that could affect their participation in the study such as:

5. known severely impaired lung function

6. active (acute or chronic) or uncontrolled severe infections.

7. liver disease such as cirrhosis, chronic active hepatitis or chronic persistenthepatitis.

8. history of hepatitis B or hepatitis C documented by history and confirmed byserology if positive for history.

9. Other concurrent severe and/or uncontrolled medical disease that could compromiseparticipation in the study (i.e., uncontrolled diabetes, uncontrolled hypertension,severe infection, severe malnutrition, chronic liver or renal disease, active upperGI tract ulceration).

10. A known history of Human Immunodeficiency Virus (HIV) seropositivity or knownimmunodeficiency.

11. Impairment of gastrointestinal function or gastrointestinal disease that maysignificantly alter the absorption of Progerinin (e.g., ulcerative disease,uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowelresection). A nasogastric tube (NG tube) or gastric tube (G tube) is allowed.

12. Subjects who have known or suspected hypersensitivity to any of the excipientsincluded in the formulation should not be treated.

13. Subjects who have used marijuana or other (Tetrahydrocannabinol) THC containingproducts either recreationally or for medical purposes within three months prior toentering the study.