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New Antiretroviral Drugs, Part I: PIs

This is the first installment of a two-part article on new antiretroviral drugs in development. This article provides details on new protease inhibitors (PIs). The second part, to appear in June, will examine NRTIs and NNRTIs in development, as well as two new classes of antiretrovirals: fusion inhibitors and integrase inhibitors.

Currently 15 antiretroviral drugs are approved or are available through expanded access programs. Therapy with combinations of these drugs, which inhibit either the viral protease or the reverse transcriptase enzyme, is associated with significantly decreased morbidity and mortality in persons with HIV-1 infection.¹ However, as many as 50% of treated patients do not have a sustained antiviral response and durable clinical benefit. Therapeutic options with the available antiretroviral agents for patients who experience virologic rebound or clinical failure are limited at best and have been poorly studied. The reasons for failing a regimen are many and include limited potency, unfavorable pharmacokinetic properties, drug class cross-resistance, intracellular resistance, patient intolerance, and poor adherence. The need for improved therapies is critical for many and is likely to increase.

Fortunately, there are at least 23 new antiretroviral drugs in clinical development that could realistically become available within the next three years. Several offer significant hope for patients and clinicians faced with finding a more potent and better-tolerated initial regimen or an effective salvage treatment. Many of the new drugs offer more favorable pharmacokinetic and resistance profiles, even within drug classes. Additionally, some of these drugs in development inhibit new viral targets, thus offering the potential for further treatment synergies than are currently available.

ABT-378, one of the most promising drugs in development, has a potency in vitro 10 times greater than that of ritonavir. As with other PIs, this drug's protein binding is high (98% to 99%). ABT-378 is metabolized primarily by CYP3A. One of the unique features of this compound is its metabolic inhibition in the presence of ritonavir -- a potent CYP3A inhibitor -- resulting in high plasma drug levels. When coadministered with as little as 50-100 mg of ritonavir, the ABT-378 trough concentrations in healthy volunteers were 20- to 83-fold above the protein binding-corrected in vitro IC₅₀ for wild-type HIV-1.² This pharmacokinetic effect is considerably greater than that observed with any of the currently available PIs when used in combination with ritonavir.

In the first clinical study of ABT-378, two groups of treatment-naive patients received a regimen containing ABT-378/ritonavir (ABT-378/r). In the first group, 32 patients received ABT-378/r at 200/100 or 400/100 mg combinations twice daily for three weeks, at which time d4T and 3TC were added. The median baseline plasma HIV-1 RNA and CD4 count were 72,000 copies/ml and 399 cells/mm³ respectively. Following the initial three-week treatment period with ABT-378/r alone, the median plasma HIV-1RNA change from baseline was 2.0 log₁₀ copies/ml.³ A second cohort of 69 subjects was randomized to ABT-378/r at 400 mg/100 mg and 400 mg/ 200 mg combinations twice daily. This group received standard doses of d4T and 3TC from the onset of therapy. The median baseline plasma HIV-1 RNA and CD4 cell count was 66,000 copies/ml and 311 cells/mm³, respectively. After 24 weeks, the median plasma HIV-1 RNA change from baseline in Group One was 2.4 log₁₀ copies/ml and 27 of 29 patients (93%) had HIV-1 RNA <400 copies/ml. At week 24, 43 of 46 patients (96%) in Group Two had HIV-1 RNA <400 copies/ml, and 73% of Group One patients had had a viral load below 50 copies/ml by ultrasensitive PCR. The CD4 count response has been robust, with increases greater than 120 cells/ mm³ after 12 weeks. The most common adverse events were generally mild and self-limited and included loose stools and/or diarrhea and headache. No study subject has discontinued therapy because of an adverse event.⁴

The preliminary analysis of this early clinical data suggest that the combination ABT-378/r is highly potent, easily administered twice daily, and very well tolerated. Another study is underway to investigate the use of ABT-378/r following virologic rebound associated with another PI-based therapy. Further development is being planned utilizing the 400-mg ABT-378 + 100 mg ritonavir dose twice daily.

L-756,423 is a chemical analogue of indinavir and a potent PI. It differs from indinavir in that it has a longer half-life and has the potential for once-daily dosing. L-756,423 is a less potent inhibitor of CYP3A than indinavir, and when the drugs are coadministered, L-756,423 exposure is increased. Dosing with food also increases exposure. There is significantly less renal excretion of L-756,423 compared with other PIs, and little unchanged drug can be detected in the urine.

Over 150 volunteers have received L-756,423 in Phase I trials. In addition to increasing drug exposure, dosing with indinavir decreases drug accumulation and decreases interpatient variability. Doses of 800 and 1,600 mg of L-756,423 have been administered with 400- and 800-mg doses of indinavir, respectively. The combinations were generally well tolerated.

Researchers have initiated two Phase II pilot studies, one in naive patients and the other in patients who have failed on indinavir-based therapy. Patients will receive L-756,423/indinavir as 1600 mg/800 mg daily or 800 mg/ 400 mg twice-daily. Naive patients will receive concomitant d4T and 3TC, and the treatment-experienced patients will receive at least one new NRTI.

L-756,423 appears promising when used in combination with indinavir because of its potential for once-daily dosing and the possibility that the high plasma levels achieved may make this drug an effective salvage therapy. Development is expected to proceed swiftly. (Personal communication, Bach-Yen Nguyen, MD, and Ben Unger, PhD.)

Tipranavir (PNU-140690) is a potent new nonpeptidic PI effective in vitro against HIV-1 isolates that are resistant to ritonavir and indinavir. Tipranavir's absorption is improved when it is taken with meals, and its steady-state plasma levels are reduced over time, suggesting a modest amount of autoinduction. In 24 PI-naive patients taking stable NRTIs, the addition of tipranavir in doses of 900, 1,200, and 1,500 mg three times daily resulted in mean plasma HIV-1 RNA reductions of 1.0, 1.3, and 1.2 log₁₀ copies/ml, respectively by day 11. However, by week four, the reductions were 0.5, 1.1, and 0.9 log₁₀ copies/ml, respectively. Although no serious adverse events were reported, the decrease in activity over time appeared to be caused by adherence problems related to gastrointestinal side effects, which required symptomatic treatment in 37% of subjects. The pill burden -- up to 30 per day -- probably also contributed to the adherence problem. It is likely that researchers will investigate new formulations.⁵ Its favorable resistance profile potentially makes tipranavir an effective treatment strategy in patients who have failed on one of the current PIs.

AG 1776 (JE 2147, KNI 764) is a novel allophenylnorstatine-containing PI active against HIV-1, HIV-2, and SIV laboratory strains as well as HIV-1 clinical isolates with a mean EC₅₀ of 47.6 nM. This agent's beneficial properties include its potency, a bioavailability of 40% in animals, and its minimal protein-binding effect.⁶ Importantly, recombinant viral strains containing V82A, G48V/ V82A, V82(F)/L90M, or I84V/L90M amino acid substitutions were shown to be fully susceptible to AG 1776, even though they exhibited significant phenotypic resistance to all other PIs tested.⁷ Trials in human subjects are about to start.

BMS-232632, a new azapeptide PI, is a potent and promising agent that has just entered clinical development. Comparative in vitro studies have shown that BMS-232632 is more potent than any of the approved PIs, even in the presence of 40% human serum EC₅₀=2-5 nM), and has additive or synergistic activity in combination with other antiretrovirals. In vitro passage of HIV-1 in the presence of BMS-232632 selected for resistant variants less readily than nelfinavir or ritonavir. BMS-232632 shows a unique protease resistance profile, and may be sensitive to virus that is resistant to nelfinavir, saquinavir, and amprenavir. However, ritonavir- and indinavir-resistant viruses displayed partial resistance to BMS-232632. On the other hand, BMS-232632-resistant virus was susceptible to saquinavir but somewhat resistant to the other PIs.

So far, BMS-232632 has been well-tolerated clinically, and early pharmacokinetic data suggest that it may be dosed once daily, an obvious advantage over other members of this potent class of antiretroviral agents.^8,9

DMP-450 is a cyclic urea compound and potent inhibitor of HIV-1 protease. Its oral bioavailability is good, and single doses of DMP-450 result in plasma levels in excess of those required to inhibit wild-type and several mutant HIV-1 variants. Based on limited data, this drug appears to offer advantages in terms of its potency, favorable pharmacokinetics, and activity against multiply-mutant variants.¹⁰

DG 17/35 is an HIV-1 PI containing a hydroxyethylhydrazide core unit. It has potent activity against HIV-1 (IC₉₀ range: 0.02-0.08 mM), HIV-2, and SIV. Intermediate resistance with this drug is associated with mutations at protease codons L24I, G48W, and A71T, whereas high-level resistance is associated with an additional mutation at W48L and a mutation in the P7/P1 gag-pol cleavage site. DG35-resistant strains have some cross-resistance to saquinavir, ritonavir, and indinavir. Despite its potent activity, DG35 has poor oral bioavailability. This drawback led to the design of DG17, a prodrug of DG35. The prodrug appears to be well-tolerated. In 12 subjects receiving either 5 or 10 mg/kg doses of DG17, all had plasma levels well above the IC₉₀. Safety and efficacy studies are underway.¹¹

— Robert L. Murphy, MD

Dr. Murphy is Associate Professor of Medicine and Director of the HIV Treatment Clinic at Northwestern University. Dr. Murphy has received research and/or consulting support from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Dupont Merck, Dupont Pharmaceuticals, GlaxoWellcome, Merck, Roche, Oxochemie, and Trimeris.)

Published in AIDS Clinical Care May 1, 1999

Citation(s):

1. Palella FJ et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998 338 853-860.

• Original article (Subscription may be required)
• Medline abstract (Free)

2. Lal R et al. Abstr. 647 5th Conference on Retroviruses and Opportunistic Infections, Chicago. February 1-5 1998 .

3. Japour A et al. Abstr. 12460 12th World AIDS Conference, Geneva. June 28-July 3 1998 .

4. Murphy R et al. Abstr. 15 6th Conference on Retroviruses and Opportunistic Infections, Chicago. January 31-February 4 1999 .

5. Wang Y et al. Abstr. 41176 12th World AIDS Conference, Geneva. June 28-July 3 1998 .

6. Ueno T et al. Abstr. 12270 12th World AIDS Conference, Geneva. June 28-July 3 1998 .

7. Patick AK et al. Abstr. 11 6th Conference on Retroviruses and Opportunistic Infections, Chicago. January 31-February 4 1999 .

8. Gong YF et al. Abstr. I-79 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego. September 24-27 1998 .

9. Robinson B et al. Abstr. I-20 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego. September 24-27 1998 .

10. Hodge CN et al. Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. Chem Biol 1996 3 301-314.

• Medline abstract (Free)

11. Tyssen D et al. Abstr. LB2 1st International Conference on the Discovery and Clinical Development of Antiretroviral Therapies, St. Thomas, USVI. 13-17 1998 Dec .