Cardiac amyloidosis: An update on diagnosis and treatment

ATTR treatment

Liver transplant for ATTRm amyloidosis for the V30M mutation that causes FAP was first described in 1990, but it has not been well validated in other mutations and is not a solution for ATTRwt.⁷⁶ Significant progress has been made over the past 2 decades in the understanding of the pathophysiologyy of ATTR, paving the way for promising advancements in pharmacotherapy. Presently, there are 3 classes of pharmacologic agents, grouped by the point of disease process each strategy targets:

• Block TTR synthesis at the translational level in hepatocytes
• Stabilize the TTR tetramer to inhibit the rate-determining step of amyloidogenesis
• Disrupt and clear the ATTR amyloid fibril.⁷⁷

Block TTR synthesis. TTR messenger RNA (mRNA) can be targeted by “silencers” preventing translation, thereby reducing the production TTR protein by hepatocytes. The resultant sustained reduction of plasma TTR should decrease or halt amyloid deposition by making less TTR available to dissociate and deposit in the heart and nerves. There are 2 approaches to silencing TTR mRNA translation: small interfering RNA (siRNA) and antisense oligonucleotide (ASO).⁷⁷

An siRNA, packaged in a lipid nanoparticle to ensure delivery to the liver, has been designed to bind to a conserved region of TTR mRNA, degrading the mRNA and reducing TTR protein expression. One siRNA, patisiran, completed the phase 3 APOLLO clinical trial (NCT01960348) in August 2017. It is an intravenous medication that requires premedication. The APOLLO trial studied patients with neuropathic variants of ATTRm, with a primary end point of neuropathy progression over 18 months. Patisrian met the primary end point and will likely be approved by the US Food and Drug Administration (FDA) by the third quarter of 2018. Given its target of a conserved 3’ untranslated region of TTR mRNA, patisiran should theoretically yield benefits not just in FAP but to both ATTRm-CA and ATTRwt-CA.^68,77

ASOs are single-stranded oligonucleotides, typically 20 nucleotides in length, that bind to mRNA and elicit enzymatic mRNA degradation and reduced protein expression. Inotersen (IONIS-TTR_Rx) is an ASO drug that targets a conserved region of TTR mRNA. Inotersen is administered by weekly subcutaneous injection. A phase 2/3 clinical trial (NCT01737398) completed in October 2017 studied the drug's efficacy in treating FAP, with a primary end point of neuropathy progression over 65 weeks. It met the primary end point and a subset of patients actually improved. Like patisiran, inotersen is likely to be approved by the FDA for a neuropathy indication by the third quarter of 2018 and may benefit patients with ATTRm-CA and ATTRwt-CA. More studies are needed in the ATTR cardiac population.^68,77

Stabilize the TTR tetramer. The TTR tetramer has 2 thyroxine binding pockets that stabilize the structure when bound preventing dissociation. Dissociation of the tetramer, the rate limiting step for ATTR fibrillogenesis, can be reduced using pharmacologic agents that bind to the thyroxine binding pockets. Both new and repurposed agents have been found to stabilize the TTR tetramer, including diflunisal, tafamidis, tolcapone, and AG10.^68,77

Diflunisal (Dolobid) is a nonacetylated salicylate nonsteroidal anti-inflammatory drug used for over 3 decades to treat arthritis and musculoskeletal pain. Unrelated to its anti-inflammatory properties, it interacts with TTR’s thyroxine binding pocket to increase the stability of the tetramer. A 2013 randomized, placebo-controlled, international multicenter trial of 130 patients with FAP demonstrated a statistically significant slowing of polyneuropathy progression; however, 67 patients (diflunisal n = 27, placebo n = 40) did not complete the study.⁷⁸ A small study revealed diflunisal to be reasonably well-tolerated in ATTR-CA, and to date it is the only readily available pharmacotherapy for ATTR supported by a randomized, placebo-controlled trial.^79,80 Diflunisal may be considered for off-label use in patients with ATTR-CA with relatively preserved kidney function and no increased bleeding risk, taken under the supervision of a cardiologist who will monitor for fluid retention and changes in renal function.⁷⁷

Tafamidis (Vyndaqel), like diflunisal, interacts with TTR’s thyroxine binding pocket and increases tetrameric stability. A phase 2 open-label clinical trial studied the efficacy and tolerance of tafamidis in 31 patients with ATTRwt and NYHA functional class 1 and 2 followed for 1 year. Twenty-eight patients completed the study and 2 patients died. TTR stabilization at 6 weeks was achieved in 30 of 31 patients (96.8%), and success at 1 year in 25 of 28 patients (89.3%). No clinical progression occurred in 16 of 31 patients (51.5%), and tafamidis was generally well-tolerated, with diarrhea the most common side effect in 7 of 31 patients (22.6% ).^81,82

A phase 3 clinical trial (NCT01994889) is studying tafamidis vs placebo in patients with ATTRm-CA or ATTRwt-CA (excluding NYHA functional class 4) with the primary outcome measure of all-cause mortality and heart failure-related hospitalizations over 30 months. This is a large trial that enrolled 446 patients and data collection is expected to be completed in February 2018.

Tolcapone, approved by the FDA for Parkinson disease, has been found to be a potent TTR stabilizer by binding both thyroxine binding pockets of the TTR tetramer simultaneously. However, tolcapone has an FDA “black box” warning due to the risk of potentially fatal acute fulminant liver failure and is not currently used in ATTR therapy.⁶⁸ Nonetheless, it will likely undergo further study for ATTR.

Recruiting is underway for a phase 1 clinical trial of AG10, a potent selective TTR stabilizer (NCT03294707).⁶⁸

Disruption and clearance of the ATTR amyloid fibril. Even though treatment directed at blocking TTR synthesis or stabilizing the tetramer may be effective at preventing further deposition, the residual amyloid deposits persist and continue to affect organ function. With that need in mind, several agents that disrupt the amyloid formation process further downstream have been evaluated at a basic science level and in a few small nonrandomized open-label studies.⁷⁷

Doxycycline is a tetracycline antibiotic with demonstrated effectiveness in disrupting mature amyloid fibrils in mouse models.⁸³ Tauroursodeoxycholic acid  is a bile acid with the ability to disrupt prefibrillar amyloid components. This combination has been studied in patients with ATTR-CA in 2 small open-label trials, with only 1 having results published. There was no progression in NT-proBNP or wall thickness in a cohort of 7 patients who completed 12 months of treatment.⁸⁴ These data are nonrandomized and hypothesis-generating, as adequate studies would need to be performed to evaluate this hypothesis further. Because there are currently no FDA-approved therapies for ATTR, patients may be offered this combination fully informed that the data are limited. (Note: ursodiol is substituted for tauroursodeoxycholic acid, which is not available in the United States.)⁶⁸

Green tea extract contains the polyphenol epigallocatechin-3-gallate, which has shown the ability for fibril disruption as well as TTR stabilization, importantly using a binding site separate from the thyroxine binding pocket (utilized in diflunisal and tafamidis). A small open-label study of 19 patients with ATTR-CA of whom 14 took green tea extract for 1 year reported a reduction in intraventricular septal wall  thickness at 1 year, and in 9 patients a reduction of 12.5% in LV mass measured by cardiac MRI.⁸⁵

Curcumin, the active ingredient in the household spice turmeric, has displayed in vitro promise as a TTR stabilizer by binding to the thyroxine binding pocket, and as an amyloid fibril disruptor by increasing macrophage degradation activity. Although there have only been preliminary animal studies, this supplement may be promising for further study in humans with ATTR-CA.⁶⁸

PRX004 is a synthetic antibody designed to bind to non-native misfolded forms of TTR with the goal of potentially preventing deposition and promoting clearance of TTR aggregates.⁸⁶ A phase 1 open-label escalation trial (NCT03336580) in 36 patients with ATTRm is planned and, hopefully, will pave the way for further study.

Heart transplant for patients with ATTR-CA. Patients with ATTRwt-CA who are young enough to undergo heart transplant have displayed favorable outcomes given that it causes clinically isolated heart disease and is an indolent process that should not affect the transplanted heart over the average life span of the allograft. Patients with the ATTRm mutation V122I have been treated with heart transplant alone, with the thought process that again, due to the indolent nature of amyloid deposition, concomitant liver transplant may not be needed.⁷⁴ Thus far, 6 patients with this mutation have undergone successful transplant at our institution with heart alone, 1 of whom is 9 years posttransplant without any recurrent amyloid in the allograft. Patients with the T60A mutation that causes both polyneuropathy and cardiomyopathy require combined heart and liver transplant.⁷⁴

Are there other therapies being studied to clear amyloid deposits and reverse organ dysfunction?

Extracellular deposits of amyloid fibrils, regardless of precursor protein, contain common elements such as calcium, glycosaminoglycans, and an SAP component. SAP stabilizes amyloid fibrils and makes them resistant to degradation. A monoclonal immunoglobulin G1 anti-SAP antibody has been designed to target the ubiquitous SAP component, signaling an immune response that leads to macrophage mediated clearance of amyloid fibrils, regardless of the type. Treatment with this approach was studied in a pilot trial of 16 patients mostly with AL, and within a 6-week period some of the patients had dramatic reversal of liver amyloid deposition.² This has paved the way for a phase 2 open-label trial to be performed in patients with AL-CA and ATTR-CA (NCT03044353) and plans for a randomized phase 3 trial in CA are in discussion. There is optimism that this therapy may achieve the holy grail of removing amyloid rather than just preventing further deposition.