Drug Delivery Technologies

LAURIAD®

Scientific Papers

Miconazole Lauriad® : Loramyc®

Lead Product:

• A Once-A-Day 50mg Mucoadhesive Buccal Tablet

Rationale:

• Early and extended release of miconazole for a pressure increase on the fungi at the infection site
• Once a day
• Non-absorbed active molecule: no drug-drug interactions
• Large spectrum and resistance issue prevention first line positioning before antifungal systemic use

Indication:

• Treatment of Oropharyngeal Candidiasis (full indication in the US and immunocompromised patients and chronic diseases in Europe)
• First Line Local Treatment

Development Status:

• Registered in France in October 2006
• Price reimbursement obtained in France
• European Mutual recognition Procedure to start in 2007
• US IND Allowed 3Q 2005
• US Phase 3 Clinical Trial ongoing
  

Epidemiology

In Oncology:

The risk of candidiasis is particularly high in patients undergoing radiotherapy or who suffer from neutropenia.

The risk of oral candidiasis is also linked with local radiotherapy and tissue insult (frequently 6 cycles of radiotherapy with risk at each cycle).

A high risk of mucositis is associated with the nature of chemotherapy (5 FU/ Methotrexate/ Xeloda/Caelix) with a risk of candidiasis in 100% of treated patients.

Other chemotherapy regimens (platinums, taxanes) are associated with a candidiasis risk of 50%. For example, all digestive cancer candidates with exposure to 5FU are at high risk of contracting candidiasis.

Other immune compromised patients:

• HIV patients
• Diabetics
• Patients with rheumatoid arthritis or inflammatory bowel disease
• Chronic corticosteroids or Asthma
• Elderly

Clinical Development Program

The development of miconazole Lauriad tablets began in 1999. Miconazole is an antifungal molecule, which belongs to the azole family and acts by inhibiting the ergo sterol synthesis. This molecule is marketed worldwide and is in particular indicated in candidiasis infections. It has been extensively described in the literature and has an established tolerance and efficacy profile for the treatment of oral and intestinal candidiasis. Its good tolerance profile is enhanced by the fact that it has a limited absorption. Of particular importance is its broad spectrum activity against different species of Candida including Candida albicans, C. krusei, C. pseudotropicalis and C. parapsilosis.

In sum, miconazole, was chosen as it:

• Possesses a good efficacy profile and is effective against Candida albicans and C. krusei, C. pseudotropicalis and C. parapsilosis
• Is indicated in oral and gastrointestinal candidiasis in the EU and many other countries in the world
• Has a good safety profile
• Has a low drug interaction profile
• Has a minimum absorption profile

The rationale for development of an extended-release bioadhesive buccal tablet is based on reaching a constant antifungal salivary concentration, increased contact time with effective concentrations in the oral cavity (above the minimum inhibitory concentration [MIC]) in order to increase efficacy and reduce the risk of resistance, and to provide a once-daily administration to improve patient compliance.

The bioadhesive tablet was designed to be applied once a day to maintain adequate miconazole saliva levels for effective treatment of oropharyngeal candidiasis. It is planned that this application will be submitted to the U.S. FDA as a 505(b)(2) NDA, based on the extensive historical use of miconazole in the United States and abroad for over 30 years for the topical treatment of fungal infections.

A pharmacokinetic study with miconazole Lauriad® tablets was conducted by BioAlliance in healthy volunteers. The study was designed as a single-center, randomized, cross-over design, performed in 18 healthy men and women, 18 -35 years of age, to evaluate the miconazole pharmacokinetic parameters in saliva and the tolerability of a 50 and 100 mg buccal tablet compared with miconazole gel. Each of the 18 subjects received the 3 treatments followed by a washout period of 7 days. Miconazole Lauriad® bioadhesive tablets were administered as a single dose. Miconazole oral gel, the comparator, was administered in the oral cavity, 125 mg 3 times per day, on the study treatment day. Pharmacokinetic parameters, as well as the local tolerability of the buccal tablets, were evaluated. Duration of exposure was much greater for the bioadhesive tablets compared with the oral gel. Saliva pharmacokinetic parameters were consistent with a once-a-day application. Plasma concentrations were essentially undetectable. The benefits of the miconazole Lauriad® tablet, compared with the miconazole oral gel, included decreased systemic exposure to miconazole, an extended exposure of the oral mucosa to miconazole, simplified treatment regimen, and improved tolerability, all of which should lead to improved patient compliance.

Based on the results of the pharmacokinetic study, the 50 mg miconazole Lauriad® tablet was selected for further evaluation in clinical trials. This decision was based on salivary concentrations, duration of exposure greater than the MIC (1 µg/mL), and better local tolerability due to the smaller size of the 50mg tablet.

A supportive Phase 3 study of miconazole Lauriad® for the treatment of oropharyngeal candidiasis was conducted in 25 HIV positive patients at 11 clinical sites in France. An analysis based on a group-sequential, response adaptive trial design based on a success rate of 70% allowed the trial, originally designed for 60 patients, to be completed early due to proven efficacy. Results from this study show clear evidence of efficacy, with a success rate of 89.5% at Day 7 and 94.7% at Day 15.

A pivotal Phase 3 study has been completed at 36 clinical sites in France and North Africa as a comparative noninferiority study versus miconazole gel. This study was an open-label, multicenter, randomized, and controlled study in 308 patients with head and neck cancer treated by radiotherapy, including a blind evaluation of clinical results. This trial was conducted in patients presenting with candidiasis and suffering from dry mouth due to radiotherapy, a low level of saliva production due to severe mucosal alterations caused by radiotherapy. Given these conditions, the efficacy and the tolerance data are particularly interesting.

The primary endpoint was clinical efficacy at Day 14 defined as a complete or partial clinical response evaluated by an independent blind assessor. The results confirm the non-inferiority of the miconazole Lauriad® 50mg tablet applied once per day for 14 days versus miconazole oral gel, 125mg applied 4 times per day for 14 days.

The EU registration dossier (filed Q3 2005) is based on the CMC dossier, pharmacokinetic data, the clinical results of the supportive Phase 3 study of oral candidiasis in HIV patients and the non-inferiority pivotal Phase 3 study in head and neck cancer patients following radiotherapy.

The Company has obtained marketing authorization in France in October 2006. Loramyc® has been approved for the treatment for oropharyngeal candidiasis in immunocompromised patients, including HIV patients and head or neck cancer patients undergoing radiotherapy. This is the first step towards obtaining regulatory approval across Europe under the European Mutual Recognition Procedure. France will present the application as the reference Member State in 2007.

Following the allowance of an IND in August 2005, BioAlliance has started a confirmatory pivotal Phase III clinical efficacy study in the US, Canada and RSA, in immunocompromised patients, to evaluate the efficacy and safety of miconazole Lauriad® tablets compared with Mycelex® (clotrimazole) Troches in a noninferiority study design. Miconazole gel is not registered in the U.S., necessitating the use of Mycelex® Troches as the comparator, currently one of the most commonly used therapies to treat oropharyngeal candidiasis in immunocompromised patients.

Scientific Papers