FDA Approves Etravirine (Intelence; TMC125), Tibotec's Next-generation NNRTI
By Liz Highleyman On Friday, January 18, the U.S. Food and Drug Administration
(FDA) granted accelerated approval of etravirine (brand name Intelence;
formerly TMC125), a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI)
developed by Tibotec (a unit of Ortho Biotech/Johnson
& Johnson). Etravirine was approved for use as part of combination
antiretroviral therapy for HIV positive adults who have experienced treatment
failure on other HAART regimens. The drug is being studied in treatment-naive
individuals, but it is not currently approved for this indication. It has not yet been studied
in children or pregnant women with HIV. NNRTIs interfere with the action of reverse transcriptase, a viral enzyme required
for HIV replication. As a next-generation NNRTI, etravirine
has demonstrated activity against HIV-1 that has developed resistance to the older
drugs in this class, efavirenz (Sustiva; also in the Atripla combination pill), nevirapine
(Viramune), and the little-used delavirdine
(Rescriptor). Approval was based on data from the Phase III DUET-1
and DUET-2 trials, which showed that etravirine led
to better virological and immunological responses compared with placebo when combined with an optimized background regimen
that included the protease inhibitor darunavir/ritonavir (Prezista),
with or without enfuvirtide (Fuzeon; T-20).
Data
from the DUET studies have been presented at several scientific meetings, most
recently the Interscience Conference on Antimicrobial
Agents and Chemotherapy this past September, and were published
in the July 7, 2007 issue of The Lancet. The
most common adverse events associated
with etravirine are ski rash and nausea. In rare cases,
severe skin reactions may occur. Patients who experience rash while taking etravirine
should promptly contact their healthcare providers. Etravirine will be sold as 100 mg tablets, to be taken as 2 tablets twice daily with
food. The wholesale cost is expected to be about $5.50 per tablet. It should be
available in pharmacies within about 1 week. Below is an edited excerpt from a Tibotec press release
announcing the new approval: FDA Approves
Intelence (etravirine) for
HIV
Combination Therapy Intelence is the first NNRTI to show antiviral
activity in patients with NNRTI-resistant virus BRIDGEWATER,
N.J., Jan. 18 – PRNewswire -- The U.S. Food and Drug
Administration (FDA) has granted accelerated approval to the anti-HIV medication
Intelence (etravirine) tablets
-- the first non-nucleoside reverse transcriptase inhibitor (NNRTI) to show antiviral
activity in treatment-experienced adult patients with HIV resistant to a NNRTI
and other antiretroviral (ARV) agents. Intelence, also
known as TMC125, was developed by Tibotec Pharmaceuticals,
Ltd. and will be marketed in the U.S. by Tibotec
Therapeutics, a division of Ortho Biotech Products, L.P. "NNRTIs
have been used in HIV combination therapy
for more than a decade, but their use has been limited by cross-resistance within
the class. Resistance to one NNRTI generally meant resistance to all NNRTIs,"
said Richard Haubrich, M.D., Professor of Medicine, Division of Infectious
Diseases, University of California, San
Diego, and investigator in the Intelence
Phase 3 DUET studies. "Etravirine breaks new ground
in the NNRTI class, and provides a new option to thousands of treatment-experienced
patients with NNRTI-resistant HIV." Intelence, in combination
with other antiretroviral agents, is indicated for the treatment of human immunodeficiency
virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients,
who have evidence of viral replication and HIV-1 strains resistant to a NNRTI
and other ARV agents. This
indication is based on Week 24 analyses from two randomized, double-blind, placebo-controlled
trials of Intelence. Both studies were conducted in
clinically advanced, three-class antiretroviral (NNRTI, N[t]RTI,
PI) treatment-experienced adults. The
following points should be considered when initiating therapy with Intelence:
•
Treatment history and, when available, resistance testing, should guide
the use of Intelence.
• The
use of other active antiretroviral agents with Intelence is associated with an
increased likelihood of treatment response.
•
In patients who have experienced virologic failure on a NNRTI-containing
regimen, do not use Intelence in combination with only N[t]RTIs [nucleoside/nucleotide
reverse transcriptase inhibitors].
•
The risks and benefits of Intelence have not been established in pediatric patients
or in treatment-naive adult patients.
FDA
accelerated approval procedures allow for earlier approval of drugs that provide
a meaningful therapeutic benefit over existing treatment for serious or life-threatening
diseases. The Intelence approval is based on the 24-week analysis of HIV viral
load and CD4+ cell counts from the pooled analysis of the DUET-1 and -2 studies.
Longer-term data will be required before the FDA can consider traditional approval
for Intelence.
"It is very inspiring to our R&D organization to
see an additional compound so quickly emerge from our pipeline and reach patients
who need it," said Roger Pomerantz, M.D., FACP, President, Tibotec Research
and Development. "With one of the most robust virology research and development
programs in the industry, we are dedicated to continuing to deliver innovative
approaches in HIV management in the years to come."
"The addition
of Intelence following the launch of our first antiretroviral just two years ago
is a significant milestone for Tibotec Therapeutics," said Glenn Mattes,
President, Tibotec Therapeutics. "In partnership with Tibotec R&D, we
are committed to continuing to bring new options to people living with HIV."
The
NNRTI Class
Intelence is the first new NNRTI to be introduced
in nearly 10 years. It is also the first NNRTI to show antiviral activity in patients
with NNRTI-resistant virus. NNRTIs block reverse transcriptase, a key enzyme the
HIV virus uses to replicate. NNRTI drug resistance occurs when HIV develops mutations
that partially or completely stop the NNRTI from binding to the reverse transcriptase
enzyme, causing the drug to lose effectiveness. As with other HIV medications,
patients can develop resistance to Intelence; for more information see the resistance
section below.
DUET-1 and -2 Study Design
The
DUET-1 and -2 studies, identical in design but conducted in different regions,
assessed the 24-week efficacy and safety of Intelence in combination with a background
regimen (BR) in treatment-experienced adult HIV-1 patients with documented evidence
of NNRTI and PI resistance. They were large randomized, controlled studies with
a primary endpoint of less than 50 copies/mL (known as undetectable viral load).
IAS-USA treatment guidelines define less than 50 copies/mL as the goal of therapy
for treatment-experienced patients when two or more potent drugs are identified.
Patients
with HIV-1 who were eligible for the DUET studies had a viral load of greater
than 5,000 copies/mL, while on a stable antiretroviral therapy regimen for at
least eight weeks and had evidence of at least one NNRTI resistance-associated
mutation, either at screening or from prior resistance tests, as well as evidence
of three or more primary PI mutations (D30N, V32I, L33F, M46I/L, I47A/V, G48V,
I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M) at screening.
DUET-1
and -2 Efficacy
Participants in the DUET studies were randomized
to receive Intelence 200 mg twice daily (599 patients) or placebo (604 patients),
each given in addition to a BR. For all patients, the BR included darunavir/ritonavir,
plus at least two investigator-selected antiretroviral drugs (N(t)RTIs with or
without enfuvirtide).
The 24-week pooled analysis of the DUET studies showed
the following results for Intelence plus BR vs. placebo plus BR:
• Significantly more patients in the
Intelence arm achieved undetectable viral load (less than 50 copies/mL); 59.8
percent vs. 40.2 percent [p<0.0001].
•
Significantly greater mean increase in CD4+ cell count from baseline;
mean increase of 81 vs. 64 cells/mm(3)[p=0.0022]
The
results of DUET-1 and DUET-2 were published separately in two articles in the
July 7, 2007 issue of The Lancet, and the pooled analysis from the DUET
studies was presented at the 47th Interscience Conference on Antimicrobial Agents
and Chemotherapy (ICAAC) in September 2007.
DUET-1
and -2 Resistance
• The presence of K103N, which was the
most prevalent NNRTI substitution in DUET-1 and -2 studies at baseline, did not
affect the response in the Intelence arm.
•
The presence at baseline of the substitutions V179D, V179F, V179T,
Y181V, or G190S was associated with a decreased virologic response to Intelence.
• In the DUET-1 and -2 studies, the
presence at baseline of three or more 2007 IAS-USA-defined NNRTI substitutions
(V90I, A98G, L100I, K101E/P, K103N, V106A/I/M, V108I, V179D/F, Y181C/I/V, Y188C/H/L,
G190A/S, P225H) resulted in a decreased virologic response to Intelence.
• For patients in the DUET-1 and -2
studies experiencing virologic failure on an Intelence -containing regimen, the
substitutions that occurred most commonly were V179F, V179I, Y181C, and Y181I
which usually emerged in a background of multiple other NNRTI resistance-associated
substitutions. Other NNRTI resistance-associated substitutions which emerged in
patients on Intelence treatment in < 10 percent of the virologic failure isolates
included K101E, K103N, V106I/M, V108I, Y188L, V189I, G190S/C and R356K.
• Cross-resistance to delavirdine, efavirenz,
and/or nevirapine is expected after virologic failure with an Intelence -containing
regimen.
DUET-1
and -2 Tolerability
In
the DUET-1 and -2 studies, the most common adverse events (> 10 percent) of
any intensity that occurred at a higher rate than placebo were rash (16.9 percent
vs. 9.3 percent) and nausea (13.9 percent vs. 11.1 percent). The most common treatment-emergent
adverse reactions (Grade 2-4) that occurred in greater than or equal to two percent
of patients receiving an Intelence-containing regimen were diarrhea, nausea, abdominal
pain, vomiting, fatigue, peripheral neuropathy, headache, rash, and hypertension.
Additional
Important Safety Information
Intelence does not cure HIV
infection or AIDS, and does not prevent passing HIV to others.
• Severe and potentially life-threatening
skin reactions, including Stevens-Johnson Syndrome, hypersensitivity reaction,
and erythema multiforme, have occurred (< 0.1 percent) in patients taking Intelence.
Treatment with Intelence should be discontinued and appropriate therapy initiated
if severe rash develops.
• In
general, in clinical trials, rash was mild to moderate, occurred primarily in
the second week of therapy, and was infrequent after Week 4. Rash generally resolved
within 1-2 weeks on continued therapy. Discontinuation rate due to rash was two
percent.
• Redistribution and/or
accumulation of body fat have been observed in patients receiving antiretroviral
(ARV) therapy. The causal relationship, mechanism, and long-term consequences
of these events have not been established.
•
Immune reconstitution syndrome has been reported in patients treated
with ARV therapy, including Intelence.
•
Intelence should be used with caution in patients with severe hepatic
impairment (Child-Pugh class C) as pharmacokinetics of Intelence have not been
evaluated in these patients.
• Intelence should not be co-administered
with the following ARVs: tipranavir/ritonavir [Aptivus], fosamprenavir/ritonavir
[Lexiva], atazanavir/ritonavir [Reyataz], full-dose ritonavir [Norvir] (600 mg
bid), protease inhibitors administered without ritonavir, and other NNRTIs.
• Intelence should not be co-administered
with carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, rifabutin
(when part of a regimen containing protease inhibitor/ritonavir) or products containing
St. John's wort (Hypericum perforatum).
•
Intelence and lopinavir/ritonavir [Kaletra] should be co-administered
with caution.
• Coadministration
of Intelence with other agents such as substrates, inhibitors, or inducers of
CYP3A4, CYP2C9, and/or CYP2C19 may alter the therapeutic effect or adverse events
profile of Intelence or the co-administered drug(s). This is not a complete list
of potential drug interactions.
Please
see full Prescribing Information for more details, available at www.INTELENCE-info.com.
Patient
Access to Intelence
Intelence is expected to be available
at the wholesale level in the U.S. within one week.
Martin Delaney of the
Fair Pricing Coalition said, "Tibotec Therapeutics continues to demonstrate
real leadership in the pharmaceutical industry by pricing Intelence fairly and
responsibly. We applaud Tibotec's responsible corporate behavior and expect to
see the drug quickly accepted on all formularies."
"With the
introduction of Intelence, Tibotec Therapeutics has demonstrated exceptional leadership
in working with the HIV community in an effort to address pricing and access issues.
Tibotec has repeatedly recognized the necessity of responsibly pricing HIV products
and should be commended for its leadership in this regard," said Lynda Dee
from the AIDS Treatment Activist Coalition.
Tibotec
Therapeutics
Tibotec Therapeutics, a division of Ortho Biotech
Products, L.P., headquartered in Bridgewater, N.J., is dedicated to delivering
innovative virology therapeutics that help healthcare professionals address serious
unmet needs in people living with HIV.
Tibotec
Pharmaceuticals Ltd.
Tibotec Pharmaceuticals Ltd., based
in Cork, Ireland, is a pharmaceutical research and development company. The Company's
main research and development facilities are in Mechelen, Belgium with offices
in Yardley, PA. Tibotec is dedicated to the discovery and development of innovative
HIV/AIDS drugs and anti-infectives for diseases of high unmet medical need.
Applications
for approval of Intelence have also been submitted to the European Agency for
the Evaluation of Medicinal Products (EMEA) and with regulatory authorities in
Canada, Switzerland, Russia and Australia.
Ortho Biotech Products, L.P.
and Tibotec Pharmaceuticals Ltd. are subsidiaries of Johnson & Johnson.
For
further information about etravirine, including complete prescribing information,
see www.intelence-info.com. For
more information about manufacturer Tibotec, see www.tibotec.com. Etravirine
overview from the National Institute of Allergy and Infectious Diseases. 1/19/08 Sources
Tibotec
Therapeutics (via PR Newswire). FDA Approves INTELENCE (etravirine) for HIV Combination
Therapy. Press release. January 18, 2008.
References P
Cahn, R Haubrich, J Leider, and others. Pooled 24-Week Results of DUET-1 and -2:
TMC125 (Etravirine; ETR) vs Placebo in 1203 Treatment-Experienced HIV-1-Infected
Patients. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy.
Chicago, IL. September 17-20, 2007. Abstract H-717. J
V Madruga, P Cahn, B Grinsztejn, and others (on behalf of the DUET-1 study group).
Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected
patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled
trial. The Lancet 370(9581): 29-38. July 7, 2007. A
Lazzarin, T Campbell, B Clotet, and others (on behalf of the DUET-2 study group).
Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected
patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled
trial. The Lancet 370(9581): 39-48. July 7, 2007. |
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