The following description of Friedreich’s ataxia (FA) may be found on the website of FARA, the Friedreich’s Ataxia Research Alliance, at wwww.curefa.org.
Friedreich’s ataxia (FA) is a debilitating, life-shortening, degenerative neuro-muscular disorder. Patients suffer progressive degeneration of the central and peripheral nervous systems, which causes impaired motion and gait; diminished vision, hearing and speech; loss of strength and coordination, leading to wheelchair use; increased risk of diabetes; and life-threatening heart complications. About one in 50,000 people in the United States have Friedreich's ataxia.
Most individuals have onset of symptoms of FA between the ages of 5 and 18 years. Adult or late onset FA is less common, <25% of diagnosed individuals, and can occur anytime during adulthood.
FA is an inherited or single gene disorder. Mutations or DNA changes in the FXN gene cause FA.
FA in inherited in an autosomal recessive manner, meaning that individuals with FA have two mutated or abnormal copies of the FXN gene, this means both biological parents must be a carrier of the disease for a child to be affected. It is estimated that 1 in 100 people are carriers, and carriers do not exhibit symptoms of FA. Each such carrier parent has one mutated gene (allele) and one normal gene (allele) in the FXN gene. Because each child gets one of the mother’s genes and one of the father’s genes in this location, there are four possible combinations of the genes passed down to the child or a 25% chance that the child will have FA.
The FA gene mutation limits the production of a protein called frataxin, which is known to be an important protein that functions in the mitochondria (the energy producing factories) of the cell. Frataxin helps to move iron and is involved with the formation of iron-sulfur clusters, which are necessary components in the function of the mitochondria and thus energy production. We also know that specific nerve cells (neurons) degenerate in people with FA, and this is directly manifested in the symptoms of the disease.
Shire is developing SHP622 as a treatment for FA on the basis that SHP622’s radical scavenging activity and metal chelation properties counteract the excess amount of iron in the mitochondria and free radicals in the bodies of FA patients.
There is no FDA approved treatment for FA; at typical orphan drug prices, FA represents a target market with worldwide peak year sales of ~ $1B ($440M-$770M in US and EU alone).
Penetration of the FA market should be rapid because of the significant unmet medical need and lack of competition.
Anti-TauC3 Monoclonal Antibody
Progressive Supranuclear Palsy
Progressive Supranuclear Palsy (PSP) is a progressive brain disorder that resembles Parkinson’s disease. PSP affects movement, control of walking (gait) and balance, speech, swallowing, vision, mood and behavior, and thinking. Classic signs of the disease are an inability to aim and move the eyes properly and blurring of vision. Symptoms begin on average after age 60 and men are affected more often than women. It is estimated that PSP affects 6 in 100,000 Americans; Incidence 2.8 per 100,000.
The exact cause of PSP is unknown. The symptoms of PSP are caused by a gradual deterioration of brain cells in specific areas in the brain, mainly in the region called the brain stem. The hallmark of the disease, and a possible cause, is the accumulation of abnormal deposits of tau and eventual toxicity in nerve cells in the brain stem. These findings suggest that the use of tau antibody therapeutics, such as such as our anti-TauC3 monoclonal antibody, may be a viable treatment approach.
There is no FDA approved treatment for PSP. No medication is effective in halting the progression of the disease; however, several medications, including dopamine agonists, tricyclic antidepressants, and methysergide, may provide modest symptomatic improvement.
Drugs in development for PSP include: BMS-968168 (Bristol-Myers Squibb) and ABBV-8E12 (AbbVie) both of which are anti-tau antibodies in Phase 1; and several drugs in preclinical stage development.
Traumatic Brain Injury
Traumatic Brain Injury (TBI) is a form of acquired brain injury, which occurs when a sudden trauma causes damage to the brain. Sports-related concussion, which includes chronic traumatic encephalopathy (CTE) is caused by direct impact forces to the head; blast-induced TBI is caused by exposure to blast shock waves.
TBI results from secondary neuronal damage caused by the impact, which leads to progressive neuronal cell death, neural loss, and axonal degeneration in the brain. Symptoms of TBI can be mild, moderate, or severe, depending on the extent of the brain damage. Patients suffer headache, light-headedness, memory loss, confusion, attention deficits, difficulty balancing, aggression, anxiety, depression, etc.
The CDC estimates that TBI affects approximately 1.7 million Americans each year, including approximately 270,000 NFL players and 200,000 war veterans.
There is no FDA approved treatment for TBI; moderately to severely injured patients receive rehabilitation that involves treatment programs in physical therapy, occupational therapy, speech/language therapy, physical medicine, psychology/psychiatry, and social support.
A common feature of TBI related diseases is deposition of the tau protein around cerebral blood vessels in the frontal cortex of the brain. Studies have indicated that military personnel who reported three or more traumatic brain injuries showed high total tau protein concentrations in plasma, in some cases long after the injuries had occurred. These findings are consistent with reports for repetitive head injury in athletes linked to progressive tauopathy, axonal injury and post-concussive disorder symptoms. These findings suggest that the use of tau antibody therapeutics, such as our anti-TauC3 monoclonal antibody, may be a viable treatment approach.