Join our experts for a one-hour CME presentation as they appraise clinical safety and efficacy data for new and emerging therapeutic agents for the treatment of hATTR amyloidosis.
hATTR amyloidosis is a genetic disorder that is characterized by the deposition of amyloid (abnormal proteins) in multiple organs. It often affects the nerves, liver, heart and kidneys, which interferes with the structure and function of those organs. Symptoms typically appear between the mid-20’s and mid-60’s. There are only about 50,000 people worldwide with this disorder.
It is transmitted in an autosomal dominant manner and caused by a mutation in the transthyretin (TTR) gene. The misfolded TTR proteins are deposited as amyloid fibrils in the nerves, heart and GI tract where they accumulate. TTR tetramers are mainly produced in the liver and then secreted as a tetramer compound of identical monomers. This tetramer is destabilized and broken into monomers, which are then misfolded and accumulated into amyloid fibrils.
The two main classifications of hereditary amyloidosis are ATTR and Non-TTR. There are about 136 different genetic variations in ATTR and approximately 60 variations in Non-TTR hereditary amyloidosis.
What are the symptoms of hATTR?
- Ocular: Dark floaters, glaucoma, abnormal blood vessels in the eyes, and abnormal pupils.
- Cardiovascular: Irregular heartbeat, heart conduction blocks, CHF, and ventricular wall thickening
- Bilateral carpal tunnel syndrome
- Spinal stenosis
- Nephropathy: Proteinuria and renal failure
- Gastrointestinal: Nausea, vomiting, early satiety, diarrhea and constipation
- Autonomic neuropathy: Orthostatic hypotension, urinary retention, recurrent UTIs, sexual dysfunction, abnormal sweating, and alternating diarrhea/constipation
- Peripheral neuropathy
Autonomic nerves typically are affected before motor nerves. When differentiating hATTR amyloidosis from other adult-onset progressive neuropathies, dysautonomia may support the diagnosis. Most of the autonomic dysfunction progression is seen in the early stages.
In general, hATTR amyloidosis is a progressive disease and if left untreated, will progress until death occurs. It can present as a mixed phenotype where some patients experience neuropathy principally whereas in others cardiac symptoms are predominant. Clinically, a vast range of phenotypes is observed. The majority of hATTR phenotypes present with both neurologic and cardiac symptoms. Since it such a rare disease, making the diagnosis can prove difficult. Biopsy is often the test of choice and samples can be obtained from salivary glands or gastric mucosa, or by an aspiration of subcutaneous fat. Sometimes multiple biopsies are needed given the patchy nature of the amyloid deposits. Genetic testing can also be done confirming the TRR mutation. If cardiac symptoms are present, endomyocardial biopsy is often the most sensitive test. EKG, echocardiography, and cardiac MRI may also prove useful.
In the APOLLO trial, a large randomized Phase 3 study, patients were recruited from 46 sites across 19 countries (all but two were academic hospitals). Patients were between the ages of 18-85 years old diagnosed with hATTR amyloidosis, had a documented TTR mutation, and a life expectancy greater than or equal to 2 years. Patients also had symptomatic polyneuropathy. Patients were randomized to receive either Patisiran (an investigational RNA interface therapeutic) 0.3 mg/kg or placebo once every 3 weeks for 18 months. On July 5, 2018, the FDA approved the use of Patisiran for the treatment of hATTR amyloidosis, the first medication approved for this indication. This followed the publication of the APOLLO study results in the NEJM, which showed a statistically significant improvement in neuropathy and quality of life versus placebo.
Clinical trials are still ongoing.
Want to learn more? Join our experts for a one-hour CME presentation on new and emerging therapeutic agents for the treatment of hATTR amyloidosis.
About the Author
Linda Girgis MD, FAAFP is a family physician practicing in South River, New Jersey. She was voted one of the top 5 healthcare bloggers in 2016. Follow her on twitter @DrLindaMD.