Experts recommend early gene-silencing treatment for hATTR-PN
Study: Regular monitoring urged to help doctors adapt treatment over time
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Hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) should be treated as early as possible once a patient has symptoms and a confirmed disease-causing genetic mutation, according to consensus recommendations from German experts.
In addition, the gene-silencing therapies Amvuttra (vutrisiran) or Wainzua (eplontersen) — marketed as Wainua in the U.S. — are the preferred first-line treatments. Treatment response should be regularly monitored to adjust medication when needed based on how the disease progresses and how the patient responds.
“Treatment decisions require careful consideration of the available evidence on efficacy and safety, as well as regulatory status, mode of administration, monitoring requirements, comorbid [co-existing] organ involvement, patient-specific factors, patient preferences, and the peculiarities of the healthcare system,” researchers wrote.
The recommendations were described in the study “Disease modifying treatment of hereditary transthyretin amyloidosis with polyneuropathy in Germany – expert consensus of the German society of amyloid diseases (DGAK) and the German neurological society (DGN),” which was published in Neurological Research and Practice.
Gene silencers reduce production of the TTR protein
In hATTR-PN, mutations in the TTR gene cause the TTR protein to become unstable, break apart, and form toxic clumps called amyloid deposits. These tend to build up mainly in the peripheral nerves that form the communication lines outside the brain and spinal cord. Gradual damage to multiple nerves causes neurological symptoms.
Current disease-modifying treatments (DMTs) include gene silencers, which reduce the production of TTR, and TTR stabilizers, which help prevent TTR from misfolding and forming amyloid deposits.
These options allow treatment to be tailored to a patient’s symptoms, other health conditions, and preferences. However, direct comparisons between DMTs are lacking, and real-world evidence remains limited.
Amvuttra, Wainzua both reduced treatment burden
To provide recommendations for treating hATTR-PN in Germany, experts from the DGAK and the DGN reviewed the available clinical evidence on how safe DMTs are and how well they work for hATTR-PN while also considering factors that are taken into account when making individualized treatment decisions.
Based on the available evidence, the experts recommend the gene silencers Amvuttra or Wainzua as first-line treatment for most people with symptoms of hATTR-PN.
They found no clear advantage of Amvuttra over Wainzua because the two treatments have not been directly compared in clinical trials. Both have shown to be effective in slowing hATTR-PN progression. Wainzua has also produced evidence of benefit for autonomic symptoms, which affect involuntary body functions such as blood pressure and digestion.
Both also reduce treatment burden compared with other options. Amvuttra is given via under-the-skin (subcutaneous) injections every three months, while Wainzua is given through monthly subcutaneous injections and can be administered at home after training.
These therapies are more convenient than Onpattro (patisiran), a hATTR-PN-approved therapy that requires regular into-the-vein (intravenous) infusions and additional medication to reduce the risk of infusion-related reactions.
Like Tegsedi (inotersen) — an older gene-silencer therapy now discontinued in North America and being discontinued in the European Union due to low utilization — the experts consider Onpattro a second-line treatment. Onpattro has produced evidence of benefit but requires more frequent treatment and intravenous administration.
However, “if patients are stable under [Onpattro] and explicitly prefer DMT continuation over DMT switch, there is no medical reasoning not to abide with the patients’ preference,” the experts wrote.
Response to treatment should be checked regularly
Tafamidis meglumine — a TTR stabilizer approved in Europe, but not in the U.S., for hATTR-PN under the brand name Vyndaqel — remains an option for select patients, particularly those with very early disease and carrying Val50Met, the most common mutation linked to hATTR-PN. However, the experts recommend switching to a gene silencer if there are signs that the disease is progressing.
Diflunisal, an oral therapy approved for hATTR-PN in Europe, but not the U.S., under the brand name Attrogy, “might be equally efficacious as tafamidis (no head-to-head comparison available) but has a more relevant safety profile (potential gastrointestinal, [heart], and [kidney] toxicity),” the experts wrote.
Response to treatment should be checked regularly. If hATTR-PN progresses while a patient is taking a TTR stabilizer, the experts recommend switching promptly to a second-generation gene silencer such as Amvuttra and Wainzua. If progression occurs during such treatment, doctors can measure blood TTR levels to check whether its production is being reduced.
There is not enough evidence to show that switching between Amvuttra and Wainzua improves a patient’s outcomes. Combining a gene silencer with a TTR stabilizer is not routinely recommended. Some evidence suggests possible benefits in people with severely progressive disease, but more research is needed before combination treatment can be recommended generally.
Treatment should not be stopped when disease becomes advanced. Some patients who can no longer walk may still benefit from continued treatment. Decisions about stopping or switching treatment should therefore be individualized and made with experienced specialists.
“Based on the available evidence and current clinical practice in Germany, the DGAK/DGN consensus recommends first-line therapy with one of the two second-generation TTR gene-silencing agents,” the experts wrote. In the future, “novel disease-modifying strategies may further reshape the therapeutic landscape.”
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