What is amyloidosis and ATTR amyloidosis? Amyloidosis is a rare clinical disorder caused by the accumulation of aggregated, misfolded proteins in organs and tissues. Based on the specific protein precursor, amyloidosis can be further divided into various subtypes, including amyloid light chain (AL) amyloidosis, amyloid A (AA) amyloidosis, and amyloid transthyretin (ATTR) amyloidosis. ATTR amyloidosis is further classified into two groups, either with wild-type or mutant transthyretin (TTR). Wild-type TTR deposits may stiffen and thicken the heart, over time leading to cardiomyopathy, but the disease onset presents much later in life. Patients with deposits composed of mutant TTR can develop either polyneurophathy or cardiomyopathy, or both, determined by the underlying TTR genetic mutations. Symptoms caused by mutant TTR amyloid deposits usually appear earlier. It is worth pointing out that the mutations in TTR gene are autosomal dominant and heritable. Survival in ATTR amyloidosis is variable, ranging from months to years, depending on whether the TTR protein precursor is wild-type or mutated and on the severity of the resulting amyloid cardiomyopathy and/or polyneuropathy.


What are the current therapies available for ATTR amyloidosis? Current drug therapies for ATTR amyloidosis include TTR stabilizers and amyloid degraders. TTR stabilizers, such as tafamidis (Pfizer’s Vyndaquel) and diflunisal (generic), are used to maintain TTR’s normal soluble tetrameric structure and to limit the number of TTR monomers in the circulation. Insoluble TTR monomers aggregate and then misfold to form TTR amyloids. Amyloid degraders such as the doxycycline/tauroursodeoxycholic acid combination therapy have the potential to remove TTR amyloid deposited in the organs. However, current therapies are not sufficiently efficacious, and no treatments other than a liver transplant can eliminate the source of aggregated TTR protein.


RNA inhibiting therapies hold promise as a treatment option for amyloidosis, but recent failure of revusiran represents as setback for this class of therapies. RNA inhibiting therapies bind the targeted mRNA and thereby suppress mRNA expression and prevent translation of the corresponding protein. The clinical results so far have indicated that small interfering RNA and antisense oligonucleotide are potent approaches to eliminate TTR protein production by triggering the degradation of TTR mRNA or inhibiting translation. However, In October 2016, Alnylam Pharmaceuticals halted the ENDEAVOR Phase III multicenter clinical study for their leading pipeline molecule revusiran, an experimental small interference RNA (siRNA), due to the higher mortality observed in the revusiran arm relative to placebo. Revusiran was being investigated as a therapy for amyloid transthyretin amyloidosis with cardiomyopathy (hATTR-CM). Promising preliminary data indicated that this agent could result in a substantial reduction in the level of the transthyretin (TTR) protein, and therefore physicians in the community were very disappointed by the discontinuation of revusiran’s clinical development. However, the development of therapies targeting ATTR amyloidosis patients continues to generate a great deal of excitement.


What is the market potential for RNA inhibiting therapies currently in development (Alnylam’s patisiran and Ionis/GSK’s inotercen) for ATTR amyloidosis? Patisiran, another siRNA therapy developed by Alnylam, is being investigated in a Phase III multicenter clinical trial (the APOLLO study) for hereditary ATTR amyloidosis patients with polyneuropathy (hATTR-PN). According to Alnylam, the development of patisiran will not be affected by the discontinuation of revusiran, as recommended by the data monitoring committee (DMC) for the trial. Ionis Pharmaceuticals and GlaxoSmithKline are also co-developing inotersen (IONIS-TTRRx), a subcutaneously administered antisense oligonucleotide targeting the same patient group as patisiran. Both the patisiran and inotersen studies are expected to report top-line clinical results from their Phase III studies in the second half of 2017. If successfully developed, both therapies are expected to compete head-to-head in this market, therefore, outcomes and clinical data from these trials will be the key for market positioning and to guide the use of these two agents in general practice. Nevertheless, physicians are very excited about these novel treatment options, and expect the rapid adoption of RNA inhibiting therapies to effectively suppress the source of malfunctioning TTR protein.


For a more in-depth analysis of dynamics in the amyloidosis therapeutic market, please see our market assessment in Amyloidosis Disease Landscape & Forecast (US&EU5).

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