The future landscape of ATTR-CM treatment
The future landscape of ATTR-CM treatment
Once-daily tafamidis 61 mg is the current standard of care in ATTR-CM
Several phase III trials are underway investigating the safety and efficacy of alternative therapies for ATTR-CM, including stabilisers and silencers of TTR
Successful alternatives to tafamidis should provide benefits versus placebo early in the course of treatment, have greater efficacy versus tafamidis and provide a benefit to a greater population of patients
"It is really an exciting time to be working with patients with ATTR-CM, there are a lot of things in development." This is how Dr Ahmad Masri, Director of the Cardiac Amyloidosis Program, Oregon Health & Science University, began his talk at this year's European ATTR meeting. Dr Masri's talk focused on the transthyretin (TTR) silencers and stabilisers that have shown potential for the treatment of transthyretin-mediated amyloidosis with cardiomyopathy (ATTR-CM) and are currently entering phase III trials.
Why do we need new therapies?
The current standard of care for adults with ATTR-CM is once-daily 61 mg tafamidis, a TTR stabiliser that was shown to reduce all-cause mortality and CV-related hospitalisations versus placebo in the ATTR-ACT phase III study.1 Although tafamidis has shown positive results, Dr Masri highlights a number of limitations of tafamidis that other drugs may be able to overcome.
- Earlier benefit: in the ATTR-ACT study, the Kaplan-Meier plot for all-cause mortality showed similar results for placebo and tafamidis until about 18 months of treatment, after which the curves began to separate. A drug that offers greater efficacy than placebo earlier on in treatment could provide better patient outcomes
- More robust relative risk reduction (RRR): in the ATTR-ACT study, tafamidis reduced the risk of all-cause mortality by 30% and CV hospitalisation by 32% versus placebo. New drugs could potentially offer greater reductions in the risk of hospitalisation or death
- Providing benefit to a greater population of patients: the RRR seen with tafamidis in the ATTR-ACT study varied between patient subgroups. Compared with placebo, tafamidis showed some benefit in terms of all‑cause mortality in patients with NYHA class III heart failure, but this benefit was smaller than in patients with NYHA class I/II and there was no benefit in terms of CV hospitalisations. Tafamidis showed improvements versus placebo in mortality and functional decline in patients with wild type (ATTRwt) and variant (ATTRv) ATTR-CM, but outcomes in ATTRv were worse than for ATTRwt. This leaves an opportunity for new therapies that can provide greater improvements in patients with NYHA class III or ATTRv
A new drug that can achieve one or more of these factors would be an attractive alternative to tafamidis. Dr Masri continued his talk by discussing some of the contenders.
AG10 is a new TTR stabiliser that works via a different mechanism to tafamidis, mimicking the super-stabilising T119 mutation. It is not yet licensed for use, but a phase III 30-month study, ATTRibute-CM, is underway to compare the efficacy of 800 mg acoramidis twice-daily with placebo twice-daily in 632 patients with ATTR-CM. The primary endpoint at 12 months is change in 6-minute walking distance from baseline, and the primary endpoints at 30 months are mortality and CV hospitalisations.
After the 12-month analysis, eligible patients will be able to receive tafamidis, which may allow for a direct comparison between AG10 and the current standard of care and help elucidate if different mechanisms of TTR stabilisation have different effects.
In vitro and phase II studies suggest that AG10 may have greater efficacy than tafamidis. In a cross comparison between ATTR-ACT and the phase II OLE with AG10, AG10 was shown to give a 44% greater reduction in all‑cause mortality and a 39% greater reduction in CV hospitalisations versus placebo at 12 months. However, Dr Masri heeds caution when interpreting these data: "…there are a lot of limitations for efficacy when talking about cross-trial comparisons, and so we should take it with a grain of salt."
One interesting result from the phase II AG10 trial, is that patients with both ATTRwt and ATTRv demonstrated near-complete stabilisation of TTR with AG10, highlighting a potential use for AG10 with patients with ATTRv.
Vutrisiran is an RNAi therapeutic that knocks down the production of both wild type and variant TTR. In a phase I, single ascending dose study, subcutaneously administered vutrisiran (5-300 mg) achieved a potent and sustained reduction in TTR levels in a dose-dependent manner,2 with a 25 mg dose of vutrisiran giving an average TTR reduction from baseline of 80%.
The efficacy and safety of 3-monthly 25 mg vutrisiran is now being investigated in patients with ATTR-CM in the HELIOS-B phase III trial (N=655).3 The primary endpoint of HELIOS-B is the composite of all-cause mortality and recurrent CV events (CV hospitalisations and urgent heart failure visits) when the last patient reaches Month 30.
Of note, patients with ATTR-CM Gillmore stage 3 (NT-proBNP >3,000 ng/L and eGFR <45 mL/min) combined with NYHA class III were excluded from the HELIOS-B trial, meaning that efficacy data will not be available for this subgroup of patients.
Patisiran is another RNAi drug, designed to inhibit the hepatic synthesis of TTR. Patisiran is already approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy, having shown improvements in neuropathy and quality of life versus placebo in the phase III APOLLO trial.4 APOLLO-B, another phase III trial, is now underway to test the efficacy and safety of patisiran in patients with ATTR-CM. Around 300 patients, who are either TTR stabiliser-naive or have shown progression whilst being treated with TTR stabilisers, will receive 0.1 mg/kg patisiran or placebo by IV infusion, once every 3 weeks.
The primary endpoint of the APOLLO-B study is the change in 6-minute walking distance from baseline after 12 months of treatment, which Dr Masri highlights as a potential limitation: "…this trial is a little bit different because it is not going to have the long duration - 30 months of hard endpoint measurement."
The results of these ongoing phase III trials may help answer a number of questions. For instance:
- does the degree of TTR reduction matter beyond a therapeutic threshold?
- could silencing be harmful?
- could circulating TTR, even stabilised, be harmful?
They may also lead to the approval of new, and potentially more effective, options for the treatment of ATTR‑CM. Dr Masri believes increased choice of drugs is a good thing - that having options is not akin to having too much choice but should allow us to improve patient care. "Continued data generation really guarantees a better future for patients living with ATTR-CM and I encourage everybody to continue to enrol patients in different trials that are ongoing so we can find more answers and generate more data."
CV: cardiovascular; eGFR: estimated glomerular filtration rate; IV: intravenous; NT-proBNP: N-terminal pro B-type natriuretic peptide; NYHA: New York Heart Association; OLE: open-label extension; RNAi: RNA interference
Based on: Masri A. Future landscape for ATTR-CM treatment. Presented at the 3rd European ATTR amyloidosis meeting for patients and doctors, 6-8 September 2021.
- Maurer M S, Schwartz J H et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379(11):1007-1016
- Habtemariam B A, Karsten V et al. Single-dose pharmacokinetics and pharmacodynamics of transthyretin targeting N‑acetylgalactosamine-small interfering ribonucleic acid conjugate, vutrisiran, in healthy subjects. Clin Pharmacol Ther 2021;109(2):372-382
- ClinicalTrials.gov. HELIOS-B: a study to evaluate vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. Available at: clinicaltrials.gov. Accessed October 2021
- Adams D, Gonzalez-Duarte A et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11-21
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