Combination therapy may be safe in FAP patients: Study
Many hATTR patients given combined treatment, despite lack of data
Combination therapy for hereditary transthyretin amyloidosis (hATTR), a group of conditions including familial amyloid polyneuropathy (FAP), appears to be safe, according to a retrospective study, but because its effects “on neurological symptoms could not be assessed,” more studies are needed to confirm its benefits, the researchers wrote.
Most of the patients whose health records were examined for the study had heart symptoms with mild neurologic involvement, the researchers said. The study, “Treatment characteristics of patients with hereditary transthyretin amyloidosis: a cohort study,” was published in the Orphanet Journal of Rare Diseases.
The hATTR conditions are caused by mutations in the TTR gene that lead to the formation of toxic clumps made up of the transthyretin (TTR) protein that accumulate in the body’s tissues. In FAP, these toxic TTR aggregates mainly accumulate in the peripheral nervous system, the nerves outside the brain and spinal cord, leading to neurological symptoms. When toxic clumps build up mostly in the heart tissue, the condition is called hATTR cardiomyopathy and is marked by heart-related symptoms.
Treatment for hATTR can take the form of gene silencers, which work by preventing the production of the abnormal thransthyretin proteins that form toxic clumps, or protein stabilizers, which stabilize the transthyretin protein so it’s less prone to forming toxic aggregates.
Gene silencers include the approved FAP therapies Amvuttra (vutrisiran), Tegsedi (inotersen), and Onpattro (patisiran). Protein stabilizers include diflunisal, which has been used off label to treat hATTR, and tafamidis meglumine, which is approved under the brand name Vyndaqel for ATTR cardiomyopathy in the U.S. and for early-stage FAP in the European Union.
Safety, efficacy data lacking
“While many patients may be on both classes of medications, there is no data available on the safety and efficacy of combination therapy,” wrote the researchers, from the University of Pennsylvania. They analyzed the electronic health records of 162 adults carrying a disease-causing TTR mutation who were followed at their center between January 2018 and December 2022.
Participants had a mean age of 65 at diagnosis, and 53.1% carried the Val122Ile mutation, which is usually associated hATTR cardiomyopathy. The Val30Met mutation, the most common FAP-causing mutation, was identified in 17 patients (10.5%).
A total of 119 patients had disease symptoms. Thirteen of them (10.9%) had neurological symptoms alone, consistent with FAP, while in 47 patients (39.5%) the disease was marked by heart-related symptoms alone, indicating hATTR cardiomyopathy. A mixed profile of both neurological and heart symptoms was reported in nearly half of the patients (49.6%).
Among FAP patients, the most common symptom was motor-related problems (46.1%), followed by carpal tunnel syndrome (30.8%), and issues in the autonomic nervous system (15.4%), which controls involuntary bodily functions such as blood pressure and gastrointestinal activity. Carpal tunnel syndrome is a condition that affects nerves in the wrist, causing finger numbness, pain, and tingling.
A total of 103 patients, including nine with FAP, received TTR-targeted therapies.
Five of these FAP patients received single therapy with either diflunisal (44.4%) or Tegsedi (11.1% ). The remaining four patients were given a combination of diflunisal with either Onpattro (33.3%) or Tegsedi (11.1%).
Four FAP patients and 34 patients with a mixed profile received a combination treatment, meaning that “a significant proportion of [hATTR] patients (about one-third) are treated with combination therapy (stabilizers and silencers),” the researchers wrote.
The combination therapy was generally well tolerated, with no limiting side effects specifically attributed to being on both classes of medications.
“Determining the safety and efficacy of combination therapy will be of paramount importance to clinicians caring for [hATTR] patients, especially with the rapidly evolving treatment landscape and the high cost of both classes of medications,” the team wrote.
Because of the small number of patients with neurological symptoms alone, few neurological follow-up assessments were completed, especially during the COVID-19 pandemic. As a result, there was insufficient data to conduct statistical analysis on changes in neurological damage with single versus combination therapy, the researchers wrote.
“Given the considerable number of patients on combination therapy, the unclear benefit of combination therapy versus monotherapy, and the high costs of these drugs, there is a need for larger studies, with longer follow-up, to determine the optimal treatment regimen for [hATTR] patients,” they concluded.
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