Phase I Trials: Prodarsan for Cockayne's Syndrome

Leiden, The Netherlands, April 23, 2008. Biotech company Pharming Group NV (Pharming) (NYSE Euronext: PHARM) announced today that its wholly owned subsidiary DNage has started a Phase I clinical study to evaluate the pharmacokinetics and tolerability of Prodarsan(R) in humans.

Premature ageing, the primary target of Prodarsan(R), is a group of rare genetic diseases which manifests itself in several forms that are genetically and clinically similar although not identical. Dependent on the specific form of the disease, patients have a strongly reduced life expectancy and exhibit many ageing-related diseases early on in their lives. There is currently no effective therapy available for these patients.

Pharming has demonstrated that Prodarsan(R) as an oral, liquid formulation has significant effects in animal models for Cockayne Syndrome (CS). CS is one of the more common forms of premature ageing and is characterized, amongst others, by growth failure, mental retardation, eye abnormalities and a reduced life expectancy. The positive effects of Prodarsan(R) in preclinical testing on life expectancy in general and more specifically on the eye abnormalities are promising for further development of the product and its testing in humans.

The Phase I trial that is now being conducted consists of a combined single and multiple dose escalating clinical study in healthy volunteers. By studying the pharmacokinetics and tolerability of Prodarsan(R) and the effects of food intake on the absorption and elimination of the product, an oral dosing scheme will be determined that targets the pharmacological effective concentration range effectively. It is expected that following a successful completion of this trial the first clinical studies in patients will start later in 2008. Source

CKN1 is caused by a defect in the Cockayne syndrome type A gene (CSA or ERCC8) located on chromosome 5. Affected persons inherit 2 mutant genes, one from each parent. Cells carrying ERCC8 mutations are hypersensitive to UV light. They do not recover the ability to synthesize ribonucleic acid (RNA) after exposure to UV light. In addition, the cells cannot remove and degrade deoxyribonucleic acid (DNA) lesions from strands that have active transcription.

Mutations in the DNA excision repair gene ERCC6 located on band 10q11 cause CS type 2 (MIM number 133540; CSB). This gene encodes helicase, a protein that is presumed to have DNA unwinding function. Mutations include a deletion of exon 4, an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein, and large deletion in the upstream region, including exon 1 of the CSA gene. The Q106P mutation could alter the propeller structure of the CSA protein, which is important for the formation of the CSA protein complex. Additionally, a missense mutation (A205P) and a nonsense (E13X) mutation have been identified, as well as a new common single nucleotide polymorphism in CKN1. No genotype-phenotype correlation exists. _ EMedicine