For decades, the only meaningful treatment for hereditary transthyretin polyneuropathy was a liver transplant — a major surgical procedure that carried all the risks and recovery burdens you would expect from organ transplantation. That era is effectively over. There are now four FDA-approved drugs that treat hATTR polyneuropathy without surgery, all of them RNA-based therapies that silence or block the production of the misfolded transthyretin protein responsible for nerve damage. The newest of these, eplontersen (brand name Wainua), earned FDA approval in December 2023 and stands apart as the first treatment patients can self-administer at home with a monthly auto-injector — no infusion center, no operating room, no transplant waiting list.
This matters for anyone navigating the overlap between rare neurological disease and cognitive decline. Hereditary transthyretin amyloidosis doesn’t just attack peripheral nerves. It can damage the heart, the autonomic nervous system, and in some cases the central nervous system. For families already dealing with dementia or neurodegenerative concerns, recognizing hATTR polyneuropathy early — and knowing that non-surgical options exist — can change the trajectory of care. This article covers how each of the four approved drugs works, what the long-term clinical data actually shows, and what patients and caregivers should weigh when comparing these treatments.
Table of Contents
- What New Drugs Treat Hereditary Transthyretin Polyneuropathy Without Surgery?
- How Eplontersen Changed the Treatment Landscape for hATTR Polyneuropathy
- Long-Term Evidence From the Patisiran Five-Year Study
- Comparing Vutrisiran, Eplontersen, and Patisiran — Which Treatment Fits Which Patient?
- The Vitamin A Problem and Other Safety Concerns Across All TTR Silencers
- Why Early Diagnosis Matters More Than Ever
- What Comes Next for hATTR Treatment
- Conclusion
- Frequently Asked Questions
What New Drugs Treat Hereditary Transthyretin Polyneuropathy Without Surgery?
Four FDA-approved medications now target hereditary transthyretin polyneuropathy in adults: patisiran (Onpattro), inotersen (Tegsedi), vutrisiran (Amvuttra), and eplontersen (Wainua). All four work by reducing the amount of transthyretin protein the liver produces — the same protein that, when mutated, misfolds and deposits as amyloid fibrils in nerves, the heart, and other tissues. They accomplish this through RNA interference or antisense technology, essentially intercepting the genetic instructions before the faulty protein gets made. The practical differences between them come down to how they are given and how often. Patisiran requires an intravenous infusion every three weeks, typically at a medical facility. Inotersen is a weekly subcutaneous injection.
Vutrisiran improved on the dosing schedule with a subcutaneous injection once every three months. And eplontersen, the most recent approval, requires only a monthly subcutaneous injection that patients can administer themselves at home using a pre-filled auto-injector. For someone already managing the demands of a progressive neurological condition — or caring for a family member who is — these differences in convenience and independence are not trivial. To put this in perspective, liver transplantation for hATTR required finding a donor organ, undergoing a complex surgery, and committing to lifelong immunosuppressive drugs to prevent rejection. Since these pharmacologic therapies became available, the number of liver transplants performed for hATTR has declined significantly. The transplant era, which began in the 1990s as the gold standard approach, has given way to treatments that patients can receive without ever entering an operating room.
How Eplontersen Changed the Treatment Landscape for hATTR Polyneuropathy
Eplontersen, developed by Ionis Pharmaceuticals and AstraZeneca, is a ligand-conjugated antisense (LICA) medicine. It works by binding to messenger RNA in liver cells, blocking the instructions that tell those cells to produce transthyretin protein. Its FDA approval in December 2023 was based on the NEURO-TTRansform Phase III trial, which showed that eplontersen reduced serum transthyretin levels by 81.2% after 35 weeks. Patients in the trial showed sustained improvements in neuropathy impairment scores (measured by the mNIS+7 composite) and quality of life measures. What makes eplontersen distinct is not just its efficacy but its practicality. It is the first and only approved hATTR polyneuropathy treatment that can be self-administered. The 45mg dose comes in a pre-filled auto-injector pen, delivered subcutaneously once a month.
For patients living in rural areas far from infusion centers, or for those whose neuropathy already makes travel difficult, this is a genuine shift in what daily life with the disease looks like. Eplontersen also built on the foundation of inotersen (Tegsedi), its predecessor, by reducing dosing frequency from weekly to monthly while maintaining the subcutaneous route. However, eplontersen is not without side effects. In clinical trials, the most common adverse reactions were decreased vitamin A levels, occurring in about 15% of patients, and vomiting, reported in 9%. The vitamin A issue is not unique to eplontersen — it is a class effect shared by all TTR-lowering therapies, since transthyretin is the protein that carries vitamin A (retinol) in the blood. Reducing TTR production inevitably lowers vitamin A transport. Patients on any of these drugs must supplement with the recommended daily allowance of vitamin A, and physicians need to monitor levels over time.
Long-Term Evidence From the Patisiran Five-Year Study
While newer drugs like eplontersen offer convenience advantages, patisiran (Onpattro) holds a unique position in the evidence base: it has the longest published follow-up data of any RNA interference therapeutic for any disease. In January 2025, JAMA Neurology published five-year results from the global open-label extension of the APOLLO trial, conducted across 43 hospitals in 19 countries from July 2015 through November 2022. Of 212 eligible patients, 211 enrolled in the extension, and 138 completed the full five years of follow-up. The results were meaningful. Among those who completed the study, 65% — 89 of 138 patients — saw their polyneuropathy disability (PND) scores remain stable or improve over five years of treatment. That is a notable finding for a progressive disease where the expected trajectory without treatment is steady deterioration.
The study also found that patients who began patisiran earlier in their disease course had significantly improved survival compared to those who started later, reinforcing the clinical urgency of early diagnosis. There is a practical limitation, though. Patisiran is administered by IV infusion, and infusion-related reactions occurred in 16.1% of patients across the study period. These reactions are generally manageable — often involving flushing, back pain, or nausea — but they require the infusion to take place in a monitored clinical setting. For patients who tolerate the infusions well and have easy access to an infusion center, patisiran’s robust long-term data may make it a compelling choice despite the less convenient delivery method. For others, the newer subcutaneous options may be preferable even though their long-term track records are shorter.
Comparing Vutrisiran, Eplontersen, and Patisiran — Which Treatment Fits Which Patient?
Choosing between these therapies involves weighing efficacy data, dosing convenience, route of administration, and individual patient circumstances. Vutrisiran (Amvuttra) occupies an interesting middle ground. Originally approved in June 2022 for hATTR polyneuropathy, it received an expanded FDA approval in March 2025 for ATTR cardiomyopathy, making it the first and only therapy approved for both the polyneuropathy and the cardiac manifestations of transthyretin amyloidosis. For patients who have both nerve and heart involvement — which is common, since the misfolded TTR protein deposits in both tissues — vutrisiran’s dual indication is clinically significant. Its dosing is a subcutaneous injection of 25mg once every three months, administered by a healthcare provider. In the HELIOS-A trial, vutrisiran reduced mean serum transthyretin at steady state by 83%, slightly edging out eplontersen’s 81.2% reduction in the NEURO-TTRansform trial, though cross-trial comparisons should be interpreted cautiously since patient populations and study designs differ.
The HELIOS-B trial extended the evidence to cardiovascular outcomes, demonstrating that vutrisiran significantly reduced cardiovascular mortality, hospitalizations for heart failure, and urgent heart failure visits compared to placebo. The tradeoff between these drugs often comes down to what matters most to the individual patient. If self-administration at home is the priority, eplontersen is the only current option. If the patient has cardiac involvement alongside polyneuropathy, vutrisiran’s dual approval is uniquely suited. If the treating neurologist places the highest value on long-term efficacy data, patisiran’s five-year track record is unmatched. And if cost, insurance coverage, or geographic access to healthcare facilities enters the equation — as it almost always does — those practical factors may ultimately drive the decision more than any clinical trial result.
The Vitamin A Problem and Other Safety Concerns Across All TTR Silencers
One safety consideration spans every drug in this class: all TTR-lowering therapies decrease serum vitamin A levels. This is not an incidental side effect but a direct pharmacological consequence. Transthyretin is the primary carrier of retinol-binding protein in the bloodstream, so when you suppress TTR production by 80% or more, you inevitably reduce the body’s ability to transport vitamin A to tissues that need it. Every patient on these medications must take supplemental vitamin A at the recommended daily allowance, and clinicians need to monitor for signs of deficiency — including night vision problems, dry skin, and impaired immune function — particularly in the early months of therapy. Beyond vitamin A, the side effect profiles diverge somewhat between the drugs.
Patisiran’s infusion-related reactions affect roughly one in six patients. Inotersen, the weekly injectable predecessor to eplontersen, carried warnings about thrombocytopenia (low platelet counts) and glomerulonephritis, requiring regular blood and urine monitoring. Eplontersen’s improved molecular design reduced these risks, but patients still require standard monitoring. For families and caregivers of people with cognitive impairment who may also have hATTR, the monitoring burden is worth understanding upfront — these are not medications you can simply start and forget about. A 2026 study published in the European Journal of Neurology, based on real-world data from a German referral center, provided practical insights into how the first-generation TTR silencing therapies (patisiran and inotersen) perform outside the controlled conditions of clinical trials. Real-world data like this is valuable because clinical trials enroll carefully selected patients who may not reflect the full complexity of the population actually living with hATTR — including those who are older, have more advanced disease, or are managing multiple comorbidities.
Why Early Diagnosis Matters More Than Ever
The five-year patisiran data contained a finding that should concern anyone involved in dementia care or neurology: early treatment initiation was associated with significantly improved survival. This is not surprising in principle — most neurodegenerative conditions respond better to intervention before irreversible damage accumulates — but it underscores a painful reality about hATTR polyneuropathy. The disease is frequently misdiagnosed. Symptoms like numbness, tingling, pain in the extremities, gastrointestinal problems, and autonomic dysfunction overlap with diabetic neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), and other far more common conditions.
Patients often spend years seeing multiple specialists before anyone tests for TTR amyloidosis. For clinicians working in dementia care specifically, this is worth flagging. A patient presenting with both progressive peripheral neuropathy and unexplained cardiomyopathy, particularly if there is a family history of either condition, warrants consideration of hereditary ATTR amyloidosis. Genetic testing can confirm the diagnosis, and now that effective non-surgical treatments exist, there is a concrete reason to look for it rather than file it away as an untreatable rarity.
What Comes Next for hATTR Treatment
The pace of progress in hATTR therapeutics over the past several years has been striking. In less than a decade, the treatment paradigm shifted from organ transplantation to self-injectable drugs patients can use at home. Gene silencing technologies — both small interfering RNA (siRNA) and antisense oligonucleotides — have proven that targeting disease at the RNA level can produce durable, clinically meaningful results in a neurodegenerative context. Vutrisiran’s expanded approval for cardiomyopathy in March 2025 suggests the field is moving toward therapies that address transthyretin amyloidosis as a systemic disease rather than treating its neurological and cardiac manifestations separately.
The question going forward is whether even more durable interventions — gene editing approaches that permanently correct the underlying mutation, for instance — will eventually make chronic drug therapy unnecessary as well. For now, the four approved medications represent a genuine transformation in what it means to receive an hATTR polyneuropathy diagnosis. It is no longer a referral to a transplant surgeon. It is a conversation about which drug best fits a patient’s life.
Conclusion
Hereditary transthyretin polyneuropathy is no longer a disease that demands surgery as its primary treatment. Four RNA-based drugs — patisiran, inotersen, vutrisiran, and eplontersen — now offer non-surgical alternatives that reduce the toxic transthyretin protein by more than 80%. Eplontersen’s December 2023 approval brought the first self-administered option, vutrisiran’s March 2025 expanded indication bridged the gap between polyneuropathy and cardiomyopathy treatment, and patisiran’s five-year data demonstrated that sustained treatment can stabilize or improve nerve function in the majority of patients who stay on therapy. For families navigating dementia care and neurological decline, the key takeaway is that progressive peripheral neuropathy with cardiac involvement and a family history should trigger a conversation about hATTR testing.
The treatments now exist to change outcomes — but only if the diagnosis is made early enough to use them. Every patient on a TTR silencer will need ongoing vitamin A supplementation and appropriate monitoring, and the choice between drugs should be guided by individual circumstances rather than any single clinical trial. The surgical era for this disease is closing. The pharmacologic era is well underway.
Frequently Asked Questions
What is hereditary transthyretin polyneuropathy?
It is a progressive genetic condition in which a mutation in the TTR gene causes the transthyretin protein to misfold and deposit as amyloid fibrils in peripheral nerves, causing numbness, pain, weakness, and autonomic dysfunction. It can also affect the heart and other organs.
Can these drugs cure hATTR polyneuropathy?
No. These therapies suppress TTR protein production and can stabilize or improve symptoms, but they do not correct the underlying genetic mutation. Treatment is ongoing and must be maintained to sustain benefit.
Is liver transplant still used for hATTR?
Rarely. Liver transplantation was the standard of care starting in the 1990s, but with four effective drug therapies now available, the number of transplants for hATTR has declined significantly. Transplant may still be considered in specific clinical scenarios, but it is no longer the default approach.
How do patients know which drug is right for them?
The choice depends on factors including whether the patient has cardiac involvement (vutrisiran is approved for both polyneuropathy and cardiomyopathy), preference for self-administration at home (eplontersen is the only self-injectable option), access to infusion centers (patisiran requires IV infusion), insurance coverage, and the treating physician’s clinical judgment.
Do all of these drugs require vitamin A supplementation?
Yes. All TTR-lowering therapies reduce the body’s ability to transport vitamin A, since transthyretin carries retinol-binding protein in the blood. Patients on any of these medications must supplement with the recommended daily allowance of vitamin A and be monitored for signs of deficiency.
