Patients treated with TEGSEDI® (inotersen) saw significant benefit in neuropathy and QoL vs placebo1

Mechanism of action

TEGSEDI targets the polyneuropathy of hereditary ATTR amyloidosis at its source1,2

TEGSEDI binds to and causes degradation of TTR mRNA in the liver, inhibiting TTR protein synthesis1

  • Transcription of TTR mRNA

    DNA diagram of TTR mRNA transcription

    The TTR gene is transcribed into mRNA that encodes the template for TTR production.1

  • TEGSEDI binds to TTR mRNA

    DNA diagram of TEGSEDI® (inotersen) binding to TTR mRNA

    TEGSEDI is a highly selective, single-stranded antisense oligonucleotide that can directly target TTR mRNA.1

  • Translation inhibited

    DNA diagram of the translation process

    The translation process is inhibited, resulting in a reduction of serum TTR protein (median range: 75% to 79%) and TTR protein deposits in tissues.1

Abbreviations: ATTR, transthyretin-mediated amyloidosis; hATTR-PN, hereditary transthyretin-mediated amyloidosis with polyneuropathy; mRNA, messenger RNA; QoL, quality of life; TTR, transthyretin.

TEGSEDI inhibits the synthesis of TTR protein in the liver through degradation of TTR mRNA1

Study designs

TEGSEDI was studied in a robust pivotal study and open-label extension study in adults with the polyneuropathy of hereditary ATTR amyloidosis1,3

  • NEURO-TTR was a phase 2/3, randomized, double-blind, placebo-controlled, multicenter clinical trial to assess TEGSEDI in both neuropathy and quality of life2,4
  • 97% (135/139) of patients who completed NEURO-TTR elected to continue on to the open- label extension study3

Open-label extension study5NEURO-TTR study design2

a112 patients in the TEGSEDI arm received at least 1 dose of the drug.3

Coprimary endpoints

Patients treated with TEGSEDI saw significant benefit in neuropathy and QoL vs placebo1

mNIS+7 results at 66 weeks

Patients treated with TEGSEDI achieved a 19.7-point benefit in mNIS+7 at 66 weeks vs patients receiving placebo1,2


Abbreviation SEM, standard error of the mean.

  • Baseline mNIS+7 was2
    • 79.2 ± 37.0 in the TEGSEDI group (n=112)
    • 74.8 ± 39.0 in the placebo group (n=60)
    • 77.6 ± 37.6 total (n=172)

37% of patients treated with TEGSEDI saw improvement at 66 weeks vs 19% of patients receiving placebo (P=0.033)2,4

a77% of patients treated with TEGSEDI and 87% of patients receiving placebo completed 66 weeks of the assigned treatment.1

Norfolk QoL-DN results at 66 weeks

Patients treated with TEGSEDI achieved an 11.7-point benefit in Norfolk QoL-DN at 66 weeks vs patients receiving placebo1,2

Line graph of Norfolk improvement

  • Baseline Norfolk QoL-DN was2
    • 48.2 ± 27.5 in the TEGSEDI group (n=112)
    • 48.7 ± 26.7 in the placebo group (n=60)
    • 48.4 ± 27.2 total (n=172)

49% of patients treated with TEGSEDI saw improvement at 66 weeks vs 23% of patients receiving placebo (P=0.008)4

Norfolk QoL-DN histogram

a77% of patients treated with TEGSEDI and 87% of patients receiving placebo completed 66 weeks of the assigned treatment.1

With a weekly injection that can be self-administered at a time of their choosing, patients are empowered to manage the polyneuropathy of hereditary ATTR amyloidosis in the comfort and security of their own homes1

SECONDARY AND TERTIARY ENDPOINTS

NEURO-TTR also assessed secondary and tertiary endpoints

Secondary endpoints

The secondary endpoints of the study were to evaluate TEGSEDI vs placebo based on the change from baseline to week 65 in measures that included4

  • Norfolk QoL-DN symptoms domain score in patients with stage 1 polyneuropathy and physical functioning/large fiber neuropathy domain score in patients with stage 2 polyneuropathy
  • Serum TTR and retinol binding protein 4 (RBP4)
  • BMI and mBMI
  • NIS and modified +7
  • Neuropathy Impairment Score +7 (NIS+7)
  • Global longitudinal strain by echocardiogram

Analysis of secondary endpoints showed a difference in favor of TEGSEDI at 66 weeks for the majority of measures. Certain measures such as mBMI and global longitudinal strain by echocardiogram did not show significance. The analysis of the secondary endpoints were not controlled for Type 1 error and therefore reflect numerical trends only.4

 

Stage subgroups

Patients treated with TEGSEDI® saw a benefit in neuropathy and QoL regardless of disease stage11

On average, in patients receiving placebo, patients with stage 2 disease experienced a faster progression of neuropathy than those with stage 1 disease11

 

TTR knockdown

In the NEURO-TTR study, TEGSEDI delivered powerful TTR knockdown (median range: 75% to 79%)1,2

Initiation of TEGSEDI therapy substantially reduced TTR protein levels, and reductions were sustained through week 65 of treatment.1

  • In the TEGSEDI group, reductions in circulating TTR reached steady-state levels by week 13 and were sustained through the end of the intervention period2
  • Similar TTR reductions were observed regardless of TTR mutation, sex, age, or race1

In patients with the polyneuropathy of hereditary ATTR amyloidosis, TEGSEDI powerfully knocks down (median range: 75% to 79%) circulating TTR protein levels and reduces formation of TTR amyloid fibril deposits1,2

Tertiary endpoint: Short-Form 36 Health Survey (SF-36)

The SF-36 questionnaire is a 36-question, non-disease-specific health survey to assess the participant’s perceived functional health and well-being. It consists of11:

  • Physical Component Summary Score (PCS)
  • Mental Component Summary Score (MCS)
  • Eight individual domain scores; physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional. and mental health

At week 65, the placebo group had experienced clinically significant worsening in mean change from baseline in physical component summary (PCS) score4

More patients on placebo experienced substantial impairment as measured by SF-36 physical functioning item responses10

aFigure shows change from baseline to week 66 in percentage of patients in each treatment group whose item response indicated substantial impairment. A patient was considered to have substantial impairment in physical functioning items if they responded they were “limited a lot” in a specific physical function or work, social, or other activity.10

The analysis of the tertiary endpoints were not controlled for Type 1 error and therefore reflect numerical trends only.

Safety

Safety outcomes in NEURO-TTR

Adverse reactions were reported in ≥5% of TEGSEDI-treated patients and ≥5% more frequently or ≥2x more frequently than in patients receiving placebo1

aIncludes bruising, erythema, hematoma, hemorrhage, induration, inflammation, mass, edema, pain, pruritus, rash, swelling, and urticaria.1

bIncludes arrhythmia, atrial fibrillation, atrial flutter, bradyarrhythmia, bradycardia, extrasystoles, sinus arrhythmia, sinus bradycardia, supraventricular extrasystoles, tachycardia, and ventricular extrasystoles.1

cIncludes bacteremia, cellulitis staphylococcal, clostridium difficile infection, conjunctivitis bacterial, cystitis
Escherichia, Helicobacter gastritis, Helicobacter infection, and staphylococcal infection.1

  • TEGSEDI can cause serious adverse reactions, including thrombocytopenia and glomerulonephritis1

    • Serious adverse reactions were more frequent in patients treated with TEGSEDI (32%) than in patients receiving placebo (21%)1

The mean rate of injection site reactions in the TEGSEDI group was 1.1% of all injections administered2

  • 97% of the events were mild in severity and no patients discontinued TEGSEDI prematurely due to injection site reactions2
  • Injection site reactions occurred in 49% of patients treated with TEGSEDI compared with 10% of patients receiving placebo1

77% of patients treated with TEGSEDI and 87% of patients receiving placebo completed 66 weeks of the assigned treatment

 

No new safety signals were reported in the open-label extension3

Platelet and renal monitoring implemented in the NEURO-TTR study was successful in identifying patients at risk of glomerulonephritis and thrombocytopenia3

  • There were no cases of grade 4 platelet count decrease or glomerulonephritis in the open-label extension study3
  • Discontinuation because of adverse events occurred in 15 patients (18%) in the TEGSEDI-TEGSEDI group and 4 patients (8%) in the placebo-TEGSEDI group3
  • Serious treatment-emergent adverse events occurred in 33 patients (39%) and 14 patients (28%) in the TEGSEDI-TEGSEDI and placebo-TEGSEDI groups, respectively, and were considered related to treatment in 4 patients (5%) and 1 patient (2%), respectively3
  • 9 fatal adverse events occurred during the open-label extension study, none were considered related to treatment3

No new safety signals were identified in the 2-year interim analysis of the open-label extension study of the patients from the NEURO-TTR population.3

The most common (≥10%) adverse events across both treatment groups were3

  • Nausea
  • Urinary tract infection
  • Vomiting
  • Diarrhea
  • Fatigue
  • Chills
  • Falls
  • Peripheral edema
  • Injection site pain
  • Thrombocytopenia
  • Syncope
  • Injection site erythema
  • Headache
  • Muscular weakness
  • Myalgia
  • Dyspnea

There were no cases of grade 4 platelet count decrease or glomerulonephritis in the open-label extension study.3

Platelet and renal monitoring were shown to be effective in the open-label extension study3,4

Open-label extension study

97% (135/139) of patients who completed NEURO-TTR elected to continue on to the open-label extension study3

  • At the conclusion of the NEURO-TTR study, patients were given the opportunity to enroll in an open-label extension study and continue on treatment with TEGSEDI or switch from placebo3
  • Enrollment in the open-label extension study was generally limited to only those patients who met eligibility criteria, completed NEURO-TTR, and elected to enroll in the open-label extension study3
  • The open-label extension (OLE) study is ongoing and the data presented here are based on an interim analysis at 2 years when 44% of patients enrolled in OLE had completed week 104 during the treatment period3
  • No statistical analyses were performed on the OLE data and thus the results are only qualitative3
  • The open-label extension study was not a placebo-controlled study and all patients in the open-label extension study were aware they were on active drug
  • 50 patients have had more than 3 years of exposure to TEGSEDI from the NEURO-TTR study and open-label extension4
    • Mean duration in the same data set was 847.2 days, and median duration of exposure was 910.5 days4
  • The primary objective of the OLE study was to assess safety and it was consistent with the pivotal study

Open-label extension study results

Patients treated with TEGSEDI saw less progression of neuropathy3

Bar graph of placebo impairment

aNo statistical analyses were performed and thus the results are only qualitative.3

Patients treated with TEGSEDI® saw a benefit in QoL vs placebo in the open-label extension

Norfolk QoL-DN outcomes in the OLE

aNo statistical analyses were performed and thus the results are only qualitative.3

Patients who continued on treatment with TEGSEDI from the pivotal study saw a benefit in SF-36 PCS Score3

cNo statistical analyses were performed and thus the result are only qualitative.3

dThe pivotal study and open-label extension study used SF-36v2.3

eA greater value indicates a greater QoL.4

Patients who switched from placebo to TEGSEDI saw a benefit in measures of neuropathy and QoL compared with a continued predicted worsening with placebo3

Quote from Sharell Quote from Sharell

When he was able to get on TEGSEDI, we started seeing him feeling better already and it was a hallelujah moment for our family. We felt so lucky.

This is one patient’s experience, individual results may vary.

Sharell | Caregiver

Quote from Chuck Quote from Chuck

You’ve given me my quality of life back—you’ve given my family their father, their brother, their grandpa back, and in a good mood. That wouldn’t happen without TEGSEDI.

This is one patient’s experience, individual results may vary.

Chuck | Actual patient taking TEGSEDI

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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. TEGSEDI [package insert]. Boston, MA: Akcea Therapeutics, Inc;. 2. 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. 3. Brannagan TH, Wang AK, Coelho T, et al; for the NEURO-TTR open-label extension investigators. Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial. Eur J Neurol. 2020;27(8):1374-1381. doi:10.1111/ene.14285. 4. Data on file. Akcea Therapeutics, Inc. 5. Rowczenio D, Wechalekar A. Mutations in transthyretin gene (TTR). Mutations in Hereditary Amyloidosis website. http://amyloidosismutations.com/mut-attr.php. Accessed February 20, 2019. 6. Wang AK, Coelho T, Waddington Cruz M, et al. Safety and efficacy of inotersen in patients with hereditary transthyretin amyloidosis with polyneuropathy (NEURO-TTR). Poster presented at: 142nd Annual Meeting of the American Neurological Association; October 15-17, 2017; San Diego, CA. 7. Adams D, Coelho T, Obici L, et al. Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study. Neurology. 2015;85(8):675-682. doi:10.1212/WNL.0000000000001870. 8. Vinik EJ, Paulson JF, Ford-Molvik SL, Vinik AI. German-translated Norfolk quality of life (QOL-DN) identifies the same factors as the English version of the tool and discriminates different levels of neuropathy severity. J Diabetes Sci Technol. 2008;2(6):1075-1086. doi:10.1177/193229680800200616. 9. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis [supplemental appendix]. N Engl J Med. 2018;379(1):1-36. doi:10.1056/NEJMoa1716793. 10. Yarlas A, Kessler AS, Lovley A, Guthrie S, Pollock M, White M. Analysis of responses to SF-36v2 items for patients with hATTR amyloidosis: results from a double-blind placebo-controlled trial. Poster presented at: ISPOR Europe 2018 meeting; November 10-14, 2018; Barcelona, Spain. 11. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersentreatment for patients with hereditary transthyretin amyloidosis [supplemental appendix]. N Engl J Med. 2018;379(1):1-36.

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