HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

ZOKINVY safely and effectively.  See full prescribing information for ZOKINVY.

ZOKINVYTM   (lonafarnib) capsules, for oral use Initial U.S. Approval: 2020

INDICATIONS AND USAGE

ZOKINVY is a farnesyltransferas e  inhibitor indicated in patients 12 months of

age and older with a body surface area of 0.39 m2 and above (1):

•   T o reduce risk of mortality in Hutchinson-Gilford Progeria Syndrome

•   For treatment of processing-deficient  Progeroid Laminopathies with either: o HeterozygousLMNAmutation with progerin-like protein accumulation o Homozygous or compound heterozygousZMPSTE24mutations

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)

DOSAGE AND ADMINISTRATION

•   Start at 115 mg/m2 twice daily with morning and evening meals (2.1)

•   After 4 months, increase to 150 mg/m2 twice daily (2.1)

•   Round all total daily doses to nearest 25 mg increment (2.1)

•   Swallow capsules whole. If unable to swallow capsules, mix contents with Ora Blend SF®, Ora-Plus®, orange juice, or applesauce (2.5).

•   See Full Prescribing Information for additional instructions on dosing, preparation and administration (2)

DOSAGE FORMS AND STRENGTHS

Capsules: 50 mg and 75 mg (3)

CONTRAINDICATIONS

•   Strong or moderate CYP3A inhibitors or inducers (4)

•   Midazolam (2.4, 4)

•   Lovastatin, simvastatin, and atorvastatin (4)

WARNINGS AND PRECAUTIONS

•  Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions: Prior to and during treatment, consider potential for drug interactions and review concomitant medications; monitor for adverse reactions (5.1, 7)

•  Laboratory Abnormalities:Monitor for changes in electrolytes, complete blood counts, and liver enzymes (5.2)

•  Nephrotoxicity:Caused nephrotoxicity in rats. Monitor renal function at regular intervals (5.3, 13.2)

•  Retinal Toxicity:Caused rod-dependent, low-light vision decline in monkeys.Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes (5.4, 13.2)

•  Impaired Fertility:Caused impaired fertility in female rats, impaired fertility and testicular toxicity in male rats, and toxicity in the male reproductive tract in monkeys.Advise females and males of reproductive potential of the animal fertility findings (5.5, 13.1, 13.2)

•  Embryo-Fetal Toxicity:Can cause fetal harm. Advise females of reproductive potential of the risk to a fetus and to use effective contraception (5.6, 8.1, 8.3)

ADVERSE REACTIONS

T he 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 Eiger BioPharmaceuticals, Inc. at 833-267-0545 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

•   Reduce to or continue at 115 mg/m2 twice daily with concomitant use of weak CYP3A inhibitors (2.3, 7.1)

•   See Full Prescribing Information for additional information regarding drug interactions (2.4, 4, 5.1, 7)

See 17 for PATIENT COUNSELING INFORMATION and FDA-

approved patient labeling

Revised: 11/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1            INDICATIONS AND USAGE

2            DOSAGE AND ADMINISTRATION

2.1       Recommended Dosage

2.2       Dosage Modifications for Gastrointestinal Adverse

Reactions

2.3      Dosage Modifications for Drug Interactions

2.4       T emporary Discontinuation for Midazolam Use

2.5       Preparation and Administration Instructions

3            DOSAGE FORMS AND STRENGTHS

4            CONTRAINDICATIONS

5            WARNINGS AND PRECAUTIONS

5.1       Risk of Reduced Efficacy  or Adverse Reactions Due

to Drug Interactions

5.2       Laboratory Abnormalities

5.3       Nephrotoxicity

5.4       Retinal T oxicity

5.5       Impaired Fertility

5.6       Embryo-Fetal T oxicity

6            ADVERSE REACTIONS

6.1       Clinical T rial Experience

7            DRUG INTERACTIONS

7.1      Effect  of Other Drugs on ZOKINVY

7.2       ZOKINVY’s Effect  on Other Drugs

8            USE IN SPECIFIC POPULATIONS

8.1       Pregnancy

8.2       Lactation

8.3       Females and Males of Reproductive Potential

8.4       Pediatric Use

8.6    Adult Use

11         DESCRIPTION

12         CLINICAL PHARMACOLOGY

12.1    Mechanism of Action

12.2    Pharmacodynamics

12.3    Pharmacokinetics

13         NONCLINICAL TOXICOLOGY

13.1    Carcinogenesis, Mutagenesis, Impairment of

Fertility

13.2    Animal T oxicology and/or Pharmacology

14         CLINICAL STUDIES

16         HOW SUPPLIED/STORAGE AND HANDLING

17         PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

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1             INDICATIONS AND USAGE

ZOKINVY is indicated in patients 12 months of age and older with a body surface area (BSA) of

1.39        m2 and above:

•      To reduce the risk of mortality in Hutchinson-Gilford  Progeria Syndrome (HGPS)

•      For the treatment of processing-deficient Progeroid Laminopathies with either: o    Heterozygous LMNAmutation with progerin-like protein accumulation o    Homozygous  or compound heterozygous ZMPSTE24mutations

Limit ations  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.

2.1                          Recommended Dosage

•      The starting dosage of ZOKINVY for patients with a BSA of 0.39 m2 and above is

115 mg/m2  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 m2[see Indications and Usage (1)].

•      After 4 months of treatment, increase the dosage to 150 mg/m2  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 remains 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/m2 twice daily.

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Table 2 provides the BSA-based dosage recommendations for the dosage of 150 mg/m2 twice daily.

2.2                           Dosage Modifications for Gastrointestinal Adverse Reactions

For patients who have increased their dose of ZOKINVY to 150 mg/m2  twice daily and are experiencing repeated episodes of vomiting and/or diarrhea resulting in dehydration or weight loss, ZOKINVY can be dose reduced to the starting dose of 115 mg/m2  twice daily (see Table 1). Ensure ZOKINVY is taken with the morning  and evening meals and with an adequate amount of water.

2.3                           Dosage Modifications for Drug Interactions

CYP3A Inhibitors

If concomitant use of ZOKINVY with a weak CYP3A inhibitor  is unavoidable  [see Warnings and Precautions (5.1), Drug Interactions (7.1)]:

•      Reduce to or continue ZOKINVY at the starting dosage of 115 mg/m2  twice daily (see Table 1).

•      Resume the previous ZOKINVY dosage 14 days after discontinuing  the concomitant use of the weak CYP3A inhibitor.

Temporarily  discontinue  ZOKINVY for 10 to 14 days before and 2 days after administration  of midazolam[see Contraindications (4), Drug Interactions (7.2)].

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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 Una ble 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

1.             For each capsule, empty contents of the capsule into a container containing 5 mL to

10 mL of the liquid.

2.             Mix thoroughly  with a spoon.

3.             Consume entire serving.

Preparation of Dose in Applesauce

1.              For each capsule, empty contents of the capsule into a container containing 1 teaspoonful to 2 teaspoonfuls of applesauce.

2.              Mix thoroughly  with a spoon.

3.              Consume entire serving.

Capsules:

•      50 mg, opaque yellow with “LNF” and “50” printed in black

•      75 mg, opaque light  orange with “LNF” and “75” printed in black

ZOKINVY is contraindicated in patients taking:

•      Strong or moderate CYP3A inhibitors  or inducers[see Drug Interactions (7.1)]

•      Midazolam[see Drug Interactions (7.2)]

•      Lovastatin, simvastatin, or atorvastatin[see Drug Interactions (7.2)]

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5.1                           Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions

Coadministration  of ZOKINVY with other drugs may result in clinically  significant  drug interactions[see Dosage and Administration (2.3, 2.4), Contraindications (4), Drug Interactions (7.1, 7.2)]. These drug interactions can lead to:

•      Reduced efficacy of ZOKINVY

•      Increased risk of adverse reactions from ZOKINVY or co-administered  drugs See Table 4 and Table 5 for steps to prevent or manage these clinically  significant  drug

interactions, including  dosage recommendations  [see Drug Interactions (7.1, 7.2)].Consider the potential for drug interactions prior to and during ZOKINVY therapy; review concomitant medications during ZOKINVY therapy; and monitor for the adverse reactions.

Some patients treated with ZOKINVY developed laboratory abnormalities  [see Adverse Reactions (6.1)].These included:

•      Electrolyte abnormalities  (43%), such as hyperkalemia,  hypokalemia,  hyponatremia, or hypercalcemia

•      Myelosuppression  (35%), such as reductions in absolute neutrophil count, white blood cell counts, lymphocytes, hemoglobin, or hematocrit

•      Increased liver enzymes, such as aspartate aminotransferase (35%), or alanine aminotransferase (27%)

These laboratory abnormalities  often improved while continuing  ZOKINVY, but it is not possible to exclude ZOKINVY as a cause of the abnormalities.  Periodically monitor electrolytes, complete blood counts, and liver enzymes, and manage abnormalities  accordingly.

Lonafarnib caused nephrotoxicity in rats at plasma drug exposures approximately equal to that achieved with the human dose [see Nonclinical Toxicology (13.2)].Monitor renal function at regular intervals during ZOKINVY therapy.

Lonafarnib caused rod-dependent, low-light  vision decline in monkeys at plasma drug exposures similar to that achieved with the human dose [see Nonclinical Toxicology (13.2)].Perform ophthalmologica l  evaluation at regular intervals and at the onset of any new visual changes during ZOKINVY therapy.

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Lonafarnib caused impaired fertility in female rats at 1.2 times the human dose based on plasma drug exposure[see Nonclinical Toxicology(13.1)].

Lonafarnib caused impaired fertility and testicular toxicity in male rats at 1.5 times the human dose based on plasma drug exposure[see Nonclinical Toxicology(13.1)], and toxicity  in the male reproductive tract in monkeys at doses lower than the human dose based on plasma drug exposure[see Nonclinical Toxicology (13.2)].

Advise females and males of reproductive potential of the animal fertility findings,  and that the impact on pubertal development and the potential for impaired fertility with ZOKINVY therapy in humans have not been adequately evaluated [see Use in Specific Populations (8.3)].

Based on findings  from animal reproduction studies, ZOKINVY can cause embryo-fetal harm when administered to pregnant women. In animal reproduction studies, oral administration  of lonafarnib in pregnant rats during organogenesis produced embryo-fetal toxicity at plasma drug exposures that were approximately equal to the recommended human dose.  In pregnant rabbits, oral administration  of lonafarnib during organogenesis produced skeletal malformations  and variations at exposures lower than the human exposure. Advise pregnant women of the risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant and to use appropriate effective contraception during treatment with ZOKINVY [see Use in Specific

Populations (8.1, 8.3)].

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/m2  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 LMNAheterozygous 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/m2  twice daily and increased to 150 mg/m2  twice daily after approximately  4 months for a total treatment duration of 24 to 30 months. Treatment naïve

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patients in Study 2 received ZOKINVY 150 mg/m2 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/m2  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 LMNAheterozygous mutation.

Table 3 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.

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1Abdominal pain includes stomach pain and abdominal pain.

2Infection  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. 3Upper respiratory infection includes bronchial infection, bronchitis, sinus infection, and upper respiratory infection.

4Electrolyte abnormalities includes hypermagnesemia, hypokalemia, hyperkalemia, hyponatremia, hypercalcemia, hyperphosphatemia, hypocalcemia, and hypernatremia.

5Myelosuppression includes absolute neutrophil count decreased, low total white blood cells, lymphopenia, decreased  hemoglobin, and hematocrit low.

6Musculoskeletal 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.

7Cerebral ischemia includes cerebral  ischemia, central nervous system hemorrhage, and ischemia cerebrovascular.

8Ocular changes include visual acuity change, corneal clouding, conjunctivitis, watering eyes, keratitis.

Gastrointestinal  Adverse Reactions

As noted in Table 3, 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 parental 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

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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 hypertriglyceride mia

and hyperglycemia  resulting  in discontinuation  of ZOKINVY.

Hype rtension

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.

7.1                           Effect of Other Drugs on ZOKINVY

Table 4 presents clinically  significant  drug interactions involving  drugs that affect ZOKINVY.

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Table 5 presents clinically  significant  drug interactions involving  drugs affected by ZOKINVY.

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Risk Summary

Based on findings  from animal studies, ZOKINVY can cause embryofetal harm when administered to a pregnant woman. There are no human data on ZOKINVY use in pregnant

women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the risk to a fetus.

In animal reproduction studies, oral administration  of lonafarnib to pregnant rats during organogenesis produced embryo-fetal toxicity at exposures that were 1.2-times the human exposure at the recommended dose of 150 mg/m2  twice daily.  In pregnant rabbits, oral administration  of lonafarnib during organogenesis produced skeletal malformations  and variations at exposures lower than the human exposure at 150 mg/m2  twice daily, and maternal toxicity  at 26 times the human exposure at 150 mg/m2 twice daily (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population  is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population,  the estimated background risk of major birth defects and miscarriage in clinically  recognized pregnancies is 2 to 4% and 15 to 20%,

respectively.

Data

Animal Data

In an embryo-fetal development  study in rats, oral administration  of lonafarnib during organogenesis produced an increase in post-implantation  loss (resorptions) and decreases in fetal

body weight and number of live fetuses at 30 mg/kg/day (1.2 times the AUC [area under the plasma concentration-time  curve] in humans at the recommended dose of 150 mg/m2  twice daily).  No effects on embryo-fetal development in rats were observed at systemic exposures lower than the human AUC at 150 mg/m2  twice daily.

In rabbits, oral administration  of lonafarnib  during organogenesis resulted in skeletal malformations  and variations at systemic exposures lower than the human AUC at the recommended dose of 150 mg/m2  twice daily, and maternal toxicity (body weight loss and abortion) at 120 mg/kg/day (26 times the human AUC at 150 mg/m2  twice daily).

No effects in offspring were observed in a pre- and postnatal development study in rats with maternal administration  of up to 20 mg/kg/day orally (AUC lower than the human AUC at 150 mg/m2  twice daily) during organogenesis through lactation.

Risk Summary

There are no data on the presence of ZOKINVY in human milk, the effects on the breastfed infant, or the effects on milk production.  Lonafarnib is excreted in rat milk (see Data).When a drug is present in animal milk, it is likely  that the drug will be present in human milk.

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The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOKINVY and any potential adverse effects of the breastfed infant from ZOKINVY or from the underlying  maternal condition.

Data

Lonafarnib is excreted in milk following oral administration  in lactating rats, with a mean milk to plasma concentration ratio of 1.5 at 12 hours.

Contraception

ZOKINVY can cause embryo-fetal harm when administered to pregnant women [see Use in

Specific Populations (8.1)]. Advise females of reproductive potential to use appropriate effective

contraception during treatment with ZOKINVY.

Infertilit y

Based on findings  in rats, ZOKINVY may reduce fertility in females and males of reproductive

potential[see Warnings and Precautions (5.5), Nonclinical Toxicology (13.1)].

The safety and effectiveness of ZOKINVY for the treatment of HGPS and processing-deficient Progeroid Laminopathies  (with either heterozygous LMNAmutation with progerin-like  protein accumulation  or homozygous  or compound heterozygous ZMPSTE24mutations) have been established in pediatric patients 12 months of age and older. Use of ZOKINVY for these indications  is supported by adequate and well controlled studies in pediatric patients 2 years of age and older [see Clinical Studies (14)].

The safety and effectiveness of ZOKINVY in pediatric patients less than 12 months of age have not been established.

The safety and effectiveness of ZOKINVY for the treatment of HGPS and processing-deficient Progeroid Laminopathies  (with either heterozygous LMNAmutation with progerin-like  protein accumulation  or homozygous  or compound heterozygous ZMPSTE24mutations) have been established in adults. Use of ZOKINVY in adults for these indications  is based on adequate and well controlled studies in pediatric patients 2 years of age and older [see Clinical Studies (14)].

ZOKINVY (lonafarnib) is a farnesyltransferase inhibitor.      The chemical name for lonafarnib is 4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-  benzo[1,2]  cyclohepta [2,4-b]pyridin­ 11-yl]piperidin-1-yl]-2-  oxoethyl]piperidine-1-carboxamide.  Its molecular formula is C27H31Br2ClN4O2, molecular mass is 638.8 g/mol, and its chemical structure is depicted below.

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ZOKINVY (lonafarnib) capsules for oral administration  contain 50 mg or 75 mg of lonafarnib  as the active ingredient and the following  inactive ingredients:  croscarmellose sodium, magnesium stearate, poloxamer 188, povidone,  and silicon  dioxide. The capsule shells of both strengths contain gelatin, titanium dioxide, and yellow iron oxide; the 75 mg capsule also contains red iron oxide. The imprinting  ink contains ammonia solution,  black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide,  propylene glycol, purified  water, and shellac.

12.1                       Mechanism of Action

Lonafarnib inhibits  farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like  proteins in the inner nuclear membrane.

No formal pharmacodynamic studies have been conducted with ZOKINVY.

The pharmacokinetics  of lonafarnib at steady state in patients with HGPS following  oral administration  of lonafarnib twice daily with food are summarized in Table 6.

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.

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Effect of Food

Following  a single oral dose of 75 mg lonafarnib in healthy subjects, the Cmax decreased 55% and AUC decreased 29% with a high-fat meal (approximately  43% fat of the total 952 calories)

compared to fasted conditions.  Cmax decreased 25% and AUC decreased 21% with a low-fat meal (approximately 12% fat of the total 421 calories) compared to fasted conditions.

Dis tributio n

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.

Eliminat io n

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.

Excretion

Following an oral administration  of 104 mg [14C]-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.

Spe cific 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 Cmax 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 Cmax 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.

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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 Cmax and AUC of lonafarnib  were increased by 270% and 425%, respectively, as compared to lonafarnib administered  alone in healthy subjects [see Dosage and Administration (2.3),

Contraindications (4), Drug Interactions (7.1)].

CYP2C9 inhibitors

Coadministration  with CYP2C9 inhibitors  may increase lonafarnib AUC and Cmax. A drug-drug

interaction study of ZOKINVY with CYP2C9 inhibitors  has not been conducted[see 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 Cmax 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 Cmax and AUC of midazolam were increased by 180% and 639%, respectively[see Dosage and Administration (2.4), 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

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twice daily for 5 days in healthy subjects, the Cmax 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 Cmax 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 Cmax and AUC of fexofenadine were increased by 21% and 24%, respectively [see Drug Interactions (7.2)].

Carcinoge ne sis

Carcinogenicity  studies have not been conducted with lonafarnib.

Mutage ne sis

Lonafarnib was not genotoxic in the bacterial mutagenicity  (Ames) assay, in vitro chromosomal aberration assay in mammalian cells, or in vivo micronucleus assay in mice.

Impair ment of Fertilit y

Lonafarnib produced impaired fertility in male rats at 90 mg/kg/day or higher (1.5 times the AUC in humans at the recommended dose of 150 mg/m2  twice daily), with a nearly complete loss of fertility  at 180 mg/kg/day (3 times the AUC in humans).  Male rats treated with

180 mg/kg/day exhibited  small testes, flaccid testes, and discolored epididymis  (84%, 56%, and

24% of males, respectively).  No effects on fertility  occurred in males at systemic exposures lower than the human AUC at 150 mg/m2  twice daily.

Female rats treated with 30 mg/kg/day lonafarnib or higher (1.2 times the human AUC at the recommended human dose of 150 mg/m2  twice daily) showed a decrease in fertility, as indicated by reductions in the number of corpora lutea and implantation  sites, and increases in pre- and post-implantation  loss.  No effects on fertility occurred in females at systemic exposures lower than the human AUC at 150 mg/m2  twice daily [see Warnings and Precautions (5.5)].

Renal toxicity occurred in a 6-month oral toxicity  study of lonafarnib in rats, with kidney lesions (interstitial  necrosis and mineralization in the inner medulla) and correlating changes in clinical chemistry (e.g., hyperphosphatemia,  hyperkalemia) and urinalysis  parameters observed at systemic exposures approximately equal to the AUC in humans at the recommended dose of

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150 mg/m2  twice daily.  No evidence of renal toxicity was observed at systemic exposures lower than the human AUC at 150 mg/m2  twice daily[see Warnings and Precautions (5.3)].

Toxicity  in the male reproductive tract occurred in a 1-year oral toxicity  study in monkeys at 10 mg/kg/day or higher (AUC lower than the human AUC at the recommended dose of

150 mg/m2  twice daily).  The lesions in the male reproductive tract included  aspermia in the epididymis  and atrophy of seminiferous tubules, seminal vesicle, and prostate gland.  Testicular

toxicity  was also observed in rats, where severe impairment  of male fertility occurred[see Warnings and Precautions (5.5), Nonclinical Toxicology (13.1)].

Ocular (retinal) toxicity occurred in a 1-year oral toxicity  study in monkeys at 40 mg/kg/day

(3.7 times the human AUC at the recommended dose of 150 mg/m2  twice daily).  The retinal injury  involved  single cell necrosis of photoreceptor cells in the layer of rods and cones and the outer nuclear layer.  No retinal toxicity was observed at 20 mg/kg/day (2.1 times the human AUC at 150 mg/m2  twice daily).  However, in a follow-up study of lonafarnib effects on visual function in monkeys as evaluated by electroretinography,  oral administration  of 15 mg/kg/day for 13 weeks or 60 mg/kg/day for 6 weeks produced adverse effects on rod-dependent, low-light vision.   The effects were observed at several time-points  throughout  the treatment period. No histological  changes in the retina were observed at study termination [see Warnings and

Precautions (5.4)].

The efficacy of ZOKINVY is based on results from the Observational Cohort Survival Study, which retrospectively compared survival data from two Phase 2 studies in patients with HGPS to those from a natural history cohort.

Study 1 (NCT00425607)  was a Phase 2 open-label, single-arm trial that evaluated the efficacy of ZOKINVY in 28 patients (26 with classic HGPS, one with non-classic HGPS, and one with processing-deficient  Progeroid Laminopathy with LMNAheterozygous mutation with progerin­ like protein accumulation).  Patients received ZOKINVY for 24 to 30 months. Patients initiated treatment with ZOKINVY 115 mg/m2  twice daily. After 4 months of treatment, patients who tolerated treatment had an increase in dose to 150 mg/m2 twice daily. Among the 28 patients

treated, 27 patients with HGPS (16 females, 11 males) were included in the survival assessment. The median age at treatment initiation  for the 27 patients was 7.5 years (range: 3 to 16 years). The body weight range was 6.6 to 17.6 kg and the BSA range was 0.38 to 0.75 m2 (ZOKINVY is

not indicated in patients with a BSA less than 0.39 m2 because the appropriate dosage strength is not available for this population).

Following  completion  of Study 1, 26 patients enrolled in a second Phase 2 open label, single-arm trial (Study 2, NCT00916747) which consisted of two study phases. In the first phase of Study 2, patients received ZOKINVY with additional  therapies for about 5 years. In the second phase of Study 2, patients received ZOKINVY 150 mg/m2  twice daily for a period of up to 3 years.

There were 35 treatment naïve patients with HGPS enrolled into the second phase of Study 2. Among the 35 treated patients (22 males, 13 females), 34 (97.1%) patients had classic HGPS and

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1 (2.9%) patient had non-classic HGPS. The median age was 6 years (range: 2 to 17 years). The body weight range was 6.7 to 22 kg and the BSA range was 0.42 to 0.90 m2.

Throughout  Study 1 and Study 2, 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.  The retrospective survival analysis was based on the mortality data from 62 treated patients (27 patients in Study 1 and 35 treatment-naïve patients in Study 2) and data from matched, untreated patients in a separate natural history cohort. The mean lifespan of HGPS patients treated with ZOKINVY increased by an average of 3 months through the first three years of follow-up and

2.5 years through the last follow-up  time (11 years) compared to untreated patients. The survival analysis summary is provided in Table 7 and Figure 1.

[1]  Includes 27 patients in Study 1 and 35 treatment-naïve patients in Study 2. [2]  Based on the area under the survival curves up to 11 years of follow-up. [3]  Based on a Cox regression model (with treatment as the only covariate) stratified by continent of residency.

Note: T reated patients were matched 1:1 to untreated patients (who were alive at the age when the treated patient began ZOKINVY) by

mutation status (classic/unknown versus non-classic), sex and continent of residence using a fixed 50th percentile matching algorithm. In the fixed 50th percentile matching algorithm, candidate untreated patients were first sorted by decreasing last known age and the candidate in the 50th percentile was selected as the match. Follow-up time for a matched pair of treated and untreated patients began at the age of the treated patient at ZOKINVY initiation.

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