Protease Inhibitors (PIs)

BMS-232632

Several presentations focussed on Bristol-Myers Squibb’s BMS-232632, the first once-daily PI. The lower dosing is due to the drug’s long half-life (time for an original amount to be reduced by half.) With once-daily dosing of either 400, 600, or 800 mg of BMS-232632, the blood level achieved is still several fold higher than the IC50 (inhibitory concentration that blocks 50% of wild-type, or nonmutated, HIV growth). In Phase I studies, the only dose-limiting adverse event was increased indirect bilirubin (bile pigment) levels. I. Sanne, MD, and colleagues from Johannesburg Hospital in South Africa presented the 16-week, Phase II results of BMS-232632 with ddI (Videx) and d4T (Zerit).

The study enrolled 92 HIV positive, treatment-naive (no previous anti-HIV treatment) persons (28% women, 48% non-White). The median baseline HIV RNA viral load was 4.8 log (63,095) copies/mL, while the CD4 cell count was 386 cells/mm3. After two weeks of BMS-232632 monotherapy (200, 400, or 500 mg), standard doses of d4T and ddI were added. BMS-232632 was taken one hour after the ddI/d4T combination due to low blood levels of the former if taken concurrently. Absorption of BMS-232632 from the stomach is increased with a light meal, with only mild increases with a high fat meal.

The 16-week, interim results showed that the percentages with an undetectable viral load were approximately 55-60% (limit of detection 400 copies/mL) and 45-50% (limit of detection 50 copies/mL) in all of the study arms. The CD4 cell count increased from 80 cells/mm3 to 175 cells/mm3. Adverse events were as follows. With increasing doses of BMS-232632, there was an increased risk of elevated indirect (unconjugated) bilirubin. Some persons had severe-to-life-threatening (grade 3-4) elevations. Some even developed jaundice (yellowing of the skin and whites of the eyes), without other symptoms or abnormalities. Other side effects were diarrhea (38%), nausea (18%), and concomitant infection (48%).

Another study examined the coadministration of 400 mg of BMS-232632 once a day with once-daily soft gel saquinavir (Fortovase, 800-1,600 mg) as a double PI drug combination. These studies revealed that BMS-232632 significantly increased the blood level of saquinavir by 5- to 7-fold, while the lowest (minimum) level increased by 7- to 18-fold. This would lead to anti-HIV benefits from both PI drugs. (Blood levels of BMS-232632 were not affected by saquinavir.) Adverse events from the combination were mild and reversible.

This prodrug of amprenavir (Agenerase) is under development by Vertex and Glaxo Wellcome. It is water-soluble and might allow for fewer daily capsules. The lead author of the presentation was Dr. A. Spaltenstein of Glaxo Wellcome.

L-756423

This PI was combined with indinavir (Crixivan) to become the experimental formulation MK-944A. L-756423 is being developed by Merck. In once-daily dosing of L-756423 1,600 mg and indinavir 800 mg with food, the minimum, maximum, and AUC (area under the curve, i.e., total exposure of drug) concentrations of L-756423 were well in excess of the IC95 (inhibitory concentration that will block 95% growth of wild-type HIV). Yet the estimated indinavir AUC concentration was 50% lower than that which occurs with standard dosing of indinavir, 800 mg every eight hours, without a second PI drug. This could lead to indinavir resistance.

Once-daily MK-944A was combined with standard dosing of d4T and 3TC (Epivir) in a double-blind study. The on-treatment analysis (including persons still taking medications, excluding dropouts) of 25 treatment-naive subjects at 12 weeks showed that 70% had an undetectable viral load (limit of detection 400 copies/mL), while the CD4 cell count increased by a mean 135 cells/mm3. In the second arm of the study, twice-daily dosing of both L-756423 800 mg and indinavir 400 mg was combined with d4T and 3TC. After 12 weeks, the undetectability rate in those 28 persons was 93%, with a mean CD4 cell count increase of 114 cells/mm3. The control arm with 26 subjects took indinavir standard dosing (800 mg, three times daily) plus d4T and 3TC. This arm had a 92% undetectability rate, with a CD4 cell count increase of 157 cells/mm3.

All three regimens were well tolerated. A stricter intent-to-treat analysis (all enrolled subjects included) was not reported. Due to kidney papillary problems in a rodent model, Merck withdrew from presenting their 24-week results of this study that was scheduled for the late-breaker session. The lead authors of the two presentations were Dr. P. Deutsch of Merck and P. Campo, MD, of the University of Miami in Florida.

MK-944A

See L-756423 above.

Tipranavir (TPV)

This drug is a unique and potent PI because it inhibits 90% of HIV growth that shows resistance to the first four Food and Drug Administration (FDA)-approved PIs. Interestingly, HIV that is resistant to saquinavir shows hypersensitivity (increased sensitivity) to TPV in laboratory tests. TPV has significant potency when combined with ritonavir (Norvir) 200 mg, both twice daily. A newly developed 300-mg soft capsule formulation allows for 75% fewer capsules to be taken compared with the original formulation. Protocol 0015 Phase II results of TPV were presented by William Freimuth, MD, from Pharmacia & Upjohn. Boehringer Ingelheim recently purchased the rights to future development and marketing of TPV, after it was originally developed by Pharmacia & Upjohn.

Three different doses of TPV were used: 1,200 mg (four capsules) twice daily as monotherapy (single drug therapy); 300 mg plus ritonavir 200 mg, both twice daily; and 1,200 mg plus ritonavir 200 mg, both twice daily. Thirty-one subjects (39% women, 55% non-White) with no previous treatment were enrolled. The median baseline HIV RNA viral load was 5.0 log copies/mL, with a median baseline CD4 cell count of 291 cells/mm3.

The two-week results showed that the two dual drug arms had HIV RNA viral load reductions that ranged from a median of -1.4 log copies/mL to -1.6 log copies/mL. The monotherapy arm had a median decrease of only -0.8 log copies/mL. The CD4 cell counts increased by a median of 73-77 cells/mm3. Pharmacokinetic (drug level/interaction) results in plasma (blood) were as follows. When compared with the monotherapy arm, the median AUC concentration of TPV in the dual therapy arms increased from 5- to 14-fold, while the trough (lowest) concentration increased by 27- to 88-fold. These measurements are quite favorable. Adverse events included diarrhea, nausea, vomiting, and fatigue. No serious adverse events were reported. The discontinuation rate was 10%, but not due to adverse events. Starting on day 15, all participants added AZT (Retrovir)/3TC (Combivir formulation) and delavirdine (Rescriptor) for a five-drug, three-drug class combination.

VX175

See GW433908 above.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Calanolide A

This drug is derived from Malaysian tropical plants in the genus Calophyllum, and therefore is a natural NNRTI. Calanolide A has activity against the double NNRTI mutations K103N and Y181C. (The K103N mutation leads to drug resistance for each of the three currently marketed NNRTIs.) The drug is being developed by Sarawak MediChem Pharmaceuticals. A dose-response relationship was reported in a two-week, Phase IB study. A total of 43 persons (26% women, 74% non-White) were enrolled in the study. The doses were twice daily of either 200 mg, 400 mg, or 600 mg. Because the half-life of the drug can extend to 20 hours, once-daily dosing may be possible. There was a high rate of side effects including fever, rash, and a decrease in the CD4 cell count that is worrisome. The CD4 cell issue will have to be resolved in future studies if this drug is to succeed.

Capravirine (CPV) is an NNRTI that is active against the K103N single mutation that causes resistance to each of the currently available NNRTIs. The drug is under development by Agouron Pharmaceuticals. CPV was combined with a stable background regimen of nelfinavir (Viracept) or indinavir plus 3TC and d4T or AZT in a 28-day, Phase II study. CPV with food was taken twice daily (175, 400, or 800 mg) for 28 days. A last group of seven persons took 1,000 mg of CPV twice daily for the first week, then with weekly increases to 1,200 mg twice daily, 1,400 mg twice daily, and then 1,800 mg twice daily. A total of 40 HIV positive persons (5% women, 28% non-White) were enrolled. Due to the small number of participants, viral load undetectability rates and CD4 cell count changes were not reported in an intent-to-treat analysis. (This study was a dose-ranging, safety study.)

esults did show a dose-response increase in CPV blood concentrations. Both nelfinavir and indinavir increased the concentration of CPV approximately 2-fold, but neither of the PIs had levels that were altered by CPV. The results also showed that CPV was safe and well tolerated. Adverse events that were moderate or worse included diarrhea (18%), nausea (5%), and 3% incidence for each of the following: vomiting, fatigue, headaches, nightmares, dry mouth, and rectal gas. Interestingly, no rashes were reported; rashes are a common side effect of the NNRTI drug class. Adverse laboratory events that were moderate or worse included neutropenia (low white cell count) (5%), increased liver enzyme AST (aspartate aminotransferase) (5%), increased bilirubin (3%), and increased muscle enzyme CPK (creatine phosphokinase) (3%). M. Jacobs, MD, of St. Francis Memorial Hospital in San Francisco was the lead author.

DPC 083 and DPC 961

These two drugs are new NNRTIs with activity against HIV that has resistance to all three marketed NNRTIs when due to the K103N mutation. In addition, each drug has activity against several K103N dual NNRTI resistance mutations. Each of them will be dosed only once daily, since the half-lives are so long. DPC 083’s half-life is more than 143 hours, while that of DPC 961 is 49 hours. Phase I studies enrolled a total of 66 healthy HIV negative volunteers (18% women) who took one drug or the other. The results were a dose-related increase in drug concentrations of up to 200 mg for DPC 083 and a less than dose-related increase for DPC 961. The lead authors of the two reports were W.D. Fiske, MD, and A.S. Joshi, MD, both from DuPont Pharmaceuticals.

GW420867X

Promising results of a Phase II study combining the experimental NNRTI GW420867X with AZT/3TC were presented. However, GW420867X causes a marked decrease in blood levels of a PI when the two are combined. Glaxo Wellcome has therefore made an interim decision to suspend further development of the drug.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

DAPD

This experimental NRTI showed anti-HIV benefits in a two-week, monotherapy Phase I/II study. The drug was well tolerated, and dose-dependent viral load decreases occurred. This drug is active against both HIV and hepatitis B virus (HBV). DAPD displays efficacy against the "69 insertion" multidrug resistance mutation and certain HIV strains that are resistant to AZT, 3TC, or abacavir (Ziagen). Interestingly, the common mutation K103N that causes resistance to the FDA-approved NNRTIs leads to DAPD hypersensitivity (in this case, increased anti-HIV benefits). Future once-daily dosing may be possible. DAPD is being developed by Triangle Pharmaceuticals.

A total of 29 HIV positive, treatment-naive persons (28% women, 66% non-White) were enrolled using DAPD monotherapy doses of 25 mg, 100 mg, 200 mg, and 300 mg, all twice daily for 14 days. Preliminary results showed that blood concentrations reached expected levels. In the highest dosing arm, the HIV RNA viral load decreased by a median of -1.5 log copies/mL at two weeks. None of 21 subjects analyzed developed any genotypic resistance in HIV’s reverse transcriptase gene. (A genotype resistance test evaluates a person’s HIV strain for mutations that have been previously associated with resistance to that drug or, in this case, drug class.) The drug was well tolerated. Adverse events included stomach/abdominal pain, nausea, vomiting, loss of appetite, headaches, and wheezing. There were no adverse events worse than grade 2, and no participant stopped treatment due to an adverse event. Adverse laboratory results included increased CPK in 17% (two persons had life-threatening elevations); low neutrophil (white cell) count; and increased triglycerides (fats) in 10%. The lead authors were Douglas Richman, MD, of the University of California at San Diego and L.H. Wang, MD, from Triangle Pharmaceuticals.

Trizivir

This new experimental combination tablet contains three NRTIs: abacavir, AZT, and 3TC. The Trizivir triple NRTI formulation, at a dosing of only one pill every twelve hours, is under development at Glaxo Wellcome. Study results showed that blood levels with the new formulation were very similar to those that occur when the three drugs are taken as separate pills. The tablet size is nearly the same as a standard Septra DS antibiotic tablet. (Septra, Bactrim, and cotrimoxazole are different names for an antibiotic used to prevent or treat Pneumocystis carinii pneumonia, or PCP.) There were no reports of swallowing difficulties or taste problems. Note that blood serum (without blood cells) measurements of the NRTIs do not reflect the active component of these drugs. The active component is the triple phosphorylated form within cells. The lead author of this study was Dr. G. Yuen of Glaxo Wellcome.

Other Experimental Drugs

Interleukin 7 (IL-7)

According to three different research groups, IL-7 represents a potential therapy or therapeutic target for treating HIV disease. Two separate groups found an inverse relationship between IL-7 blood levels and T-cell counts. A third research group found that IL-7 increases T-cell output from the thymus gland. T.J. Fry, MD, and colleagues from the U.S. National Cancer Institute (NCI) reported that IL-7 increases when the T-cell counts are low, and it decreases after HAART causes T-cell counts to increase. There was no correlation between IL-7 levels and levels of other cytokines (cellular messengers). Similar findings were reported by L.A. Napolitano, MD, and colleagues from San Francisco General Hospital. Dr. Napolitano also found that the stromal cells in lymph glands detect a low CD4 cell count and then respond by producing IL-7. A third research report about IL-7 was presented by Y. Okamoto, MD, and colleagues from the University of Texas Southwestern in Dallas. Dr. Okamoto found that in the laboratory, IL-7 can stimulate thymus gland production of T-cells in fetal and infant thymuses. Dr. Okamoto suggested the possibility using IL-7 with HAART to promote T-cell reconstitution.

Experimental Dosing of Approved Drugs

Amprenavir plus ritonavir

This combination might be able to be taken only once a day, according to simulated calculations by Dr. Brian Sadler of Glaxo Wellcome. Once-daily amprenavir 1,200 mg plus once-daily ritonavir 200 mg would provide more favorable blood concentrations of the former than the standard dosing of amprenavir alone, which is twice daily. The minimum concentration was more than 4-fold greater, the AUC concentration was 20% greater, and the maximal concentration was 9% less. Ritonavir levels were not changed significantly by amprenavir. The once-daily dosing is being planned for clinical trials in HIV positive persons.

Indinavir plus ritonavir

In a very small clinical study, evidence of antiviral success was demonstrated by using the experimental dosing of once-daily indinavir 800 mg plus ritonavir 200 mg and standard dosing of AZT/3TC. The lead author was J. Mallolas, MD, and colleagues from Barcelona. In the 16 treatment-naive subjects, the mean lowest indinavir concentration was 7-fold greater than its IC50. Thirteen percent, however, had minimum levels that were no greater than 2-fold higher than the IC50. Dr. Mallolas did not report the AUC concentrations. The four-drug regimen led to a viral undetectability rate of 94% (limit of detection 5 copies/mL) at 24 weeks. There were no severe or life-threatening adverse effects.