Treatment switches in FAP are common, reasons numerous: Study
Researchers suggest structured way to guide decisions
Treatment switches in people with familial amyloid polyneuropathy (FAP) are common, with Amvuttra (vutrisiran) emerging as a preferred option due to its more convenient administration route and safety profile, according to small study in Germany.
“Disease progression was the primary reason for therapy switches,” researchers wrote. However, “while the availability of disease-modifying treatment options has expanded significantly, the absence of evidence-based guidelines for therapy switching and sequencing remains a major clinical challenge.”
Based on the “manifold” reasons why patients switched treatments, researchers suggested a structured way to guide decisions. It involves checking for worsening symptoms or side effects, considering the method of delivery and the patient’s preference, and discussing newly approved medications openly.
The study, “Real-world treatment management in hereditary transthyretin amyloidosis — an experience report and proposal for therapy switch decision criteria,” was published in BMC Neurological Research and Practice by a team of researchers in Germany. Some authors have received funding, speaker fees, or travel support from Alnylam Pharmaceuticals, which markets Amvuttra.
‘Head-to-head comparisons of disease-modifying treatment strategies lacking
FAP is a form of hereditary ATTR amyloidosis (hATTR), a group of conditions caused by mutations in the TTR gene that result in the production of a faulty version of the transthyretin protein. This faulty protein forms toxic clumps that accumulate in the body’s tissues, leading to progressive damage.
In people with FAP, transthyretin clumps build up mainly in the nerves outside the brain and spinal cord, causing neurological symptoms. Some patients may also show aggregate accumulation in the heart that causes damage to the organ, with this condition being called a mixed phenotype.
Several medications can help slow the disease and ease symptoms. However, because they work by using different mechanisms, patients may need to switch treatments depending on how the disease progresses or how well they tolerate side effects.
However, “head-to-head comparisons of disease-modifying treatment strategies remain notably lacking,” the researchers wrote, adding that “no clear guidelines or recommendations for treatment initiation or switches exist.”
With this in mind, the team analyzed data from 13 adults (nine men and four women) with hATTR who were treated at a single German center. Most (61.5%) had FAP, while the remaining participants (38.5%) had a mixed phenotype at presentation. There were no cases of heart involvement alone.
Four participants (30.8%) carried the Val50Met (Val30Met) mutation, the most common cause of FAP. Their median age at diagnosis was 66, and there was a median two-year delay between symptom onset and treatment initiation. Participants’ current therapy had been started following a median of two years of treatment with other agents.
More than half of treatment switches due to disease progression
During the course of the study, a total of 23 treatment switches were documented, about half (52.2%) due to disease progression.
All but three people (76.9%) started their treatment with 20 mg of tafamidis meglumine — an oral therapy approved under the brand name Vyndaqel for early-stage FAP in the European Union and a number of other countries, but not in the U.S. It works by stabilizing the transthyretin protein, preventing the formation of toxic clumps.
However, the majority of these (83.3%) had to switch due to disease progression. Notably, neurological deterioration was observed in 80% of the 10 people starting treatment with tafamidis meglumine, while additional or isolated heart disease progression was observed in 50%.
Most of these patients eventually switched to Amvuttra, a FAP-approved therapy injected under the skin, or subcutaneously, every three months. It works by suppressing the production of the transthyretin protein.
Two participants switched from Tegsedi (inotersen), a weekly subcutaneous therapy approved for FAP that also works by suppressing transthyretin production, to other treatments due to side effects. Two other people switched from Onpattro (patisiran) — Alnylam’s predecessor of Amvuttra that is infused into the bloodstream every three weeks — due to side effects.
Among those who switched from Onpattro to Amvuttra, 65% said they preferred the easier, less frequent dosing of Amvuttra.
Majority of participants were on Amvuttra at study’s end
By the end of the study, two-thirds of participants (66.7%) were on Amvuttra. None of them discontinued this medication during the study, suggesting it was both effective and easier to tolerate.
Two other people were on Onpattro and two were on Vyndamax, which contains a higher dose of tafamidis meglumine and is approved for transthyretin amyloid cardiomyopathy, an FAP-related disease marked mainly by heart damage.
The team also analyzed data from 13 patients who did not switch treatments during the study period. These participants showed stable disease, as assessed with clinical and laboratory measures, regardless of the therapy’s mechanism.
This “underlines that individual assessment of therapy effect is essential for detection of potential non-responders and indication for therapy switch,” the researchers wrote.
Based on the reasons why patients switched treatments, the researchers suggested treatment switches should be guided by four key points: monitoring for worsening symptoms or side effects, consideration of how the medication is given, respect for patients and their preferences, and discussion of new treatment options while keeping costs and access in mind.
“Individualized therapeutic decisions should … be a result of an interdisciplinary discussion and justification facing the respective cost bearer,” the researchers wrote. “There is an urgent need for prospective real-world, long-term and/or [multicenter] studies comparing treatment strategies, development of validated biomarkers to guide therapeutic decisions, as well as consensus guidelines incorporating real-world evidence.”
About the Author
