TAGline/Volume 4 Issue 10
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The FDA's Oncologic Drug Advisory Committee Decides the Fate of Two Drugs
for AIDS-Related Malignancies
Nowhere near bowled over
On June 23rd, the FDA's Oncologic Drug Advisory Committee held a hearing to
determine the fate of Bristol Myers-Squibb's supplemental new drug
application for paclitaxol (Taxol) as second-line treatment for
AIDS-related Kaposi's sarcoma. Taxol is a popular, potent chemotherapeutic
agent which had originally been approved by the FDA for use in breast
cancer, and is also used off-label for ovarian cancer.
Bristol's application included 85 patients with progressive KS from two
Phase II studies: #174 conducted at the National Cancer Institute and #281
conducted at University of Southern California and Harvard. Because Bristol
was seeking an indication for Taxol as second-line KS therapy (that is,
patients who have failed or are intolerant to first-line treatment), the
main focus was on the 59 patients (69%) who had received prior systemic
therapy. The vast majority of the 59 patients were considered "poor
prognosis" candidates for therapy because they had a median CD4 count of
16, other prior opportunistic infections (86%), and flu-like symptoms (54%)
typical of abnormal activation of one's B cells. Their KS involvement was
pronounced: only 7% had KS limited to their skin, 42% also had oral
involvement and 30% had KS in their lungs.
According to the FDA's assessment, an overall response was documented in 35
of the 59 patients, 2 with a "complete response" and 33 with a "partial
response." The median time to the first response was 8.1 weeks (range 2.9-36.0 weeks, and the median time to progression for all 59 patients was 6.2
months (95% range: 4.6-8.7 months). Median survival for all patients
(including the ones who had neither a complete nor a partial response to
treatment) was 13.7 months. For those patients with prior systemic therapy,
the median survival was 14.1 months, but of those, patients with pulmonary
KS had a median survival of about half that time (7.4 months). Overall, 84%
of patients developed secondary opportunistic infections during the
treatment for KS. At the time of the analysis, over half of the total
patients (forty-six of eighty-five) were dead.
AdvertisementNeutropenia (a dangerously low number of bacteria-fighting white blood
cells) was the major toxicity associated with Taxol, with 100% of the
patients in study 174 and 62% of those in study 281 developing grade 3 or 4
neutropenia. (Co-administration of G-CSF was more common in #281 than in
#174.) Fever associated with neutropenia developed in 55% and 9% of the
#174 and #281 patients, respectively. Other toxicities included, alopecia
(hair loss) in 91% of patients, asthenia (weakness or loss of strength) in
84%, nausea/vomiting in 69%, diarrhea in 79%, arthralgia or myalgia (joint
or muscle pain) in 64%, peripheral neuropathy in 58%, alterations in SGOT
liver enzymes in 49%, and renal (kidney) toxicity in 24%. Even with such
high rates of toxicity, only 7 (8%) patients discontinued Taxol due to
After all these data were presented to the FDA's Oncologic Drug Committee,
a vote of 8 to 4 was rendered in favor of approving Taxol as second-line
treatment for patients with KS. Bristol got its KS indication for Taxol,
but the FDA stipulated that when used to treat KS in HIV-infected patients,
Taxol must always be administered with G-CSF.
Two Taxol post-marketing studies generated by the AIDS Committee of the
NCI's Eastern Cooperative Oncology Group (ECOG) are soon to open: a Phase
II study which will test the.pharmacological drug interactions of Taxol
with all approved protease inhibitors, and a Phase III study of Taxol
versus Doxil for first-line treatment of progressive KS. The endpoints for
the Phase III study are efficacy, toxicity, and clinical benefit.
On the same day as the Taxol hearing, Ilex Pharmaceuticals presented its
data on mitoguazone (MGBG) for the treatment of patients with HIV-related
non-Hodgkin's lymphoma (NHL) who have previously failed at least one
"potentially curative" regimen. Currently, there are no approved drugs (or
a standard of care) for patients with HIV-related lymphoma who have failed
or are intolerant to standard, first-line chemotherapy.
The MGBG application included a total of 90 relapsed or refractory NHL
patients who were enrolled in two open-label, single-arm Phase II studies.
Of the 90 patients, 65 patients (72%) had more than 3 "poor prognostic"
factors; only one patient had none.
According to Ilex, six patients achieved a "complete response" and 7
achieved a "partial response." Median time-to-response was 53 days, and the
median duration of response was 144+ days. Overall, time-to-tumor
progression was 40 days, time-to-treatment failure was 30 days, and the
median survival time was 84+ days. For the responders, time-to-tumor
progression was 163+ days, time-to-treatment failure was 151 days, and the
median survival time was 269 days.
After closely examining Ilex's methods for assessing treatment responses,
the FDA medical officer adjusted Ilex's reported 14.4% overall response
rate down to 6% due to either patient ineligibility, protocol violation or
simple disbelief. Even at 14.4%, the Oncologic Drug Committee members were
nowhere near bowled over by MGBG's purported success rate, but when even
that unimpressive response rate was whittled down to a single digit, they
wanted nothing more to do with the drug-period! They promptly voted 0 to 12
against approving MGBG. Since the FDA usually follows its advisory
committee's decisions, it seems highly unlikely that MGBG will be approved.
While it may have been rational for the Committee to vote against approval
of MGBG in light of the FDA's data analysis, some activists and lookers-on
are concerned that the FDA did not give Ilex adequate time to formally
respond to the response rate discrepancy. So too, they are, while the
Oncologic Drug Committee is honorably staffed with a phalanx of
distinguished breast, prostate, lung and ovarian cancer doctors,
representation of AIDS physicians is sorely lacking. And the differences
between HIV-related and non-HIV lymphoma are striking. For the future
review of new AIDS malignancy agents, the FDA must insure that its
oncologic drug advisory committee has adequate representation of AIDS
oncologists so that it may professionally, logically and sensibly advise.
And, Not-So-New Drugs
Three New Antivirals Trickle From the Pipeline, But Will They Provide Any
Benefit for Those Who Need Them Most?
Whose needs served?
A group of new anti-HIV therapies are about to enter expanded access
programs, but heavily pre-treated patients aren't out of the woods yet. Due
to cross resistance, at least one of the new products isn't expected to
work in people with extensive prior nucleoside experience, and it may be
difficult to cobble together a regimen from the two remaining new agents
that can reasonably be expected to produce sufficient virologic
1592 -- late for nearly everyone
Thanks to Glaxo-Welcome's crack marketing team (and a cynically delayed
release designed so as not to cannibalize the recent launch of "Combivir"),
perhaps the most hotly anticipated of the new therapies is Wellcome's
1592U89 (now known by the name "abacavir"). Early study results suggested
as much as a 2 log reduction in plasma HIV RNA when treatment naïve
patients were treated with 1592. Data recently presented by Dr. David Hardy
to an investigator's meeting sponsored by Glaxo-Wellcome, however, suggests
that heavily pre-treated patients may not benefit from 1592. While patients
pre-treated with ddI or d4T experienced relatively normal reductions in
plasma HIV RNA (about 1.5 log) after twelve weeks of 1592 treatment,
patients with extensive AZT or AZT+3TC double nucleoside therapy were much
less responsive: after twelve weeks of therapy, patients with more than a
year of prior AZT treatment had only a .05 log reduction while patients
with extensive AZT+3TC therapy had only a 0.05 log reduction. Since the
lion's share of the traditional expanded access population will have
received loads of prior AZT (and invariably 3TC too), it is unlikely that
they will receive much benefit from 1592 -- at least based on the results from
Due to community pressure, plans for expanded access to 1592 keep changing.
The most recent plan was for 1592 to become available beginning September
15, with participating sites allowed to enroll 2 patients per week until
the end of the year, some 16 weeks. Eligible patients would have a CD4+
T-cell count < 100 and a plasma viral load > 30,000. The program plans to
enroll approximately 2,400 patients in North America and another 900
patients in Europe. Separate (and smaller) expanded access programs will
make 1592 available for pediatrics as well as for adults with HIV dementia.
Sustiva, sustava, sustain me
In contrast to the disappointing cross-resistance news with 1592,
DuPont-Merck's new non-nucleoside reverse transcriptase inhibitor (NNRTI)
DMP-266 (now with the generic name "efavirenz" and trade name "Sustiva"),
seems to be active against the most common resistance mutation (Y181)
associated with use of nevirapine and delavirdine, the two commercially
available NNRTIs. As long as only one mutation (181) is present, current
dosing of DMP should be enough to suppress virus, however when two NNRTI
resistance mutations (Y181 and K103) are present, DMP may not be enough to
suppress replication. Early studies suggest that DMP may be taken once a
day, and can reduce viral RNA counts by about 1.5 logs. The most common
side effects are lightheadedness and rash.
DuPont-Merck recently announced an expanded access program for DMP that
will be available to a limited number of patients (approximately 2,000)
through the end of 1997, and will then broaden to include additional
patients in early 1998. Patients with < 50 T-cells who are failing current
therapeutic regimens are eligible for the program as it is currently
designed. Participants, though, will be required to take DMP with a second
new drug, such as 1592 or adefovir (see below). DuPont Merck expects to
file its NDA for efavirenz in March of next year. For more information on
the program, patients and physicians can call 1-800-998-6854.
Gilead Science's adefovir dipivoxil (formerly known as bis-POM PMEA) is a
nucleotide analogue which will also be made available through an expanded
access program said to be very similar to DuPont Merck's program for
DMP-266. Adefovir, to be marketed under the trade name Preveon, is active
against the hepatitis B virus and CMV as well as HIV. The drug has been
reported to deplete the body's store of L-carnitine levels (which is made
by the body to help supply energy to muscles), so supplementation (500 mg
once daily) with this amino acid is recommended for people taking adefovir.
Gilead's expanded access for adefovir is slated to begin mid-November.
Eligible patients will be required to 1) have failed a regimen containing
at least two commercially available nucleoside RTIs and one commercially
available protease inhibitor; 2) have a CD4 cell count < 50 cells/mm3 3) a
plasma HIV RNA copy number > 30,000 within the past 2 months; and 4) not
qualify for other adefovir clinical trials. Participants in the adefovir
program will also be advised, as in the DMP expanded access program, to add
at least one new antiretroviral agent to the mix. Adefovir is administered
as a 120 mg tablet once daily. For more information about the adefovir
expanded access program, call Gilead at (800) GILEAD-5.
The bottom line...
While two new protease inhibitors, Glaxo-Welcome's GW-141 and Abbott
Laboratories' ABT-378 are in the pipeline, there are not yet estimates on
when these drugs will become available. Early reports suggest that GW-141
will be cross-resistant with indinavir and ritonavir, however in vitro
studies suggest that ABT-378 may be effective against viral strains that
are resistant to other protease inhibitors. (More critical on-lookers warn
that the 84 mutation knocks ABT-378 on its back.)
Cross-resistance between anti-HIV therapies is continuing to baffle design
of expanded access programs. Those patients for whom expanded access is
intended -- patients with few other therapeutic options -- will often be the
patients least likely to benefit from new therapies. This creates powerful
disincentives for companies to make drug available -- just witness the
incredibly shrinking expanded access programs over recent years.
On the flip side, companies such as Glaxo-Wellcome have also learned that
expanded access schemes represent a powerful promotional tool for
manipulating the HIV/AIDS communities. When Glaxo-Wellcome limited access
to 3TC just prior to approval, it created strong pressure from AIDS
activists to approve the drug despite serious limitations in the available
knowledge regarding use of the product. That the company seems to be
repeating this pattern with 1592 (Witness, for example, the relentless
headline-making paeans from patients with advanced disease who dutifully
propose that, "This product could save my life."), is testament to the
manufacturer's marketing skills and the community's collective amnesia.
Programs like expanded access and accelerated approval were designed to
make available therapies that were desperately needed by patients with few
other treatment options. When new products are unlikely to be effective in
these patients, AIDS activists will have to ask themselves if programs such
as expanded access and accelerated approval are serving their needs, or are
simply highly effective pre-approval marketing efforts by pharmaceutical
manufacturers. These difficult questions are likely to haunt the AIDS
communities for the foreseeable future.
- David Ho proposes immunotherapeutic vaccination to help the immune system
clear the long-lived "3rd" compartment of HIV-infected cells. These
latently infected CD4+ T-cells with integrated HIV DNA currently represent
the greatest obstacle to the potential eradication of HIV infection. And a
British study may just beat him to the punch: Frances Gotch (London)
reported that her group will randomize patients to HAART plus 1) an
immunomodulator, 2) the Salk (Immunogen) vaccine, 3) both or 4) placebo.
- On the other side of the Atlantic, Dr. Luc Montaigner proposes the use of
an HIV-nef vaccine in order to immunize uninfected persons from productive
infection with HIV. In an open plenary lecture at the Sixth European
Conference on Clinical Aspects and Treatment of HIV Infection in Hamburg,
Germany (October 11-15), the official discoverer of HIV explained that
HIV's regulatory proteins nef and tat are responsible for the continual
propagation of what would ordinarily be a containable infection with HIV.
Montaigner's goal: by inactivating nef early on, the pool of activated CD4+
cells susceptible to infection would be small enough for -- perhaps -- the
body's own immune response to clear the initial infection.
- Jean-Pierre Sommadossi (UAB) presents compelling evidence of what is
being called "pharmacologic resistance" to the entire nucleoside class of
drugs after long-term AZT use. Changes in the cellular metabolism of AZT
resulted in reduced efficacy of the other nucleoside analogue agents.
Whether or not -- or to what extent -- this sort of pharmacologic resistance
develops after prolonged use of the other nukes (and other classes of
antiretroviral agents) is not known.
- On behalf of the Delta coordinating committee, London's A. Babiker showed
that changes in CD4+ T-cells and HIV plasma RNA levels break down as
surrogate markers over the long term. "Similar RNA responses with different
treatments do not have similar associations with clinical outcome," Babiker
explained. He speculates that a large part of this dis-association is
likely due to the increased toxicity of combination regimens -- ill-effects
not directly captured by changes in viral load or T-cell counts.
- Scott Eastman, speaking at one of the many commercial "satellite"
symposia during the two days prior to the Hamburg meeting, presented
disturbing data about the variation in blood levels of different
antiretroviral drugs. It's not just indinavir where you see significant
variation in plasma drug levels, Eastman explained. While plasma levels of
indinavir varied up to 8-fold, plasma levels of 3TC and nevirapine were
also found to vary significantly (3-5 fold).
- Two-year follow-up of the high-profile Merck 035 study provides both good
news and disconcerting news, depending on how carefully you look at the
data. While the number that made it into the newspapers was "80% still
undetectable at 2 years," that's using the bDNA assay with a lower limit of
detection of 500 copies/mL. Using the more sensitive Roche UltraDirect
assay (with a lower limit of 20 copies/mL), the proportion of 035 patients
with "undetectable" plasma HIV RNA fall to 60%. (Which is beginning to look
more like INCAS!) While experts disagree on how significant the difference
between <500 and <20 copies/mL is, emerging clinical data are becoming more
and more convincing that a nadir of <20 assures a significantly more
durable response to treatment.
- In a French study of similar design called AVANTI 2, which treated drug
naïve patients with the same triple combo (AZT+3TC+indinavir), the
proportion of study participants with plasma HIV RNA < 20 copies/mL at 52
weeks was also 60% -- the same proportion seen at 2 years in 035's
- A study of indinavir in combination with DMP-266 found that 82% of the
IDV+DMP recipients whose RNA fell to between 1-400 copies/mL experienced
viral rebound (defined as any RNA measurement > 400 copies/mL) within 100
days of initiation of treatment compared to only 25% of patients whose
plasma viral load fell to < 1 copy/mL after initiation of the double
combination treatment. The ultra, ultra sensitive assay used in this study
was the new (experimental) Amplicor assay.