Calanolide A is a new, experimental non-nucleoside reverse transcriptase inhibitor (NNRTI) and a synthetic version of a compound found in nature. The compound was discovered by researchers from the National Cancer Institute, who isolated it from extracts from the latex produced by a tree (Calophyllum lanigerum) native to the tropical rain forest of Sarawak, Malaysia. Since the plant source is relatively rare, a chemical version was synthesized. The form in current use is formulated for oral administration and produced by Sarawak MediChem. Based in Lemont, Illinois, MediChem specializes in custom organic synthesis.
In laboratory studies calanolide A is active against various laboratory and clinical isolates of HIV-1 (but not HIV-2). Calanolide A appears to bind to reverse transcriptase in a manner unlike the other NNRTIs, and is therefore a member of a distinct class of NNRTIs. It appears active against drug-resistant strains of HIV, including strains resistant to AZT, nevirapine, and other nucleoside reverse transcriptase inhibitors (NRTIs).
In vitro studies of calanolide A in combination with other drugs, both nucleoside analogs and other NNRTIs, showed significant antiviral synergy (enhanced effects by combining drugs). Drugs with which calanolide A displays synergistic anti-HIV activity include AZT, ddI, ddC, and nevirapine. Calanolide A was active in human cells such as fresh peripheral blood leukocytes (white cells) and macrophages.
In vitro, calanolide A selects for a drug-resistant isolate with a previously unidentified mutation (at codon 139, known as T139I). The mutation is susceptible to all other anti-HIV agents, including other NNRTIs.
In Vivo Effects
Animal studies indicate that the compound crosses the blood-brain barrier, allowing it to penetrate viral reservoir sites like the lymph nodes.
In clinical studies conducted thus far, calanolide A appears to be generally well tolerated. At the 6th Conference on Retroviruses and Opportunistic Infections (CROI) this past February, researchers reported on a phase IA dose-escalating study conducted in HIV negative subjects that indicated that doses of up to 600 mg are well tolerated. In this study, single doses were followed by multiple escalating doses.
Participants were randomized to receive a single dose of 200 mg, 400 mg, 600 mg, or 800 mg. Three of the four cohorts received multiple doses of 200 mg, 400 mg, or 600 mg twice daily for five days. Adverse reactions, which were not related to dosage, were all considered mild and transient.
The most common adverse effect was complaint of an "oily aftertaste" (19 of 32). Also reported were transient dizziness, rated as "mild" by 12 subjects and "moderate" by two. Some participants reported mild nausea. Eight people reported headache and five reported dyspepsia (heartburn). The only adverse effect considered significant by investigators was one report of "grade 3 lipase [a pancreatic enzyme] &which was completely asymptomatic and which resolved spontaneously" in an individual who had taken a 600 mg single dose. At a follow-up visit, a routine blood test revealed an elevation of the pancreatic enzyme lipase--the participant had no other symptoms--that researchers believe was unrelated to calanolide A.
Researchers also report that calanolide A is absorbed and circulated by the bloodstream more efficiently than expected, based on animal data. Bioavailability is good overall and the half-life relatively long. Since food does not seem to affect total drug absorption, taking the drug may be thankfully free of the sorts of dietary restrictions that complicate regimens that include other antiretroviral drugs.
Ongoing and Upcoming Research
Ongoing research will continue to collect data on safety and pharmacokinetics, as well as efficacy. Thus far, according to Tom Flavin of MediChem Pharmaceuticals, investigators suspect that 400 mg b.i.d. (taken twice daily) will be the most useful dose, although further evaluation is necessary to confirm that that level is optimal.
A dose-ranging phase IB/IIA study currently underway is looking at the effects of calanolide A in HIV positive, antiretroviral-naive participants. Researchers are currently collecting data on viral load and viral resistance as well as immunologic effects.
This ongoing study is randomizing participants to receive calanolide A or placebo. If no adverse effects are seen at the lowest dose given to the first enrollees, the next group of participants enrolled will receive a higher dose or placebo. Participants will not know which they are receiving until the study ends after approximately one month. Entrance criteria include having at least 350 CD4 cells/mm3 and a viral load of 10,000 copies/mL or greater. Prior use of any antiretroviral drugs is not allowed.
The study, roughly 50% enrolled, is still open to new participants. Research sites are Boston (617-414-5404), Chicago (312-572-3796), Galveston (409-747-0241), Nashville (615-936-1164), New York City (212-420-4519), Pittsburgh (800-711-5878), and Vero Beach (561-978-9556).
MediChem investigators, such as Ze-qi Xu, MD, principal investigator of the calanolide A studies, are waiting to see the results of the phase IB study, which are expected to be available relatively soon. Tentative plans are being developed for phase IIB studies. The next stage of clinical research will evaluate the effects of combination therapy with calanolide A and approved antiretroviral agents in people with more advanced HIV disease who have previously used anti-HIV medications.
Leslie Hanna is Editor of BETA.
Flavin, M.T. and others. "In vitro anti-human immunodeficiency virus (HIV) activity of (+)-calanolide A", 4th Conference on Retroviruses and Opportunistic Infections. New Orleans. 1997. Abstract 527.
Flavin, T. MediChem Pharmaceuticals. Personal communication. March 2, 1999.
Ruckle, J. and others. "Clinical safety and pharmacokinetics of (+)-calanolide A, a naturally occurring NNRTI in normal healthy and HIV-infected volunteers", 6th Conference on Retroviruses and Opportunistic Infections. Chicago. January 31-February 4, 1999. Abstract 606.
Sarawak MediChem Pharmaceuticals, Inc. PRNewswire. February 5, 1998; September 30, 1998.