Janssen Submits Phase 3 Study Data to the European Medicines Agency and U.S. Food and Drug Administration for SIRTURO® (bedaquiline)
STREAM Stage 2 study data submitted as part of Type II Variation to European Medicines Agency and supplemental New Drug Application to U.S. FDAData aim to support the full and traditional approval in the European Union and U.S., respectively
New Brunswick, N.J., (November 7, 2023) – The Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen), announced today the submission of a Type II Variation application to the European Medicines Agency (EMA) for the Company’s medicine SIRTURO® (bedaquiline). A supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) was also submitted in August 2023. SIRTURO® is indicated in adults and pediatric patients (5 years to less than 18 years of age and weighing at least 15 kg) as part of combination therapy of pulmonary tuberculosis (TB) due to multi-drug resistant Mycobacterium tuberculosis. The approved indication may vary per country.i,ii These submissions reflect the Company’s longstanding commitment to patients affected by multidrug-resistant TB (MDR-TB), one of the world’s most significant global health challenges.
The applications include data from the Phase 3 STREAM Stage 2 study (NCT02409290), which is a Post-Marketing Requirement in the U.S., a Specific Obligation in the EU and a Post-Marketing Commitment in several other countries. STREAM Stage 2 is the first large-scale, randomized, multi-country clinical study to evaluate the efficacy and safety of an all-oral bedaquiline-containing regimen for MDR-TB. The study compared an all-oral, nine-month bedaquiline-containing regimen to the control regimen of a nine-month injectable-based regimen for the treatment of MDR-TB. The results were published in The Lancet in November 2022.iii
SIRTURO®, a product of Janssen Pharmaceutica NV, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, was first granted accelerated approval by the FDA in December 2012 and conditional approval by the EMA in March 2014 following positive Phase 2 study data.iv,v If approved, these new applications will support the traditional approval in the U.S. and full approval in the European Union.
Johnson & Johnson’s Commitment in the Fight Against TB
The traditional/full approval of SIRTURO® would mark the latest milestone in Johnson & Johnson’s efforts to make the medicine available to people with MDR-TB around the world.
When Johnson & Johnson introduced SIRTURO®, it was the first targeted 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 a bedaquiline-containing regimen. To date, more than 700,000 courses of the medicine have been delivered to 159 countries around the world, including the 30 countries with the highest burdens of TB.
Earlier this year, 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® (bedaquiline) for the majority of low-and middle-income countries. In September 2023, the Company confirmed its intent not to enforce patents it owns and controls for SIRTURO® in 134 low- and middle-income countries, building on two decades of collaborative work in the fight against TB.
In collaboration with many others, the Company has spent the past decade, since introducing its medicine, investing in critical TB systems capacity, such as healthcare professional training, resistance testing and surveillance, and supply chain security, to help ensure the medicine is accessible, while not compromising its effectiveness as drug resistance increases globally.
To learn more about Johnson & Johnson’s efforts in the fight against TB, visit www.jnj.com/TB.
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.
▼In line with EMA regulations for new medicines and those given conditional approval, bedaquiline is subject to additional monitoring.
SIRTURO® (bedaquiline) is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adult and pediatric patients (5 years and older and weighing at least 15 kg) with pulmonary MDR-TB. Reserve SIRTURO® for use when an effective treatment regimen cannot otherwise be provided.
This indication is approved under accelerated approval based on time to sputum culture conversion. Continued approval for this indication has been submitted for approval.
Limitations of Use
Do not use SIRTURO for the treatment of latent, extrapulmonary or drug-sensitive tuberculosis or for the treatment of infections caused by non-tuberculous mycobacteria. Safety and efficacy of SIRTURO in HIV-infected patients with MDR-TB have not been established, as clinical data are limited.
IMPORTANT SAFETY INFORMATION
BOXED WARNINGS: INCREASED MORTALITY AND QT PROLONGATION
- 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. Only use SIRTURO® in patients 5 years of age and older when an effective treatment regimen cannot otherwise be provided.
- QT prolongation can occur with SIRTURO®. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue SIRTURO® if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops.
Warnings and Precautions
Increased Mortality: 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 (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. Only use SIRTURO® in patients 5 years of age and older when an effective treatment regimen cannot otherwise be provided.
QT Prolongation: SIRTURO® prolongs the QT interval. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with SIRTURO®. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor electrolytes if QT prolongation is detected. SIRTURO® has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.
The following may increase the risk for QT prolongation when patients are receiving SIRTURO®: use with other QT prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine; a history of Torsade de Pointes; a history of congenital long QT 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.
If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit risk assessment and with frequent ECG monitoring.
Discontinue SIRTURO® and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG).
If syncope occurs, obtain an ECG to detect QT prolongation.
Risk of Development of Resistance to Bedaquiline: A potential for development of resistance to bedaquiline in Mycobacterium tuberculosis exists. Bedaquiline must only be used in an appropriate combination regimen for the treatment of pulmonary MDR-TB 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 to treat tuberculosis compared to other drugs used to treat tuberculosis 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:
- aminotransferase elevations are accompanied by total bilirubin elevation greater than two times the upper limit of normal
- aminotransferase elevations are greater than eight times the upper limit of normal
- aminotransferase elevations are greater than five times the upper limit of normal and persist beyond two weeks
CYP3A4 Inducers/Inhibitors: Bedaquiline is metabolized by CYP3A4 and its systemic exposure and therapeutic effect may therefore be reduced during co-administration with inducers of CYP3A4. Avoid co-administration of strong CYP3A4 inducers such as rifamycins (ie, rifampin, rifapentine, and rifabutin) or moderate CYP3A4 inducers such as efavirenz, during treatment with SIRTURO®. Co-administration of SIRTURO® with strong CYP3A4 inhibitors may increase the systemic exposure to bedaquiline, which could potentially increase the risk of adverse reactions. Therefore, avoid the use of strong CYP3A4 inhibitors used for more than 14 consecutive days while on SIRTURO®, unless the benefit of treatment with the drug combination outweighs the risk. Appropriate clinical monitoring for SIRTURO®-related adverse reactions is recommended.
Use in Specific Populations
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 tuberculosis 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.
Clinical Considerations: Disease-associated Maternal and/or Embryo/Fetal Risk Active tuberculosis 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.
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 [see Adverse Reactions (6)].
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, 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.
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.
Adult: Adverse reactions that occurred more frequently than placebo during treatment with SIRTURO® included: nausea (38% vs 32%), arthralgia (33% vs 22%), headache (28% vs 12%), hemoptysis (18% vs 11%), chest pain (11% vs 7%), anorexia (9% vs 4%), transaminases increased (9% vs 1%), rash (8% vs 4%), and blood amylase increased (3% vs 1%).
Pediatric: 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, (Study 4).
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 MDR-TB infection 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 MDR-TB infection 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®.
Please read full Prescribing Information, including Boxed Warnings and Medication Guide for more details.
About the Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we are creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension.
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Cautions Concerning Forward-Looking Statements
This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995. The reader is cautioned not to rely on these forward-looking statements as they 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 current expectations and projections of Janssen Pharmaceutica NV, EU Janssen-Cilag International 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 January 1, 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 Pharmaceutica NV, EU Janssen-Cilag International NV nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.
iEuropean Medicines Agency. SIRTURO Summary of Product Characteristics. May 2023. Available at: SIRTURO, INN- bedaquiline (europa.eu). Accessed: November 2023.
iiiGoodall, Ruth LAdilaa, Oyunchimeg 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.