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New Therapy Promising for Genital Herpes

Joan Stephenson, PhD

Istanbul: An experimental immunity-enhancing drug administered as a topical gel shows promise in substantially delaying onset of recurrent genital herpes lesions, researchers reported here at the 11th European Congress of Clinical Microbiology and Infectious Diseases.

"One episodic treatment seems to act like a vaccination and prolong the time to the next recurrence," explained Spotswood Spruance, MD, at a symposium sponsored by St Paul, Minn–based 3M Pharmaceuticals. If the findings are confirmed in large-scale studies, the new agent, resiquimod, would provide an alternative to current suppressive therapy for genital herpes, said Spruance, of the University of Utah School of Medicine in Salt Lake City.

Currently approved treatment for recurrent genital herpes comprises a trio of systemic antiviral medications: the nucleoside analogs acyclovir, famciclovir, and valacyclovir.

These drugs can decrease the duration of viral shedding and time to healing of lesions when patients take them at onset of symptoms. Chronic suppressive therapy in the form of a daily dosage of one of these antiviral drugs can help suppress future attacks. But episodic treatmenttaking the drugs only during an outbreakhas no effect on the frequency of recurrences, said Richard Whitley, MD, of the University of Alabama at Birmingham.

Resiquimod is one of a family of immune response–modifying drugs in development by 3M Pharmaceuticals. The company's first-generation immune response modifier, imiquimod, was approved by the US Food and Drug Administration in 1997 for treatment of genital warts.

Although the exact mechanism of action of imiquimod and resiquimod is still under study, these agents appear to induce the production of certain cytokines, leading to an effective virus-suppressing immune response, said Spruance. Further evidence that such agents can alter the immune system's ability to suppress virus came to light in the clinical trials of imiquimod for genital warts, when investigators noticed the drug not only eradicated warts but also helped prevent recurrence.

Studies of resiquimod indicate that the drug, which is 100 times more potent than imiquimod, induces interferon , interleukin 12, and other cytokines. The effect is an altered immune response, particularly enhanced cell-mediated immunity, said Richard Miller, PhD, of 3M Pharmaceuticals.

Some patients who contract genital herpes do not experience recurrences, presumably because their immune system has succeeded in containing the virus. The rationale for treating patients with recurrent disease with immune response modifiers is that these drugs appear to have effects that can shift the ineffective immune response seen in people who have recurrences to the kind of response seen in outbreak-free individuals, said Spruance.

"I believe that treating people [with the drug] at the time of an active herpes recurrence is equivalent to an autologous therapeutic vaccination with adjuvant," he said. During the outbreak, the patient's own herpes simplex virus acts as the "vaccine" by exposing the immune system to viral antigens, and resiquimod acts as an adjuvant to raise the immune response.

In the study, 52 patients at two centers (the University of Utah School of Medicine and the University of Texas Medical School at Galveston) were randomized to receive the drug (in one of four different dosing regimens0.05% resiquimod gel once or twice a week or 0.01% twice or three times a week) or placebo (the drug vehicle). All patients, whose ages ranged from 18 to 60, had a history of recurrent genital herpes, with an average of 10 episodes per year.

Patients applied the drug within 24 hours of the onset of symptoms for 3 weeks and were observed for 6 months after treatment. The drug was generally well tolerated at the lower dosages, but not at the highest dosage (0.05% twice a week), which caused redness, blistering, and ulcers.

The median time to recurrence was 57 days for patients treated with vehicle alone vs 169 days for those who received the druga difference that is statistically significant, said Spruance. Patients who received placebo had a median of 5.5 recurrences during the 6-month observation period compared with one recurrence among those who received resiquimod.

"Among the vehicle-treated patients, only 6% remained recurrence-free during observation, but as much as one third of the people who received resiquimod had no recurrences at all during the observation period," he noted. "And some of these individuals followed after the study ended still have had no recurrences 2 years later."

Many questions remain to be answered, such as the effects of repeated treatment on subsequent recurrences and whether the drug reduces viral shedding. But if the early findings are confirmed in ongoing trials, the drug could provide a welcome alternative for patients who find daily suppressive therapy with nucleoside analogs a psychological and financial burden, said Spruance.

Phase 3 clinical trials involving about 2000 patients with recurrent genital herpes infection are now under way in the United States.

(http://www.herpestrial.com) and Europe (http://www.herpesgenitalis.nl [information in Dutch]). Results are expected in 2004.

© 2001 American Medical Association. All rights reserved.

Update

3M, Eli Lilly suspend drug trial
Benno Groeneveld
Web Reporter
3M Co. and pharmaceutical giant Eli Lilly & Co. have suspended clinical trials of an experimental drug to treat genital herpes.

The two companies said that the drug, resiquimod, was not effective in the tested dosages. "The data have not indicated any safety concerns with the drug," 3M and Eli Lilly said in a joint statement. In earlier studies, the companies said, the drug had shown promise.

3M and Eli Lilly said they will continue to study the drug, but will delay their planned submission to regulators. Originally, the companies had said they hoped to submit the drug for approval by the end of 2004 or in 2005.

Resiquimod was originally developed by Maplewood-based 3M as part of a series of so-called "immune response modifiers." 3M had licensed Lilly to develop resiquimod as a treatment for herpes in September 2001.

The companies had predicted that, if proven effective, resiquimod could eventually generate sales of more than $1 billion per year.

The decision to suspend trials of resiquimod has no influence on the development and sales of other drugs in the same class of compounds. For example, 3M has been selling an immune response modifier under the brand name Aldara since 1997. That drug is used for treating genital warts caused by a virus. "Aldara is the number one therapy in the category, and sales are more than $100 million per year," said 3M spokesman John Cornwell.