BEYONTTRA 356 mg film-coated tablets (acoramidis) approved for Transthyretin Amyloidosis Cardiomyopathy

BEYONTTRA, a new medication containing the active ingredient acoramidis, has received approval for the treatment of transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in adult patients with wild-type or hereditary forms of the disease. This development marks a significant advancement in the therapeutic landscape for a condition historically challenging to manage. The drug, developed by Bayer HealthCare SAS, is a specific transthyretin stabilizer designed to address the underlying pathology of ATTR-CM.

The recommended dosage for BEYONTTRA is 712 mg, administered orally twice daily in the form of two 356 mg film-coated tablets, resulting in a total daily dose of 1,424 mg. The medication is available through both hospital and community pharmacies. It is currently reimbursed at 30% of its cost, reflecting its approved indication. Prescribing BEYONTTRA requires an initial hospital prescription and an annual prescription reserved for cardiologists, although subsequent renewals are not restricted.

Understanding Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)

Transthyretin amyloidosis (ATTR) is a progressive and often fatal disease characterized by the deposition of misfolded transthyretin protein in various organs, most notably the heart. Transthyretin is a protein produced primarily in the liver that transports thyroxine and retinol (vitamin A) in the blood. In ATTR, this protein becomes unstable, detaches from its transport functions, and misfolds into amyloid fibrils. These fibrils then accumulate in tissues, leading to organ dysfunction.

There are two main types of ATTR:

• Hereditary ATTR (ATTRv): This form is caused by genetic mutations in the TTR gene, leading to the production of an unstable variant of transthyretin. It is inherited in an autosomal dominant pattern, meaning a person only needs to inherit one copy of the mutated gene from one parent to be affected. Over 120 different mutations have been identified, with symptoms typically emerging around age 60, though onset can vary.
• Wild-Type ATTR (ATTRwt): Also known as senile amyloidosis, this form occurs due to the natural aging process. The transthyretin protein, even without a genetic mutation, becomes unstable and misfolds, leading to amyloid deposition. This is the more common form of ATTR, with an estimated prevalence of around 10% in individuals over 80 years old.

ATTR-CM develops when these amyloid deposits accumulate in the heart muscle, leading to a stiffening of the heart walls and impaired pumping function. This can manifest as heart failure with preserved ejection fraction (HFpEF), where the heart’s ability to relax and fill with blood is compromised, even if the heart’s squeezing function (ejection fraction) appears normal on initial assessment.

Diagnosis of ATTR-CM is often suspected in patients presenting with symptoms of heart failure, particularly those with preserved ejection fraction. A key diagnostic clue is the presence of left ventricular parietal hypertrophy, a thickening of the heart’s main pumping chamber. This hypertrophy is considered significant when it exceeds 13 to 14 millimeters in thickness. In hereditary forms, genetic testing through sequencing of the TTR gene can confirm the presence of a causative mutation, especially in individuals with a family history of ATTR and suggestive symptoms. Genetic counseling is recommended for asymptomatic relatives who may carry a mutation, given the hereditary nature of the condition.

The prevalence of ATTR is considered rare globally, estimated at approximately 1 in 100,000 people. However, in France, the incidence of ATTR with cardiomyopathy was estimated at 8,950 patients between 2011 and 2019, suggesting a significant and potentially underestimated patient population.

Acoramidis: Mechanism of Action

Acoramidis functions as a specific transthyretin stabilizer. Its mechanism of action involves enhancing the stability of the transthyretin tetramer, the functional form of the protein. By inhibiting the dissociation of the tetramer into individual monomers, acoramidis slows down the amyloidogenic process that underlies ATTR-CM. This targeted approach aims to reduce the formation of toxic amyloid fibrils and their subsequent deposition in cardiac tissue.

The current treatment landscape for transthyretin amyloid cardiomyopathy has historically been limited, with options focusing on symptom management or slowing disease progression through different mechanisms. The introduction of acoramidis represents a new therapeutic strategy aimed directly at the protein misfolding defect.

Clinical Evaluation and Regulatory Review

BEYONTTRA’s efficacy and safety profile were evaluated in the Phase III ATTRibute-CM study, a randomized, placebo-controlled trial that enrolled 632 patients diagnosed with ATTR-CM. The primary composite endpoint of the study included all-cause mortality, cardiovascular hospitalizations, changes in NT-proBNP levels (a biomarker for heart strain), and changes in the 6-minute walk test distance, assessed over 30 months.

The Transparency Commission (CT) in France has assessed the benefit-risk ratio of acoramidis as moderate. This assessment was influenced by methodological limitations observed in the trial, particularly concerning the primary composite endpoint. The CT noted that the results were predominantly driven by changes in NT-proBNP levels rather than a significant impact on all-cause mortality.

The safety profile of acoramidis appears favorable, with limited data available up to 42 months of follow-up. However, the CT highlighted the absence of direct comparative studies between acoramidis and other approved treatments for ATTR-CM. While an indirect comparison with tafamidis was explored, its methodological robustness was considered limited, preventing a definitive hierarchical ranking of acoramidis against clinically relevant comparators.

Consequently, the CT concluded that BEYONTTRA (acoramidis) offers a moderate medical service (SMR) and no additional medical benefit (ASMR V) compared to existing therapeutic options. This evaluation led to the recommendation of a 30% reimbursement rate.

Key Considerations for Prescribing BEYONTTRA

The approval of BEYONTTRA signifies a new avenue for managing ATTR-CM, but its introduction comes with specific prescribing guidelines and administrative considerations.

Dosage and Administration:

• Recommended Dose: 712 mg (two 356 mg tablets) orally, twice daily.
• Total Daily Dose: 1,424 mg.
• Administration: Tablets should be swallowed whole with water, with or without food.
• Packaging: Available in boxes of 120 tablets, providing a 30-day supply.

Patient Population and Limitations:

• BEYONTTRA is not indicated for use in pediatric patients.
• Data regarding the use of BEYONTTRA in pregnant women are not available, and its use in this population is not recommended without further investigation.

Adverse Effects:
While the overall safety profile is considered favorable, certain adverse effects are frequently reported (affecting more than 1 in 10 people). These may include:

• Gastrointestinal disorders
• Urinary tract infections
• Nasopharyngitis (common cold symptoms)
• Upper respiratory tract infections

Administrative Identity:

• Classification: List I (indicating a prescription-only medication).
• Prescription Requirements: Initial prescription must be issued by a hospital physician (PIH). Annual renewal prescriptions are reserved for cardiologists.
• Renewal: Subsequent renewals are not restricted.
• Packaging: Box of 120 tablets (CIP code: 3400930311066).
• Public Price: €4,421.08 (inclusive of VAT).
• Reimbursement: 30% by social security.
• Collective Agreements: Approved for collective reimbursement schemes.
• Marketing Authorization Holder: Bayer HealthCare SAS.

Future Outlook and Implications

The approval of BEYONTTRA is a welcome development for patients and clinicians managing ATTR-CM. The estimated patient population targeted by this treatment in France ranges between 10,500 and 12,500 individuals. The Commission de la Transparence anticipates that this number is likely to increase in the coming years due to improved diagnostic capabilities and increased awareness of the disease.

The availability of a new therapeutic option, particularly one that targets the underlying mechanism of the disease, offers hope for improved patient outcomes. However, the moderate SMR and absence of ASMR assigned by the CT suggest that further research and real-world data will be crucial in establishing the long-term impact and comparative effectiveness of acoramidis. The limited direct comparative data and the nuances of the primary endpoint analysis in the pivotal trial underscore the ongoing need for robust evidence to guide treatment decisions.

The increased diagnosis rate, as predicted by the CT, will likely place a greater demand on healthcare resources and specialist expertise. It also highlights the importance of continued research into less invasive diagnostic methods and more accessible genetic testing and counseling services. The economic implications of a new, high-cost medication will also require careful consideration within healthcare systems, particularly given the partial reimbursement rate.

In conclusion, BEYONTTRA represents a significant step forward in the management of ATTR-CM. Its approval provides a new therapeutic choice for adult patients, addressing a critical unmet need. While its exact place in the treatment algorithm and its long-term comparative benefits are still being elucidated, the introduction of acoramidis signifies progress in the fight against this complex and debilitating disease. Continued research, enhanced diagnostic efforts, and careful clinical implementation will be key to maximizing the benefits of this new treatment for patients.