Rare monogenic human diseases are typically treated with therapeutics known as orphan drugs with a prevalence of the disease less than 200,000 Americans (source: FDA website). Monogenic means that the disease is caused by a malfunction in a single gene product. Each gene is represented by two copies or alleles, with the exception of genes carried on the sex chromosomes. Genes represented twice in the genome are often referred to as autosomal genes. Diseases resulting from monogenic mutations may be classified into three general groups: dominant, caused by a mutation in a single allele; recessive, a mutation in both alleles; or sex linked, a mutation in a gene represented only once on the sex chromosomes.
Rare monogenic diseases are often the result of autosomal recessive mutations in essential genes causing dire and usually life threatening diseases. In order for a disease to result from a recessive trait, a child must inherit a mutated gene from both parents. Therefore, each parent is a carrier but does not manifest the disease. The children of two carrier parents have a probability of one in four to manifest the disease, two in four to be carriers, and one in four to inherit two alleles free of mutations.
The frequency of human diseases that qualify as orphan drug diseases range from about 0.1 to 67 per 100,000 people. Evidence suggests that there are 10,000 monogenic human diseases (source: World Health Organization). Many of these orphan diseases are listed in the Online Mendelian Inheritance in Man website. Monogenic diseases are responsible for a heavy loss of human life. Typically, these rare diseases result in physical and mental deformities and death often occurs in adolescent or teenage years. The global prevalence of all single-gene diseases at birth is approximately 1 in 100. It is estimated that taken together, monogenic diseases account for up to 40% of the work of hospital-based pediatric practice (Campeau, Scriver, Mitchell (1995) Molec Gen Metab 95:11-16).
The orphan drug designation provides 7 years of market exclusivity from the date of FDA market approval, regardless of patent coverage. In addition, there are other economic incentives like shorter and less costly clinical trials and sometimes reimbursement for some of these costs. Because of the large cost of treatment of these life-threatening rare diseases, high drug prices are usually justified and supported by the medical insurance industry. Therefore, even though the number of patients using the drug may be small, the world market may be significant.
Rare monogenic human diseases are typically treated with protein replacement therapies. This involves cloning or obtaining the cDNA encoding the protein, expression into protein in a biological system, and formulation of the protein into a drug. These drugs require preclinical animal studies and clinical trials for approval from the FDA for marketing.
Scientists at Icogenex have been involved with the cloning, expression, and development of a number of protein therapeutics including successful collaborative contract research projects with HemeBiotech (now Zymenex). These included porphobilinogen deaminase which lead to a successful Phase I clinical trial, alpha-mannosidase to successful Phase II trial, and arylsulfatase A to successful Phase II clinical trial resulting in the sale of the project by Zymenex to Shire PLC for $135 million and a ZymoGenetics NovoNordisk collaboration resulting in the marketing of Factor VIIa (NovoSeven®) with currently over $1 billion yearly market sales.