Janssen Announces U.S. FDA Accelerated Approval for SIRTURO^® (bedaquiline) as Part of Combination Therapy to Treat Adolescents with Pulmonary Multidrug-Resistant Tuberculosis

Label expansion marks important milestone in Johnson & Johnson’s pediatric research and development program for bedaquiline

TITUSVILLE, NJ, August 9, 2019 — The Janssen Pharmaceutical Companies of Johnson & Johnson today announced that the U.S. Food and Drug Administration (FDA) has granted approval for SIRTURO^® (bedaquiline) tablets as part of combination therapy in pediatric patients – those over the age of 12 and younger than 18 and weighing at least 66 pounds (30 kilograms) – with pulmonary multidrug-resistant tuberculosis (MDR-TB), when an effective treatment regimen cannot otherwise be provided. Approved under the FDA’s accelerated approval pathway based on time to sputum culture conversion, bedaquiline can now be used as part of combination therapy for eligible MDR-TB patients aged 12 years and over in the U.S. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

The FDA approval marks the first regulatory milestone as part of the company’s global pediatric research and development (R&D) program for bedaquiline, with additional global regulatory filings planned. Further research is ongoing in children younger than 12 years of age using a pediatric formulation of bedaquiline.

TB is the world’s deadliest infectious disease, claiming 1.6 million lives every year – more than HIV and malaria combined.ⁱ While TB often affects adults in their most productive years, all age groups are at risk. In 2017, an estimated 1 million children became ill with TB and 230,000 children died of the disease^[i], underscoring the urgent need for effective pediatric TB treatments. Approximately 95% of childhood deaths from TB occur in Asia and sub-Saharan Africa.^[ii]

“We are proud of what today’s approval means for adolescent patients in the U.S., and we are hopeful about the future of our pediatric R&D program,” said Paul Stoffels, M.D., Vice Chair of the Executive Committee and Chief Scientific Officer, Johnson & Johnson. “Despite being a major global health issue, TB lacks the attention and resources it requires – and the issue of TB in children is even more neglected. At Johnson & Johnson, we are committed to developing solutions that address the needs of all TB patients, including the youngest and most vulnerable.”

Today’s U.S. FDA approval is supported by evidence from a single-arm, open-label, Phase 2 study that enrolled 15 pediatric patients with confirmed or probable MDR-TB infection. The patients were treated with the recommended dosage of bedaquiline for 24 weeks in combination with a background regimen. Bedaquiline was administered on the same schedule as it is for adults: 400 mg once daily for the first two weeks and 200 mg three times per week for the following 22 weeks. In the subset of patients with culture positive pulmonary MDR-TB at baseline, treatment with bedaquiline resulted in conversion to a negative culture in 6/8 (75%) patients at Week 24.

The most common adverse drug 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 bedaquiline. Observed laboratory abnormalities were comparable to those in adults.

“In the past, MDR-TB was a diagnosis that left patients with few options. But fortunately, new treatments and other tools have brought a renewed sense of hope for patients,” said Jaak Peeters, Global Head, Johnson & Johnson Global Public Health, Janssen-Cilag GmBH. “At Johnson & Johnson, we won’t rest until we have optimized and helped to deliver effective MDR-TB treatment to patients of every age, wherever they may be.”

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About the Bedaquiline Global Pediatric Development Program
As part of the company’s commitment to the continued clinical development of bedaquiline, Janssen is conducting a Phase 2 sequential pediatric pharmacokinetic and safety study, C211, with four cohorts of patients in different age groups. The U.S. FDA approval of the use of bedaquiline in adolescents (≥12 to <18 years and > 30 kg) is supported by the results from Cohort 1 of the study. Cohort 2 of the study (≥5 to <12 years) is fully enrolled, and recruitment is about to start for Cohort 3 (≥2 to <5 years old). Based on interim data from Cohort 3, the company plans to select a dose and begin enrollment of Cohort 4 (<2 years).

For adolescents (12 to less than 18 years of age and weighing at least 30 kg), the formulation (100 mg tablet) and the dosing recommendation are the same as those approved for adults. For Cohorts 2-4, the company has developed and is evaluating an age-appropriate formulation for children.

Janssen has also filed for approval of the use of bedaquiline in adolescents with the European Medicines Agency (EMA), with a decision anticipated later this year. The Company also plans to submit forthcoming data for Cohort 2 (patients ≥5 to <12 years of age) to the U.S. FDA and EMA in the coming months. As data becomes available, further pediatric regulatory filings for bedaquiline will be pursued, including in high-burden countries.

Learn more about TMC207-C211 at ClinicalTrials.gov (identifier: NCT02354014).

About Johnson & Johnson’s Commitment to TB
Johnson & Johnson has been a committed partner in the fight against TB for more than two decades. When bedaquiline received its initial accelerated approval by the U.S. FDA in 2012 to treat MDR-TB in adults, as part of combination therapy, it was the first targeted TB medicine with a novel mechanism of action in more than 40 years. Today, it is approved for use in 61 countries, with regulatory pathways identified for all United Nations (UN) Member States. In total, over 125,000 courses of bedaquiline have been delivered to 127 countries, including the 30 countries with the highest burdens of MDR-TB.

Building on this commitment, in September 2018, Johnson & Johnson announced a comprehensive 10-year initiative in support of the United Nations Sustainable Development Goal target of ending the TB pandemic by 2030. With the goal of saving an estimated 1.8 million lives and preventing 12 million new TB infections in the next decade, Johnson & Johnson will work with partners to improve detection of undiagnosed TB cases, broaden access to bedaquiline for MDR-TB, and accelerate research & development (R&D) to discover next-generation TB treatments.

Learn more about our work on TB at www.jnj.com/TB.

About TB & MDR-TB
Tuberculosis (TB) is the world’s deadliest infectious disease. Nearly one-quarter of the world’s population — 1.7 billion people — are infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis. In most of them, the infection is in a dormant state. But every year, 10 million people develop active tuberculosis and approximately 1.6 million people die of it.^[iii]

Multidrug-resistant TB (MDR-TB) is a particularly complicated form of the bacterial infection and is characterized by resistance to at least two of the most powerful drugs in the first-line treatment regimen (isoniazid and rifampicin). Globally, MDR-TB is a growing threat. In 2017, there were more than 450,000 new cases of MDR-TB, and drug-resistant TB now accounts for approximately one-third of all deaths from antimicrobial resistance (AMR).[iv]

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INDICATION

SIRTURO^® (bedaquiline) is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adult and pediatric patients (12 to less than 18 years of age and weighing at least 30 kg) with pulmonary multi-drug resistant tuberculosis (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 may be contingent upon verification and description of clinical benefit in confirmatory trials.

Limitations of Use
Do not use SIRTURO^® for the treatment of:

• Latent infection due to Mycobacterium tuberculosis
• Drug-sensitive tuberculosis
• Extra-pulmonary tuberculosis
• Infections caused by non-tuberculous mycobacteria

The safety and efficacy of SIRTURO^® in the treatment of HIV-infected patients with MDR-TB have not been established as clinical data are limited.

IMPORTANT SAFETY INFORMATION

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 12 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.

Hepatotoxicity: In clinical trials, more hepatic-related adverse drug reactions were reported 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 14 to less than 18 years of age.

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

Drug Interactions
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. 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

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 tuberculosis during pregnancy.

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.

Lactation

Risk Summary:
There is no information regarding the presence of bedaquiline in human milk. Minimal data are available on the effects of the drug on the breastfed infant. No data are available on the effects of the drug on milk production. Bedaquiline is concentrated in the milk of rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need foR SIRTURO^® and any potential adverse effects on the breastfed infant from SIRTURO^® or from the underlying maternal condition.

Pediatric Use
The safety and efficacy of SIRTURO^® in pediatric patients less than 12 years of age and/or weighing less than 30 kg have not been established.

Renal Impairment
SIRTURO^® has mainly been studied in adult patients with normal renal function. 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.

Adverse Reactions

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 of the single-arm, open-label trial, TMC207-C211, in 15 pediatric patients. The trial was designed to enroll patients 12 to less than 18 years of age (but only 14 to <18 year old patients were enrolled) with confirmed or probable pulmonary MDR-TB infection who received SIRTURO® in combination with a background regimen.

The most common adverse drug 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.

Please read full Prescribing Information including Boxed Warnings and Medication Guide for more details.

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About Johnson & Johnson
At Johnson & Johnson, we believe good health is the foundation of vibrant lives, thriving communities and forward progress. That’s why for more than 130 years, we have aimed to keep people well at every age and every stage of life. Today, as the world’s largest and most broadly-based healthcare company, we are committed to using our reach and size for good. We strive to improve access and affordability, create healthier communities, and put a healthy mind, body and environment within reach of everyone, everywhere. We are blending our heart, science and ingenuity to profoundly change the trajectory of health for humanity. Learn more at www.jnj.com. Follow us at @jnjglobalhealth.

About the Janssen Pharmaceutical Companies
At Janssen, we’re 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, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.

Learn more at www.janssen.com. Follow us at www.twitter.com/JanssenGlobal. Janssen Therapeutics, Division of Janssen Products, LP, and Janssen-Cilag GmBH are part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

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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 regarding the launch of an international research consortium to combat tuberculosis. 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 Therapeutics, Division of Janssen Products, LP, any of the other Janssen Pharmaceutical Companies, 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 commercial success and of obtaining regulatory approvals; 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; manufacturing difficulties and delays; 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 30, 2018, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” in the company’s most recently filed Quarterly Report on Form 10-Q and in the company’s subsequent 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. Neither the Janssen Pharmaceutical Companies nor Johnson & Johnson not undertakes to update any forward-looking statement as a result of new information or future events or developments.

[i] World Health Organization. Tuberculosis. Last accessed July 2019. Available at: https://www.who.int/news-room/fact-sheets/detail/tuberculosis
[ii] UNICEF. Change the Game: An agenda for action on childhood tuberculosis. 2018.
[iii] World Health Organization. Global Tuberculosis Report 2018. Last accessed July 2019. Available at: https://www.who.int/tb/publications/global_report/en/
[iv] Interagency Coordination Group on Antimicrobial Resistance. No Time to Wait: Securing the Future From Drug-Resistant Infections Report to the Secretary-General of the United Nations. Last accessed July 2019. Avaiable at: https://www.who.int/antimicrobial-resistance/interagency-coordination-group/IACG_final_report_EN.pdf?ua=1