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19 Articles in Volume 20, Issue #2
20/20 with Peter Staats, MD: The Future of Pain Medicine
Ask the APP: How useful and practical are pain assessment tools?
Ask the PharmD: What are the recommendations for preventing and treating pediatric migraine?
Axial Spondyloarthritis: Updated Medication and Imaging Recommendations
CGRP Monoclonal Antibodies for Chronic Migraine Prevention: Evaluation of Adverse Effects Using A Checklist
Chronic Low Back Pain: Can We Find a Treatment Consensus?
Correspondence: Are ESIs Still Worth It? Benzocaine for Orofacial Pain.
Could Pulsed RF Provide Lasting Chronic Headache Relief in Refractory Patients?
Diagnosis Is Everything: Low Back Pain As a Symptom of an Underlying Condition or Conditions
Editorial: From Just Say No, to Say Now and Say Know
Erenumab and Onabotulinumtoxin A Show Additive Effect in Refractory Chronic Migraine
Experts Roundtable: Finding a Bottom Line in Back Pain Care
Inside the Potential of RNAi to Target the Etiology of hATTR Neuropathy
Muscle Dysfunction in Head and Neck: Pain Causes, Osteopathic Options
New Migraine Medications: Oral Gepants, Ditan Tablet, and More
Root Cause of Sacroiliac Joint Dysfunction: Four-Step Exercise Protocol
The Emotional Impact of Chronic Low Back Pain
The Rise in Tianeptine Abuse: Our Next Kratom Problem?
The Sensory Component of Pain: Modifying Its Emotional and Cognitive Meaning

Inside the Potential of RNAi to Target the Etiology of hATTR Neuropathy

RNAi and antisense oligonucleotides are novel therapeutic modalities that have the potential to be game-changers for diseases with genetic etiologies: the growing potential of patisiran and inotersen.
Pages 25-28

In addition to using analgesics targeted at pain signaling pathways, pain management clinicians must ensure patients are receiving therapy to slow or reverse the underlying etiology of their pain. Patisiran (branded Onpattro, developed by Alnylam Pharmaceuticals) is an etiology-directed therapy that reduces painful polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR). It received orphan drug designation as the first RNA interference (RNAi) therapy approved by the FDA in August 2018.

hATTR is an autosomal dominant, progressive, multisystemic disease caused by mutations within the gene encoding transthyretin.1 hATTR is estimated to affect 50,000 people worldwide, with a median onset age of 39 years.2 Tetrameric transthyretin proteins are made primarily by the liver and released into the circulatory system. They function as a protein transport for vitamin A and approximately 15% of circulating thyroxine. When mutations arise in the transthyretin gene, the tetramer destabilizes, causing monomers to misfold and aggregate in transthyretin amyloid fibrils.3

Transthyretin amyloids deposit in multiple locations, including the central and peripheral nervous systems, heart, kidney, bones, and gastrointestinal tract. The buildup of these amyloid deposits can lead to polyneuropathy and life-shortening cardiomyopathy.1,3 The treatment goal for persons with hereditary transthyretin amyloidosis is to stabilize and/or decrease the amount of circulating transthyretin, which slows disease progression in these patients.


Figure 1. Percentage of patient improvement in mNIS+7 from baseline. In the placebo group (A), improvement in mNIS+7 occurred in 4% of patients (95% CI, 0-8) whereas in the patisiran group (B), mNIS+7 improvement occurred in 56% of patients (95% CI, 48-64). Odds ratio 39.9 (95% CI, 11.0- 144.4, P < 0.001). Based on Reference 1.

Figure 2. Percentage of patient improvement in Norfolk QOL-DN from baseline. In the placebo group (A) improvement in Norfolk QOL-DN occurred in 10% of patients (95% CI, 4-17). In the patisiran group (B), QOL-DN improvement reported in 51% of patients (95% CI, 43-59). Odds ratio 10.0 (95% CI, 4.4-22.5). Based on Reference 1.


RNAi is an endogenous mechanism for controlling gene expression.Small interfering RNAs (siRNAs) mediate the cleavage of specific messenger RNAs (mRNA), which prevents protein formation.1-5 Patisiran siRNA targets the 3´ untranslated region in both wild-type and mutant transthyretin mRNA. Lipid nanoparticles deliver siRNAs to the site of action, for patisiran, the hepatocytes, which results in a large reduction in the circulating expression of the gene.

At a Glance

  • Category: Transthyretin Gene Silencers
  • Products: Patisiran (branded as Onpattro) by Alnylam Pharmaceuticals, is a siRNA molecule targeting transthyretin, approved by FDA in August 2018.  Inotersen (branded as Tegsedi) by Akcea Therapeutics is an antisense oligonucleotide inhibitor of both mutant and wild-type TTR protein, approved by FDA in October 2018.
  • Indications: Both drugs are FDA indicated for polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adults. Both have orphan drug designation.
  • PPM Rating: 4 out of 5 stars. See full review below.

The Evidence to Date

In the APOLLO Phase III trial, researchers set out to determine how patisiran, when compared to placebo, worked at improving or halting disease progression in patients diagnosed with hATTR who also had polyneuropathy. Patients were randomized 2:1 to patisiran. The primary endpoint was the change in neuropathy, as measured by the modified Neuropathy Impairment Score+7 (mNIS+7).This scoring tool measures multiple types of neuropathy, including motor, sensory, and autonomic, with higher scores indicating worse impairment. Secondary endpoints included quality of life (as measured by the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy [QOL-DN], motor strength, disability, gait speed (as measured in meters per second), nutritional status (measured by modified body-mass index), and patient-reported autonomic symptoms.1 Exploratory endpoints included serum transthyretin and vitamin A levels, cardiac structure and function measurement, and assessment of neuropathy stage.

Patisiran demonstrated a rapid and sustained reduction in transthyretin during the study period. The median reduction in the serum transthyretin level at the end of the trial was 81%.1


Treatment response was observed across the patisiran group, with 74% of patients having a less than 10-point increase in mNIS+7 at 18 months, compared with 14% observed in placebo.1 The least-squares mean change (± standard error) in mNIS+7 indicated a favorable impact of patisiran on neuropathy at the end of the study, with an improvement of 6.0 ± 1.7 points from baseline compared to a worsening of 28.0 ± 2.6 points in the placebo group.1 The effect of patisiran on improving neuropathy was identified as early as 9 months, which is when the first interim analysis took place.1 Figure 1 shows the percentage of patients in each category who noted improvement in mNIS+7 at 18 months.

The use of patisiran in the trial population also demonstrated favorable outcomes in patients’ quality of life, with patients receiving patisiran having a 20-point average increase in quality of life, as reported using the Norfolk QOL-DN. Figure 2 identifies the percentage of patients who reported improvement in Norfolk QOL-DN at 18 months. For all secondary endpoints, between group differences in favor of patisiran were evident during the first efficacy assessment point.1 Exploratory endpoints also favored patisiran.1 When compared to placebo, patisiran treatment was associated with better cardiac structure and function.


Patisiran utilizes weight-based dosing at 0.3 mg/kg (capped at 30 mg) intravenously (IV) every three weeks. Patisiran requires quite a bit of specialized product preparation. It is important that those who assist with sterile product preparation review the package insert for specific guidance. Patients require pretreatment before each infusion with acetaminophen, dexamethasone, H2 blocker, and H1 blocker starting 60 minutes prior to infusion.3-4 Patisiran should be administered over approximately 80 minutes.1-5 During the first 15 minutes of the infusion, the rate should be set at 1 mL/min. The rate can then be increased to approximately 3 mL/min for the remainder of the infusion. If extravasation is suspected, this should be managed like non-vesicants.

Adverse Reactions and Monitoring

Overall, patisiran is well tolerated when compared to placebo.1,4 Peripheral edema and infusion reactions were the most common side effects occurring at a higher frequency with patisiran versus placebo in the Phase III trial (see Figure 3).1 During Phase I and Phase II trials, infusion-related reactions occurred in 79% of patients within the first two infusions, with the frequency of reaction decreasing with time.3-5 The most common symptoms of infusion-related reactions included flushing, back pain, nausea, abdominal pain, dyspnea, and headache.1-5

Since transthyretin is responsible for transporting vitamin A, there is a correlation between vitamin A and transthyretin levels. Serum vitamin A levels should be monitored, as patients may become deficient. If patients begin to develop ocular symptoms suggestive of vitamin A deficiency, such as xerosis, nyctalopia, or retinopathy, they should be advised to see an ophthalmologist.6

Comparison to Inotersen

Shortly after patisiran was approved, the FDA approved inotersen (branded Tegsedi, from Akcea Therapeutics). Inotersen and patisiran have yet to be studied in a comparative trial. However, inotersen also favorably improved mNIS+7 and Norfolk QOL-DN in trials (19.7 points and 11.7 points, respectively). Inotersen and patisiran differ in formulation, dosing frequency, and adverse effect profiles.7 Patisiran is administered as an IV infusion every three weeks, whereas inotersen is administered as a subcutaneous injection every week. Patisiran is generally well tolerated with no documented black box warnings. Inotersen has multiple black box warnings, including thrombocytopenia and glomerulonephritis, requiring a risk evaluation and mitigation program.7


Patisiran is the first RNA interfering drug to market. Prior to this agent coming to market, diflunisal and tafamidis, with or without liver transplantation, were used in the management of hereditary transthyretin amyloidosis. Tafamidis gained FDA approval in 2019 for cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis but has been used in other countries for many years. These agents are tetramer stabilizers; however, patients treated with these agents continue to have disease progression.1

Patisiran data from the APOLLO trial looks quite promising when compared to placebo, however based on exclusion criteria for the study, patients enrolled in the APOLLO trial could not take diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid for at least a 14-day washout prior to starting patisiran and during the trial. Either tafamidis or diflunisal was taken by 53% of patients prior to the trial.4 Comparing patisiran to placebo instead of currently used therapies for hATTR makes it difficult to determine patisiran’s relative efficacy. However, current data indicate patisiran vs. placebo has a greater effect on polyneuropathy and quality of life than does tafamidis compared to placebo.8,9 A lingering unanswered question is whether using patisiran to reduce transthyretin levels and a tetramer stabilizer like tafamidis would synergistically improve polyneuropathy and slow disease progression.


Therapies for neuropathy of hATTR have expanded in the past decade, with transthyretin gene silencers, patisiran and inotersen, representing novel mechanisms to halt the production of transthyretin during translation. RNAi and antisense oligonucleotides are novel therapeutic modalities that have the potential to be game-changers for diseases with genetic etiologies, but it remains to be seen if targeted gene editing, such as CRISPR/Cas9, will eclipse RNAi or antisense oligonucleotides as therapeutic modalities moving forward. 

Experts Weigh In: by PPM Editors-at-Large Jeff Gudin, MD, and Jeffrey Fudin, PharmD

Healthcare providers often forget about the rare diseases that contribute to chronic pain syndromes. This review highlights one of those conditions with a genetic basis, a disease known as hereditary transthyretin- mediated amyloidosis (hATTR). This condition not only shortens life expectancy but also leads to a chronic painful peripheral neuropathy. As most clinicians realize, the treatment options available for neuropathic pain are often suboptimal and wrought with adverse effects. Although we have yet to find a cure for neuralgia secondary to diabetes, herpes zoster, chemotherapy, or phantom limb, this review highlights one uncommon disease state for which treatment is now available. Given the described products’ unique pharmacology approach and effectiveness, we give 4 out of 5 stars.

*Star-rating based on: novelty, risk-benefit ratio, clinical utility, scientific rigor of studies, and market potential, along with the reviewer’s expertise and opinion. 


See PPM's ongoing Analgesics of the Future series:

Last updated on: March 12, 2021
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