Single-dose tablet effective for labial herpes

Houston - A novel delivery system of an old drug designed to treat herpes labialis resulted in fewer recurrences of next herpes episodes, shorter durations of episodes, and increased incidence of blocked episodes.

“We found that a drug (acyclovir) that has been around for 30 years was quite safe and effective in a new route,” says Stephen Tyring, M.D., Ph.D., principal investigator of a phase 3 double-blind, placebo-controlled trial on Sitavig (50 mg acyclovir, BioAlliance Pharma), a muco-adhesive buccal tablet that uses a proprietary technology that effectively delivers a single low dose of acyclovir to treat labial herpes. “The reduction of subsequent (herpes) outbreaks is thought to be but not known to be due to the reduction of viral load.”

The Food and Drug Administration approved Sitavig in 2013, and with a commercial launch scheduled for this year, it will be available for patients in the United States.

Attacking the herpes simplex virus (HSV), the most widely spread virus in the herpes family of viruses, the drug met the primary endpoint of shortening an outbreak if an outbreak did occur when it was applied during the prodrome, says Dr. Tyring, a clinical professor of dermatology at the University of Texas Health Science Center, Houston, Texas.

Reducing outbreaks

While the drug has optimal efficacy when applied during the prodromal phase, it did also reduce the number of full-blown outbreaks when the drug was applied subsequent to the prodromal phase, he says.

“If it can’t prevent the outbreak, it can shorten the duration of the outbreak,” Dr. Tyring says. “There are longer delays between outbreaks, and when a person has an outbreak, the outbreak is less severe. The greatest benefit, however, was applied during the prodrome.”

The phase 3 investigation involving 775 patients with recurrent herpes labialis revealed that the use of the drug decreases the risk to experience a recurrence in nine-month follow-up by 22.7 percent, and the next recurrence of herpes episode was delayed by a mean of 105 days in patients whose herpes lesions recurred. In addition, there was a statistically significant difference in the median duration of herpes episodes, p=0.003, that favored the novel delivery of acyclovir. Furthermore, the incidence of blocked herpes episodes rose by 24.2 percent with this form of acyclovir.

The tablet uses Lauriad technology so that a tablet adheres to the gum, above the incisor tooth on the side of the lip that is infected with a cold sore, providing sustained release local exposure of acyclovir in oral mucosa, says Pierre Attali, M.D., M.Sc., chief operating officer, Strategy and Medical Affairs, BioAlliance Pharma, the company that developed the technology.

“The key is milk protein concentrate in the formulation, which facilitates the tablet to adhere to the gum,” Dr. Attali says. “This milk protein concentrate also makes it have a slower release.”

Milk protein concentrate is commonly used as a food additive and found in many dairy products, he says.

Next: Novel delivery method

Delivery method

In an oral formulation, acyclovir is not as bioavailable and even in a topical formulation applied directly to the site of the cold sore, according to Dr. Attali.

“The drug is released by the tablet for 12 to 15 hours, which covers the period where the virus is replicating,” Dr. Attali says. “If you look at the concentrations (of the drug) in saliva and mucosa, they are very high during that period. The use of this delivery system means that the lesion can abort. There are symptoms for one or two days, and then the lesion disappears.”

Indeed, acyclovir selectively inhibits HSV viral DNA replication, but systemic concentrations are reduced, delayed, and transient in the deep layers of mucosa and skin, thus poorly targeting the mucosal reservoir of HSV-1.

The amount of milk protein concentrate in the formulation is extremely low, so even patients with lactose intolerance can safely use this formulation. Younger patients can take it as well, Dr. Tyring says.

Apart from a significant advantage in terms of bioavailability, this formulation requires one application and eliminates the challenge of compliance that has existed with the oral formulation as well as the topical formulation of acyclovir, he says.

“There have been obstacles to overcome to ensure the optimal use of acyclovir and optimal healing,” Dr. Tyring says. “Compliance was always an issue when it was used five times a days in the oral form. We began recommending that patients use it three times a days and double the dose. In the case of the topical use of the medication, patients need to constantly reapply it. With this type of application, they simply put it in the right place and it stays there.”

In terms of side effect profile, there have been some rare instances, less than 1 percent, of application site irritation. The incidence of headache that has been reported with systemic acyclovir therapy has been 10 percent, and the incidence is much lower with this delivery system.

Disclosures: Dr. Tyring reports that the clinical studies were supported by a grant from Innocutis, the manufacturer of Sitavig. Dr. Attali is an employee of BioAlliance Pharma.