FDA Accepts NDA for Review of New Imiquimod 3.75% EGW Indication
Results from a Phase III program evaluating imiquimod 3.75% and 2.5% creams for the treatment of EGW, applied once daily for up to 8 weeks, demonstrated that both were well-tolerated and more efficacious than placebo, according to data presented at the annual Human Papillomavirus (HPV) Conference in Montreal, July 3 – 8. Investigators found that efficacy was greatest for imiquimod 3.75% with an enhanced safety profile. The data were included in a New Drug Application (NDA) accepted for review by the U.S. Food and Drug Administration for an eight-week treatment regimen of imiquimod 3.75% for the treatment of EGW.
Two Phase III double-blind, placebo-controlled efficacy and safety studies of imiquimod cream evaluated both per-protocol (PP) populations (only participants who completed the study) and intent-to-treat (ITT) populations (all participants who began the study regardless of whether they completed it). Complete clearance of all warts – defined as clearance of baseline and emergent warts across several anatomical locations – in the PP population was achieved in 33.8 percent of patients on imiquimod 3.75% cream, compared to 11.5 percent on placebo cream. Complete clearance of all warts in the ITT population was achieved in 28.3 percent of patients on imiquimod 3.75% cream, compared to 9.4 percent on placebo cream. Additionally, efficacy was greater in females in both the PP and ITT populations than males for all primary and secondary efficacy measurements, and in the PP population 43.1 percent of females on the 3.75% formulation achieved complete clearance compared to 22.7 percent of males.
In subjects with complete clearance, 12-week sustained complete clearance was assessed. Of those who achieved initial complete clearance and entered the 12-week follow-up, complete clearance was sustained in 69.6 percent of subjects on imiquimod 3.75% cream.
“From a clinical perspective, I’m encouraged that we saw strong efficacy results with the 3.75% formulation along with an enhanced safety profile,” said Daron Ferris, M.D., Departments of Family Medicine and Obstetrics and Gynecology, Medical College of Georgia at Augusta. “Most notably, there was a low incidence of treatment-related adverse event reports of itching (2.5%), burning (5.8%) or pain (6.8%) at the application site, and no treatment-related reported systemic adverse events of headache or flu-like symptoms.”
In the Phase III program, 1.5 percent, 1.6 percent and 0.5 percent of subjects discontinued early due to safety-related reasons for imiquimod 3.75%, 2.5% and placebo, respectively. Rest periods from treatment for adverse reactions were required in 31.5 percent, 27.4 percent and 2.0 percent of subjects on imiquimod 3.75%, 2.5% and placebo, respectively. Severe local skin reactions were experienced by 16.3 percent, 15.0 percent and 1.0 percent of subjects on imiquimod 3.75%, 2.5% and placebo, respectively.
The approved 5% imiquimod formulation, called Aldara®, is indicated for the treatment of EGW, for use three times a week, for up to 16 weeks, a lengthy dosing schedule. The intent of the clinical studies for imiquimod 3.75% and 2.5% was to fill the need for a shorter treatment regimen which may increase patient adherence to treatment. Additionally, the key efficacy endpoint in the imiquimod 3.75% trial was clearance of all warts (those visible at baseline and those that appeared during treatment) in all anatomic locations while the efficacy endpoint of the original Aldara, imiquimod 5%, Phase III program was to clear only baseline/target warts in a defined area.
“One of the goals with imiquimod 3.75% was to develop an EGW product with a more manageable treatment regimen,” said James Lee, M.D., Ph.D., Chief Medical Officer, Graceway Pharmaceuticals, LLC. “Patient compliance can be a challenge with treatments that last up to 4 months. With a more intuitive daily dosing schedule over a shorter duration, complemented by an enhanced safety profile, we hope that patients will be more motivated to complete treatment and experience the full benefit of therapy.”
About the studies
In two Phase III, double-blind, placebo-controlled efficacy and safety studies of imiquimod cream, 981 patients with 2 – 30 external genital / perianal warts in an area of at least 10 mm2 were randomized to either placebo, imiquimod 2.5% or 3.75% (1:2:2). Patients applied up to 250 mg of cream daily for up to 8 weeks or until complete clearance of all (baseline and new) warts. Primary efficacy was assessed 8 weeks post-treatment. In subjects with complete clearance, 12-week sustained complete clearance was assessed.
Data from the two studies revealed that both the 3.75% and 2.5% imiquimod formulations applied once daily were statistically superior to placebo. In the PP population patients treated with imiquimod 3.75% had 33.8 percent complete clearance of EGW versus 11.5 percent for placebo. The 2.5% imiquimod treated patients showed 27 percent complete clearance of EGW versus 11.5 percent for placebo. Imiquimod treatment also resulted in higher partial clearance rates, defined as >75 percent reduction in wart count, in 45.9 percent (imiquimod 3.75%), and 36.3 percent (imiquimod 2.5%) of patients, versus only 13.4 percent of placebo treated patients, in the PP population.
Complete clearance of all warts in the ITT population was achieved in 28.3 percent of patients on imiquimod 3.75% cream, compared to 22.1 percent using 2.5% imiquimod cream and 9.4 percent on placebo cream.
Of subjects who achieved initial complete clearance and entered the 12-week follow-up, complete clearance was sustained in 69.6 percent (n=71), 59.5 percent (n=44) and 92.3 percent (n=12) of subjects for imiquimod 3.75%, 2.5% and placebo, respectively.
In the Phase III program, 1.5 percent, 1.6 percent and 0.5 percent of subjects discontinued early due to safety-related reasons for imiquimod 3.75%, 2.5% and placebo, respectively. Rest periods from treatment for adverse reactions were required in 31.5 percent, 27.4 percent and 2.0 percent for imiquimod 3.75%, 2.5% and placebo, respectively. Severe local skin reactions were experienced by 16.3 percent, 15.0 percent, and 1.0 percent for imiquimod 3.75%, 2.5% and placebo, respectively.
EGW are caused by human papillomavirus (HPV), a sexually transmitted disease passed through genital contact. Overall, 5.6 percent of 18-to 59-year olds in the U.S. reported that they had ever been diagnosed with EGW, according to the National Health and Nutrition Examination Survey data collected from 1999 – 2004.
Warts usually appear as a small bump or groups of bumps in the genital area and can be small or large, raised or flat, or shaped like a cauliflower. Warts can appear within weeks or months after sexual contact with an infected partner – even if the infected partner has no signs of genital warts.
The treatment goal for EGW is the eradication of visible disease rather than the elimination of the HPV infection.
About Zyclara™ (imiquimod) Cream, 3.75%
Zyclara Cream is a prescription medicine for use on the face or balding scalp only (a topical medicine) to treat actinic keratosis (AK). Do not use Zyclara cream in or on your eyes, nostrils, mouth or vagina.
When using Zyclara Cream, the most common side effects involve skin reactions in the application area. These include redness, scabbing or crusting, flaking, scaling or dryness, swelling, sores or blisters, and draining (weeping).
When using Zyclara Cream do not use sunlamps or tanning beds, and avoid sunlight as much as possible. Use sunscreen and wear protective clothing if you go outside during daylight.
For more information on Zyclara, visit www.ZyclaraCream.com.
Aldara is the brand name for imiquimod cream, 5%, which is an immune-response modifier. Aldara Cream is a skin-use only (topical) prescription medicine used to treat external genital and perianal warts in people 12 years and older. When using Aldara Cream, the most common side effects involve skin reactions in the application area. These include redness, swelling, erosions, weeping, scabbing, itching and burning. Most skin reactions are considered mild to moderate. The effect of Aldara Cream on the transmission of external genital warts is unknown. Aldara Cream may weaken condoms and diaphragms. Sexual contact should be avoided while the cream is on the skin. New external genital warts may develop during treatment. For full prescribing information, visit www.aldara.com/ie/pdfs/aldara_ppi.pdf.
About Graceway® Pharmaceuticals, LLC
Graceway Pharmaceuticals, LLC (“Graceway”), headquartered in Bristol, TN, is a pharmaceutical company focused on acquiring, in-licensing, and developing branded prescription pharmaceutical products. Graceway has acquired or licensed products from 3M (NYSE: MMM), Pfizer (NYSE: PFE) and Gilead (NASDQ: GILD). Current prescription products marketed by Graceway include Zyclara™ (imiquimod) Cream, 3.75%, Aldara® (imiquimod) Cream, 5%, Maxair®Autohaler® (pirbuterol acetate inhalation aerosol), Atopiclair® Nonsteroidal Cream, and Estrasorb® (estradiol topical emulsion). Zyclara™, Aldara®, Maxair®, Autohaler®, Atopiclair®, and Estrasorb® are trademarks owned by or licensed to Graceway. For more information on Graceway’s products, including important safety information, please visit www.gracewaypharma.com.