Sponsored by Alnylam Pharmaceuticals, Inc.
In the U.S., a rare disease is defined as a condition that affects fewer than 200,000 people, and the National Institutes of Health (NIH) estimates that more than 7,000 rare diseases exist. Although the diseases are rare, their overall prevalence is not. About one in 10 people in the United States has a rare disease — that is approximately 30 million people.1 While it is unrealistic for a physician to have deep knowledge of each of the thousands of rare diseases that exist, it is important to consider the possibility of a rare disease when a patient presents with red-flag symptoms and an atypical diagnostic process.
One rare disease that affects approximately 50,000 people worldwide is hereditary transthyretin-mediated (hATTR) amyloidosis.2 hATTR amyloidosis is an inherited, rapidly progressive, debilitating and often fatal disease caused by variants in the transthyretin (TTR) gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid deposits to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in sensory-motor neuropathy, autonomic neuropathy and/or cardiomyopathy, as well as other disease manifestations.3-7 This is not a complete list of symptoms that may be experienced with hATTR amyloidosis.
The multisystem nature of hATTR amyloidosis impacts many organs. Presenting symptoms are often variable and can mirror those of more common conditions, so misdiagnosis is common.8 Patients with hATTR amyloidosis may not receive a correct diagnosis until 3 to 6 years after symptom onset, resulting in significant disease progression.9,10 The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.9,11
Michael Polydefkis, MD, MHS, Professor, Johns Hopkins Neurology, hATTR amyloidosis expert and HELIOS-A study investigator, spoke with us to share more information about when to suspect hATTR amyloidosis, how it is diagnosed, changes in the treatment landscape, as well as the importance of advocating for patients. Dr. Polydefkis is a paid consultant of Alnylam Pharmaceuticals and was compensated for his participation in this article.
1. Can you explain why early diagnosis of hATTR amyloidosis is so crucial?
Given the rapidly progressive nature of hATTR amyloidosis, it often leads to significant disability in patients, so a timely diagnosis is critical for early intervention. Unfortunately, because it is a rare disease and due to the way the disease manifests, misdiagnosis or delays in diagnosis are quite common. Given the inherited nature of the disease, when diagnosis is delayed, entire families may be affected.2,8,12
Ensuring an open and thorough two-way dialogue with a patient can help narrow down their symptoms and rule out other possible conditions.13 When we are able to confirm a diagnosis early, we can work with patients together to evaluate their symptoms and determine an appropriate management approach. Additionally, other family members can be screened and identified proactively.
2. What are some symptoms and health factors that should raise a doctor’s level of suspicion for hATTR amyloidosis?
There are two major red flags I consider when I suspect a patient may have hATTR amyloidosis. The first is family history. If the patient’s family has a known history of hATTR amyloidosis that would of course be a factor, but even more generally speaking, if there is a family history of an undiagnosed neurodegenerative condition or many of the symptoms that can be associated with the disease (such as heart failure, malabsorption, carpal tunnel syndrome), that could be a clue as well. Keep in mind that the symptoms of hATTR amyloidosis can vary widely among people with the condition, even within families, and different symptoms may appear at different times for each person.12 That is one of the reasons hATTR amyloidosis can be so challenging to diagnose and why it is so important to probe deeply when trying to reach a diagnosis. I encourage my patients to be as detailed as possible when speaking about their symptoms. Also, it’s worth noting that a family member may inherit the TTR gene variant, but having the variant does not necessarily mean they will develop symptoms of hATTR amyloidosis.8
The second is multisystem involvement. If a patient is experiencing a combination of symptoms such as with the somatic nervous system, the cardiovascular system and/or the autonomic nervous system, that raises my suspicion for hATTR amyloidosis – especially in patients who present with or have a history of carpal tunnel syndrome or spinal stenosis. Some other common symptoms I see in patients are gastrointestinal issues, neuropathic pain and numbness and difficulty walking.12 It is the symptoms constellation and the company they keep.
3. How is a diagnosis of hATTR amyloidosis confirmed?
Once clinical suspicion is raised, there are a number of assessments that can help confirm a diagnosis of hATTR amyloidosis. These include neurological and/or cardiac evaluations, such as nerve conduction study (NCS), electrocardiography (ECG/EKG), and echocardiography (echo), as well as tissue biopsy.13-15 Then, in order to establish the diagnosis, genetic testing can confirm presence of a TTR variant.8
4. How has the treatment landscape for the polyneuropathy of hATTR amyloidosis changed?
Up until 2018, there were no FDA-approved treatments for the polyneuropathy of hATTR amyloidosis, which meant there were no medications available that could potentially help slow progression of these symptoms. Without treatment, patients risk losing mobility and ultimately becoming wheelchair bound as the polyneuropathy symptoms progress. They also lived with the reality that their family members may inherit this disease without treatment options, as well.16,17
Fortunately, over the last several years, a handful of treatment options have been approved by the U.S. FDA to treat the polyneuropathy of hATTR amyloidosis. The most recent approval took place in June 2022, when the U.S. FDA approved AMVUTTRA® (vutrisiran), an RNAi therapeutic administered via subcutaneous injection once every three months for the treatment of the polyneuropathy of hATTR amyloidosis in adults. AMVUTTRA does not treat all of the symptoms of hATTR amyloidosis. AMVUTTRA is a double-stranded small interfering RNA (siRNA) formulated for targeted delivery to hepatocytes, the primary source of TTR protein production. By decreasing the amount of TTR protein made in the liver, AMVUTTRA helps to decrease the amount of amyloid that deposits in tissues.18
The FDA approval of AMVUTTRA was based on positive 9-month results from the HELIOS-A Phase 3 study evaluating adult patients with the polyneuropathy of hATTR amyloidosis. In the study, AMVUTTRA demonstrated a significant improvement versus an external placebo group across multiple endpoints. The most common adverse reactions that occurred in patients treated with AMVUTTRA during the HELIOS-A clinical trial were arthralgia, dyspnea and vitamin A decreased. As a subcutaneous injection with a dosing regimen of once every three months, this treatment option is a welcome addition for patients with the polyneuropathy of hATTR amyloidosis.18
5. As a physician, why is advocating for your patients so important?
Following what can be a challenging and lengthy diagnosis process, ensuring open and robust two-way communication with your patients is essential to fully understand their needs. While I always encourage patients to advocate for themselves – whether through requesting a second opinion or writing a list of their symptoms for easy reference – I find that advocating for my patients as their physician is equally as important.
For example, one patient with hATTR amyloidosis who was experiencing polyneuropathy progression was referred to me so we could determine their management options. After discussing his family history, lifestyle and details of his journey with hATTR amyloidosis, I felt that he may benefit from participating in the HELIOS-A Phase 3 study. The trial was full at the time, but eventually a spot opened, and he was one of the last people enrolled. Once the study concluded, he continued treatment and has noticed an improvement in the numbness in his legs and feet, though every patient is different and should speak with their physician about treatment options and potential side effects. Patients often ask why AMVUTTRA treatment results in low serum vitamin A levels. This happens because TTR protein transports vitamin A throughout the body, and AMVUTTRA reduces the amount of TTR protein made in the liver. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking AMVUTTRA. Please read the Important Safety Information and full Prescribing Information.
The patient recently shared with me that he hopes, “anyone who suspects they may have a family history of hATTR amyloidosis get tested early, so that they can make their families aware and work with their physicians to help manage their disease as early as possible.”
As physicians, we are in a unique position to not only ask the usual questions, but to also listen, probe and engage so we can really make a difference in changing the course of a patient’s disease journey and their family’s, as well.
For more information on AMVUTTRA, please visit https://www.amvuttrahcp.com/.
AMVUTTRA is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
Important Safety Information
Reduced Serum Vitamin A Levels and Recommended Supplementation
AMVUTTRA treatment leads to a decrease in serum vitamin A levels.
Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking AMVUTTRA. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with AMVUTTRA, as serum vitamin A levels do not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).
The most common adverse reactions that occurred in patients treated with AMVUTTRA were arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%).
Please see the full Prescribing Information.
Content sponsored by Alnylam Pharmaceuticals. Intended for U.S. Audiences only. AMVUTTRA and its associated logo are trademarks of Alnylam Pharmaceuticals.
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18 AMVUTTRA Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.