Bulevirtide

HEPCLUDEX is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in adults without cirrhosis or with compensated cirrhosis. This indication is approved under accelerated approval based on a decrease in HDV RNA and alanine aminotransferase (ALT) normalization [see Clinical Studies (14) ] . An improvement in disease-related clinical outcomes has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). HEPCLUDEX is a sodium taurocholate co-transporting polypeptide (NTCP)-directed HDV attachment inhibitor indicated for the treatment of chronic HDV infection in adults without cirrhosis or with compensated cirrhosis. This indication is approved under accelerated approval based on participants who achieved a decrease in HDV RNA and alanine aminotransferase (ALT) normalization. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 , 14 )

Recommended dosage in adults: HEPCLUDEX 8.5 mg once daily by subcutaneous injection. ( 2.1 ) Instructions for Use should be followed for preparation and administration of HEPCLUDEX. ( 2.2 )

2.1 Recommended Dosage in Adults The recommended dosage in adults is HEPCLUDEX 8.5 mg once daily administered by subcutaneous injection. HEPCLUDEX should be continued as long as it is associated with a response to treatment. The optimal treatment duration is unknown. In all patients, manage the underlying hepatitis B virus (HBV) infection as clinically appropriate. If a dose is missed, that dose should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and resume the original schedule.

2.2 Dose Preparation and Administration See the HEPCLUDEX full Instructions for Use for details on the preparation and administration of HEPCLUDEX. Healthcare professionals should train patients or caregivers on the proper reconstitution and administration of HEPCLUDEX, and subcutaneous injection techniques. Consider preparation and administration of the first dose under healthcare professional supervision. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Aseptically reconstitute HEPCLUDEX lyophilized powder or cake by adding 1 mL of Sterile Water for Injection to the HEPCLUDEX vial. Administer entire contents of vial by subcutaneous injection into the upper thigh, lower abdomen, or back of the upper arm (only if administered by a caregiver). Use reconstituted product immediately. Do not store for later use.

For injection: 8.5 mg as a white to off-white lyophilized powder or cake in a single-dose vial for reconstitution. For injection: 8.5 mg as a lyophilized powder or cake, in a single-dose vial. ( 3 )

None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Including Anaphylaxis: Hypersensitivity reactions have been reported with HEPCLUDEX. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue HEPCLUDEX and initiate appropriate treatment. ( 5.2 )

5.1 Exacerbation of Hepatitis D and B After Discontinuation of Treatment Severe acute exacerbations of HDV and HBV infection may occur after HEPCLUDEX is discontinued, especially in patients with cirrhosis, who may be at increased risk of more severe flares or progression to hepatic decompensation. Monitor hepatic function closely with both clinical and laboratory follow-up, including monitoring HBV DNA and HDV RNA viral load, for at least six months in patients who discontinue HEPCLUDEX. Resumption of antiviral therapy may be warranted.

5.2 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis, have been reported with HEPCLUDEX. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue HEPCLUDEX and initiate appropriate treatment [see Adverse Reactions (6.2) ] .

7.1 Effects of HEPCLUDEX on Other Drugs No CYP enzyme or transporter mediated inhibition or induction by bulevirtide is anticipated at clinically relevant concentrations [see Clinical Pharmacology (12.3) ].

7.2 Effects of Other Drugs on HEPCLUDEX Due to peptide catabolism of bulevirtide, the drug-drug interaction potential of other drugs to impact bulevirtide pharmacokinetics, via CYP enzymes, is low [see Clinical Pharmacology (12.3) ].

The following adverse reactions are discussed in other sections of the labeling: Exacerbation of Hepatitis D and B After Discontinuation of Treatment [see Warnings and Precautions (5.1) ]. The most common adverse reactions (incidence greater than or equal to 10%, all grades) observed with treatment with HEPCLUDEX are injection site reactions, headache, abdominal pain, fatigue, and pruritus . ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials 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. The overall safety profile of HEPCLUDEX is based on Phase 2 and Phase 3 data from 165 adults with chronic HDV infection without cirrhosis or with compensated cirrhosis who received at least 48 weeks of HEPCLUDEX 8.5 mg subcutaneous injection once daily. Trial MYR301 was a Phase 3 randomized, multi-center, open-label, parallel-arm trial in 101 adults. In this trial, 50 adults received 8.5 mg HEPCLUDEX daily for 144 weeks and 51 adults who were in the Delayed Treatment group received no HDV treatment for the first 48 weeks; 50 adults in the Delayed Treatment group then received HEPCLUDEX 8.5 mg once daily for 96 weeks [see Clinical Studies (14) ]. Table 1 displays the frequency of the adverse reactions (all grades) ≥ 10% in the HEPCLUDEX group at Week 48. No participant discontinued treatment with HEPCLUDEX due to an adverse reaction through Week 48. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (All Grades) Reported in ≥ 10% of Participants with Chronic HDV Infection Without Cirrhosis or With Compensated Cirrhosis Receiving HEPCLUDEX in Trial MYR301 (Week 48 Analysis) Adverse Reaction HEPCLUDEX (N=50) Delayed Treatment Participants who received no HDV treatment in Trial MYR301 for the first 48 weeks. (N=51) Injection site reactions Grouped term includes injection site abscess, injection site erythema, injection site reaction, injection site pruritus, injection site swelling, injection site hematoma, injection site rash, injection site dermatitis, and injection site pain. 30% 0 Headache 20% 0 Abdominal pain Grouped term includes abdominal pain, abdominal pain lower, and abdominal pain upper. 18% 2% Fatigue 14% 2% Pruritus 14% 0 A similar safety profile was observed through Week 144 in Trial MYR301 and for participants in the Delayed Treatment group who switched to treatment with HEPCLUDEX at Week 48 through to Week 144. Additionally, a similar safety profile was observed through Week 96 in Phase 2b Trial MYR204. Laboratory Abnormalities Eosinophil Count Increased: In MYR301, increases in eosinophil counts were reported in 33% of participants (all Grade 1) receiving HEPCLUDEX; there were no associated clinical sequelae, hepatic adverse reactions, or significant liver-related laboratory abnormalities. Total Bile Salts Increased: HEPCLUDEX inhibits sodium taurocholate co-transporting polypeptide (NTCP)-mediated bile acid transport. Consistent with this, elevations in total serum bile salt levels were observed in clinical trials of HEPCLUDEX. In MYR301, all participants who received HEPCLUDEX had elevated serum bile salts. Bile salt levels showed visit-to-visit variability and peaked by Week 8 of treatment in both participants without cirrhosis and those with compensated cirrhosis, although median levels trended higher in the latter group. Bile salt elevations resolved upon discontinuation of HEPCLUDEX. In MYR301, 14% of HEPCLUDEX recipients experienced Grade 1 or 2 pruritus that was self-limited. The magnitude of total serum bile salt elevations did not correlate with the severity of pruritus.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of HEPCLUDEX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: hypersensitivity, including anaphylactic reaction

No data are available on overdose of HEPCLUDEX in patients. Treatment of overdose with HEPCLUDEX should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with HEPCLUDEX. Hemodialysis is unlikely to result in significant removal of bulevirtide since bulevirtide is highly bound to plasma protein.

8.1 Pregnancy Risk Summary There are insufficient human data on the use of HEPCLUDEX during pregnancy to inform a drug-associated risk of birth defects and miscarriage. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. In nonclinical reproductive toxicity studies, bulevirtide demonstrated no adverse effect on embryofetal development when administered to pregnant rats and rabbits at systemic exposures (AUC) 4- and 37-fold relative to exposure in humans at the recommended human dose (RHD). Data Animal Data Bulevirtide was administered via subcutaneous injection to pregnant rats and rabbits (2.5 mg/kg/day) on Gestation Days 6 through 17 and 6 through 20, respectively, and also to rats from Gestation Day 6 to Lactation/Postpartum Day 20. There were no adverse effects on embryofetal development in rats and rabbits. During organogenesis, exposure in rats and rabbits was 4 and 37 times higher, respectively, than the exposure in humans at the RHD. In a pre/postnatal development study in rats, bulevirtide (2.5 mg/kg/day) was administered via subcutaneous injection from Gestation Day 6 to Lactation Day 21. No effects were observed in the offspring at maternal exposures 3 times the exposure at the RHD.

8.2 Lactation Risk Summary It is not known whether bulevirtide is present in human breast milk, affects human milk production, or has effects on the breastfed infant. In nonclinical pre- and postnatal developmental rat studies, bulevirtide was not measured in the plasma of pups or in the milk of nursing animals. However, due to its high protein binding, liver tropism, and high specificity for NTCP, bulevirtide is not likely to be secreted in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HEPCLUDEX and any potential adverse effects on the breastfed child from HEPCLUDEX or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of HEPCLUDEX in pediatric patients less than 18 years of age have not been established.

8.5 Geriatric Use Clinical trials of HEPCLUDEX did not include participants aged 65 and over to determine whether they respond differently from younger participants [see Clinical Pharmacology (12.3) ].

8.6 Renal Impairment No dosage adjustment of HEPCLUDEX is recommended in patients with mild, moderate, or severe renal impairment (creatinine clearance [CrCl] greater than or equal to 15 mL per minute) [see Clinical Pharmacology (12.3) ]. HEPCLUDEX has not been studied in patients with end-stage renal disease (CrCl less than 15 mL per minute).

8.7 Hepatic Impairment No dosage adjustment of HEPCLUDEX is recommended in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3) ]. The safety and efficacy of HEPCLUDEX have not been studied in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

Risk Summary There are insufficient human data on the use of HEPCLUDEX during pregnancy to inform a drug-associated risk of birth defects and miscarriage. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. In nonclinical reproductive toxicity studies, bulevirtide demonstrated no adverse effect on embryofetal development when administered to pregnant rats and rabbits at systemic exposures (AUC) 4- and 37-fold relative to exposure in humans at the recommended human dose (RHD). Data Animal Data Bulevirtide was administered via subcutaneous injection to pregnant rats and rabbits (2.5 mg/kg/day) on Gestation Days 6 through 17 and 6 through 20, respectively, and also to rats from Gestation Day 6 to Lactation/Postpartum Day 20. There were no adverse effects on embryofetal development in rats and rabbits. During organogenesis, exposure in rats and rabbits was 4 and 37 times higher, respectively, than the exposure in humans at the RHD. In a pre/postnatal development study in rats, bulevirtide (2.5 mg/kg/day) was administered via subcutaneous injection from Gestation Day 6 to Lactation Day 21. No effects were observed in the offspring at maternal exposures 3 times the exposure at the RHD.

The safety and effectiveness of HEPCLUDEX in pediatric patients less than 18 years of age have not been established.

Clinical trials of HEPCLUDEX did not include participants aged 65 and over to determine whether they respond differently from younger participants [see Clinical Pharmacology (12.3) ].

Bulevirtide-gmod is an NTCP-directed HDV attachment inhibitor. Bulevirtide as an acetate salt, is a 47-amino acid protein with a fatty acid myristoyl residue at the N-terminus and an amidated C-terminus. All chiral amino acids are in the L-configuration. The counter ion acetate is bound in ionic form to basic groups of the peptide molecule in a nonstoichiometric ratio. Bulevirtide acetate has a molecular formula of C 248 H 355 N 65 O 72 (net) and a molecular weight of 5398.9 Da (average mass, net), and has the following structural formula: HEPCLUDEX (bulevirtide-gmod) for injection is a sterile, preservative-free, white to off-white lyophilized powder or cake for subcutaneous injection after reconstitution. Each single-dose vial delivers 8.5 mg of bulevirtide-gmod (equivalent to approximately 8.6 mg of bulevirtide acetate). The inactive ingredients are histidine (3.3 mg), mannitol (51 mg), and sucrose (8.5 mg), and may include hydrochloric acid and/or sodium hydroxide to adjust the pH to 8.5. HEPCLUDEX requires reconstitution prior to administration by subcutaneous injection [see Dosage and Administration (2.2) ]. Chemical Structure

HEPCLUDEX is an antiviral drug [see Microbiology (12.4) ].

Bulevirtide is a synthetic 47-amino acid lipopeptide with a myristoylated N-terminus and an amidated C-terminus derived from amino acids 13-59 of the L-HBsAg preS1 domain from an HBV genotype (GT)-C consensus sequence (corresponding to GT-D preS1 amino acids 2-48). Bulevirtide inhibits HDV infection by binding to the HDV receptor NTCP on the plasma membrane of hepatocytes, blocking HDV attachment to NTCP.

HEPCLUDEX 8.5 mg once daily was associated with a higher percentage of trial participants with undetectable HDV RNA at Week 144 compared to a lower once daily dose.

The pharmacokinetic properties of bulevirtide were characterized after intravenous administration in healthy participants, and after subcutaneous administration in healthy participants and participants with chronic HDV infection. The systemic exposure of bulevirtide increased in a more than proportional manner with increasing doses. At steady state, AUC and C max increased by approximately 2-fold compared to the AUC and C max after the first dose. The pharmacokinetic parameters of bulevirtide are provided in Table 2 . The steady-state PK parameters of bulevirtide (based on population PK analysis of participants with chronic HDV infection) are provided in Table 3 . Table 2 Pharmacokinetic Parameters of Bulevirtide Absorption % absolute bioavailability 57 T max (h) (range) 3.00 (1.00 - 4.00) Distribution % bound to human plasma proteins > 99 Elimination t 1/2 (h) t 1/2 values refer to mean terminal plasma half-life. (range) 3 (2 - 6) Metabolism Metabolic pathway Bulevirtide, a linear peptide consisting of L-amino acids, is expected to be degraded to smaller peptides and individual amino acids. No active metabolites are expected. Catabolized by peptidases to amino acids Excretion Major route of elimination Excreted as smaller peptides and amino acids Table 3 Steady-State Pharmacokinetic Parameters of Bulevirtide Following Subcutaneous Administration of HEPCLUDEX in Adults with HDV Infection Empirical Bayesian post hoc exposure estimates from Population pharmacokinetic analysis in MYR301 trial, N=100. Parameter Geometric Mean (90% CI) CI=Confidence Interval C max (ng/mL) 184 (160 - 211) AUC 0-24h (ng

• h/mL) 1935 (1680 - 2230) Specific Populations Age (18 to 65 years), sex, race (87.5% White, 1.9% Black, 10.3% Asian, 0.2% Other), or body weight (39.7 to 110 kg) did not have a clinically relevant impact on the systemic exposure of bulevirtide. Geriatric Patients The pharmacokinetics of bulevirtide have not been evaluated in elderly participants with HDV infection (65 years of age and older) [see Use in Specific Populations (8.5) ]. Patients with Renal Impairment In a Phase 1, open-label study in participants without HDV infection, the steady state pharmacokinetics of bulevirtide were similar among participants with normal renal function and participants with severe renal impairment (CrCl 15 to less than 30 mL per minute), and no clinically relevant differences in total bile acid elevations were observed between the two groups. The pharmacokinetics of bulevirtide have not been evaluated in participants with end-stage renal disease (CrCl less than 15 mL per minute), including those on dialysis. As bulevirtide is greater than 99% protein bound, dialysis is not expected to alter exposures of bulevirtide [see Use in Specific Populations (8.6) ]. Patients with Hepatic Impairment In a Phase 1, open-label study in participants without HDV infection, the steady-state pharmacokinetics of bulevirtide were approximately 27% lower in participants with moderate hepatic impairment (Child-Pugh Class B) than participants with normal hepatic function. The steady state pharmacokinetics of bulevirtide were similar among participants with severe hepatic impairment (Child-Pugh Class C) and participants with normal hepatic function [see Use in Specific Populations (8.7) ]. Drug Interaction Studies Effect of Bulevirtide on Other Drugs Cytochrome P450 (CYP) Enzymes: In vitro studies have shown, bulevirtide is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Bulevirtide is not an inducer of CYP1A2, CYP2B6, or CYP3A4. Consistent with in vitro results, bulevirtide at steady state did not impact the pharmacokinetics of the CYP3A4 probe substrate midazolam, administered as an oral 30 μg microdose, in clinical drug-interaction studies. Transporter Systems: In vitro studies have shown that no clinically relevant interactions are expected for efflux transporters including MDR1, BCRP, BSEP, MATE1, and MATE2K and uptake transporters including OATP2B1, OAT1, OAT3, OCT1, and OCT2. In vitro studies have shown that bulevirtide inhibits the organic anion transporting polypeptides, OATP1B1 and OATP1B3, with IC 50 values of 0.5 and 8.7 μM, respectively, and taurocholate uptake via NTCP receptors with an IC 50 value of 0.320 μM; however, no clinical drug interaction is expected for OATP1B or NTCP substrates at clinically relevant concentrations of bulevirtide. Steady state exposures of bulevirtide administered once daily did not impact the pharmacokinetics of TDF (at 300 mg) in a dedicated clinical drug-interaction study. Effect of Other Drugs on Bulevirtide Based on the population PK evaluation of drug interactions for bulevirtide, no clinically relevant drug interactions have been observed with PEG-IFNα and TAF or TDF.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ) for proper preparation and administration instructions. Important Preparation and Administration Considerations Healthcare professionals should train patients or caregivers in the proper technique for reconstituting HEPCLUDEX with Sterile Water for Injection and administering subcutaneous injections using a syringe and consider preparation and administration of the first dose under the supervision of a healthcare provider. Inform patients that the Sterile Water for Injection, syringes, and needles needed for preparation and injection of HEPCLUDEX are obtained separately from the pharmacy. Exacerbation of Hepatitis D and B after Discontinuation of Treatment Inform patients that discontinuation of HEPCLUDEX may result in severe acute exacerbations of hepatitis D and B. Advise the patient to inform their healthcare provider before they discontinue HEPCLUDEX [see Warnings and Precautions (5.1) ]. Hypersensitivity Reactions Including Anaphylaxis Advise patients that hypersensitivity reactions, including anaphylaxis, have been reported with HEPCLUDEX. Advise patients to immediately discontinue HEPCLUDEX and alert their healthcare provider if signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur [see Warnings and Precautions (5.2) ] . Missed Dosage Inform patients that it is important to take HEPCLUDEX on a regular dosing schedule and to avoid missing doses. If a dose is missed, that dose should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and resume the original schedule [see Dosage and Administration (2.1) ]. Treatment Duration Advise patients that in the treatment of chronic hepatitis D, the optimal duration of treatment is unknown [see Dosage and Administration (2.1) ].