By Mary Welch

Triangle Pharmaceuticals Inc. said 83 percent of the HIV-infected patients who took Coactinon (emivirine) in a pivotal trial had undetectable levels of the virus after 24 weeks compared with 39 percent of those who didn't take drug.

"It's highly statistically significant," said David Barry, chairman and CEO of the Durham, N.C.-based company. "The p factor was equal to .001."

In the study, Coactinon (formerly known as MKC-442) was used in a first-line, protease inhibitor-sparing regimen in conjunction with two nucleoside reverse transcriptase inhibitors (NRTIs) - d4T (stavudine) and 3TC (lamivudine). The combination produced a rapid and significant suppression of HIV-1 RNA replication in treatment-naove HIV-infected patients.

Coactinon functions as a non-nucleoside reverse transcriptase inhibitor, an important class of compounds, said Barry. The company is now analyzing 48-week results of the drug.

The randomized, double-blind trial's intent was to examine the antiviral activity, safety and tolerability of Coactinon in a first-line regimen that didn't include protease inhibitors. Of the 162 patients, 45 percent were women, 55 percent men. They were randomized to receive 750 mg of Coactinon twice a day or a placebo in combination with 40 mg of d4T twice a day and 150 mg of 3TC twice a day. The patients had median baseline HIV-1 RNA levels of 4.3 log₁₀ copies/ml and median baseline CD4+ counts of 418 cells/mm³.

"What this trial seems to indicate is that Coactinon clearly looks good when used in combination with nucleoside reverse transcriptase inhibitors," Barry said. "It most likely will find a place in the protease-sparing regimens that keep viral load low without using protease inhibitors. The other good news was that it was well tolerated in all groups with mild to moderate adverse events, such as nausea, headaches and dizziness occurring. These results suggest that the tolerability of Coactinon in first-line regimens may be enhanced by the use of lead-in dose-escalation strategies."

The tolerability results were welcome, especially since only weeks earlier the company gave patients in another pivotal trial the option of continuing taking Coactinon in combination with a three-drug regimen, including protease inhibitors, or switching to one without Coactinon.

The actions were taken as a result of an increase in side effects, particularly nausea and dizziness. In addition, patients were showing no additional clinical benefit from adding Coactinon to the highly active anti-retroviral therapy. (See BioWorld Today, Oct. 12, 1999, p. 1.)

It turned out that the combination of nelfinavir and Coactinon had an unfortunate metabolic interaction that raised side effects to an "unacceptable rate," Barry said.

What happened in that trial is that the two drugs are metabolized by the same liver enzyme. Nelfinavir prevented the metabolism of Coactinon, while Coactinon doubled the metabolism of nelfinavir, leaving high levels of Coactinon in the bloodstream and very low levels of nelfinavir, he said.

The side effects in the that pivotal trial has set back the filing of a new drug application, which was scheduled to be submitted in the fourth quarter of this year. Triangle is in discussions with the FDA, Barry said.

Triangle is developing Coactinon and five other products for treating HIV and hepatitis B. All are partnered with Abbott Laboratories, of Abbott Park, Ill. Abbott paid $335 million, including buying $118.2 million worth of Triangle's stock, for product rights. (See BioWorld Today, June 4, 1999, p. 1.)

Also Tuesday, the company reported that net profit rose 71 percent to $1.2 million for the third quarter of 1999, which ended Sept. 30, compared to $706,854 for the comparable period last year. Revenues increased 13 percent to $6.6 million for the quarter, compared to $5.8 million for the same time last year.

Triangle's stock (NASDAQ:VIRS) closed Tuesday at $15.5, down 62.5 cents. Two weeks ago, when the negative drug interaction news was disclosed, the stock fell $3.75 to close at $15.875.