IDrugs. 1998 Oct;1(6):700-11.

Efavirenz DuPont Pharmaceuticals Co.

IDrugs : the investigational drugs journal

B J Dong

PMID: 18465625

Abstract

Efavirenz is the lead compound of a series of benzoxazinones originally developed by DuPont Merck. It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) under development for the potential treatment of viral infections, including HIV. In June 1998, the company submitted an NDA to the US FDA for the use of efavirenz (as Sustiva) for the treatment of HIV infection [289361]. In July 1998, DuPont purchased Merck's interest in DuPont Merck and the company's name changed to DuPont Pharmaceuticals. The two companies decided to continue to share marketing rights to Sustiva (to be marketed by Merck as Stocrin outside the US, Canada, and certain European countries) [291738]. As of October 1997, triple combination studies of efavirenz were ongoing, or planned, with nelfinavir, indinavir or ritonavir, or other retroviral inhibitors, for the treatment of opportunistic and pediatric viral infections [265945]. Efavirenz is also being evaluated as monotherapy and in combination with zidovudine (Retrovir, AZT) and lamivudine (Epivir, 3TC) (qv). Results of a study in eight HIV-infected patients, reported at the 12th World AIDS Conference in July 1998, showed that efavirenz administration, in dual and triple combinations, achieved HIV-RNA levels in plasma and cerebrospinal fluid (CSF) below the level of detection (fewer than 400 copies/ml) [290881,293994]. In March 1998, Merck signed a letter of intent with Trimeris to conduct a trial of efavirenz in combination with Trimeris's HIV fusion inhibitor, T-20, (qv). The trial will enroll up to 48 HIV-infected individuals at three sites in the US. All enrolled patients will be those who have begun to fail their existing triple combination therapy. Prior exposure to NNRTIs and protease inhibitors, other than indinavir, will be among the exclusion criteria for the study. The first 10 days of the study were planned as a dose-optimization period to assess the safety, pharmacokinetics and antiviral activity of multiple ascending doses of T-20. After completion of this period, subjects will be eligible to participate in an extension period of at least six months, during which T-20 will be administered in combination with efavirenz and two protease inhibitors [281696]. A 137-patient phase III study showed that efavirenz, in combination with zidovudine and lamivudine, caused significant reduction in viral levels and increased CD4 cell levels. The results were presented at the Sixth European Conference on Clinical Aspects and Treatment of HIV Infection (Hamburg, Germany, October 1997) [265945]. At the Fourth Conference on Retroviruses and Opportunistic Infections, in January 1997, data were presented from a clinical trial of efavirenz in combination with indinavir, which showed that, in 82% of the patients, viral load was reduced to undetectable levels, as measured by the Amplicor assay [231410]. Further retrospective analysis showed that the viral load was a significant predictor of long-term (over 52 weeks) viral suppression [265945]. A double-blind, phase II pilot study of efavirenz showed significant activity in HIV-RNA suppression and CD4 cell recovery when evaluated for two weeks alone, and even better results when used in combination with indinavir (Crixivan, qv); 80% of patients achieved HIV-RNA below level of quantification and CD4 cell count elevation averaging 140 cells/mm3. The study evaluated 16 patients for 12 weeks and is ongoing [219671,227966]. A total of 21 patients received indinavir (800 mg, eight hourly) for two weeks, followed by combination therapy with efavirenz (200 mg, once daily). Another group of nine patients received indinavir alone for 26 weeks, followed by the addition of stavudine (Zerit) and efavirenz. In combination use, indinavir dosing was 1.0 g every eight hours. At 26 weeks, approximately 40% of the patients receiving indinavir alonehad plasma levels below 400 copies/ml of HIV-RNA. After stavudine and efavirenz were added, and following 16 weeks of the triple combination, 83% of the patients had plasma levels below 400 copies/ml [247754].

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