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FDA Grants Accelerated Approval for SIRTURO™ (bedaquiline) as Part of Combination Therapy to Treat Adults with Pulmonary Multi



    FDA Grants Accelerated Approval for SIRTURO™ (bedaquiline) as Part of
   Combination Therapy to Treat Adults with Pulmonary Multi-Drug Resistant
                                 Tuberculosis

PR Newswire

TITUSVILLE, N.J., Dec. 31, 2012

TITUSVILLE, N.J., Dec. 31, 2012 /PRNewswire/ -- Janssen Therapeutics, Division
of Janssen Products, LP, today announced the U.S. Food and Drug Administration
(FDA) has granted accelerated approval to SIRTURO™ (bedaquiline) Tablets for
the treatment of pulmonary multi-drug resistant tuberculosis (MDR-TB) as part
of combination therapy in adults. The accelerated approval is based on the
surrogate endpoint of time to sputum culture conversion.

"SIRTURO™ was first discovered in our laboratories more than a decade ago and
it is gratifying to see our discovery and development lead to the accelerated
approval of the first TB therapy in 40 years with a new mechanism of action.
This underscores our commitment as a company to discover, develop and
responsibly deliver innovative medicines that address serious unmet medical
needs," said Paul Stoffels, M.D., Chief Scientific Officer and Worldwide
Chairman, Pharmaceuticals, Johnson & Johnson.

SIRTURO™ inhibits mycobacterial ATP (adenosine 5'‑triphosphate) synthase, an
enzyme that is essential for the generation of energy in Mycobacterium
tuberculosis.

SIRTURO™ is a diarylquinoline antimycobacterial drug indicated as part of
combination therapy in adults (greater than or equal to 18 years) with
pulmonary MDR-TB. Reserve SIRTURO™ for use when an effective treatment regimen
cannot otherwise be provided. SIRTURO™ should be administered by directly
observed therapy (DOT). This indication is based on analysis of time to sputum
culture conversion from two controlled Phase 2 trials in patients with
pulmonary MDR-TB. The safety and efficacy of SIRTURO™ for the treatment of
latent infection due to Mycobacterium tuberculosis has not been established.
The safety and efficacy of SIRTURO™ for the treatment of drug-sensitive TB has
not been established. In addition, there are no data on the treatment with
SIRTURO™ of extra-pulmonary TB (e.g., central nervous system). Therefore, use
of SIRTURO™ in these settings is not recommended.

The prescribing information for SIRTURO™ includes Boxed Warnings regarding
increased risk of death and occurrence of QT prolongation. The Warnings and
Precautions section provides additional information regarding these risks and
includes risk of hepatic-related adverse drug reactions, drug
interactions, use in HIV-TB co-infected patients and treatment failure. The
most common adverse drug reactions were nausea, arthralgia and headache.
Additional adverse events were hemoptysis and chest pain. Please see Important
Safety Information below for more details.

MDR-TB is considered an orphan disease in the U.S., with 98 reported patients
in 2011. MDR-TB is characterized by resistance to two of the most powerful
medicines in today's four-drug standard TB treatment regimen. MDR-TB treatment
is complex and requires up to two years of treatment with companion drugs in
accordance with national TB treatment guidelines and local MDR-TB treatment
practice, along with extensive medical supervision. The World Health
Organization (WHO) estimates more than two million people will develop MDR-TB
between 2011 and 2015. ^

"The accelerated approval of SIRTURO™ is a significant step in the fight
against MDR-TB, which is a more difficult to treat form of TB that affects
approximately 630,000 people in the world and is on the rise in many areas
worldwide," said Dr. Stoffels.

"This is the first time a new drug is being introduced specifically for
MDR-TB, for which the current needs are so great," said Lee Reichman, M.D.,
Executive Director, New Jersey Medical School Global Tuberculosis Institute.
"It is an important step in the development of new compounds for this serious
and contagious disease."

The FDA accelerated approval of SIRTURO™ was based on data from TMC207-C208
Study 1 and Study 2. The primary endpoint was time to sputum culture
conversion, defined as the interval in days between the first dose of study
drug and the date of the first of two consecutive negative sputum cultures
collected at least 25 days apart during treatment.

TMC207-C208 Study 1 is a placebo-controlled, double-blind, randomized trial
conducted in newly diagnosed patients with multi-drug resistant pulmonary
Mycobacterium tuberculosis. Patients were randomized to receive treatment with
either SIRTURO™ and other drugs used to treat MDR-TB (SIRTURO™ treatment
group) (n=79) or placebo plus other drugs to treat MDR-TB (placebo treatment
group) (n=81): the other drugs used to treat MDR-TB consisted of a combination
of five other antimycobacterial drugs (ethionamide, kanamycin, pyrazinamide,
ofloxacin, and cycloserine/terizidone or available alternative). SIRTURO™ was
administered as 400 mg once daily for the first two weeks and as
200 mg three times per week for the following 22 weeks. After the 24 week
study drug (SIRTURO™ or placebo) treatment phase patients continued to receive
their other drugs used to treat MDR-TB until a total treatment duration of
18 to 24 months was achieved, or at least 12 months after the first confirmed
negative culture.

The SIRTURO™ ^ treatment group had decreased time to culture conversion and
improved culture conversion rates compared to the placebo treatment group at
week 24. Median time to culture conversion was 83 days for the SIRTURO™
treatment group, compared to 125 days for the placebo treatment group.

At week 24, culture conversation status results were:

  o 77.6 percent of patients in the SIRTURO™ treatment group reached treatment
    success vs. 57.6 percent of patients in the placebo treatment group
    (p=0.014).
  o 22.4 percent of patients in the SIRTURO™ treatment group experienced
    treatment failure vs. 42.4 percent of patients in the placebo treatment
    group.
  o 7.5 percent of patients in the SIRTURO™ treatment group vs. 24.2 percent
    in the placebo treatment group experienced lack of conversion.
  o Discontinuation rates were 14.9 percent for SIRTURO™ treatment group vs.
    18.2 percent for the placebo treatment group.

At week 72, culture conversation status results were:

  o 70.1 percent of patients in the SIRTURO™ treatment group reached treatment
    success vs. 56.1 percent of patients in the placebo treatment group
    (p=0.092).
  o 29.9 percent of patients in the SIRTURO™ treatment group experienced
    treatment failure vs. 43.9 percent of patients in the placebo treatment
    group.
  o 4.5 percent of patients in the SIRTURO™ treatment group vs. 10.6 percent
    in the placebo treatment group experienced lack of conversion.
  o Discontinuation rates were 25.4 percent for SIRTURO™ treatment group vs.
    33.3 percent for placebo treatment group.

TMC207-C208 Study 2 is a smaller, placebo-controlled study designed similarly
to Study 1 except that SIRTURO™ or placebo was given for only 8 weeks instead
of 24 weeks. Patients were randomized to either SIRTURO™ and other drugs used
to treat MDR-TB (SIRTURO™ treatment group) (n=23) or placebo and other drugs
used to treat MDR-TB (placebo treatment group) (n=24). Twenty-one patients
randomized to the SIRTURO™ treatment group and 23 patients randomized to the
placebo treatment group had confirmed MDR-TB based on subjects' baseline M.
tuberculosis isolate obtained prior to randomization. The SIRTURO™ treatment
group had a decreased time to culture conversion and improved culture
conversion rates compared to the placebo treatment group at week 8. At weeks 8
and 24, the differences in culture conversion proportions were 38.9 percent
and 15.7 percent, respectively.

Important Safety Information

WARNINGS:

  o 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. Only use SIRTURO™ when an effective treatment
    regimen cannot otherwise be provided. 
  o QT prolongation can occur with SIRTURO™. Use with drugs that prolong the
    QT interval may cause additive QT prolongation.

Warnings and Precautions

Increased Mortality: An increased risk of death was seen in the SIRTURO™
treatment group.

QT Prolongation: SIRTURO™ prolongs the QT interval. An electrocardiogram (ECG)
should be obtained before initiation of treatment, and at least 2, 12 and 24
weeks after starting treatment with SIRTURO™. Serum potassium, calcium, and
magnesium should be obtained at baseline and corrected if abnormal.
Discontinue SIRTURO™ and all other QT prolonging drugs if the patient develops
clinically significant ventricular arrhythmia or a QTcF interval of > 500 ms
(confirmed by repeat ECG).

The following may increase the risk for QT prolongation when patients are
receiving SIRTURO™ and therefore ECGs should be monitored closely: 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 cogenital long QT syndrome; a history of
hypothyroidism and bradyarrhythmias; a history of uncompensated heart failure,
serum calcium, magnesium, or potassium levels below the lower limits of
normal.

SIRTURO™ has not been studied in patients with ventricular arrhythmias or
recent myocardial infarction.

Hepatic-related Adverse Drug Reactions: More hepatic-related adverse drug
reactions were reported with the use of SIRTURO™ plus other drugs 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 diminished hepatic reserve. Monitor liver-related
laboratory tests. Discontinue SIRTURO™ if aminotransferase elevations are
accompanied by total bilirubin elevation >2xULN; aminotransferase elevations
are >8xULN; aminotransferase elevations persist beyond 2 weeks.

Drug Interactions: Co-administration of rifamycins (e.g., rifampin,
rifapentine and rifabutin) or other strong systemic CYP3A4 inducers should be
avoided. Co-administration with strong systemic CYP3A4 inhibitors for more
than 14 consecutive days should be avoided. Appropriate clinical monitoring
for SIRTURO™-related adverse reactions is recommended.

HIV-TB Co-Infected Patients: There are no clinical data on the combined use in
HIV/MDR-TB co-infected patients and only limited clinical data on the use in
HIV/MDR-TB co-infected patients who were not receiving antiretroviral therapy.

Treatment Failure: SIRTURO^™ should be administered by directly observed
therapy. SIRTURO^™ should only be administered in combination with at least 3
drugs active against the patient's TB isolate. Non-adherence to the treatment
regimen could result in failure or resistance.

Adverse Reactions

The most common adverse drug reactions reported in greater than or equal to
10% of patients treated with SIRTURO™ compared to the placebo treatment
group are nausea (38% vs. 32.1%), arthralgia (32.9% vs. 22.2%), headache
(27.8% vs. 12.3%) and additional adverse events reported in greater than or
equal to 10% of patients are hemoptysis (17.7% vs. 11.1%) and chest pain
(11.4% vs. 7.4%).

Please see full Prescribing Information and Medication Guide for more details.

About SIRTURO™ (bedaquiline)

SIRTURO™ was discovered by researchers at Janssen and is currently under
review by three regulatory bodies including the European Medicines Agency
(EU), State Food and Drug Administration (China) and Medicines Control Council
(South Africa).

About Janssen Therapeutics

At Janssen, we are dedicated to addressing and solving some of the most
important unmet medical needs of our time in HIV and other infectious
diseases. Driven by our commitment to patients, we develop innovative
products, services and healthcare solutions to help people throughout the
world. Headquartered in Titusville, New Jersey, Janssen Therapeutics, Division
of Janssen Products, LP, is one of the Janssen Pharmaceutical Companies of
Johnson & Johnson. Visit www.JanssenTherapeutics.com for more information and
follow us on Twitter at @JanssenUS.

Dr. Reichman is a paid consultant of Janssen.

(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. These statements are based on
current expectations of future events. If underlying assumptions prove
inaccurate or unknown risks or uncertainties materialize, actual results could
vary materially from the expectations and projections of Janssen Products, LP
and/or Johnson & Johnson. Risks and uncertainties include, but are not limited
to, general industry conditions and competition; economic factors, such as
interest rate and currency exchange rate fluctuations; technological advances,
new products and patents attained by competitors; challenges inherent in new
product development, including obtaining regulatory approvals; challenges to
patents; changes in behavior and spending patterns or financial distress of
purchasers of health care products and services; changes to governmental laws
and regulations and domestic and foreign health care reforms; trends toward
health care cost containment; increased scrutiny of the health care industry
by government agencies; manufacturing difficulties or delays; and product
efficacy or safety concerns. A further list and description of these risks,
uncertainties and other factors can be found in Exhibit 99 of Johnson &
Johnson's Annual Report on Form 10-K for the fiscal year ended January 1,
2012. Copies of this Form 10-K, as well as subsequent filings, are available
online at www.sec.gov, www.jnj.com or on request from Johnson &
Johnson. Neither Janssen Products, LP nor Johnson & Johnson undertake to
update any forward-looking statements as a result of new information or future
events or developments).

Media Contacts:
Pamela Van Houten
Phone: (908) 295-7367
pvanhou5@its.jnj.com

Daniel De Schryver
Phone: +49 (173) 76 89 149
dschryv@its.jnj.com

Investor contacts:
Stan Panasewicz
Phone: (732) 524-2524

Louise Mehrotra
Phone: (732) 524-6491

SOURCE Janssen Therapeutics

Website: http://www.JanssenTherapeutics.com
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