AAN 2023: Better health outcomes likely with combination therapy
Study in 103 hATTR patients on treatment, either a combo or single therapy
People with hereditary transthyretin amyloidosis (hATTR) who are treated with a combination of therapies appear to have better health outcomes than those given only one type of medication.
That’s according to new findings presented at the 75th American Academy of Neurology (AAN) annual meeting, being held April 22-27 in Boston and virtually. The presentation was titled “Treatment characteristics in a cohort of patients with hereditary transthyretin amyloidosis.”
Hereditary transthyretin amyloidosis is caused by mutations in the gene that provides instructions for making the transthyretin protein. As a consequence of these mutations, an abnormal protein is produced that forms toxic clumps in the body’s tissues, causing damage that drives disease symptoms.
Familial amyloid polyneuropathy (FAP) is a specific form of hATTR characterized by damage to the nerves, or neuropathy, outside the brain and spinal cord. hATTR also often causes damage to the heart (cardiomyopathy).
Study into use of one or more therapies within two categories of treatment
Several treatments are currently available for FAP and/or other types of hATTR, and they can be broadly divided into two categories: gene silencers and protein stabilizers.
Gene silencers — including the approved FAP therapies Amvuttra (vutrisiran), Tegsedi (inotersen), and Onpattro (patisiran) — work by preventing the production of abnormal transthyretin proteins.
Protein stabilizers, as the name suggests, work by stabilizing the transthyretin protein so it is less prone to forming toxic clumps. These include Vyndaqel (tafamidis), which is approved in the U.S. for hATTR cardiomyopathy but is being investigated as a potential FAP therapy, and the anti-inflammatory medication diflunisal (sold as Dolobid), which has been used off-label to treat hATTR.
“To date, there have not been any studies that have looked at the effects of monotherapy — one class of these medications — versus those patients that are on combination therapy with both these classes of medications,” said Taha Qarni, MD, a neurology resident at Penn Medicine, University of Pennsylvania Health System, who presented the findings at the AAN meeting.
To fill this knowledge gap, Qarni and colleagues retrospectively reviewed data from 162 people with hATTR who were seen at the university’s amyloidosis center between 2018 and 2022. “This is amongst the largest [group] of [hATTR] patients studied outside a clinical trial in the U.S.,” Qarni said.
A total of 119 patients (73.5%) had overt disease symptoms, and 103 of them (86.6%) were started on a disease-specific treatment. The most common disease-causing mutations among these patients included V122I (53%), T60A (19%), and V30M (11%).
Of the 103 treated patients, 53 (51.5%) had co-occurring heart and neurological symptoms, and 34 (64.2%) were on a combination therapy, mainly with Vyndaqel plus Onpattro. The other 19 people in this patient group (35.8%) were on monotherapy, mainly with Vyndaqel.
A total of 41 patients had cardiomyopathy alone, and all were being treated with Vyndaqel. Another nine patients had neuropathy alone and five (55.6%) were on monotherapy, mainly with diflunisal, while the other four (44.4%) were on combination therapies, typically diflunisal plus Onpattro.
In total, over a third of all treated hATTR patients were on combination therapy, including most of those with both neuropathy and cardiomyopathy, Qarni noted.
Among patients with both neurological and heart symptoms, those not on combination therapy mostly were people who “were lost to neurology follow-up and thus were not started on the newly approved [gene] silencing therapy,” Qarni said.
“Given the large number of patients on combination therapy, there exists a need for larger studies to determine the optimal treatment regimen” in hATTR, he added. Anecdotally, Qarni noted that safety issues among patients on combination therapy generally is not beyond what would be expected with either therapy in isolation.
Over the course of follow-up, 18 of the 103 patients died, and one discontinued all treatment.
Combo shows potential for fewer hospitalizations, less severe heart symptoms
Among the 119 patients with symptoms, those showing neuropathy alone were younger at symptom onset (median age of 50) than those with both neuropathy and cardiomyopathy (median of 62 years old) and those experiencing heart symptoms alone (median age of 70).
Next, the researchers focused on the 94 patients with cardiomyopathy, with or without neuropathy. Those given combination therapy tended to be significantly younger than those on monotherapy both at symptom onset (median of 60 vs. 69 years) and when they started treatment (median 67 vs. 75 years).
Patients on combination therapy tended to have less severe heart symptoms at the study’s start. Over a median of 40 months of follow-up, about 3.3 years, these patients also had fewer hospitalizations (29.4% vs. 46.7%) and a 63% lower risk of death than those on monotherapy.
However, these differences failed to reach statistical significance, meaning there’s a non-negligible likelihood the differences noted are due to random chance. Findings for hospitalizations may be due to the fact that the monotherapy group had worse heart symptoms at the study’s start, Qarni noted.
Likewise, “although there is a trend towards decreased mortality, this does not hold up in terms of statistical significance,” he said.
“This is the first study demonstrating to date that a significant minority of these patients are on combination therapy with both a silencer and a stabilizer,” Qarni added, which “has implications for both future clinical and treatment guidelines.”
The neurology resident noted that the analysis was limited by its use of retrospective clinical data, which is prone to biases — for instance, patients with distinct initial symptom severity may tend to get different treatments, which could skew results when comparing outcomes.
Qarni also pointed out that many of the approved hATTR therapies only became available in recent years, so the timeframe of this study is probably too short to reliably evaluate long-term events like mortality and hospitalization rates.
As such, Qarni stressed a need for larger studies following patients over time to better understand the effect of combination versus monotherapy in hATTR patients.
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