Sublingual Ragwitek Backed FDA Panel for Ragweed Allergy

Larry Hand

January 28, 2014

The Allergenic Products advisory committee of the US Food and Drug Administration (FDA) voted to recommend MK-3641 (Ragwitek, Merck Sharp & Dohme Corp), an allergen extract from short ragweed (Ambrosia artemisiifolia) pollen, as a sublingual immunotherapy for adults aged 18 to 65 years with ragweed-induced allergic rhinitis (AR) with or without allergic rhinoconjunctivitis (ARC).

AR/ARC affects 10% to 25% of the US population and short ragweed pollen is one of the most common seasonal allergens to cause symptoms, according to a company briefing document.

Ragwitek comes in the form of a tablet that is placed under the tongue, where it dissolves in about 10 seconds. Recommended US dosage is 12 Amb a 1 units. The allergen Amb a 1 produces most allergenic activity in short ragweed, and each Amb a 1 unit is equal to about 1 mcg of the allergen. A self-injected dose of epinephrine included with Ragwitek is recommended if needed. This is the first approval step for Ragwitek, categorized as a sublingual immunotherapy.

Merck recommends that dosage be started 12 weeks prior to the start of ragweed season and continue daily until after the season ends. The first dose is administered by a healthcare provider in-office to monitor for any side effects, and subsequent doses can be taken at home.

Ragwitek offers an additional pathway to pharmacotherapy allergy treatments and an alternative to subcutaneous immunotherapy, during which patients are treated with injections. The Ragwitek dosage remains the same throughout the year, in contrast to injections that start out at low doses and build up to higher doses over time.

The dosage level was a conscious decision on the developer's part because the first treatment is the point at which patients are more at risk for side effects, according to Hendrik Nolte, MD, PhD, section head of respiratory clinical development at Merck. "That's where patients are most naive to the treatment," he said.

The FDA accepted the biologic license application (BLA) for Ragwitek in May 2013. Merck's BLA included data from 5 clinical studies in adults aged up to 85 years. The committee vote was partially split, however, because the 2 phase 3 efficacy studies involved only persons aged up to 50 years, and not people aged 50 to 65 years, for which approval has been requested.

Efficacy

The 2 phase 3 efficacy studies were conducted over 52-week periods from 2009 through 2011. Of 560 participants in one trial, conducted in the United States and Canada, one third received Ragwitek 12 Amb a1, another third received Ragwitek 6 Amb a 1, and another third received placebo.

The total combined score (TCS), consisting of the daily symptom score and daily medication score, was the primary endpoint, with the desired result being a reduction in symptoms, other medication use, and overall score during primary ragweed season.

Compared with placebo, 12 Amb a 1 Ragwitek produced a TCS of -26.49 (-38.74 — 14.59, 95% confidence interval [CI]) in one trial). FDA guidelines call for at least a -15% result.

Of 783 participants in another trial, conducted in the United States, Canada, Hungary, Ukraine, and Russia, 4 groups received 12, 6, or 1.5 Amb a 1 Ragwitek or placebo. Ragwitek produced a TCS of -24.16 (-36.47 — 11.31, 95% CI) compared with placebo.

With 9 members of the advisory committee voting, 6 voted yes that the data provided evidence of efficacy, 2 voted no, and 1 abstained. Those 3 members, however, agreed that if the language of the question they were asked to vote on had been restricted to people aged up to 50 years, they would have voted yes.

Safety

In the safety investigation of Ragwitek, Merck enrolled 2517 participants in 5 trials, including the 2 efficacy trials, with 1747 participants taking doses of Ragwitek and 770 taking placebo. The primary safety study was a 28-day study not conducted during ragweed season (the recommendation is to start preseason and not during the season).

In that study, 56.5% of Ragwitek participants reported treatment-related adverse events, compared with 37.6% of placebo participants. In the 52-week efficacy studies, 80.6% of Ragwitek participants reported adverse events, compared with 68.4% of placebo participants.

At least 1 serious adverse event was reported in 20 (1.5%) of the Ragwitek participants and in 8 (1.1%) of the placebo recipients. Ninety Ragwitek participants (74 treatment-related) discontinued the study because of adverse events, compared with 7 for placebo.

Jennifer Maloney, MD, director of respiratory clinical development for Merck, characterized adverse events during the trial as being consistent with known risks when exposing a person to a known allergen and no unexpected or unanticipated safety problems emerged.

She said most of the adverse events consisted of itching and swelling in and around the mouth where the tablet is placed under the tongue.

With 9 members of the advisory committee voting, 8 voted yes that the data provided evidence of safety, and 1 abstained.

Going Forward

Future studies on Ragwitek by Merck include investigation in pediatric populations, which were not included in the first efforts because efficacy has to be proved in adults first, Merck officials said.

Advisory committee members also recommended that Ragwitek also be investigated among more diverse populations (most study participants were white), among people with gastrointestinal problems and food allergies, and during multiple seasons as opposed to 1 year.

The advisory committee members have disclosed no relevant financial relationships.

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