Recombinant human alpha-mannosidase is intended to supplement or replace alpha-mannosidase, the enzyme that catalyses the sequential degradation of high-mannose hybrid and complex oligosaccharides in the lysosome. Through this action, recombinant human alpha-mannosidase may reduce the accumulation of mannose-rich oligosaccharides in patients with alpha-mannosidosis. Recombinant human alpha-mannosidase is administered by intravenous (IV) infusion at between 22 and 35mg per week based on a dosage of 1mg/kg once weekly (in a paediatric population) on a continuing, lifelong basis.
Like most mucopolysaccharide diseases, alpha-mannosidosis is very variable with different individuals presenting with different aspects of the condition. Poorly functioning white blood cells results in immune deficiency, and recurrent respiratory and inner ear infections are common, particularly within the first year. Almost half of patients are affected by seizures or fits. Individuals may present with learning difficulties and developmental delay, ranging from mild to severe. Problems with bone formation and growth are common and lead to a range of musculoskeletal abnormalities. Most patients become wheelchair users. This loss of independence means patients increasingly require full-time, personal care as well as psychological support.
Due to the rarity of the condition, there is limited information available on the prevalence of alpha-mannosidosis; 14 patients are thought to have been diagnosed in the UK since 1961. There have only been approximately 200 cases reported worldwide, but there are likely to be many more patients that have not been diagnosed.
There are currently no disease-modifying treatment options available for alpha-mannosidosis except for haematopoietic stem cell transplantation (HSCT). Recombinant human alpha-mannosidase has completed one phase II clinical trial assessing its effect on mannosidase activity through the measurement of oligosaccharides found in patients’ urine, and a number of functional activity tests and laboratory parameters. It is currently also undergoing three phase III trials and one phase II clinical trial.
Nitisinone is in clinical development for the treatment of alkaptonuria. Alkaptonuria is a rare metabolic disorder, in which patients lack a functional enzyme that prevents the body fully breaking down two amino acids called tyrosine and phenylalanine. This results in a build-up of a chemical called homogentisic acid (HGA) in the body, which is deposited as black pigment in tissues, in a process called ochronosis. This results in dark colouration of urine, joint problems, breathing difficulties and heart, kidney and prostate problems. In the later stage, patients may experience physical disability and inability to perform daily activities. Early recognition and management of alkaptonuria is desirable to slow the progression of this disease.