Beerse, Belgium (July 2, 2024) – Johnson & Johnson announced today that the U.S. Food and Drug Administration (FDA) has issued traditional approval for SIRTURO^® (bedaquiline) as part of combination therapy in adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampicin and isoniazid. With the FDA’s approval, label restrictions that were included when the medicine was granted accelerated approval in the U.S. in December 2012 are removed. The European Commission (EC) has also granted full approval of SIRTURO^®, converting its Conditional Marketing Authorisation to a Standard Marketing Authorisation, following a positive opinion in April 2024 from the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).

The approvals were supported by results from the Phase 3 STREAM Stage 2 study (NCT02409290), the first large-scale, randomized, multi-country open-label clinical study to evaluate the efficacy and safety of an all-oral bedaquiline-containing regimen for treatment of MDR-TB. Results confirmed that a bedaquiline-containing regimen offered a significant improvement in treatment outcomes compared to injectable-containing regimens. Findings from the study were published in The Lancet in November 2022.ⁱ

SIRTURO^® was granted accelerated approval by the FDA in December 2012 and conditional approval by the EMA in March 2014 following positive Phase 2 study data. A supplemental New Drug Application was submitted to the FDA in August 2023 to support the transition to full approval in the U.S. in addition to a Type II variation filed with the European Medicines Agency (EMA) in November 2023 to support the transition to Standard Marketing Authorisation.

Johnson & Johnson’s Commitment to TB Patients
Johnson & Johnson has long been committed to helping end tuberculosis. When Johnson & Johnson introduced SIRTURO^®, it was the first medicine for TB with a novel mechanism of action to be introduced in over 40 years. Today, it is a core component of World Health Organization-recommended treatment guidelines for drug-resistant TB, and three of every four MDR-TB patients on treatment are receiving an all-oral regimen containing bedaquiline. More than 845,000 courses of the medicine have been shipped to 160 countries.

Johnson & Johnson has spent the decade since the introduction of SIRTURO^® partnering with healthcare providers, communities, governments and non-governmental organizations to help ensure the medicine is accessible and remains effective for patients today and tomorrow. These efforts include investing in critical TB systems capacity, such as healthcare professional training, resistance testing and surveillance, and supply chain security. The Company also supports community-centered initiatives to help identify adults and children living with TB and bring them into treatment, expanding access to TB medicines.

In 2023, Johnson & Johnson granted the Stop TB Partnership’s Global Drug Facility (GDF) a license that enabled GDF to tender, procure and supply generic versions of SIRTURO^® for the majority of low-and middle-income countries (LMICs). The Company also confirmed its intent not to enforce bedaquiline patents in 134 low- and middle-income countries.

To learn more about Johnson & Johnson’s efforts in TB, visit https://www.jnj.com/tb.

About SIRTURO^®
EU
For a full list of adverse events and information on dosage and administration, contraindications and other precautions when using bedaquiline, please refer to the Summary of Product Characteristics.

U.S.
SIRTURO^® is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to at least rifampin and isoniazid.

Limitations of Use
Do not use SIRTURO^® for the treatment of latent infection due to Mycobacterium tuberculosis (M. tuberculosis), drug-sensitive pulmonary or extra-pulmonary tuberculosis or for the treatment of infections caused by non-tuberculous mycobacteria.

IMPORTANT SAFETY INFORMATION

WARNING: QTc PROLONGATION

• QTc prolongation can occur with SIRTURO^®. Use with drugs that prolong the QTc interval may cause additive QTc prolongation. Monitor ECGs. Discontinue SIRTURO^® if significant ventricular arrhythmia or QTc interval greater than 500 ms develops.

Warnings and Precautions
QTc Prolongation: SIRTURO^® prolongs the QTc interval. Use with drugs that prolong the QTc interval may cause additive QTc prolongation. In Study 4, where SIRTURO^® was administered with the QTc prolonging drugs clofazimine and levofloxacin, 5% of patients in the 40-week SIRTURO^® treatment group experienced a QTc ≥500 ms and 43% of patients experienced an increase in QTc ≥60 ms over baseline. Of the clofazimine- and levofloxacin-treated patients in the 40-week control arm, 7% of patients experienced a QTc ≥500 ms and 39% experienced an increase in QTc ≥60 ms over baseline.

Obtain an ECG before initiation of treatment, 2 weeks after initiation, during treatment, as clinically indicated and at the expected time of maximum increase in the QTc interval of the concomitantly administered QTc prolonging drugs (as applicable). Obtain electrolytes at baseline and during treatment and correct electrolytes as clinically indicated.

The following may increase the risk for QTc prolongation when patients are receiving SIRTURO^®: use with other QTc prolonging drugs; a history of Torsade de Pointes; a history of congenital long QTc syndrome; a history of or ongoing hypothyroidism; a history of or ongoing bradyarrhythmias; a history of uncompensated heart failure; serum calcium, magnesium, or potassium levels below the lower limits of normal.

Discontinue SIRTURO^® if the patient develops clinically significant ventricular arrhythmia or a QTc interval of greater than 500 ms (confirmed by repeat ECG). If syncope occurs, obtain an ECG to detect QTc prolongation.

Mortality Imbalance in Clinical Trials: An increased risk of death was seen in the SIRTURO^® treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial in adults (Study 1; based on the 120 week visit window). One death occurred during the 24 weeks of administration of SIRTURO^®. The imbalance in deaths is unexplained. No discernible pattern between death and sputum culture conversion, relapse, sensitivity to other drugs used to treat tuberculosis, HIV status, or severity of disease could be observed. In a subsequent active-controlled trial in adults (Study 4), deaths by Week 132 occurred in 11/211 (5.2%) patients in the 40-week SIRTURO^® treatment group, 8/202 (4%) patients in the active-control treatment group including four of 29 patients who received SIRTURO^® as part of a salvage treatment, and 2/143 (1.4%) patients in the 28-week SIRTURO^® treatment group.

Risk of Development of Resistance to Bedaquiline: A potential for development of resistance to bedaquiline in M. tuberculosis exists. Bedaquiline must only be used in an appropriate combination regimen for the treatment of pulmonary TB due to M. tuberculosis resistant to at least rifampin and isoniazid, to reduce the risk of development of resistance to bedaquiline.

Hepatotoxicity: In clinical trials, more hepatic-related adverse reactions were reported in adults with the use of SIRTURO^® plus other drugs used to treat TB compared to other drugs used to treat TB without the addition of SIRTURO^®. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO^®, especially in patients with impaired hepatic function. Hepatic-related adverse reactions have also been reported in pediatric patients 5 years of age and older.

Monitor symptoms (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at baseline, monthly while on treatment, and as needed. Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening liver dysfunction occurs. Discontinue SIRTURO^® if:

• transaminase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal
• transaminase elevations are greater than eight times the upper limit of normal
• transaminase elevations are greater than five times the upper limit of normal and persist beyond two weeks

Drug Interactions

CYP3A4 Inducers: Coadministration of SIRTURO^® with a moderate or strong CYP3A4 inducer decreases the systemic exposure of bedaquiline and may reduce the therapeutic effect of SIRTURO^®. Avoid coadministration of SIRTURO^® with moderate or strong CYP3A4 inducers, such as efavirenz and rifamycins (i.e., rifampin, rifapentine and rifabutin).

CYP3A4 Inhibitors: Coadministration of SIRTURO^® with CYP3A4 inhibitors increases the systemic exposure of bedaquiline, which may increase the risk of adverse reactions. Closely monitor patient safety (e.g., liver function) when SIRTURO^® is coadministered with CYP3A4 inhibitors.

Adverse Reactions

Clinical Studies Experience: Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Refer to the prescribing information of the drugs used in combination with SIRTURO^® for their respective adverse reactions.

Clinical Studies Experience in Adults: Adverse reactions for SIRTURO^® were identified from safety data from 335 patients who received SIRTURO^® for eight weeks (Study 2) and 24 weeks (Studies 1 and 3), and 354 patients who received SIRTURO^® for 40 weeks or 28 weeks (Study 4). In these studies, patients received SIRTURO^® in combination with other antimycobacterial drugs.

The most common adverse reactions reported in 10% or more patients treated with SIRTURO^® and occurred more frequently than the placebo arm were nausea, arthralgia, headache, hemoptysis and chest pain.

In the 28-week SIRTURO^®-containing arm (N=143), in which SIRTURO^® was used in combination with other antimycobacterial drugs, the most common selected adverse reactions (greater than 10%) were QTc prolongation (56%), arthralgia (55%), nausea (43%), vomiting (29%), pruritus (25%), transaminases increased (21%), dizziness (21%), chest pain (17%), abdominal pain (17%), headache (16%), rash (12%), and hemoptysis (11%).

Clinical Studies Experience in Pediatric Patients: The safety assessment of bedaquiline is based on the Week 24 analysis from 30 pediatric patients in an ongoing, single-arm, open-label, multi-cohort trial.

Pediatric Patients (12 years to less than 18 years of age): The first cohort was designed to enroll patients 12 years to less than 18 years of age (fifteen patients 14 years to less than 18 years of age were enrolled) with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampin who received SIRTURO^® (400 mg once daily for the first 2 weeks and 200 mg 3 times/week for the following 22 weeks) in combination with a background regimen.

The most common adverse reactions were arthralgia in 6/15 (40%) patients, nausea in 2/15 (13%) patients, and abdominal pain in 2/15 (13%) patients. Among the 15 patients, no deaths occurred during treatment with SIRTURO^®. Observed laboratory abnormalities were comparable to those in adults.

Pediatric Patients (5 years to less than 12 years of age): The second cohort was designed to enroll patients 5 years to less than 12 years of age (fifteen patients aged 5 years to less than 11 years of age were enrolled) with confirmed or probable pulmonary TB due to M. tuberculosis resistant to at least rifampin who received SIRTURO^® (200 mg once daily for the first 2 weeks and 100 mg 3 times/week for the following 22 weeks) in combination with a background regimen.

The most common adverse reactions were related to elevations in liver enzymes (5/15, 33%), and led to discontinuation of SIRTURO^® in three patients. Elevations in liver enzymes were reversible upon discontinuation of SIRTURO^® and some of the background regimen drugs. Among these 15 pediatric patients, no deaths occurred during treatment with SIRTURO^®.

Use in Specific Populations

Pregnancy
Risk Summary: Available data from published literature of SIRTURO^® use in pregnant women are insufficient to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with active TB during pregnancy.

Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to oral administration of bedaquiline to pregnant rats and rabbits during organogenesis at exposures up to 6 times the clinical dose based on AUC comparisons.

The estimated background risk of major birth defects and miscarriage for the indicated populations 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.

Clinical Considerations: Disease-associated Maternal and/or Embryo/Fetal Risk: Active TB in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death.

Data: Animal Data: Pregnant rats were treated with bedaquiline at 5, 15 and 45 mg/kg (approximately 0.7, 2 and 6 times the clinical dose based on AUC comparisons) during the period of organogenesis (gestational Days 6 to 17, inclusive). Pregnant rabbits were treated with bedaquiline at 10, 30 and 100 mg/kg (approximately 0.05, 0.2 and 1.5 times the clinical dose based on AUC comparisons) during the period of organogenesis (gestational Days 6 to 19, inclusive). No embryotoxic effects were found in rats or rabbits at dose exposures up to 6 times the clinical dose exposures based on AUC comparisons.

Lactation
Risk Summary: Data from a published clinical lactation study demonstrate higher bedaquiline concentrations in breast milk compared to maternal plasma, suggesting that bedaquiline accumulates in breast milk (see Data). Data are insufficient to determine effects of the drug on the breastfed infants. No data are available on the effects of the drug on milk production. Because of the potential for serious adverse reactions in a breastfed infant, including hepatotoxicity, advise patients that breastfeeding is not recommended during treatment with SIRTURO^® and for 27.5 months (5 times the half-life) after the last dose unless infant formula is not available.

Clinical Considerations: If an infant is exposed to bedaquiline through breast milk, monitor for signs of bedaquiline-related adverse reactions, such as hepatotoxicity.

Data: A clinical lactation study was conducted in two lactating women who were approximately 7 weeks’ postpartum. Bedaquiline and M2, its active metabolite, levels were measured between approximately 27 and 48 hours after the last bedaquiline dose, and concentrations of bedaquiline and M2 ranged from 2.61 to 8.11 mg/L and 0.27 to 0.81 mg/L, respectively. The milk:plasma ratios for bedaquiline and M2 at 27 to 48 hours after the last dose of bedaquiline ranged from approximately 19 to 29 and 4 to 6, respectively.

Pediatric Use: The safety and effectiveness of SIRTURO^® have been established in pediatric patients 5 years and older weighing at least 15 kg. The use of SIRTURO^® in this pediatric population is supported by evidence from the study of SIRTURO^® in adults together with additional pharmacokinetic and safety data from the single-arm, open-label, multi-cohort trial that enrolled 30 pediatric patients 5 years to less than 18 years of age with confirmed or probable pulmonary TB caused by M. tuberculosis resistant to at least rifampin who were treated with SIRTURO^® for 24 weeks in combination with a background regimen.

The safety, effectiveness and dosage of SIRTURO^® in pediatric patients less than 5 years of age and/or weighing less than 15 kg have not been established.

Geriatric Use: Clinical studies of SIRTURO^® did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Hepatic Impairment: The pharmacokinetics of bedaquiline were assessed after single-dose administration to adult patients with moderate hepatic impairment (Child-Pugh B). Based on these results, no dose adjustment is necessary for SIRTURO^® in patients with mild or moderate hepatic impairment. SIRTURO^® has not been studied in patients with severe hepatic impairment and should be used with caution in these patients only when the benefits outweigh the risks. Clinical monitoring for SIRTURO^®-related adverse reactions is recommended.

Renal Impairment: SIRTURO^® has mainly been studied in adult patients with normal renal function. Renal excretion of unchanged bedaquiline is not substantial (less than or equal to 0.001%). No dose adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis, SIRTURO^® should be used with caution. Monitor adult and pediatric patients for adverse reactions of SIRTURO^® when administered to patients with severe renal impairment or end stage renal disease requiring hemodialysis or peritoneal dialysis.

Please read the full Prescribing Information for more details.

About Johnson & Johnson
At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at https://www.jnj.com/.

Cautions Concerning Forward-Looking Statements
This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding bedaquiline. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen-Cilag International NV, Janssen Pharmaceutica NV and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in Johnson & Johnson’s subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of Janssen-Cilag International NV, Janssen Pharmaceutica NV nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

© Janssen-Cilag International NV. All rights reserved.

Footnotes
ⁱ Goodall, Ruth L, et al. “Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.” The Lancet, Volume 400, Issue 10366, 1858 – 1868. Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02078-5/fulltext

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Source: Johnson & Johnson