First
Integrase Inhibitor, Raltegravir (Isentress), Receives FDA Approval for Treatment-experienced
HIV Patients By
Liz Highleyman
On October 12, the U.S. Food and Drug Administration (FDA)
approved another new antiretroviral drug, Merck’s raltegravir
(Isentress; formerly MK-0518) for use by treatment-experienced
HIV patients with prior treatment failures. As previously reported, an
FDA panel recommended the drug’s approval
in September.
Coming on the heels of the the approval
in August of Maraviroc (Selzentry), the first CCR5 co-receptor antagonist,
people with HIV have 2 novel classes of drugs to which HIV in unlikely to be resistant
-- a particular benefit for heavily treatment-experienced patients who have developed
resistance to the 3 older antiretroviral drug classes.
Raltegravir works by preventing HIV from inserting
its genetic material into the DNA of the host cell, which the virus must do in
order to use the cell’s machinery to replicate. The drug inhibits the action of
integrase, the enzyme required for this step in the HIV lifecycle.
With the approval of raltegravir, there are now drugs targeting all 3 HIV replicative enzymes (the others being reverse transcriptase
and protease).
The approval of raltegravir
was based on the twin BENCHMRK studies (Phase 3), which included about 700 treatment-experienced
patients with documented drug resistance in North and South America, Europe, and
Asia [1,2]. The studies showed that at 16-24 weeks, participants who took
raltegravir plus optimized background therapy (OBT) were about
twice as likely to achieve a viral load below 50 copies/mL than those taking OBT plus placebo (61%-62% vs 33%-36%, respectively). CD4 cell gains were also larger in the raltegravir arm (85 vs about 35 cells/mm3). Raltegravir
worked best in people who started another active drug to them at the same time.
Longer-term data from an earlier Phase 2 trial [3]
showed that raltegravir continued to be effective after 48 weeks, with
64% of patients taking the 400 mg dose having a viral load below 50 copies/mL, while CD4 counts increased by 110 cells/mm3.
Among a subset of patients followed for up to 72 weeks, about 70% maintained a
viral load below 400 copies/mL.
Raltegravir was well tolerated overall, with less than
2% of study participants in the BENCHMRK studies discontinuing therapy due to
adverse events. The most common side effects were nausea, diarrhea, headache, fever, and skin rash. Patients
taking raltegravir were more likely to have elevated blood levels
of creatine kinase, an enzyme associated
with muscle damage. Although early data indicated that more people in the raltegravir arms developed cancer, this appears to be attributable
to an unusually low rate of cancer in the placebo groups, and the rates evened
out with longer follow-up.
Another recent study, published in the advance online
edition of the Journal of Acquired Immune Deficiency Syndromes (August
23, 2007) [4], showed that raltegravir
worked as well as efavirenz (Sustiva) in treatment-naive patients after 48 weeks. However,
raltegravir has not yet been approved for such individuals.
Merck is also studying raltegravir in children with HIV. It has not been tested in
pregnant women.
Raltegravir is expected to be available in pharmacies
within a few weeks. The approved dose is 400 mg twice daily. It does not need
to be boosted with ritonavir (Norvir). The price was
set at about $27 per day, or $9,800 per year. Advocates had pressured Merck to
set the price in line with that of the newest protease inhibitors, which the company did. (The new protease inhibitors darunavir [Prezista] and atazanavir [Reyataz] both cost about
$9,500 per year; maraviroc costs about $10,600.)
Below
is an excerpt from Merck’s press release announcing the approval. FDA Approves ISENTRESS (raltegravir)
Tablets,
First-in-Class Oral HIV-1
Integrase InhibitorWHITEHOUSE
STATION, N.J., Oct. 12, 2007 - Merck & Co., Inc., announced today
that the U.S. Food and Drug Administration (FDA) granted ISENTRESS (raltegravir)
tablets accelerated approval for use in combination
with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced
adult patients who have evidence of viral replication and HIV-1 strains resistant
to multiple antiretroviral agents. This
indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks
in two controlled studies of ISENTRESS [pronounced i-sen-tris]. These
studies were conducted in clinically advanced, three-class antiretroviral [nucleoside
reverse transcriptase inhibitors (NRTIs), non-nucleoside
reverse transcriptase inhibitors (NNRTIs) and protease
inhibitors (PIs)] treatment-experienced adults. The use of other active agents
with ISENTRESS is associated with a greater likelihood of treatment response. The
safety and efficacy of ISENTRESS have not been established in treatment-naïve
adult patients or pediatric patients. There are no study results demonstrating
the effect of ISENTRESS on clinical progression of HIV-1 infection. Longer
term data will be required before the FDA can consider traditional approval for
ISENTRESS. ISENTRESS
is the first medicine to be approved in a new class of antiretroviral drugs called
integrase inhibitors. ISENTRESS works by inhibiting the insertion
of HIV DNA into human DNA by the integrase enzyme. Inhibiting
integrase from performing this essential function limits
the ability of the virus to replicate and infect new cells. There are drugs
in use that inhibit two other enzymes critical to the HIV replication process
- protease and reverse transcriptase - but ISENTRESS is the only drug approved
that inhibits the integrase enzyme. The
FDA's decision was based on a 24-week analysis of clinical trials in which ISENTRESS
in combination with optimized background therapy (OBT)
in treatment-experienced patients, provided significant reductions in HIV RNA
viral load and increases in CD4 cell counts. "The
development of ISENTRESS is a significant milestone in the history of HIV/AIDS
therapy because we now have a drug that's potent against another key enzyme essential
for viral replication," said Joseph J. Eron Jr.,
M.D., professor of medicine, Division of Infectious Diseases, UNC Chapel Hill
School of Medicine. "It's important for physicians to know that ISENTRESS
should always be used in combination
with other active agents." Data
from two ongoing Phase III multi-center, double-blind, randomized, placebo-controlled
studies (BENCHMRK-1 and BENCHMRK-2) in 699 treatment-experienced adult patients
with documented resistance to at least one drug in each of three classes (NRTIs, NNRTIs and PIs) of antiretroviral
therapies showed that ISENTRESS 400 mg dosed twice daily in combination with OBT was significantly more effective
at both reducing levels of HIV viral RNA and increasing CD4 cell counts in these
patients living with HIV, when compared
to a regimen of placebo plus OBT. Pooled
analyses from the two Phase III studies showed that after 24 weeks of therapy,
75.5 percent of patients (216 out of 286) receiving ISENTRESS in combination
with OBT achieved HIV viral RNA load reduction to below 400 copies/mL compared to
39.3 percent of patients (59 out of 150) receiving placebo plus OBT. In addition,
after 24 weeks of therapy, 62.6 percent of patients (179 out of 286) receiving
ISENTRESS plus OBT achieved viral load reduction to below 50 copies/mL compared to
33.3 percent of patients (50 out of 150) receiving placebo plus OBT. After
24 weeks of therapy, increases in CD4 cell counts from baseline were 89 and 35
cells/mm3 for patients receiving ISENTRESS plus OBT and for those receiving
placebo plus OBT, respectively. Important
safety information about ISENTRESS ISENTRESS
does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare
providers should know that immune reconstitution syndrome has been reported in
patients treated with antiretroviral therapy, which may necessitate further evaluation
and treatment. The
most commonly reported adverse experiences of any severity
(mild, moderate or severe) regardless of drug relationship were diarrhea (16.6
percent vs. 19.5 percent), nausea (9.9 percent vs. 14.2 percent), headache (9.7
percent vs. 11.7 percent), and fever (4.9 percent vs. 10.3 percent) for ISENTRESS
plus OBT and placebo plus OBT, respectively. Creatine kinase elevations
were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have
been reported; however, the relationship of ISENTRESS to these events is not known.
ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such
as patients receiving concomitant medication
known to cause these conditions. Safety
and tolerability profile of ISENTRESS Results
from pooled safety analyses from three separate studies in treatment-experienced
patients taking 400 mg of ISENTRESS dosed twice daily plus OBT or placebo plus
OBT showed that after 24 weeks of therapy the rates of discontinuation of therapy
due to adverse experiences were 2.0 percent in patients receiving ISENTRESS plus
OBT and 1.4 percent in patients receiving placebo plus OBT. In addition,
drug-related clinical adverse events of moderate to severe intensity occurring
in greater than or equal to 2.0 percent of patients were diarrhea (3.7 percent
vs. 4.6 percent), nausea (2.2 percent vs. 3.2 percent), and headache (2.4 percent
vs. 1.4 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively. Drug
interactions Based
on the results of drug interaction studies and the clinical trials data, no dose
adjustment of ISENTRESS is required when coadministered
with other antiretroviral agents. Also, preclinical studies show that ISENTRESS
is not metabolized by cytochrome P450 enzymes. Caution
should be used when coadministering ISENTRESS with strong
inducers of uridine diphosphate
glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of ISENTRESS. About
ISENTRESS ISENTRESS
is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS
does not require boosting with ritonavir. Merck
has worked closely with the HIV community
regarding the price of ISENTRESS. The wholesale acquisition cost (WAC) of
ISENTRESS will be $27 per day, comparable
to the price of several available ritonavir-boosted
protease inhibitors. "ISENTRESS
is the first drug in a new class of medications and the Fair Pricing Coalition
is pleased to report that Merck has acted responsibly in its pricing of the drug. While
we still believe that lower prices are always possible, Merck has avoided the
temptation to set ever higher prices for each new HIV drug," said Martin
Delaney of the Fair Pricing Coalition (FPC) and Project Inform. The FPC is
a nationwide network of activists and organizations concerned with drug pricing
that works with pharmaceutical companies to set responsible prices. To
help patients in the United States
who cannot afford treatment with ISENTRESS, the SUPPORT program is available. The
SUPPORT program is a patient assistance program to help patients who have been
prescribed ISENTRESS by providing personalized support and patient advocacy regarding
individual reimbursement issues. In addition, Merck also participates in
the Partnership for Prescription Assistance program, a single point of access
to more than 475 public and private patient assistance programs. ISENTRESS
will be available in pharmacies in approximately two weeks. For
more information on ISENTRESS, visit www.isentress.com. Expanded
access program ISENTRESS
is currently available worldwide to qualified patients through an expanded access
clinical research program, EARMRK. This global program provides early access
to ISENTRESS for patients failing current therapy whose HIV is resistant to drugs
in three existing classes (NRTIs, NNRTIs,
PIs) of antiretroviral medications. Information about the program can be
found at www.benchmrk.com. Merck
HIV research Merck
is committed to developing innovative therapies that offer
advances in the treatment of infectious diseases - including HIV. Merck's
efforts to develop investigational treatments for HIV/AIDS have been under way
for more than 20 years and continue today. Merck began its HIV integrase inhibitor research in 1993 and was the first to
demonstrate inhibition of HIV integrase in vitro and in vivo. About
Merck Merck
& Co., Inc. is a global research-driven pharmaceutical company
dedicated to putting patients first. Established in 1891, Merck currently
discovers, develops, manufactures and markets vaccines and medicines to address
unmet medical needs. The Company devotes extensive efforts to increase access
to medicines through far-reaching programs that not only donate Merck medicines
but help deliver them to the people who need them. Merck also publishes
unbiased health information as a not-for-profit service. For
more information, visit www.merck.com. |
10/16/07 Source Merck & Co. FDA Approves ISENTRESS
(raltegravir) Tablets, First-in-Class Oral HIV-1 Integrase
Inhibitor. Press release. October 12, 2007.References 1.
D Cooper, J Gatell, J Rockstroh,
and others. Results from BENCHMRK-1, a phase III study evaluating
the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant
virus. 14th Conference on Retroviruses and Opportunistic
Infections (CROI). Los Angeles,
February 25-28, 2007. Abstract 105aLB. 2.
R Steigbigel, P Kumar, J Eron,
and others. Results from BENCHMRK-2, a phase III study evaluating
the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant
virus. 14th CROI. Los Angeles, February 25-28, 2007. Abstract 105bLB. 3. B Grinsztejn, B Nguyen, C
Katlama, and others. 48 week efficacy and
safety of MK-0518, a novel HIV-1 integrase inhibitor,
in patients with triple-class resistant virus. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy.
Chicago, September
17-20, 2007. Abstract H-713. 4. M Markowitz,
BY Nguyen, E Gotuzzo,
and others. Rapid and Durable Antiretroviral Effect of the HIV-1
Integrase Inhibitor Raltegravir
as Part of Combination Therapy in Treatment-Naive Patients. JAIDS. August 23, 2007 [Epub
ahead of print].
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