First Generation Pharmaceutical Treatments for Transthyretin Amyloidosis Continue to Make Progress

Perhaps a score of the countless proteins in the human body misfold in large amounts in later life. The misfolded form is insoluble, leading to solid deposits of the protein in and around cells. These problem proteins are known as amyloids, and the accumulation of amyloids is one of the root causes of aging. Amyloidosis conditions arise from the presence of amyloid and the disruptive effect it has on cellular biochemistry. The best known form of amyloid is the amyloid-β thought to cause Alzheimer's disease, but the research community is beginning to appreciate that other forms may be just as big a problem over the course of aging. The topic for today is transthyrein amyloid, and the efforts to produce therapies to address it and its consequences.

Transthyretin, or TTR, amyloid is of particular note in the cardiovascular system. Evidence suggests that transthretin amyloidosis is the full stop at the upper end of the natural human life span; the majority of the tiny fraction of people who survive everything else that aging can throw at the human form, and manage to become supercentenarians living to age 110 or later, will die because TTR amyloid clogs their cardiovascular system to the point of failure. In earlier old age, studies have suggested that at least 10% of heart failure patients suffered that outcome as the result of TTR amyloid. Beyond this, TTR amyloid may contribute to osteoarthritis, spinal stenosis, and cartilage degeneration.

The first generation of pharmaceutical therapies targeting transthyretin started out as efforts to target the hereditary form of this amyloidosis, in which genetic mutation greatly speeds up the process of amyloid formation. Not all of these development initiatives are applicable to the natural, age-related form of the condition. Those that are function by attempting to stabilize the protein, preventing it from assuming the harmful, misfolded configuration. Generally this results in marginal, incremental gains; it can only slow progression, and has little impact on existing amyloid deposits.

Alternative approaches that can remove existing amyloid deposits should be far superior for all the obvious reasons. A range of methods are at various stages in development, but it has been (and continues to be) slow going. Pentraxin's work on CPHPC as a therapy is ten years in, with a successful clinical trial a few years ago, but the folk in charge seem to be in no hurry to move ahead. Covalent's work on catalytic antibodies has been around for some time, but has not yet made the leap to very active and focused translational development. Other antibody-based efforts are still at earlier stages in development. So for now, the inferior approaches are those gaining all of the funding, and those advancing most rapidly to the clinic.

Drug Reduces Deaths from Underdiagnosed Form of Heart Failure

A phase three clinical trial has shown that a drug called tafamidis significantly reduces deaths and hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive form of heart failure that may be more common than doctors realize. If tafamidis receives FDA approval for transthyretin amyloid cardiomyopathy, it would be the first medical therapy for this life-threatening disease. Compared to a placebo, the drug reduced deaths by 30 percent, reduced cardiovascular-related hospitalizations by 32 percent, and slowed the decline in quality of life among the 441 patients enrolled in the 2.5-year study.

ATTR-CM occurs when a protein called transthyretin becomes unstable and clumps together and forms sticky amyloid in heart muscle. (Amyloid deposits also occur in Alzheimer's disease, but those develop through a different mechanism and cannot be treated with the drug tested in this study). The disease is most common in men over the age of 60 and is caused by heritable genetic mutations or age-related changes in the regulation of transthyretin. Tafamidis acts by stabilizing transthyretin, preventing its dissociation and ability to form amyloid. "Tafamidis prevents progression of the disease, and like other preventive drugs, it should be given as early as possible. We'll need to diagnose people with ATTR-CM earlier for this drug to have the biggest benefit. Currently, patients are diagnosed with advanced disease, and we need to change that."

Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy

In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalization. In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo. Tafamidis was associated with lower all-cause mortality than placebo (29.5% versus 42.9%; hazard ratio, 0.70) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68.

Pfizer surprises ATTR rivals with tafamidis success

Over the course of the past several years, Alnylam and Ionis have pushed their respective treatments for hereditary TTR amyloidoisis (ATTR) through late-stage clinical testing to regulatory review by the Food and Drug Administration. Alynlam's drug, called patisiran, is seen by many analysts as more potent and efficacious in easing the symptoms of the rare disease - which causes progressively more severe organ damage, leading to neuropathy and cardiomyopathy. Ionis may win FDA approval for its rival candidate inotersen first, while Alnylam won't be far behind. But Pfizer's results could complicate the competitive mix.

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