Hereditary ATTR amyloidosis with polyneuropathy is under-recognized, debilitating, and progressive, and early diagnosis is critical1-4

Human body outline displaying areas where the polyneuropathy of hATTR amyloidosis can manifest

POLYNEUROPATHY MANIFESTATIONS

The polyneuropathy of hereditary ATTR amyloidosis can manifest in a variety of ways

Peripheral sensorimotor neuropathy3

  • Numbness, tingling, swelling, burning, and other abnormal feelings in hands and feet
  • Neuropathic pain
  • Walking disability
  • Loss of balance

Autonomic neuropathy2

  • Orthostatic hypotension
  • Diarrhea and constipation that may alternate
  • Early satiety
  • Sweating abnormalities
  • Urinary retention associated with incontinence
  • Erectile dysfunction

Patients may present with a range of signs and symptoms including polyneuropathy, cardiomyopathy, bilateral carpal tunnel syndrome, lumbar spinal stenosis, nephropathy, gastrointestinal disturbances, and ocular manifestations, among others. Patients with hereditary ATTR amyloidosis may present with a mixed phenotype, including both polyneuropathy and cardiomyopathy.2,3,5*

*TEGSEDI is not approved for and has not been shown to be safe and effective for the treatment of cardiomyopathy in patients with hereditary ATTR amyloidosis. The NEURO-TTR study was not designed to assess the impact of TEGSEDI on cardiomyopathy symptoms.

Abbreviations: ATTR, transthyretin-mediated amyloidosis; hATTR-PN, hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Due to the systemic nature of hereditary ATTR amyloidosis, it is imperative to perform a complete workup of diagnosed patients for all potential manifestations2

Disease progression

The polyneuropathy of hereditary ATTR amyloidosis can progress rapidly if left undiagnosed or untreated1,4

Progression of FAP6

Diagram of hATTR amyloidosis progression by FAP stages
Diagram of hATTR amyloidosis progression by FAP stages

Abbreviations: FAP, familial amyloid polyneuropathy; PND, polyneuropathy disability.

  • The hereditary nature of the disease is particularly challenging for families who have observed the progressive decline of family members3
  • Without treatment, patients will experience greater difficulty with daily tasks (eg, turning a key in a lock or fastening buttons on clothing) and walking will become more difficult3
Quote from Chuck

Before I became symptomatic, I was very active. I used to love riding my bicycle, dancing, racing motorcycles, so it was devastating when I couldn’t do these things anymore due to my condition.

Chuck | Patient living with the polyneuropathy of hereditary ATTR amyloidosis and taking TEGSEDI

Quote from Lane

I have come to believe that perhaps my cardiac issues may have sort of masked other issues that were probably brewing behind the scenes… I began to develop symptoms of polyneuropathy including GI issues.

Lane | Patient living with the polyneuropathy of hereditary ATTR amyloidosis and taking TEGSEDI

Mechanism of disease

Hereditary ATTR amyloidosis with polyneuropathy is characterized by the deposition of amyloid fibrils throughout the body, including the nerves2

  • Liver

    Mechanism of disease - TTR synthesis

    The TTR protein is primarily synthesized by the liver.1,7

  • TTR tetramer

    Mechanism of disease – formation of TTR tetramers

    TTR proteins are excreted from the liver as tetramers.1,7

  • TTR monomer

    Mechanism of disease – dissociation into monomers

    Tetramers dissociate into monomers due to TTR gene mutations.1,7

  • Misfolded TTR proteins

    Mechanism of disease – aggregation into fibrils

    Monomers can misfold and aggregate into fibrils.1,7

  • Amyloid fibrils

    Mechanism of disease – deposition of amyloid

    Amyloid fibrils can deposit in various organs and cause systemic dysfunction.1,7

  • The aggregation of amyloid in organs and tissues, including nerves, causes the symptoms of hereditary ATTR amyloidosis1,7

Abbreviation: TTR, transthyretin.

Hereditary ATTR amyloidosis with polyneuropathy has significant morbidity and can have debilitating physical symptoms that significantly impact patients’ QoL2,3

Suspect and diagnose

Look for red-flag symptoms in patients with peripheral sensorimotor neuropathy

Suspect and diagnose hereditary ATTR amyloidosis with polyneuropathy early by looking for clusters of the following findings2,8:

  • Family history of hereditary ATTR amyloidosis
    Family history of hereditary ATTR amyloidosis
  • Bilateral carpal tunnel syndrome
    Bilateral carpal tunnel syndrome
  • Vitreous opacities
    Vitreous opacities
  • Renal abnormalities
    Renal abnormalities
  • Cardiovascular manifestations
    Cardiovascular manifestations
    • Chronic heart failure
    • Ventricular wall thickening with preserved ejection fraction
    • Conduction disturbances/syncope
  • GI symptoms
    GI symptoms that may be uncontrollablea
    • Diarrhea
    • Constipation
    • Alternating diarrhea and constipation
    • Unexplained weight loss
  • Autonomic conditions
    Autonomic conditions
    • Orthostatic hypotension
    • Urinary retention leading to recurrent urinary tract infections
    • Sexual dysfunction
    • Sweating abnormality
  • Additional alert signs and symptoms
    Additional alert signs and symptoms
    • Rapid disease progression
    • Failure to respond to prior therapies for another diagnosis

Abbreviation: GI, gastrointestinal.
aGI symptoms may result from autonomic neuropathy and/or amyloid deposition within the gastrointestinal tract.2,4

Look for clusters of symptoms in your patients with sensorimotor neuropathy to identify hereditary ATTR amyloidosis with polyneuropathy as early as possible2,9

Identify patients who may be appropriate for treatment with TEGSEDI

  • Manifestations of polyneuropathy

    Manifestations of polyneuropathy

    • Signs and symptoms can include sensory, motor, and autonomic neuropathy2
    • FAP staging and PND scoring can assess patients’ neuropathic impairment at time of treatment initiation6
  • Genetic confirmation

    Genetic confirmation of hereditary ATTR amyloidosis

    • Diagnosis can include assessment of clinical symptoms and evidence of amyloid deposition, and ultimately requires a genetic test3,10
    • ICD-10-CM code for hereditary ATTR amyloidosis is E85.1

TEGSEDI is indicated for the treatment of the polyneuropathy of hereditary ATTR amyloidosis in adults.11

TEGSEDI is contraindicated in patients with11

  • Platelet count below 100 × 109/L
  • History of acute glomerulonephritis caused by TEGSEDI
  • History of a hypersensitivity reaction to TEGSEDI

Genetic testing with hATTR Compass can confirm a diagnosis of hereditary ATTR amyloidosis with polyneuropathy early to optimize management1,3,10

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Important Safety Information
INDICATION

TEGSEDI is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

IMPORTANT SAFETY INFORMATION
  • Warning: thrombocytopenia and glomerulonephritis
  • Thrombocytopenia
    • TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening. One clinical trial patient died from intracranial hemorrhage
    • TEGSEDI is contraindicated in patients with a platelet count below 100 x 109/L
    • Prior to starting TEGSEDI, obtain a platelet count. During treatment, monitor platelet counts weekly if values are 75 x 109/L or greater, and more frequently if values are less than 75 x 109/L
    • If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible. The patient should not receive additional TEGSEDI unless a platelet count is determined to be interpretable and acceptable by a medical professional
    • Following discontinuation of treatment for any reason, continue to monitor platelet count for 8 weeks, or longer if platelet counts are less than normal, to verify that platelet counts remain above 75 x 109/L
  • Glomerulonephritis
    • TEGSEDI can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure. One clinical trial patient who developed glomerulonephritis and did not receive immunosuppressive treatment remained dialysis-dependent. In clinical trials, cases of glomerulonephritis were accompanied by nephrotic syndrome, which can have manifestations of edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection
    • TEGSEDI should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1000 mg/g or higher
    • Prior to starting TEGSEDI, measure the serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and perform a urinalysis. During treatment, monitor serum creatinine, eGFR urinalysis, and UPCR every 2 weeks. TEGSEDI should not be given to patients who develop a UPCR of 1000 mg/g or higher or eGFR below 45 mL/minute/1.73 m2, pending further evaluation of the cause
    • If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In patients with UPCR of 2000 mg/g or higher, perform further evaluation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued
  • TEGSEDI REMS Program
    • Because of the risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis, both of which require frequent monitoring, TEGSEDI is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program
CONTRAINDICATIONS

TEGSEDI is contraindicated in patients with

  • Platelet count below 100 x 109/L
  • History of acute glomerulonephritis caused by TEGSEDI
  • History of a hypersensitivity reaction to TEGSEDI
WARNINGS AND PRECAUTIONS
Thrombocytopenia

TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In Study 1, platelet counts below 100 x 109/L occurred in 25% of TEGSEDI-treated patients compared with 2% of patients on placebo. Platelet counts below 75 x 109/L occurred in 14% of TEGSEDI-treated patients compared with no patients on placebo. One patient in a clinical trial experienced a fatal intracranial hemorrhage. Do not initiate TEGSEDI in patients with a platelet count below 100 x 109/L. Follow recommended monitoring and treatment recommendations for platelet count.

Symptoms of thrombocytopenia can include unusual or prolonged bleeding (eg, petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache. Patients and caregivers should be instructed to be vigilant for symptoms of thrombocytopenia and seek immediate medical help if they have concerns.

Glomerulonephritis and Renal Toxicity

TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. In Study 1, glomerulonephritis occurred in 3 (3%) TEGSEDI-treated patients compared with no patients on placebo. One patient did not receive immunosuppressive treatment and remained dialysis-dependent. If glomerulonephritis is suspected, pursue prompt diagnosis and initiate immunosuppressive treatment as soon as possible. Follow recommended monitoring and treatment recommendations for renal parameters. TEGSEDI should generally not be initiated in patients with a UPCR of 1000 mg/g or greater. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued.

TEGSEDI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program because of risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis.

Stroke and Cervicocephalic Arterial Dissection

TEGSEDI may cause stroke and cervicocephalic arterial dissection. In clinical studies, 1 of 161 (0.6%) TEGSEDI-treated patients experienced carotid artery dissection and stroke. Educate patients on the symptoms of stroke and central nervous system arterial dissection. Instruct patients to seek help as soon as possible if symptoms of stroke or arterial dissection occur.

Inflammatory and Immune Effects

Inflammatory and immune changes are an effect of some antisense oligonucleotide drugs, including TEGSEDI. In clinical studies, serious inflammatory and immune adverse reactions occurred in TEGSEDI-treated patients, including immune thrombocytopenia and glomerulonephritis, as well as a single case of antineutrophil cytoplasmic autoantibody (ANCA)–positive systemic vasculitis.

Liver Injury

In clinical studies, 8% of TEGSEDI-treated patients had an increased alanine aminotransferase (ALT) at least 3 times the upper limit of normal (ULN) compared with 3% of patients on placebo; 3% of TEGSEDI-treated patients had an ALT at least 8 times the ULN compared with no patients on placebo. Monitor ALT, aspartate aminotransferase, and total bilirubin at baseline and every 4 months during treatment with TEGSEDI. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction, promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with TEGSEDI, as appropriate.

Liver Transplant Rejection

In a clinical study, cases of liver transplant rejection were reported 2-4 months after starting TEGSEDI in patients whose liver allografts had previously been clinically stable (for over 10 years) prior to starting TEGSEDI. In these cases, the patients clinically improved and transaminase levels normalized after glucocorticoid administration and cessation of TEGSEDI.

In patients with a history of liver transplant, monitor ALT, AST, and total bilirubin monthly. Discontinue TEGSEDI in patients who develop signs of liver transplant rejection.

Hypersensitivity Reactions/Antibody Formation

TEGSEDI can cause hypersensitivity reactions. In clinical studies, 6 of 161 (4%) TEGSEDI-treated patients stopped treatment because of a hypersensitivity reaction. These reactions generally occurred within 2 hours of administration of TEGSEDI. Antibodies to TEGSEDI were present when the reactions occurred. If a hypersensitivity reaction occurs, discontinue administration of TEGSEDI and initiate appropriate therapy. Do not use in patients who have a history of hypersensitivity reactions to TEGSEDI.

Uninterpretable Platelet Counts: Reaction Between Antiplatelet Antibodies and Ethylenediaminetetraacetic acid (EDTA)

In Study 1, 23% of TEGSEDI-treated patients had at least 1 uninterpretable platelet count caused by platelet clumping compared with 13% of patients on placebo. If there is suspicion of EDTA-mediated platelet clumping, perform a repeat platelet count using a different anticoagulant (eg, sodium citrate, heparin) in the blood collection tube. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable. Hold TEGSEDI dosing until an acceptable platelet count is confirmed with an interpretable blood sample.

Reduced Serum Vitamin A Levels and Recommended Supplementation

TEGSEDI treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking TEGSEDI. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (eg, night blindness).

ADVERSE REACTIONS

The most common adverse reactions that occurred in at least 20% of TEGSEDI-treated patients and more frequently than in those on placebo were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever. Serious adverse reactions were more frequent in TEGSEDI-treated patients (32%) than in patients on placebo (21%).

DRUG INTERACTIONS

Because of the risk of thrombocytopenia, caution should be used when using antiplatelet drugs (including nonprescription products that affect platelets) or anticoagulants concomitantly with TEGSEDI. Because of the risk of glomerulonephritis and renal toxicity, caution should be used when using nephrotoxic drugs and other drugs that may impair renal function concomitantly with TEGSEDI.

Please see full Prescribing Information, including boxed WARNING regarding the risk of thrombocytopenia and glomerulonephritis.

References: 1. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22-31. doi:10.1056/NEJMoa1716793. 2. Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9. doi:10.1111/jns.12153. 3. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31. doi:10.1186/1750-1172-8-31. 4. Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(suppl 7):S107-S112. 5. Donnelly JP, Hanna M. Cardiac amyloidosis: an update on diagnosis and treatment. Cleve Clin J Med. 2017;84(12 suppl 3):12-26. doi:10.3949/ccjm.84.s3.02. 6. Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv Neurol Disord. 2013;6(2):129-139. doi:10.1177/1756285612470192. 7. Ueda M, Ando Y. Recent advances in transthyretin amyloidosis therapy. Transl Neurodegener. 2014;3:19. doi:10.1186/2047-9158-3-19. 8. Coelho T, Maurer MS, Suhr OB. THAOS—the Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63-76. doi:10.1185/03007995.2012.754348. 9. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412. doi:10.1161/CIRCULATIONAHA.116.021612/-/DC1. 10. Adams D, Suhr OB, Hund E, et al; from European Network for TTR-FAP (ATTReuNET). First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. 2016;29(suppl 1):S14-S26. doi:10.1097/WCO.0000000000000289. 11. TEGSEDI [package insert]. Boston, MA: Akcea Therapeutics, Inc; 2019.

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