Tafamidis clinches top spot in ATTR-CM treatment

With its recent approval in Singapore, tafamidis (Vyndamax^®) made headway as the first disease-modifying therapy for transthyretin amyloid cardiomyopathy (ATTR-CM), a devastating disease with a formidable symptom burden and an average survival of 2–5 years from diagnosis.

The disease is often underdiagnosed but is estimated to account for up to 13 percent of patients with heart failure (HF) and preserved ejection fraction.

The phase III, double-blind, landmark ATTR-ACT* trial, backed the efficacy and safety of tafamidis in patients with hereditary and wild-type ATTR-CM. [N Engl J Med 2018;379:1007-1016]

Patients (n=441) with ATTR-CM from 13 countries were randomized to tafamidis at 80 mg or 20 mg daily, or placebo, and followed prospectively for 30 months. At 30 months, all-cause mortality was 29.5 percent in tafamidis recipients vs 42.9 percent in controls, for a statistically significant and clinically important 30-percent relative risk reduction, establishing tafamidis role in ATTR-CM. Cardiovascular-related hospitalization was also lower with tafamidis (0.48 vs 0.70 per year for placebo; relative risk ratio, 0.68).

In the long-term extension of the ATTR-ACT trial, reported at the recent European Society of Cardiology Heart Failure Discoveries virtual meeting, treatment with tafamidis 80 mg/day provided a significantly greater survival benefit than dosing at 20 mg/day in ATTR-CM patients. [Abstract LBS session 1, Clinical Trial Update]

At a median follow-up of 39 months since ATTR-ACT began, patients on 80 mg/day tafamidis had an adjusted 33 percent reduction in the risk of a composite of all-cause mortality, heart transplantation, or implantation of a ventricular assist device compared with patients on 20 mg/day. At that point, everyone in the long-term extension was switched to tafamidis 61 mg once daily, which is bioequivalent to four 20 mg capsules.

At a median follow-up of 51 months, patients originally on tafamidis 80 mg displayed a highly significant adjusted 43 percent reduction in the risk of the composite endpoint vs those who had been on 20 mg per day, according to investigator Dr Thibaud Damy from the University Hospital Henri Mondor, Creteil, France. The findings support the efficacy and safety of tafamidis over time. [https://www.escardio.org/Sub-specialty-communities/Heart-Failure-Association-of-the-ESC-(HFA)/Research-and-Publications/HFA-Discoveries, accessed 26 August 2020]

Now that tafamidis 61 mg capsule is available in Singapore – rightfully positioned to slow or halt ATTR-CM progression and favourably affect clinical outcomes – early diagnosis of ATTR-CM is critical to afford the best treatment efficacy.

 

Assistant Professor Lin Weiqin

MIMS Doctor had a one-on-one with Assistant Professor Lin Weiqin on what matters most when managing ATTR-CM and the type of patients who should be started on tafamidis.

The ATTR-ACT study has shown that tafamidis is an effective therapy for patients with ATTR-CM. Which patients would benefit most from tafamidis?

The ATTR-ACT study demonstrated outcome benefits for patients with ATTR-CM, when treated with tafamidis, compared with placebo. For the first time, we have a disease-modifying drug for ATTR-CM with proven clinical efficacy. Based on the trial design, a patient with proven ATTR-CM (hereditary or wild-type ATTR-CM) with a history of clinical HF with mild-to-moderate symptoms would benefit from tafamidis. Patients with New York Heart Association (NYHA) class IV symptoms, however, are unlikely to benefit much from this drug due to the advanced stage of HF, and were rightly excluded from the ATTR-ACT study.

The drug was approved for use in Singapore in February 2020. It was touted as the first and only approved oral treatment for ATTR-CM. How does an oral ATTR stabilizer such as tafamidis fit in the overall treatment algorithm for managing ATTR-CM?

Tafamidis 61 mg capsule (Vyndamax^®) is the dose form approved for use in Singapore by the Health Sciences Authority (HSA). Till tafamidis, no disease-modifying treatment was available for patients with ATTR-CM. They could only receive symptomatic management with diuretics and drugs with less established benefits (eg, doxycycline and diflunisal). Tafamidis is thus the first medication available for this group of patients, which can potentially alter the disease trajectory of ATTR-CM.

What are the circumstances wherein you would initiate patients on tafamidis?

Patients with biopsy or scintigraphy proven ATTR-CM with previous episodes of clinical HF would be eligible for initiation of tafamidis, provided they do not have advanced kidney or liver dysfunction.

Is there any advantage for tafamidis vs FDA-approved ATTR silencers that are administered either through infusion or injection?

Tafamidis is, to date, the only disease-modifying treatment for ATTR-CM approved for use in Singapore. This is backed by results from the ATTR-ACT study. Other novel therapeutic agents, such as ATTR silencers, have previously been studied in patients with transthyretin familial amyloid polyneuropathy, but not in dedicated ATTR-CM patients. That being said, randomized controlled clinical trials for ATTR silencers in ATTR-CM (APOLLO-B, HELIOS-B) are currently ongoing and we eagerly await the results of these trials.

Any advice that you feel may be useful for clinicians managing ATTR-CM patients?

In patients with unexplained left ventricular hypertrophy (absence of hypertension), especially when coupled with neurological/orthopaedic complaints of carpal tunnel syndrome and spinal stenosis, the possibility of ATTR-CM should always be considered. This condition is underdiagnosed and is likely more common than previously thought.

Your takeaway message to clinicians who may be using tafamidis for the first time on their patients?

There have been rapid developments in the field of transthyretin amyloidosis over the past decade, especially in the diagnostic and therapeutic areas. We now have a disease-modifying treatment available for patients with ATTR-CM, with tafamidis being the first agent to be approved by the US Food and Drug Administration (FDA) and the Singapore HSA, for the treatment of ATTR-CM. When seeing a patient with ATTR-CM, we should always consider whether they are candidates for initiation of tafamidis, given the outcome benefits demonstrated in the ATTR-ACT study.

In the ATTR-ACT study, no major safety concerns were identified with the use of tafamidis compared with placebo. However, tafamidis should not be used in patients with advanced kidney or liver disease as these patients were excluded in the ATTR-ACT study and the safety and efficacy of tafamidis in these patients is unknown.