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BioAlliance Pharma Presents Results from Phase III Study of Miconazole Lauriad Bioadhesive Buccal Tablets for Treatment of Oropharyngeal Candidiasis in Head & Neck Cancer Patients.

PARIS -- BioAlliance Pharma, a biopharmaceutical company focused on the field of drug resistance, announced today that a randomized Phase III trial evaluating the Company's miconazole Lauriad(R) 50mg Bioadhesive Buccal Tablets in head and neck cancer patients suffering from oropharyngeal candidiasis following radiotherapy, demonstrated efficacy with 10 times less drug and on a more convenient schedule than the miconazole oral gel comparator. These results suggest definite potential for better compliance in treating oropharyngeal candidiasis in patients with altered mucosa and xerostomia.

The study (Abstract #5527) of 306 patients conducted at 36 clinical sites in France and North Africa was presented at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida.

"These results represent an important medical advance for the local treatment of oropharyngeal candidiasis," said Dominique Costantini, M.D., president and CEO of BioAlliance Pharma. "Our goal is to provide physicians with an effective option for local treatment of this fungal infection that obviates the need to prescribe systemic therapies due to its enhanced potential for improved patient compliance and avoidance of systemic drug-drug interaction and development of drug resistance."

Study Objectives

The main objective was to demonstrate that the efficacy of the miconazole Lauriad(R) 50mg Bioadhesive Buccal Tablet administered once daily for 14 days, was not inferior to that of miconazole oral gel 500mg delivered in 4 divided doses for 14 days. Secondary objectives were to compare other efficacy criteria at days 7 and 14, and the safety profile between both drugs.

Inclusion Criteria

Patients included in the study were head and neck cancer patients who had undergone radiotherapy and were suffering from documented oropharyngeal candidiasis (first episode or relapse) diagnosed on clinical criteria and mycological examination (direct exam and fungal cultures), aged 18 to 75. This is a patient population that suffers from severe local and medical conditions such as low salivary flow, poor mucosal status and associated mucositis induced by the radiotherapy.

Patients were not included if candidiasis had spread outside the oropharynx area, and if they were in poor general condition (ECOG greater than 2), had hepatic insufficiency, milk allergy or concomitant treatment which could interfere with miconazole antifungal treatment. Pregnant or breast feeding female or women of childbearing age without effective contraception were excluded.

Study Treatment

Patients were allocated to either miconazole Lauriad(R) 50mg Bioadhesive Buccal Tablets, one tablet daily to be applied in the cuspid fossa in the morning after teeth brushing and to remain in the oral cavity until the tablets complete erosion without being sucked or chewed; or miconazole gel 500mg daily in 4 divided doses (gel to be kept in the mouth for as long as possible before being swallowed).

Methodology

This trial was carried out according to an open-label, comparative, two parallel arms, randomized design. In order to control the absence of a double blind double dummy design, clinical efficacy was assessed blind at day 14 in each centre by an healthcare team member unaware of the treatment allocated to patients.

This study was planned as a noninferiority trial for the primary endpoint with an efficacy rate estimated at 50% and a difference between miconazole Lauriad(R) 50mg Bioadhesive Buccal Tablet and miconazole gel lower than 20%. In the absence of data on the efficacy rate of topical miconazole gel or any other antifungal treatment in the selected patient population, a 50% efficacy rate was assumed. Based on these assumptions, 103 patients had to be included per treatment arm (i.e., 227 patients for the study including 10% for premature withdrawals or major violations). Two populations were analyzed: modified intent to treat (mITT) and per protocol (PP).

Results

306 patients were included: the mITT and PP populations comprised 282 and 213 patients, respectively. At baseline, demography, patient characteristics and disease history were not different between the 2 groups. All patients had been treated by radiation therapy and more than half, 66.67% of the mITT population and 69.95% of the PP population, had received chemotherapy with cancer of the cavum being the most frequent localization. 54% of patients were suffering from mucositis and 40% of all enrollees reported a history of candidiasis infection. These previous infections had been treated either with topical (approximately 35% of patients) or with systemic antifungal drugs (approximately 16% of patients).

Of note, salivary secretion, which was dramatically reduced and even absent in 20% of patients, was statistically marginally more reduced and candidiasis lesions were also statistically marginally more extended in the miconazole Lauriad(R) treated patients than in the miconazole gel treated patients (P = 0.099 and P = 0.069 respectively), suggesting that the former patients were slightly more severely affected than the latter.

At day 14, in the mITT population, the clinical success rate in the miconazole Lauriad group (56.03% (79/141)) was statistically significantly not inferior (P less than 0.0001, (CI95: -19.0%; 4.8%), non inferiority margin = 4.8%) to that observed in the miconazole gel group (48.94% (69/141)). At day 14, in the PP population (blind evaluation) the clinical success rate in the miconazole Lauriad group (57.94% (62/107)) was statistically significantly not inferior (P less than 0.0001, (CI95:-16.7%; 10.3%), non inferiority margin = 10.3%) to that observed in the miconazole gel group (54.72% (58/106). Complete clinical responses were 52.48% and 45.40% respectively (P less than 0.0001 (CI95: -19.0%; 4.8%), non inferiority margin = 4.8%).

At day 14, burning had disappeared in 53.52% and 51.39% and odynophagia in 50% and 43.64% of mITT miconazole Lauriad and miconazole gel groups (P = NS). Improvement in oral lesions was not different between both groups: disappearance in erythema, it was 47.12% vs 46.85%, in inflammation, 51.96% vs 52.43% and in mucositis 42.11% vs 56.96% respectively for the mITT miconazole Lauriad(R) and miconazole gel groups (P = NS for all). Results were similar in the PP population.

Relapse rate at day 60 in complete responders was 21.62% and 17.19% in the mITT miconazole Lauriad and miconazole gel groups, respectively.

Conclusions

This trial showed that the efficacy of the miconazole Lauriad(R) 50mg Bioadhesive Buccal Tablet administered once daily, for 14 days was not inferior to that of miconazole gel 500mg in four times in the treatment of head and neck cancer patients suffering from oropharyngeal candidiasis.

About Oropharyngeal Candidiasis

Fungal infections of the oral mucosa are most frequently caused by Candida species, with C. albicans being the most common species associated with such infections. Oropharyngeal candidiasis is commonly found in immunocompromised patients, including HIV and cancer patients, diabetics, and the elderly. The clinical presentation of oropharyngeal candidiasis is variable with symptoms including soreness, burning, and/or altered taste. The signs of clinical candidiasis usually include white pseudomembraneous plaques and patches (thrush), erythematous lesions or occasionally angular cheilitis. Left untreated, it may progress to involve the esophagus or to more serious systemic complications. Oropharyngeal candidiasis is the most frequently occurring infection in head and neck cancer patients undergoing radiation therapy.

About Miconazole Lauriad(R)

Miconazole is an antifungal agent effective against all types of oropharyngeal candidiasis with similar antimicrobial activity to ketonazole. Topical treatments are preferred first line therapy of oropharyngeal candidiasis. Miconazole Lauriad(R) is an oral bioadhesive buccal tablet containing miconazole developed to optimize local antifungal activity in the oropharyngeal cavity by ensuring the extended release of a dosage resulting in miconazole saliva concentrations greater than 1 ug/mL which is the required minimum inhibitory concentration (MIC) level to treat oropharyngeal candidiasis. Miconazole Lauriad(R) is designed to be administered once daily, applied to the upper gum, while providing adequate local miconazole concentrations in the saliva and negligible plasma concentrations. This compares to other topical treatments, such as gels, rinses, or lozenges, which require multiple applications or intakes per day.

About BioAlliance Pharma

BioAlliance Pharma is a privately held late stage biopharmaceutical company focused on drug resistance through development and commercialization of innovative therapeutics targeting markets in cancer, HIV, severe infections and supportive care. The company has two broad proprietary drug delivery systems represented by the Lauriad(R) adhesive technology and the Transdrug(R) nanoparticle technology that provide multiple product opportunities. Together with a New Chemical Entities program focused on development of new drugs in oncology and HIV, the company is able to address worldwide markets in the EU, US, and Asia.

The company's lead product within its adhesive technology program, the miconazole Lauriad(R) 50 mg Bioadhesive Buccal Tablet, is being investigated in two recently completed Phase III trials in Europe for treatment of oropharyngeal candidiasis in cancer and HIV patients. A pivotal Phase III trial in the same indication is planned for the U.S. later this year. A Phase I/II trial in hepatocellular carcinoma utilizing the company's doxorubicin Transdrug(R) nanoparticle delivery technology is ongoing in Europe, where it has been granted an orphan medicinal product designation by the EMEA.

For additional company background, please visit the BioAlliance Pharma web sites at: www.BioAlliancepharma.com and www.viralliance.com.
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Date:May 17, 2005
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