The entry of new players and new approaches into the ATTR-CM space could help bring down the cost of treatment, experts say.
Recent late-phase data from Alnylam highlights the race to develop the next generation of therapies for transthyretin amyloid cardiomyopathy—a competition experts say could lower the overall cost of treatment for the rare cardiovascular disease.
A potentially fatal disorder, transthyretin amyloid cardiomyopathy (ATTR-CM) occurs when the transthyretin protein misfolds and amyloid deposits build up in the extracellular space of the heart’s muscle tissues. This causes the heart walls to become stiff, and the regular pumping of blood is affected.
The only approved drugs for the condition are Pfizer’s Vyndaqel and Vyndamax, oral formulations with the same active ingredient, tafamidis. The drugs, transthyretin stabilizers, currently enjoy the total market share. Pfizer generated revenue of $1.3 billion in the second quarter of 2024, a 69% boost from the same quarter in 2023.
But competition is on the way, with companies including Alnylam and AstraZeneca testing their versions of RNA-silencing treatments for ATTR-CM in clinical trials. In June, Alnylam revealed topline data from the Phase III HELIOS-B trial of Amvuttra (vutrisiran), showing that the treatment could lower the risk of death and recurrent cardiovascular events in ATTR-CM. Alnylam plans to file a New Drug Application with the FDA later this year.
“Assuming regulatory approval, Amvuttra has the potential to be the first alternative RNAi treatment option available for these patients with an unmet need,” an Alnylam spokesperson told BioSpace in an email.
Mathew Maurer, a professor of cardiology at Columbia University Irving Medical Center, noted that the ATTR-CM space is a good example of precision medicine. “It is an exciting and rapidly evolving area,” he said in an email. “All recent late phase trials in this space have met their primary endpoint, which is because therapies have emerged from a solid understanding of the protein that causes [ATTR-CM], and how patients are affected.” This is why many companies are getting this space, he added.
High Unmet Need
There are two types of ATTR-CM, genetic and wildtype. The most common form is wildtype, which is generally seen in older adults. The genetic type occurs when individuals inherit a variant in the transthyretin gene that leads to protein misfolding, causing disease at a younger age.
Patients with the condition experience ongoing debilitating heart damage, often resulting in progressive heart failure, which leads to death within three to five years of disease onset in the absence of treatment. While there are an estimated 5,000 to 7,000 new cases of ATTR-CM diagnosed in the U.S. each year, Anubhav Jain, a cardiologist at McLaren Port Huron Hospital, said the disease might be underdiagnosed. “ATTR-CM is called an orphan disease. However, there is another school of thought that it is more prevalent in society,” he told BioSpace.
According to Jain, ATTR-CM diagnosis picked up after 2019 when non-invasive diagnostics became available. “Since then, we started getting more enthusiastic about this disease,” he said.
RNA Therapies Enter the Space
Pfizer’s drugs, Vyndaqel and Vyndamax, work by stabilizing the malformed TTR protein. They attach to the protein, preventing it from breaking apart and leaving deposits in the heart walls. The clinical trial data, which led to the drugs’ 2019 approval, showed a reduction in all-cause mortality and cardiovascular hospital admissions among ATTR-CM patients.
However, Maurer pointed out that while Vyndaqel and Vyndamax slow disease progression, they don’t reverse it, which is why they work better for people in the early to intermediate stages of the disease. “There’s still a high residual mortality and morbidity, hence the reason investigators are trying to develop new therapies,” Maurer said.
A new class of drug aims to stop the production of the mutated TTR protein by targeting its RNA. Alnylam’s vutrisiran, sold under the brand name Amvuttra for polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis, is an RNA interference (RNAi) therapy that silences the defective TTR mRNA.
An Alnylam representative said the company believes its treatment could be the first alternative to protein stabilizers. “Through surveys we have conducted of healthcare professionals, we understand that a majority of stabilizer patients experience limited or no treatment response,” a company representative told BioSpace in an email.
In a Sept. 3 response, Marianna Bruno, U.S. ATTR-CM medical team lead in the chief medical affairs office at Pfizer, said, “Vynadaqel/Vyndamax are the only approved treatments for the cardiomyopathy of wild type or hereditary ATTR-CM in adults proven to reduce cardiovascular mortality and cardiovascular-related hospitalization. They are supported by more than a decade of research, including five years of data from the pivotal ATTR-ACT clinical trial and its long-term extension study.”
Meanwhile, British multinational AstraZeneca, in collaboration with Ionis Pharmaceuticals, has also entered the space. The companies’ Wainua (eplontersen), an antisense RNA silencing therapy, was approved by the FDA in December 2023 to treat hATTR amyloidosis. The partners are now studying the medicine for ATTR-CM in the Phase III CARDIO-TTRansform study.
Maurer said that using RNA-based drugs to stop the production of TTR is “theoretically” more beneficial than stabilization. However, he cautioned that there are no head-to-head comparative studies. “The field of amyloidosis is rapidly evolving already. The new therapies look effective. As medical providers, we don’t know which one to give first,” he said. “We also don’t know whether to combine them with the existing treatment.”
Meanwhile, Maurer and Jain pointed out that the treatments are costly. For instance, tafamidis costs more than $225,000 per patient per year, making it one of the most expensive medications for cardiovascular disease.
Jain said he is hopeful the ATTR-CM market will become more competitive with multiple players and that this might result in the costs decreasing. “I am hoping the entry of new drugs will improve access to treatment and raise more awareness about the condition.”
Editor’s note (Sept. 3): This article was updated from its original version to include comments from Pfizer.
