Experimental Treatments for HIV
Protease Inhibitor Drugs BMS-232632, DMP-450, Tipranavir
The interim results of a phase II study of BMS-232632 were presented by I. Sanne,
MD of Johannesburg Hospital in South Africa.
This drug is an experimental protease (PI) inhibitor that has a once
daily dosing, without ìboostingî from a second PI drug. A total of 422 HIV positive patients
were enrolled; 32% were women, 40% were non-Caucasian and 13% had a history of
injection drug use. Less than four
weeks of previous NRTI drug experience and less than one week of previous NNRTI
or PI drug experience was allowed. The
median baseline CD4 count was 318 cells per microliter, with an HIV RNA viral
load of 4.7 log (50,118) copies per milliliter. In this double-blind study (medication type and dose not know
by patient or physician), patients took BMS-232632 as the only drug for two
weeks. They were randomized to a
dose of 200, 400 or 500 mg once daily. A
control arm took nelfinavir (Viracept, PI drug) 750 mg 3-times daily. After two weeks, stavudine (d4T, Zerit)
and didanosine (Videx, ddI, both NRTI drugs) were added. A sub-group of 98 patients have completed 24 of the planned
46 weeks, while the remaining have completed only 16 weeks.
The interim results in the first sub-group after 24 weeks
showed that up to 35% had an undetectable viral load, with a lower limit of 50
copies per milliliter (strict ìintent-to-treatî analysis, all patients
included). In the larger subgroup,
the three doses and their respective percentages with an undetectable viral load
after 12 weeks were: 200 mg (39%), 400 mg (31%) and 500 mg (50%) (Editorial comment: the larger subgroup was started after the first
sub-group, and was a larger study (n=300 or more; about 80 per arm), and
patients were recommended to take BMS-232632 with food which enhances drug
exposure and reduces drug level variability significantly). In general, the viral load decreased by
approximately 2.5 log (316-fold) at 12-16 weeks. In the larger subgroup, the CD4 count increased by
approximately 75-100 cells per microliter after 12 weeks. The most common side effects were
nausea, diarrhea, stomach area (gastrointestinal) pain, infection and headache. As has been previously reported, the blood bilirubin (bile
pigment) increased in all three dosing armsóthis was treated by reducing the
dose of BMS-232632. In seven of
these cases, the patients had jaundice (yellow appearance to skin and whites of
eyes). There were five cases of
life-threatening (grade 4) increases. On
the other hand, there were only minimal increases or no changes in total blood
cholesterol, ìLDLî (ìbadî or low density lipoprotein) cholesterol or
triglycerides (blood fats). Whereas,
the nelfinavir control arm did have increases in those measurements of
cholesterol and triglycerides.
In a second presentation about BMS-232632, Edward OíMara
MD of Bristol-Myers Squibb showed that there were no significant changes in
blood levels of BMS-232632 when it is taken at a 400 mg dose with 200 mg of
ketoconazole (Nizoral, anti-fungal antibiotic). In a third presentation about BMS-232632, Dr. OíMara
reported initial results suggesting a genetic marker increases the risk of
increased bilirubin (see side effects above) from the drug. The marker is called ìUDP-GT 1A1î (see reference list). This marker also should be tested for
the same side effect that occurs among some patients when they take the PI drug
indinavir (Crixivan). In a fourth
presentation about BMS-232632, Richard Colonno, PhD of Bristol-Myers showed that
the drug has ìno obvious mutational patternÖother than a requirement of
several [PI drug] mutations to be present.î
See NATAP ICAAC Report on
BMS-232632:
once a day protease inhibitor in early human development
References
Colonno RJ and others. Efficacy of BMS-232632 against a panel
of HIV-1 clinical isolates resistance to currently used protease inhibitors.
Abstract 2114.
OíMara E and others. Relationship between uridine
diphosphate-glucuronosyl transferase (UDP-GT) 1A1 genotype and total bilirubin
elevations in healthy subjects receiving BMS-232632 and saquinavir. Abstract and poster 1645.
OíMara E and others. Steady-state pharmacokinetic interaction
study between BMS-232632 and ketoconazole in healthy subjects. Abstract and poster 1646.
Sanne I and others. Safety and antiviral efficacy of a
once-daily HIV-1 protease inhibitor BMS-232632: 24 weeks results from a phase II
clinical study. Abstract 691.
There were three presentations about DMP-450, an experimental PI drug under development by Triangle
Pharmaceuticals. A phase I/II study
included 40 HIV positive patients. Women
represented 13%; race-ethnic background was not reported. None had previously taken anti-HIV
drugs. The median baseline viral
load was 4.6-5.3 (39,810-177,827) log copies per milliliter with a median CD4
count of 234-285 cells per microliter. The
dose of DMP-450 was 750 mg 3-times daily, 1250 mg 3-times daily or 1,250 mg
twice daily. The two NRTI drugs
also taken by all patients were stavudine (d4T, Zerit) and lamivudine (3TC,
Epivir).
The results showed that after up to 48 weeks, 87% had an
undetectable viral load using a lower limit of 50 copies per milliliter (strict
ìintent-to-treatî analysis, all patients included). Side effects included diarrhea, nausea, muscle aches,
headache and rash. There were mild
increases in blood cholesterol. The
authors concluded that DMP-450 was tolerated well, had significant anti-HIV
benefits with few differences when comparing the three doses. Interestingly, the 1,250 mg 3-times daily dosing led to equal
or marginally better drug concentrations than the 1,250 mg twice daily dosing. This included the maximal, minimal and
total (ìarea-under-the-curveî) concentrations. This suggests that DMP-450 might be
dosed twice daily, which is associated with better adherence to dosing in other
studies. Dr. G. Moralles of
Triangle Pharmaceuticals has reported previously that this PI drug has a
relatively lower cost of production that could lead to marketing in
resource-poor countries.
In a second presentation about DMP-450, Dr. Laurene Wang of
Triangle Pharmaceuticals reported drug interactions when it was added to either
indinavir (Crixivan) or saquinavir (Fortovase, both PI drugs). Healthy HIV negative volunteers were
enrolled. Neither of those two PI
drugs affected the blood concentrations of DMP-450. However, 1000 mg of DMP increased the
minimal and total (ìarea-under-the-curveî or ìAUCî) concentration of
indinavir by approximately 40%. Yet,
the maximal concentration and ìhalf-lifeî (time until an original amount is
metabolized by half) were not changed. When
DMP-450 was added to saquinavir, the maximal concentration increased 5-fold, the
ìAUCî concentration 10-fold and the ìhalf-lifeî by 2.5-fold. This information is important before
clinical studies could be devised that would combine DMP with either indinavir
or saquinavir.
There was a third presentation about side effects of
DMP-450 authored by Dr. Gregory Chitick of Triangle Pharmaceuticals. The results were a lesser increase in
total blood cholesterol when compared to indinavir (Crixivan, PI drug) and
similar increases in triglycerides (fats) and glucose (sugar). Dr. Chitick concluded that 2,000 mg
twice daily of DMP-450 ìappears to be the maximum tolerated dose.
References
Chittick GE and others. Effects of a novel HIV-1 protease
inhibitor, DMP 450, on cardiac tracing, serum lipids and glucose tolerance, as
compared to indinavir. Abstract and
presentation 1648.
Sierra J and others. Preliminary profile of the antiviral
activity, metabolic effects, safety and pharmacokinetics of DMP-450, a novel
cyclic urea protease inhibitor. Abstract
and presentation 540.
Wang LH and others.
Effects of a novel HIV-1 protease inhibitor, DMP 450, on the
pharmacokinetics of indinavir and saquinavir.
Abstract and presentation 1647.
Information about resistance to tipranavir was presented by Dr. Sharon Kemp of Virco. This experimental PI drug has activity
against numerous HIV strains (isolates) that are resistant to PI drugs currently
available by prescription. Dr. Kemp
concluded, ìThere does not appear to be any obvious common combinations of the
known PI mutations that clearly confer tipranavir resistance.î She was able to generate moderate
resistance with eleven primary and secondary mutations seen with other PI drugs.
Reference
Kemp S and others. Site-directed mutagenesis and in vitro drug selection studies have
failed to reveal a consistent genotypic resistance pattern for tipranavir. Abstract 2113.
A more detailed report was shown by Sharon Kemp at the
Resistance Workshop. Here's the link to NATAP Report:
Tipranavir:
in vitro resistance data on a protease inhibitor for PI resistance
NNRTI Drugs
Capravirine, R165335
The results of a phase I study of capravirine (AG1549) were presented by Dr. S. Hayashi of Agouron
Pharmaceuticals. This drug is an
experimental NNRTI drug with activity against the common ìK103Nî mutation
that causes resistance to each of the three NNRTI drugs currently available. A total of 45 HIV negative volunteers
included 53% women, 22% African-American and 16% Hispanics. The results showed that, when compared
to fasting (empty stomach), blood concentrations of capravirine were increased
2-fold when taken with a meal that was either low-fat, low-calorie or high-fat,
high-calorie. Those concentrations
included minimal, maximal and total (ìarea-under-the-curveî). The ìhalf-lifeî (time until an
original amount is metabolized by half) was not changed. The dose was two 700 mg tablets.
Reference
Hayashi S and others. Effects of fasting, high-fat and low-fat
meals on the pharmacokinetics of a single dose of capravirine (AG1549), an NNRTI,
in healthy volunteers. Abstract and
presentation 1667.
Laboratory testing of a ìthird generationî NNRTI drug
called ìR165335î were presented
by researchers from Janssen Research Foundation and Tibotec. This compound had anti-HIV activity at
ìnanomolarî (extremely low) concentrations.
It also retained activity against several HIV strains (isolates) with one
or two resistance mutations that renders any of the three FDA-approved NNRTI
drugs ineffective. Also, its
activity is not affected by human proteins albumin and ìalpha 1 acid
glycoproteinî that can bind several of the marketed anti-HIV drugs. Further development is proceeding.
References
Andries K and others. R165335-TMC125, a novel non nucleoside
reverse transcriptase inhibitor (NNRTI) with nanomolar activity against NNRTI
resistance HIV strains. Abstract
1840.
De Bethune MP and others. R165335-TMC125, a third generation non
nucleoside reverse transcriptase inhibitor (NNRTI) inhibits 98% of more than
2,000 recombinant HIV clinical isolates at 100nM.
Abstract 1841.
NtRTI Drug Tenofovir
There were three presentations about tenofovir disoproxil (PMPA). This drug is an experimental nucleotide reverse transcriptase inhibitor drug
(NtRTI) under development by Gilead Sciences.
It is dosed once daily and has activity against HIV strains (isolates)
with specific resistance to several NRTI drugs (see 2nd next
paragraph). The NtRTI drugs differ
from the NRTI drugs in that they only require two steps for activation rather
than three that are required for the NRTI drugs.
An update of tenofovir in patients with advanced disease was presented by
Robert Schooley, MD of the University of Colorado at Denver. The study was ìdouble blindî
(medication type not known by patient or physician) and ìplacebo-controlledî
(one arm takes a ìdummy,î inactive drug or sugar pill). Enrolled patients must have had a
detectable viral load on a stable anti-HIV regimen for at least two months. Tenofovir was added at a dose of 75 mg,
150 mg, or 300 mg. All patients,
including those randomized to placebo took 300 mg of tenofovir after week 24. The 189 enrolled patients had taken
anti-HIV medication for a mean of 4.6 years with a mean baseline viral load
(when starting this study) of 375 cells per microliter. At that time, 97% had ìgenotypeî
resistance mutations to NRTI drugs.
The results after 48 weeks showed the following viral load
reductions: 300 mg (decrease of 0.7 log copies per milliliter or 5-fold); 150 mg
(decrease of 0.6 log copies per milliliter or 4-fold); 75 mg (decrease of 0.4
log or 2.5-fold); and placebo changed to 300 mg (decrease of 0.7 log or 5-fold). The CD4 count increases were: 300 mg (11
cells per microliter); 150 mg (16 cells per microliter); 75 mg (11 cells per
microliter); and placebo changed to 300 mg (25 cells per microliter). At 48 weeks, 20% had stopped tenofovir,
compared to 25% in the 300 mg arm up to 24 weeks.
Dr. Schooley reported that there was no dose-related toxicity. The percentage of patients with an
undetectable viral load was not presented.
In a separate presentation, Michael Miller, PhD of Gilead
presented information about tenofovir
resistance. HIV strains
(isolates) with the common lamivudine (3TC)-induced mutation ìM184Vî are
ìhypersensitiveî (less drug needed to achieve the same effect as with
ìwild-typeî virus without mutations) to tenofovir. Almost all strains with high-level
resistance to zidovudine (AZT, Retrovir) also were sensitive to tenofovir. Adding ìM184Vî to those strains
increased tenofovir sensitivity somewhat. A
combination of NRTI mutations (ìQ151Mî) that lead to multi-drug NRTI
resistance did not decrease tenofovirís effectiveness, with or without
ìM184V.î However, another group
of multi-drug resistance mutations (ì69 insertionsî) were resistant to
tenofovir, but became more sensitive (ìintermediate resistance, 6-fold
decreaseî) when ìM184Vî was added. The
ìK65Rî resistance mutation (due to abacavir, didanosine or zalcitabine)
decreased sensitivity to tenofovir somewhat, but this was nearly reversed when
ìM184Vî was added. These
results indicate the unique effectiveness of tenofovir against HIV with several
types and groupings of mutations that cause NRTI drug resistance.
In a third presentation, Dr. L.K. Naeger of Gilead
presented other information that might explain part of the reason for
tenofovirís effectiveness against HIV strains with various NRTI mutations. Resistance to zidovudine and stavudine (d4T, Zerit) has been
partly explained by two different mechanisms.
They are called ìpyrophosphorolysisî and ìdinucleotide
polyphosphate synthesis.î In a
series of experiments, Dr. Naeger showed that tenofovir is much less susceptible
to these resistance mechanisms than zidovudine is.
References
Miller MD and others. Antiviral activity of tenofovir (PMPA)
against nucleoside-resistant HIV samples. Abstract
and presentation 2115.
Naeger LK and others. Tenofovir (PMPA) is less efficiently
removed through pyrophosphorolysis and dinucleotide polyphosphate synthesis than
zidovudine by HIV-1 wild-type RT and RT mutations. Abstract and presentation 1265.
Schooley R and others. Tenofovir disoproxil fumarate (TDF) for
the treatment of antiretroviral experienced patients, a double blind,
placebo-controlled study. Abstract
and presentation 692.
NRTI Drugs: emtricitabine
(Coviracil), DAPD
Emtricitabine
(FTC, Coviracil) is a NRTI drug with activity against HIV and HBV (hepatitis B
virus). Safety results were
presented by Dr. T.B. Grizzle of Triangle Pharmaceuticals. In various tests in the laboratory, including small animals,
essentially no toxicity (including cancers and birth defects) was detected. At a dose more than 100-times that used
in humans, anemia (low red cell count) occurred in female monkeys and resolved
after the drug was stopped. At a
dose almost 1,000-times that used in humans, the same side effect occurred in
mice. In several laboratory tests
for ìmitochondrialî toxicity, none was found.
(Mitochondria are the energy producers of cells and several NRTI drugs
are toxic to them.) In a small
study of 40 patients that combined FTC with didanosine (ddI, Videx) and
efavirenz (Sustiva) in a once-daily regimen, 95% achieved an undetectable HIV
viral load (lower limit 400 copies per milliliter) after 48 weeks (see
reference). None had had prior
treatment for HIV. This strongly
suggests very high potency of that triple drug combination. A second report at ICAAC presented DAPD
results in children when testing safety and drug metabolism.
References
Grizzle TB and others. Emtricitabine: summary of toxicology and
nonclinical pharmacology evaluations. Abstract
and poster 1631.
Molina J-M and others.
Once-daily therapy with emtricitabine, didanosine and efavirenz in treatment naÔve
HIV-infected adults: 48-week follow-up of The ANRS 091 Trial. Late Breaker
abstract 648 at the 38th Annual Meeting of
the IDSA (Infectious Diseases Society of America); September 7-10, 2000; New
Orleans, Louisiana.
Wiznia AA and others. An evaluation of the pharmacokinetics
and safety of single oral doses of emtricitabine (Coviracil) in HIV-infected or
exposed children. Abstract and
poster 1665.
The results of a phase I/II study of DAPD were presented by Joseph Eron, MD of the University of North
Carolina at Chapel Hill. DAPD is a
NRTI drug and has activity against HIV and HBV (hepatitis B virus). It also has activity against HIV strains
with selected resistance to zidovudine (AZT, Retrovir), lamivudine (3TC, Epivir)
and/or abacavir (Ziagen). HIV
positive patients without previous treatment for HIV were enrolled. The DAPD dose was twice daily of 25 mg,
100 mg, 200 mg, 300 mg, or 500 mg. The
maximum HIV RNA viral load reduction after 15 days of the drug was 1.5 log
(31-fold) copies per milliliter at the 300 mg dose. The drug was tolerated well,
without any discontinuations due to drug adverse effects (side effects). No ìgenotypeî resistance associated
with NRTI drugs was detected at the end of the 15-day study. In a treatment
experienced group, a 1.1 log reduction in viral load has been seen in small 15
day study using the 500 mg dose.
Other Drugs in Pre-Human Testing
There were a few other drugs or ìcompoundsî presented
at ICAAC that are in ìpreclinicalî (before use in humans) development. The first group of integrase inhibitors called ìbutanoic acidsî was described by
Dr. John S. Wai from Merck. PRO 140, an entry inhibitor drug, is an antibody (type of protein) to the
ìCCR5 receptorî on human immune cells to which HIV binds. In lab tests, ìlow nanomolarî
(extremely low) concentrations of PRO 140 blocked infection of blood
ìmononuclear cellsî by HIV strains that use ìCCR5î to enter. Dr. W. C. Olson of Progenics presented
the study. In a separate
presentation, Dr. Olson found that combining the two HIV entry inhibitor drugs PRO 542 and T-20 led to ìsynergisticî (enhanced effects by
combining) benefits in the laboratory. (T-20
is already in phase III human studies and is also called an HIV ìfusionî
inhibitor.) In yet another
presentation, Dr. C. L. Tremblay of Massachusetts General Hospital in Boston
reported anti-HIV ìsynergyî when T-20 was combined with the ìCCR5î
receptor inhibitor TAK-779. Previously, Dr. Tremblay has reported a
similar synergistic effect in the laboratory when T-20 was combined with AMD-3100, an entry inhibitor of the
CXCR4 receptor on human T cells that HIV uses to enter. AMD 3100 was reported to be absorbed
into the blood of rabbits when they took the experimental medication by mouth. Dr. R. T. MacFarland of AnorMED Inc.
presented the report at ICAAC. Two
experimental ìribonucleotide reductaseî inhibitors showed anti-AIDS benefits
in an animal (ìmurineî) AIDS model, either alone or when combined with
didanosine (ddI, Videx). Both Trimidox and Didox are
similar to hydroxyurea (Hydrea), but showed much less toxicity than hydroxyurea. The report was presented by Dr. C. N.
Mayhew of the University of Wolverhampton in the UK.
References
MacFarland RT and others. An orally bioavailable CXCR4 antagonist
for inhibition of HIV replication. Abstract
1845.
Mayhew CN and others. Comparison of novel ribonucleotide
reductase inhibitors, Didox and Trimidox, to hydroxyurea regarding
antiretroviral activity and toxicity in murine AIDS. Abstract 553.
Olson WC and others. Potent, broad spectrum inhibition of
HIV-1 by the CCR5 antibody PRO 140. Abstract
550.
Olson WC and others. Potent, synergistic inhibition of HIV-1
by combinations of the viral entry inhibitors PRO 542 and T-20. Abstract 549.
Tremblay CL and others. In vitro synergy observed between the
fusion inhibitor T-20 and a CCR5 inhibitor TAK-779. Abstract 1164.
Wai JS and others. 4-aryl-2,4-dioxobutanoic acid inhibitors
of HIV-1 integrase and viral replication in cells. Abstract and presentation 1844.