Viropharma Picovir Oral Contraceptive Study Data Expected This Summer

Viropharma expects to have data from a Phase I drug interaction study of oral contraceptives and Picovir (pleconaril) in two to four months.

The company hopes that the study will reassure FDA that pleconaril does not significantly reduce the efficacy of progestin/ethinyl estradiol combination OCs, a concern expressed by FDA's Antiviral Drugs Advisory Committee.

The committee unanimously voted not to recommend Picovir for approval for the treatment of acute picornaviral upper respiratory illness (common cold) in adults on March 19.

While the majority of committee members agreed that Viropharma had demonstrated that Picovir is effective, all members had unresolved concerns about the safety of the drug.

Some argued that the likelihood of advanced prescribing of pleconaril meant it should be held to more stringent safety standards (see ¹ (Also see "Viropharma Picovir Pre-Prescribing Raises Risk Management Issues" - Pink Sheet, 25 Mar, 2002.) ).

One principal safety concern involved clinical data from a six-week prophylaxis study showing that two women on an OC out of 156 study subjects became pregnant while taking pleconaril.

In addition, 3.1% of women taking concomitant OC and pleconaril experienced menstrual disorders including breakthrough bleeding in Phase III trials. Less than 1% of women on placebo/OCs and .1% of patients receiving pleconaril alone experienced a disorder, such as epimenorrhea, amenorrhea or intermenstrual bleeding.

FDA noted that the effect appeared to be dose-related. Data from a six-week prophylaxis trial showed that 53% of women taking 400 mg pleconaril daily with OCs had a menstrual disorder compared to 69% of women on 400 mg pleconaril twice daily/OC and 25% of placebo/OC patients.

"The question right now, to me, is a safety question: how do we...get the agency comfortable with the safety...with the drug interaction profile that we have which...is not a huge effect," Viropharma VP-Research & Development Mark McKinlay said following the committee meeting.

"What we need to do is sit with the agency, sit with the people from the biopharmaceutical division, and discuss what makes the most sense to get the kind of data that will make everyone sure," McKinlay said.

The company's ongoing OC efficacy study involves dosing patients with 400 mg of pleconaril twice daily for three weeks. Patients will be observed through a total of two menstrual cycles to assess the maximum pharmacokinetic and pharmacodynamic effects of pleconaril on the birth control drugs, focusing on total hormone levels and induction of the CYP3A enzyme.

If the enzyme is over-produced, oral contraceptives are not as effective, and women are advised to use an additional method of birth control.

Viropharma is also conducting a Phase I study on the duration of CYP3A induction resulting from a five-day 400 mg twice daily course of pleconaril. Results of that trial are also expected in several months.

While noting that the number of pregnancies occurring in clinical trials was small, some committee members argued that any possibility of unwanted pregnancy significantly impacts the risk-benefit calculus for approving Picovir.

"It seems that any increased risk of an inadvertent pregnancy is almost unacceptable in the context of this symptomatic indication," voting committee consultant Eric Brass, MD/PhD, UCLA School of Medicine, said.

"Are we going to trade a day's decrease in a runny nose for a frequent event for breakthrough bleeding and...the potential risk for diminished efficacy of oral contraceptives?" voting committee consultant Barth Reller, MD, Duke University Medical Center asked.

The committee also suggested that Viropharma conduct additional studies to assess the safety of pleconaril in the elderly, those with co-morbid conditions and those taking multiple medications.

FDA noted that "only 4% of patients were 65 years of age...which precluded an assessment of safety or efficacy in this population." Patients who were immunocompromised, had active allergic rhinitis or had pulmonary or cardiac conditions were also excluded from the trials.

"If you want me to believe that as a primary care provider it's okay for me to give this drug to a 67 year-old man post-coronary bypass surgery on eight drugs, at least one of those has to be someplace in the study population," Brass said.

"I think there does need to be interaction studies with other select drugs that I would phrase as frequently used and would have serious consequences of therapeutic failure. And I think these studies ought to go beyond just a numerical pharmacokinetic study," committee member Courtney Fletcher, University of Colorado School of Pharmacy, added.

In one theophylline interaction study, three of 15 subjects experienced tachycardia and palpitations with concomitant administration. The same adverse events were recorded by seven patients with no cardiac history who were treated with pleconaril in clinical trials (.3%), versus two patients on placebo (.1%). Four of the pleconaril-treated patients discontinued treatment due to the events.

Several committee members also asked Viropharma to provide more data on the potential for Picovir to encourage resistance in rhinoviruses. Viropharma reported that after a seven-day course of pleconaril, viruses in 10.7% of patients had "reduced drug susceptibility."

"It's concerning that a drug, which would be given so much, could rapidly produce widespread resistance and this would render it ineffective," committee member Jonathan Schapiro, MD, Stanford University School of Medicine, said.

Committee member Victor DeGrutolla, Harvard School of Public Health, suggested that Viropharma might consider randomizing families in trials and tracking the transmission and mutation of the virus.

"There are other agents being developed that target the same area. We don't know if this will or will not produce a degree of cross-resistance," Schapiro added.

Several other companies have treatments for the common cold in development, including CFY Biomedicals, CV Technologies, BioCryst Pharmaceuticals and Agouron.

The Pharmaceutical Research & Manufacturers of America has argued that the approval of more antiviral drugs could be an overall benefit to the issue of drug resistance: drugs like pleconaril could offer physicians a treatment for viruses commonly inappropriately treated with antibiotics, leading to bacterial resistance (² (Also see "Antimicrobial Drug Consortium Could Speed Resistant Pathogen Trials" - Pink Sheet, 4 Mar, 2002.), p. 36).