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Novel Candidiasis Therapy

Oral Rinse for Candidiasis

Candida species are fungi which are part of the normal flora of humans and the environment. C. albicans, the most commonly identified human pathogen, usually lives in balance with the other microorganisms in the body. When this balance is disturbed by immune system changes (AIDS, immunosuppressants), broad-spectrum antibiotics, or mucous barrier disrupters, endogenous C. albicans can become pathogenic and cause disease. Candidiasis has emerged as the most common opportunistic fungal disease.

A Demegen licensee is developing P113 in a rinse formulation for the treatment and prevention of oral candidiasis.  This condition, also known as oral thrush, is an AIDS-defining opportunistic illness that is highly prevalent in HIV-infected individuals. Up to 40% of AID patients experience symptoms of oral candidiasis.  Other immunocompromised individuals, including cancer patients receiving chemotherapy, are also susceptible to oral fungal infections. Oropharyngeal candidiasis also develops in up to 30% of asthmatics using inhaled corticosteriods. The disease causes pain, inability to eat, and increased risk of additional infection. If the infection becomes systemic, it can be life-threatening. Resistance to current therapies is increasing.  Oral candidiasis outbreaks often recur and maintenance therapy may be needed.

The product under development is an alcohol-free mouthrinse that can be swallowed to help protect the esophagus from infection.  The rinse contains a novel active ingredient, P113, which is a 12 amino-acid antimicrobial peptide that has demonstrated a high level of in vitro activity against Candida albicans, including drug-resistant HIV patient isolates.  The benefits of this product over current treatments are its demonstrated safety in humans, which is related to its natural origin, and the reduced risk of drug resistance due to P113’s unique mechanism of action.  P113 is based on naturally occurring antimicrobial proteins found in human saliva called “histatins,” which play an important role in the body’s natural defense against disease in the oral cavity.  

Safety

The amino acid sequence of P113 is derived from histatins, which are compounds found naturally in human saliva. Toxicology studies performed to date as well as experience in the clinic with a P113 mouthrinse being developed for the treatment of gingivitis have shown P113 to be safe and well tolerated. The gingivitis product has progressed through Phase 2 clinical studies and has been tested in over 300 subjects. 

Efficacy

The antimicrobial activity of histatins was initially established using Candida albicans. Activity against this organism was used in a screen of histatin peptide fragments which lead to the discovery of P113 as being the smallest histatin fragment which retained antimicrobial activity equivalent to that of the parent compound. Additional in vitro testing has shown that P113 has very potent activity against a variety of isolates of C. albicans, C. glabrata, C. parapsilosis and C. tropicalis, all with MIC values of 3.1 mg/mL or less. Resistance to fluconazole had no bearing on the sensitivity of these organisms to P113.

P113 has also been shown to have very potent antibacterial activity against a variety of organisms. In vitro testing has shown P113 to be effective against both Gram (-) and (+) species including E. coli, H. influenzae, P. aeruginosa, S. typhimurium, S. aureus, S. epidermidis, S. mutans and S. sobrinus. In the case of P aeruginosa and S. aureus, antibacterial activity has been demonstrated against a variety of clinical isolates, many of which were resistant to traditional antibiotics. For both bacteria and fungi, 

P113 has been shown to kill cells as opposed to simply inhibiting their growth. Experiments conducted using P. aeruginosa have shown that P113 acts by binding to the cell surface, kills very quickly (within minutes), and acts by permeablizing both the outer and inner membranes of the cell. 

P113 has been shown to bind to tissues in the oral cavity. In a clinical study, it was shown that approximately 30% of the peptide administered in a mouthrinse was retained in the oral cavity following rinsing. 

Market Opportunity

Up to 40% of AID patients experience symptoms of oral candidiasis. The disease is seen in up to 18% of cancer patients undergoing chemotherapy or radiation therapy and up to 75% of patients undergoing bone marrow transplant. Oral candidiasis occurs in up to 30% of asthmatics using inhaled corticosteroids. The disease causes pain, inability to eat, and increased risk of additional infection. Resistance to current therapies is increasing. Oral candidiasis outbreaks often recur and maintenance therapy may be needed. The CDC has recommended that all AIDS patients receive prophylactic treatment for oral candidiasis.

The current worldwide market opportunity for a novel, safe and effective, oral candidiasis therapy is US $250 million. Global sales of topical antifungal drugs represent nearly a US $2 billion market. The growth of this market and demand for effective anti-fungals is driven by a rising incidence of immunocompromised patient populations including individuals with HIV, cancer, asthma and diabetes, among others

Asthma: Prolonged use of oral steroids causes a localized immunosuppression in the mouth, throat, and upper airways that leads to a high frequency of Candidiasis in asthma patients. Approximately half of the 15,000,000 asthmatics in the United States use inhaled steroids to manage their disease.

Cancer: Candidiasis occurs with high frequency in cancer patients due to either disease-related or treatment-related immunosuppression. Both radiation and chemotherapy lead to a suppression of the immune system.

Diabetes: The Centers for Disease Control and Prevention report that there are about 21 million diabetics in the United States. Diabetics are predisposed to oral Candidiasis due in part to poor glycemic control providing a ready food source for candida and in part to a reduction in immune function.

HIV/AIDS: The frequency of oral candidiasis in AIDS patients varies with the disease state and is reflective of the underlying level of immune function. The frequency of OPC in HIV-infected individuals with good immune function is in the range of 7% to 48%, but rises to more than 90% in those with advanced disease. Furthermore, HIV patients frequently have a relapse of oral Candidiasis within 2 weeks to 3 months following completion of antifungal treatment. An estimated 1.1 million people are living with HIV/AIDS in the United States alone. In Asia, Japan and Western Europe, there are an additional 8.5 million HIV/AIDS patients.

Xerostomia: Dry mouth is a common side effect on a number of medications. Drugs causing this condition include many commonly used drugs such as: antidepressants, anticholinergics, antihypertensives, antipsychotics, anti- Parkinson agents, antihistamines, diuretics and sedatives. These medications are broadly prescribed and exacerbate the development of Candidiasis.