Lonafarnib

1 INDICATIONS AND USAGE ZOKINVY is indicated in patients 12 months of age and older with a body surface area (BSA) of 0.39 m 2 and above: To reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS) For the treatment of processing-deficient Progeroid Laminopathies with either: Heterozygous LMNA mutation with progerin-like protein accumulation Homozygous or compound heterozygous ZMPSTE24 mutations ZOKINVY is a farnesyltransferase inhibitor indicated in patients 12 months of age and older with a body surface area of 0.39 m 2 and above: ( 1 ) To reduce risk of mortality in Hutchinson-Gilford Progeria Syndrome. For treatment of processing-deficient Progeroid Laminopathies with either: Heterozygous LMNA mutation with progerin-like protein accumulation. Homozygous or compound heterozygous ZMPSTE24 mutations. Limitations of Use Not indicated for other Progeroid Syndromes or processing-proficient Progeroid Laminopathies. Based upon its mechanism of action, ZOKINVY would not be expected to be effective in these populations. ( 1 ) Limitations of Use ZOKINVY is not indicated for other Progeroid Syndromes or processing-proficient Progeroid Laminopathies. Based upon its mechanism of action, ZOKINVY would not be expected to be effective in these populations.

2 DOSAGE AND ADMINISTRATION Start at 115 mg/m 2 twice daily with morning and evening meals. ( 2.1 ) After 4 months, increase to 150 mg/m 2 twice daily. ( 2.1 ) Round all total daily doses to nearest 25 mg increment. ( 2.1 ) See full prescribing information for dosage modifications due to adverse reactions. ( 2.2 ) See full prescribing information for preparation and administration instructions. ( 2.4 ) 2.1 Recommended Dosage The starting dosage of ZOKINVY for patients with a BSA of 0.39 m 2 and above is 115 mg/m 2 twice daily with morning and evening meals (see Table 1 ) to reduce the risk of gastrointestinal adverse reactions [see Adverse Reactions ( 6.1 )] . An appropriate dosage strength of ZOKINVY is not available for patients with a BSA of less than 0.39 m 2 [see Indications and Usage ( 1 )] . After 4 months of treatment, increase the dosage to 150 mg/m 2 twice daily with morning and evening meals (see Table 2 ). Round all total daily dosages to the nearest 25 mg increment (see Table 1 and Table 2 ). If a dose is missed, take the dose as soon as possible with food, up to 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, skip the missed dose, and resume taking ZOKINVY at the next scheduled dose. Table 1 provides the BSA-based dosage recommendations for the starting dosage of 115 mg/m 2 twice daily. Table 1: Recommended Dosage and Administration for 115 mg/m 2 Body Surface Area-Based Dosing BSA (m 2 ) Total Daily Dosage Rounded to Nearest 25 mg Morning Dosing Number of Capsule(s) Evening Dosing Number of Capsule(s) ZOKINVY 50 mg ZOKINVY 75 mg ZOKINVY 50 mg ZOKINVY 75 mg 0.39 - 0.48 100 1 1 0.49 - 0.59 125 1 1 0.6 - 0.7 150 1 1 0.71 - 0.81 175 2 1 0.82 - 0.92 200 2 2 0.93 – 1 225 1 1 2 Table 2 provides the BSA-based dosage recommendations for the dosage of 150 mg/m 2 twice daily. Table 2: Recommended Dosage and Administration for 150 mg/m 2 Body Surface Area-Based Dosing BSA (m 2 ) Total Daily Dosage Rounded to Nearest 25 mg Morning Dosing Number of Capsule(s) Evening Dosing Number of Capsule(s) ZOKINVY 50 mg ZOKINVY 75 mg ZOKINVY 50 mg ZOKINVY 75 mg 0.39 - 0.45 125 1 1 0.46 - 0.54 150 1 1 0.55 - 0.62 175 2 1 0.63 - 0.7 200 2 2 0.71 - 0.79 225 1 1 2 0.8 - 0.87 250 1 1 1 1 0.88 - 0.95 275 2 1 1 0.96 – 1 300 2 2 2.2 Dosage Modifications Due to Adverse Reactions and Drug Interactions Table 3: Recommended ZOKINVY Dosage Modifications Adverse Reaction Severity Monitoring and Dose Modifications for ZOKINVY QTc Interval Prolongation [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )] If the QTc interval is greater than or equal to 500 msec Withhold ZOKINVY until QTc interval is less than 470 msec, then resume ZOKINVY at same dosage. Monitor electrocardiograms (ECGs) prior to initiating ZOKINVY, during treatment, and as clinically indicated. Gastrointestinal Adverse Reactions [see Adverse Reactions ( 6.1 )] For patients who have increased their dose of ZOKINVY to 150 mg/m 2 twice daily and are experiencing repeated episodes of vomiting and/or diarrhea resulting in dehydration or weight loss The dose of ZOKINVY can be reduced to the starting dose of 115 mg/m 2 twice daily (see Table 1 ). Ensure ZOKINVY is taken with the morning and evening meals and with an adequate amount of water. CYP3A Drug Interactions [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.1 ), Drug Interactions ( 7.1 )] When moderate CYP3A inhibitors are added for a patient already on steady state ZOKINVY No dosage adjustment for ZOKINVY is recommended. When initiating ZOKINVY in a patient who is concurrently on a moderate CYP3A inhibitor The patient may be at increased risk of adverse reactions. Monitor the patient closely for adverse reactions for at least the first 7 days after initiating ZOKINVY. If the patient experiences an adverse reaction during the first 7 days of the starting dose or thereafter, consider an alternative therapy that is not a moderate CYP3A inhibitor. 2.3 Temporary Discontinuation for Midazolam Use Temporarily discontinue ZOKINVY for 10 to 14 days before and 2 days after administration of midazolam [see Contraindications ( 4 ), Drug Interactions ( 7.2 )] . 2.4 Preparation and Administration Instructions Administer ZOKINVY orally with the morning and evening meals. Patients Able to Swallow Capsules Administer ZOKINVY capsules whole with a sufficient amount of water. Do not chew the capsules. Patients Unable to Swallow Capsules The entire contents of ZOKINVY capsules can be mixed with Ora Blend SF ® or Ora-Plus ® or, for patients unable to access or tolerate Ora Blend SF or Ora-Plus, the contents of ZOKINVY capsules can be mixed with orange juice or applesauce (see preparation instructions below). Do not mix with juice containing grapefruit or Seville oranges [see Contraindications ( 4 ) , Drug Interactions ( 7.1 )] . The mixture must be prepared fresh for each dose and taken within approximately 10 minutes of mixing. Preparation of Dose in Ora Blend SF, Ora-Plus, or Orange Juice For each capsule, empty contents of the capsule into a container containing 5 mL to 10 mL of the liquid. Mix thoroughly with a spoon. Consume entire serving. Preparation of Dose in Applesauce For each capsule, empty contents of the capsule into a container containing 1 teaspoonful to 2 teaspoonfuls of applesauce. Mix thoroughly with a spoon. Consume entire serving.

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥25%) are vomiting, diarrhea, infection, nausea, decreased appetite, fatigue, upper respiratory tract infection, abdominal pain, musculoskeletal pain, electrolyte abnormalities, decreased weight, headache, myelosuppression, increased aspartate aminotransferase, decreased blood bicarbonate, cough, hypertension, and increased alanine aminotransferase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sentynl Therapeutics, Inc. at 1-888-507-5206 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 84 subjects were treated with at least one dose of ZOKINVY with or without additional therapy, of which 8 were treated at a dosage of at least 115 mg/m 2 twice daily for greater than or equal to 10 years. The safety profile of ZOKINVY is based on 128 patient-years of treatment exposure (62 patients with HGPS and 1 patient with processing-deficient Progeroid Laminopathy with LMNA heterozygous mutation) and pooled results from two Phase 2 open-label, single-arm trials (n=63: 28 patients from Study 1 and 35 treatment naïve patients from Study 2). In Study 1, ZOKINVY treatment was initiated at 115 mg/m 2 twice daily and increased to 150 mg/m 2 twice daily after approximately 4 months for a total treatment duration of 24 to 30 months. Treatment naïve patients in Study 2 received ZOKINVY 150 mg/m 2 twice daily for up to 36 months. In both studies, ZOKINVY was administered orally via capsules or the capsule contents were mixed with Ora Blend SF or Ora-Plus and administered orally as a suspension. In these two studies, a total of 63 patients received ZOKINVY for a median duration of 2.2 years, with approximately 1.9 years at the recommended dose of 150 mg/m 2 twice daily. The population was 2 to 17 years old, with a similar proportion of males (33 [52%] patients) and females (30 [48%] patients). Most patients had classic HGPS (60 [95%] patients) compared to non-classic HGPS (2 [3%] patients) and 1 (2%) patient had Progeroid Laminopathy with LMNA heterozygous mutation. Table 4 summarizes adverse reactions reported in the clinical trials. The most common adverse reactions (≥25%) in the clinical trials were vomiting, diarrhea, infection, nausea, decreased appetite, fatigue, upper respiratory tract infection, abdominal pain, musculoskeletal pain, electrolyte abnormalities, decreased weight, headache, myelosuppression, increased aspartate aminotransferase, decreased blood bicarbonate, cough, hypertension, and increased alanine aminotransferase. Table 4: Adverse Reactions in ≥5% of Patients in Study 1 and Treatment-Naïve Patients in Study 2 Receiving ZOKINVY Adverse Reactions ZOKINVY n=63 n (%) 1 Abdominal pain includes stomach pain and abdominal pain. 2 Infection includes abdominal infection, candidiasis, chicken pox, Clostridium difficile colitis, colitis, croup, dengue fever, flu syndrome, flu-like symptoms, fungal infection, gastroenteritis, gastrointestinal infection, Helicobacter pylori infection, infection, infection viral, influenza, nail infection, otitis media, parotitis, perirectal abscess, pneumonia, small intestine infection, submandibular lymphadenitis, tonsillitis, viral infection. 3 Upper respiratory infection includes bronchial infection, bronchitis, sinus infection, and upper respiratory infection. 4 Electrolyte abnormalities include hypermagnesemia, hypokalemia, hyperkalemia, hyponatremia, hypercalcemia, hyperphosphatemia, hypocalcemia, and hypernatremia. 5 Myelosuppression includes absolute neutrophil count decreased, low total white blood cells, lymphopenia, decreased hemoglobin, and hematocrit low. 6 Musculoskeletal pain includes arthritis, back pain, bone pain, foot pain, intercostal pain, joint pain, knee pain, leg pain, musculoskeletal pain, pain in ankle/extremity/fingers/hip/leg/limb/lower limbs/left arm, shoulder pain, unilateral leg pain. Excludes musculoskeletal pain for abdomen. 7 Cerebral ischemia includes cerebral ischemia, central nervous system hemorrhage, and ischemia cerebrovascular. 8 Ocular changes include visual acuity change, corneal clouding, conjunctivitis, watering eyes, keratitis. Gastrointestinal disorders Vomiting 57 (90%) Diarrhea 51 (81%) Nausea 35 (56%) Abdominal pain 1 30 (48%) Constipation 14 (22%) Flatulence 4 (6%) General disorders and administration site conditions Fatigue 32 (51%) Pyrexia 9 (14%) Infections and infestations Infection 2 49 (78%) Upper respiratory tract infection 3 32 (51%) Rhinitis 12 (19%) Investigations Decreased appetite (anorexia) 33 (53%) Electrolyte abnormalities 4 27 (43%) Weight decreased 23 (37%) Myelosuppression 5 22 (35%) Increased aspartate aminotransferase 22 (35%) Decreased blood bicarbonate 21 (33%) Hypertension 18 (29%) Increased alanine aminotransferase 17 (27%) Dehydration 3 (5%) Musculoskeletal and connective tissue disorders Musculoskeletal pain 6 30 (48%) Nervous system disorders Headache 23 (37%) Cerebral ischemia 7 7 (11%) Ophthalmic Ocular changes 8 15 (24%) Psychiatric disorders Depressed mood 3 (5%) Respiratory, thoracic and mediastinal disorders Cough 21 (33%) Epistaxis 13 (21%) Skin and subcutaneous tissue disorders Rash 7 (11%) Pruritus 5 (8%) Mucositis 5 (8%) Gastrointestinal Adverse Reactions As noted in Table 4 , gastrointestinal adverse reactions were the most frequently reported adverse reactions. Of the 57 patients who experienced vomiting, 30 (53%) patients had mild vomiting (defined as no intervention required), 26 (46%) patients had moderate vomiting (defined as outpatient intravenous hydration; medical intervention required), and 1 (2%) patient had severe vomiting (defined as tube feeding, total parenteral nutrition, or hospitalization indicated). Of the 35 patients who experienced nausea, 34 (97%) patients had mild nausea (defined as loss of appetite without alteration in eating habits) and 1 (3%) patient had moderate nausea (defined as oral intake decreased without significant weight loss, dehydration, or malnutrition). During the first four months of treatment in Study 1, 19 (68%) patients had vomiting and 10 (36%) patients had nausea. By the end of therapy, 4 (14%) patients who were still on ZOKINVY required antiemetics or anti-nauseants. A total of 4 patients discontinued ZOKINVY, mostly due to nausea or vomiting. Of the 51 patients who experienced diarrhea, the majority of patients (approximately 92%) experienced mild or moderate diarrhea; 38 (75%) patients reported mild diarrhea (defined as an increase of less than 4 stools per day over baseline) and 9 (18%) patients reported moderate diarrhea (defined as an increase of 4 to 6 stools per day over baseline; limiting instrumental activities of daily living). Four (8%) patients reported severe diarrhea (defined as an increase of seven or more stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care activities of daily living). During the first four months of treatment in Study 1, 23 (82%) patients had diarrhea; by the end of therapy, 3 (11%) patients had diarrhea. Twelve (43%) patients were treated with loperamide. Alanine Aminotransferase and Aspartate Aminotransferase Elevations Increased alanine aminotransferase was commonly reported (17 [27%] patients). Of the 17 patients with increased alanine aminotransferase, 14 (82%) patients had mild increases (defined as greater than upper limit of normal (ULN) to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times ULN if baseline was abnormal), 1 (6%) patient had moderate increases (defined as greater than 3.0 to 5.0 times ULN if baseline was normal or abnormal), and 2 (12%) patients had severe increases (defined as greater than 5.0 to 20.0 times ULN if baseline was normal or abnormal). Increased aspartate aminotransferase was also commonly reported (22 [35%] patients). Of the 22 patients with increased aspartate aminotransferase, 21 (95%) patients had mild increases (defined as greater than ULN to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times ULN if baseline was abnormal) and 1 (5%) patient had a severe increase (defined as greater than 5.0 to 20.0 times ULN if baseline was normal or abnormal). One patient with alanine and aspartate aminotransferase elevations also experienced hypertriglyceridemia and hyperglycemia resulting in discontinuation of ZOKINVY. Hypertension Increases in blood pressure have been documented in patients treated with ZOKINVY. At baseline, 22 (35%) patients had either a systolic blood pressure or a diastolic blood pressure or both above the 95th percentile. Over the course of the trials, 18 (29%) patients had hypertension based on systolic blood pressure or diastolic blood pressure measurements above the 95th percentile on 3 or more occasions. Five (8%) patients who were normotensive at baseline had either systolic blood pressure or diastolic blood pressure above the 95th percentile at the end of treatment.

12.3 Pharmacokinetics The pharmacokinetics of lonafarnib at steady state in patients with HGPS following oral administration of lonafarnib twice daily with food are summarized in Table 7 . Table 7: Summary of Pharmacokinetic Parameters of Lonafarnib at Steady State after Oral Administration Twice Daily to Patients with HGPS Lonafarnib Dose Median (range) t max (hr) Mean (SD) C max (ng/mL) Mean (SD) AUC 0-8hr (ng*hr/mL) Mean (SD) AUC tau (ng*hr/mL) 115 mg/m 2 N 23 23 23 15 Results 2 (0, 6) 1777 (1083) 9869 (6327) 12365 (9135) 150 mg/m 2 N 18 18 18 8 Results 4 (0, 12) 2695 (1090) 16020 (4978) 19539 (6434) Absorption The absolute bioavailability of lonafarnib following oral administration has not been determined. Following oral administration of lonafarnib 75 mg and 100 mg twice daily in healthy subjects under fasted conditions, the geometric mean (CV%) maximum peak plasma concentrations of lonafarnib were 834 (32%) ng/mL and 964 (32%) ng/mL, respectively. Effect of Food Following a single oral dose of 75 mg lonafarnib in healthy subjects, the C max decreased 55% and AUC decreased 29% with a high-fat meal (approximately 43% fat of the total 952 calories) compared to fasted conditions. C max decreased 25% and AUC decreased 21% with a low-fat meal (approximately 12% fat of the total 421 calories) compared to fasted conditions. Distribution In vitro plasma protein binding of lonafarnib was greater than or equal to 99% over the concentration range between 0.5 to 40.0 μg/mL. The apparent volumes of distribution were 87.8 L and 97.4 L, respectively, at steady state following oral administration of lonafarnib 100 mg and 75 mg twice daily in healthy subjects. Elimination The mean half-life was approximately 4 to 6 hours following oral administration of lonafarnib 100 mg twice daily in healthy subjects. Metabolism Lonafarnib is primarily metabolized by CYP3A and to a lesser extent by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 in vitro. In a Phase 1 study in healthy subjects, autoinhibition activity of lonafarnib was demonstrated following repeated dosing of lonafarnib. Specifically, the clearance of lonafarnib following multiple-dose lonafarnib administration was reduced by 75% compared with that following single-dose lonafarnib administration. Excretion Following an oral administration of 104 mg [ 14 C]-lonafarnib under fasted conditions in healthy subjects, approximately 62% of the total radiolabeled dose was recovered in feces and <1% of the total radiolabeled dose was recovered in urine up to 240 hours post-dose. The two most predominant metabolites were HM17 and HM21 (an active metabolite) accounting for 15% and 14% of plasma radioactivity, respectively. Specific Populations Patients with Renal Impairment or Hepatic Impairment ZOKINVY has not been studied in patients with renal impairment or in patients with hepatic impairment. Male and Female Patients Following a single oral dose of 100 mg lonafarnib in healthy subjects, the plasma lonafarnib AUC and C max were 44% and 26% higher in female subjects, respectively, compared to male subjects. The observed exposure difference by sex in healthy subjects is not considered clinically meaningful. Geriatric Patients Following a single oral dose of 100 mg lonafarnib in healthy subjects, the plasma lonafarnib AUC and C max were 59% and 27% higher in subjects ≥65 years, respectively, compared to subjects 18 to 45 years of age. The observed higher exposure in geriatric subjects is not considered clinically relevant. Drug Interaction Studies In Vitro Studies Lonafarnib is a CYP3A substrate and a potent CYP3A time-dependent and mechanism-based inhibitor. Lonafarnib is an inhibitor of CYP2C8 and CYP2C19. Lonafarnib is not considered an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, or CYP2D6. Lonafarnib is unlikely to be an inducer of CYP1A2, CYP2B6, and CYP3A. Lonafarnib is not a substrate of transporters OATP1B1, OATP1B3, or BCRP, but is likely a marginal substrate of P-gp. Lonafarnib is an inhibitor of P-gp, OATP1B1, OATP1B3, and BCRP. Clinical Studies: Effects of other Drugs on Lonafarnib CYP3A inhibitors Lonafarnib is a sensitive substrate for CYP3A. With coadministration of a single oral dose of 50 mg lonafarnib following 200 mg ketoconazole (a strong CYP3A inhibitor) once daily for 5 days, the C max and AUC of lonafarnib were increased by 270% and 425%, respectively, as compared to lonafarnib administered alone in healthy subjects [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Fluconazole Coadministration of steady-state lonafarnib with multiple-dose fluconazole (a moderate inhibitor of CYP3A and CYP2C9) did not increase lonafarnib C max or AUC, as compared to lonafarnib administered alone in healthy subjects. [see Dosage and Administration ( 2.2 ), Drug Interactions ( 7.1 )] . CYP3A inducers With coadministration of a single oral dose of 50 mg lonafarnib (combined with a single oral dose of 100 mg ritonavir) following 600 mg rifampin once daily for 8 days, the C max of lonafarnib was reduced by 92% and the AUC was reduced by 98%, as compared to without rifampin coadministration in healthy subjects [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Clinical Studies: Effects of Lonafarnib on other Drugs CYP3A Substrates Lonafarnib is a strong inhibitor of CYP3A. With coadministration of a single oral dose of 3 mg midazolam with multiple oral doses of 100 mg lonafarnib twice daily for 5 days in healthy subjects, the C max and AUC of midazolam were increased by 180% and 639%, respectively [see Dosage and Administration ( 2.3 ), Contraindications ( 4 ), Drug Interactions ( 7.2 )] . Loperamide With coadministration of a single oral 2 mg dose of loperamide (primarily metabolized by CYP2C8 and CYP3A and a substrate of P-gp) with multiple oral doses of lonafarnib 100 mg twice daily for 5 days in healthy subjects, the C max and AUC of loperamide were increased by 214% and 299%, respectively [see Drug Interactions ( 7.2 )] . CYP2C19 Substrates Lonafarnib is a moderate CYP2C19 inhibitor. With coadministration of a single oral dose of 40 mg omeprazole with multiple oral doses of lonafarnib 75 mg twice daily for 5 days in healthy subjects, the C max and AUC of omeprazole were increased by 28% and 60%, respectively [see Drug Interactions ( 7.2 )] . P-gp and OATP1B Substrates With coadministration of a single oral dose of 180 mg fexofenadine (a P-gp and OATP1B substrate) with multiple oral doses of 100 mg lonafarnib twice daily for 5 days in healthy subjects, the C max and AUC of fexofenadine were increased by 21% and 24%, respectively [see Drug Interactions ( 7.2 )] .