Amyloidoses is an umbrella term depicting the disorders that are related to protein conformation and metabolism. It occurs because of abnormal protein deposits in various tissues of the body, causing organ dysfunction and eventually leading to death. Among the various types of amyloidoses, the most common type is the “ATTR” amyloidosis, characterized by transthyretin (TTR) protein deposition causing several autonomic and peripheral neuropathies, sometimes cardiac or renal disease, leading to death within 5-15 years of symptom onset. ATTR Amyloidosis has further been classified into hereditary amyloidosis (hATTR), caused by the mutations and wild-type ATTR, caused by the misfolding of TTR.
There are three major forms of hereditary amyloidosis that can be differentiated on the basis of the symptoms and affected body organs. The “neuropathic form” majorly affects the peripheral and the autonomic nervous system, leading to the Familial Amyloid Polyneuropathy (FAP) and difficulty in body movement of the patient. The “leptomeningeal form” primarily affects the central nervous system and the “cardiac form” majorly affects the heart, the latter leading to a condition known as Familial Amyloid Cardiomyopathy (FAC).
Typical symptoms of ATTR Amyloidosis includes hyperesthesia, pain, temperature, motor weakness, impotence, decreased bowel motility, diarrhea, and weight loss. Carpal Tunnel Syndrome is another common clinical manifestation related to ATTR Amyloidosis. Since the symptoms of this disease overlap with other conditions, it requires careful investigation and diagnosis.
Although the exact prevalence of transthyretin amyloidosis is unknown, it is found to be more prevalent in Portugal, Sweden, and Japan, with many scattered cases across the United States and Europe. DelveInsight estimates that ATTR Amyloidosis is more prevalent in the United States as compared to the EU5 (UK, Spain, Italy, France, and Germany) and Japan. It was also observed that though Carpal tunnel syndrome is one of the most common prevalent symptom in ATTR Amyloidosis patients, only a fraction of patients opt for carpal tunnel surgery treatment. Though it is life-threatening, there is only one approved therapy, Vyndaquel (tafamidis meglumine) by Pfizer, it that is available in EU and Japan for the treatment of TTR-FAP.
The current treatment of ATTR Amyloidosis is dominated by symptomatic therapies like diflunisal, loop diuretics, aldosterone antagonists, angiotensin-converting enzyme inhibitors etc. However, liver transplantation remains the gold standard for therapy and is generally recommended in the early stages of the disease.
In the search for an effective therapy for the treatment of ATTR, many drugs are currently in the development phase. Prominent drugs currently in Phase-III of development include Inotersen by Ionis Pharmaceuticals Inc. and Patisiran by Alnylam Pharmaceuticals- Sanofi. Phase II drugs include CRX-1008 (Corino Therapeutics Inc.).
These upcoming drugs have better safety and efficacy profiles than those existing in the market and are expected to help expand the use of drugs for the treatment of ATTR Amyloidosis. However, since these mentioned drugs are focused on the treatment of TTR-FAP, this still leaves a significant opportunity for therapies for the other types of ATTR Amyloidosis such as FAC and wild-type ATTR.