Pretomanid Tablet Drug Class: Antimycobacterial Agent Prepared For: MO Healthnet Prepared By: Conduent

Drug Monograph

Drug Name: Pretomanid tablet Drug Class: Antimycobacterial Agent Prepared For: MO HealthNet Prepared By: Conduent

New Criteria Revision of Existing Criteria

Executive Summary

The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be made available on an open Purpose: access basis to prescribers, require a clinical edit or require prior authorization for use.

Pretomanid is available as an oral tablet containing 200 mg of pretomanid. Dosage Forms:

Manufacturer: Manufactured for: Mylan Speciality L.P. Morgantown, WV, 26505.

The efficacy of Pretomanid, as part of a combination regimen with bedaquiline and linezolid, for the treatment of adults with pulmonary extensively drug resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB) was demonstrated in one single- arm, open label study enrolling 109 patients. The primary outcome measure was the incidence of bacteriologic failure, relapse or clinical failure through Summary of follow up until 6 months after the end of treatment. Clinical success was Findings: demonstrated in 95 of the first 107 patients after 6 months of treatment and 6 months of post-treatment follow-up. Additionally, 1,168 people who have received pretomanid in 19 clinical trials that have evaluated the drug’s safety and efficacy.

Status Clinical Edit PA Required Recommendation: Open Access PDL

Type of PA Appropriate Indications Non-Preferred Criteria: No PA Required Preferred

Purpose The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be considered a prior authorization drug, a clinical edit drug or an open access drug. While prescription expenditures are increasing at double-digit rates, payers are evaluating ways to control these costs by influencing prescriber behavior and guide appropriate medication usage. This review will assist in the achievement of qualitative and economic goals related to health care resource utilization. Restricting the use of certain medications can reduce costs by requiring documentation of appropriate indications for use, and where appropriate, encourage the use of less expensive agents within a drug class.

Introduction (1,2) Tuberculosis (TB) remains one of the top 10 causes of death worldwide and affects nearly 10,000 people in the US. Roughly 1.5% of those cases in the US are MDR, according to the Centers for Disease Control and Prevention. The most common symptoms of TB are a bad cough lasting 3 weeks or longer, pain in the chest, coughing up blood or sputum, weakness, weight loss, fever and night sweats. Currently, the global treatment success rate is 56% for MDR-TB.

Dosage Form (3) Pretomanid is available as an oral tablet containing 200 mg of pretomanid.

Manufacturer (3) Manufactured for: Mylan Speciality L.P. Morgantown, WV, 26505.

Indication(s) (3) Pretomanid is indicated, as part of a combination regimen with bedaquiline and linezolid, for the treatment of adults with pulmonary extensively drug resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB). Approval of this indication is based on limited clinical safety and efficacy data. This drug is indicated for use in a limited and specific population of patients.

Clinical Efficacy (3,4,5) (mechanism of action/pharmacology, comparative efficacy) Pretomanid is a nitroimidazooxazine antimycobacterial drug that kills actively replicating Mycobacterium tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. Under anaerobic conditions, against non-replicating bacteria, pretomanid acts as a respiratory poison following nitric oxide release. All of these activities require nitro-reduction of pretomanid within the mycobacterial cell by the deazaflavin-dependent nitroreductase, Ddn, which is dependent on the reduced form of the cofactor F420. Reduction of F420 is accomplished by the F420-dependent glucose-6-phosphate dehydrogenase, Fgd1.

Pharmacokinetics: Volume of 97 L (fasting) to 180 L (fed) Distribution Metabolism Metabolized by multiple reductive and oxidative pathways, with no single pathway considered as major. CYP3A4 accounts for up to approximately 20% of metabolism. Excretion Urine: 53% (primarily metabolites; approximately 1% as unchanged drug) Feces: 38% Half-life 16 hours

Clinical Trials Experience STUDY 1 Single-arm, open-label study (n = 109) DESIGN INCLUSION  Provide written, informed consent prior to all trial-related procedures (if CRITERIA under 18, include consent of legal guardian).  Body weight of ≥35 kg  Willingness and ability to attend scheduled follow-up visits and undergo study assessments  Provide consent to HIV testing. If HIV status is a confirmed known positive, repeated HIV test is not needed provided documentation is available.  Male or female, aged 14 years or above.  Subjects with one of the following pulmonary TB conditions: a. XDR-TB with i. documented culture positive (for M.tb.) results within 3 months prior to screening or M.tb. confirmed in sputum based on molecular test within 3 months prior to or at screening; ii. documented resistance to isoniazid, rifamycins, a fluoroquinolone and an injectable historically at any time or at screening; b. MDR-TB documented by culture positive results (for M.tb.) within 3 months prior to or at screening with documented non-response to treatment with the best available regimen for 6 months or more prior to enrolment who in the opinion of the Investigator have been adherent to treatment and will be adherent to study regimen; c. MDR-TB documented by culture positive (for M.tb.) results within 3 months prior to or at screening who are unable to continue second line drug regimen due to a documented intolerance to: i. PAS, ethionamide, aminoglycosides or fluoroquinolones; ii. Current treatment not listed above that renders subject eligible for the study in the Investigator's opinion.  Chest X-Ray picture consistent with pulmonary TB in the opinion of the Investigator.  Be of non-childbearing potential or using effective methods of birth control. EXCLUSION  Any condition in the Investigator's opinion (i.e., an unstable disease such CRITERIA as uncontrolled diabetes or cardiomyopathy, extra-pulmonary TB requiring extended treatment), where participation in the trial would compromise the well-being of Subject or prevent, limit or confound protocol specified assessments.  Abuse of alcohol or illegal drugs.  The patient is not expected to survive for more than 12 weeks.

 Karnofsky score < 50 within 30 days prior to entry.  Body Mass index (BMI) < 17 kg/m²  History of allergy or known hypersensitivity to any of the trial Investigational Medicinal Products or related substances.  HIV infected Subjects having a CD4+ count ≤ 50 cells/μL; For HIV infected Subjects having a CD4+ count >50 cells/μL; a. Currently treated with or will need to initiate antiretroviral therapy (ART) which is not compatible with the allowed ARTs and is not considered an appropriate candidate for switching to a regimen of ARVs which is allowed. Examples of allowed treatment include but are not limited to the following. If there are any questions, discuss with the Sponsor Medical Monitor for confirmation of appropriate ARV regimen. i. Nevirapine based regimen consisting of nevirapine in combination with any NRTIs; ii. Lopinavir/ritonavir (Aluvia™) based regimen with any NRTIs; iii. The combination of tenofovir/lamivudine/abacavir should be considered in patients with normal renal function to address myelosuppression cross toxicity of idovudine and linezolid; iv. An alternate regimen that may be considered if the above are not appropriate is a triple nucleosidase reverse transcriptase inhibitors (NRTI) based regimen consisting of zidovudine, lamivudine and abacavir may be used with caution. Regimens including zidovudine should be used with special caution as zivovudine and linezolid may both cause peripheral nerve toxicity; v. Raltegravir in combination with nucleoside reverse transcriptase inhibitors (NRTIs). b. Cannot ensure a 2 week interval between commencing IMP and the start of ART, if not already on ARTs.  Having participated in other clinical studies with dosing of investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational study that includes treatment with medicinal agents.  Significant cardiac arrhythmia requiring medication.  Subjects with the following at Screening: o QTcF interval on ECG >500 msec. Subjects with QTcF > 450 must be discussed with the sponsor medical monitor before enrolment. o History of additional risk factors for Torsade de Pointes, (e.g., heart failure, hypokalemia, family history of Long QT Syndrome); o Clinically significant ventricular arrhythmias; o Subjects with other cardiac abnormalities that may place them at risk of arrhythmias must be discussed with the sponsor medical monitor before enrolment. Such abnormalities include: Evidence of ventricular pre-excitation (e.g., Wolff Parkinson White syndrome); Electrocardiographic evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; Evidence of second or third degree heart block; Intraventricular conduction delay with QRS duration more than 120 msec.  Females who have a positive pregnancy test at Screening or already known to be pregnant, breastfeeding, or planning to conceive a child during the study or within 6 months of cessation of treatment. Males planning to conceive a child during the study or within 6 months of cessation of treatment.

 A peripheral neuropathy of Grade 3 or 4, according to DMID (Appendix 2). Or, subjects with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator.  Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) or prior use within 2 weeks of treatment assignment.  Concomitant use of serotonergic antidepressants or prior use within 3 days of treatment assignment if Investigator foresees potential risks for serotonin syndrome when combined with linezolid.  Concomitant use of any drug known to prolong QTc interval  Concomitant use of any drug known to induce myelosuppression.  Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes. Exceptions may be made for subjects that have received 3 days or less of one of these drugs or substances, if there has been a wash-out period before administration of IMP equivalent to at least 5 half-lives of that drug or substance.  Subjects may have previously been treated for DS/MDR-TB (with specific exceptions for Bedaquiline and/or linezolid as noted below) provided that treatment is/was discontinued at least 3 days prior to treatment assignment.  Subjects should not receive more than 2 weeks of bedaquiline or linezolid prior to enrolment/first dose of IMP.  Subjects with the following toxicities at Screening (labs may be repeated) as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (November 2007): o Serum potassium less than the lower limit of normal for the laboratory; o Hemoglobin level grade 2 or greater (< 8.0 g/dL); o Platelets grade 2 or greater(<75,000/mm3); o Absolute neutrophil count (ANC) < 1000/ mm3; o Aspartate aminotransferase (AST) grade 3 or greater (> 3.0 x ULN) to be excluded; Greater than ULN must be discussed with and approved by the sponsor Medical Monitor o Alanine aminotransferase grade 3 or greater (> 3.0 x ULN) to be excluded greater than ULN must be discussed with and approved by the sponsor medical monitor ; o Total bilirubin: Grade 3 or greater (≥2.0 x ULN), or if ≥1.5 up to 2.0 x ULN when accompanied by an increase in other liver function test (ALT, AST, Alk Phos or GGT); 1-1.5 x ULN must be discussed with and approved by the sponsor Medical Monitor o Direct bilirubin: Greater than ULN to be excluded o Serum creatinine level greater than 2 times upper limit of normal o Albumin <32 g/L TREATMENT Patients received a combination regimen of bedaquiline 400 mg once daily for REGIMEN 2 weeks then 200 mg three times a week plus Pretomanid 200 mg once daily, and linezolid 1200 mg once daily for 6 months with 24 months of follow-up. RESULTS The primary outcome measured was the incidence of bacteriologic failure or relapse or clinical failure through follow up until 6 months after the end of treatment. (Note: Bacteriologic failure was defined as failure to attain culture

conversion to negative during the treatment period; Bacteriologic relapse was defined as failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline, during the follow-up period; Clinical failure was defined as a change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB- related death). Clinical success was demonstrated in 95 of the first 107 patients after 6 months of treatment and 6 months of post-treatment follow-up. Additionally, 1,168 people who have received pretomanid in 19 clinical trials that have evaluated the drug’s safety and efficacy. SAFETY Discussed in the Adverse Effects section below.

Contraindications (3,4)  Pretomanid tablets used in the combination regimen with bedaquiline and linezolid are contraindicated in patients for whom bedaquiline and/or linezolid are contraindicated. Refer to the bedaquiline and linezolid prescribing information.

Warnings and Precautions (3,4)  Hepatic adverse reactions were reported with the use of the combination regimen of pretomanid, bedaquiline, and linezolid. Monitor symptoms and signs and liver-related laboratory tests. Interrupt treatment with the entire regimen if evidence of liver injury occurs.  Myelosuppression was reported with the use of the combination regimen of pretomanid, bedaquiline, and linezolid. Monitor complete blood counts. Myelosuppression is a known adverse reaction of linezolid. Decrease or interrupt linezolid dosing if significant myelosuppression develops or worsens.  Peripheral and optic neuropathy were reported with the use of the combination regimen of pretomanid, bedaquiline, and linezolid. Neuropathy is a known adverse reaction of long-term linezolid use. Monitor visual function. Obtain an ophthalmologic evaluation if there are symptoms of visual impairment. Decrease or interrupt linezolid dosing if neuropathy develops or worsens.  QT prolongation was reported with the use of the combination regimen of pretomanid, bedaquiline, and linezolid. QT prolongation is a known adverse reaction of bedaquiline. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECG’s. Discontinue the combination regimen of pretomanid, bedaquiline, and linezolid if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops.  Reproductive effects: Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated.  Lactic acidosis was reported with the use of the combination regimen of pretomanid, bedaquiline, and linezolid. Lactic acidosis is a known adverse reaction of linezolid. Consider interrupting linezolid or the entire combination regimen of pretomanid, bedaquiline, and linezolid dosing if significant lactic acidosis develops.

Adverse Effects (3,4)

Most common, ≥ 5% (n = 109) % Peripheral neuropathy 81 Acne 39 Anemia 37 Nausea 37 Vomiting 34 Musculoskeletal pain 29 Headache 28 Transaminases increased 28 Dyspepsia 24 Decreased appetite 22 Rash 21 Pruritus 20 Abdominal pain 19 Pleuritic pain 19 Gamma-glutamyltransferase increased 17 Lower respiratory tract infection 15 Hyperamylasemia 14 Hemoptysis 13 Cough 12 Visual impairment 12 Hypoglycemia 11 Abnormal loss of weight 10 Diarrhea 10 Constipation 8 Gastritis 8 Neutropenia 8 Dry skin 7 Hypertension 7 Electrocardiogram QT prolongation 6 Hyperlipasemia 6 Thrombocytopenia 6 Insomnia 6 *Adverse reaction rates of clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug, due to widely varying conditions. When pretomanid tablets are administered in combination with bedaquiline and linezolid, refer to the prescribing information for the respective drugs for a description of the adverse reactions associated with their use.

Drug Interactions (3,4)  CYP3A4 inducers: Co-administration of pretomanid with rifampin and efavirenz resulted in a decrease in pretomanid plasma concentrations. Avoid co-administration of the combination regimen of pretomanid, bedaquiline, and linezolid with rifampin, efavirenz, or other strong or moderate CYP3A4 inducers. Refer to the prescribing information for bedaquiline for additional information about drug interactions with CYP3A4.  The effect of co-administration of pretomanid on the pharmacokinetics of organic anion transporter-3 (OAT3) substrates in humans is unknown. However, in vitro studies indicate that pretomanid significantly inhibits the OAT3 drug transporter, which could result in increased concentrations of OAT3 substrate drugs clinically and may increase

the risk of adverse reactions with these drugs. If pretomanid is co-administered with OAT3 substrate drugs (e.g., methotrexate), monitor for OAT3 substrate drug-related adverse reactions and consider dosage reduction for OAT3 substrate drugs, if needed. Refer to the prescribing information of the co-administered drug for dosage reduction information.

Dosage and Administration (3,4) Pretomanid must be administered only as part of a regimen in combination with bedaquiline and linezolid. Administer pretomanid 200 mg orally once daily for 26 weeks. Swallow pretomanid tablets whole with water. Administer the combination regimen with food. Cost **Wholesale Acquisition Cost

Generic Name Brand Name Manufacturer Dose Cost** Pretomanid Pretomanid Mylan 200 mg tablet $19.78/tab Conclusion Pretomanid, an antimycobacterial agent, is indicated, as part of a combination regimen with bedaquiline and linezolid, for the treatment of adults with XDR or MDR-TB. The efficacy of Pretomanid was demonstrated in one single-arm, open label study enrolling 109 patients. The primary outcome measure was the incidence of bacteriologic failure, relapse or clinical failure through follow up until 6 months after the end of treatment. Clinical success was demonstrated in 95 of the first 107 patients after 6 months of treatment and 6 months of post-treatment follow-up. Additionally, 1,168 people who have received pretomanid in 19 clinical trials that have evaluated the drug’s safety and efficacy. The most common adverse drug reactions (>20%) in patients taking the 3-drug combination include peripheral neuropathy, acne, anemia, nausea, vomiting, musculoskeletal pain, headache, transaminases increased, dyspepsia, decreased appetite, rash, and pruritus.

Recommendation The MO HealthNet Division recommends Open Access status for this product.

References 1) Trends in Tuberculosis, 2018. Centers for Disease Control and Prevention. https://www.cdc.gov/tb/publications/factsheets/statistics/tbtrends.htm. Accessed March 13, 2020. 2) Tuberculosis. World Health Organization. 2019. https://www.who.int/tb/global-report-2019. Accessed March 13, 2020. 3) Product Information: Pretomanid. 2019. Mylan, Laboratories Limited, Hyderabad, 500 096, India. 4) Pretomanid: Drug Information. Lexi-Drugs. Wolters Kluwer Clinical Drug Information Inc. 5) A Phase 3 Open-label Trial Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects With Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB) or Treatment Intolerant / Non-responsive Multi-drug Resistant Tuberculosis (MDR-TB). NCT02333799. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02333799?term=02333799&draw=2&rank=1. Accessed March 13, 2020.

Prepared by: Jaci Schowengerdt, PharmD Date: March 13, 2020