TEGSEDI® (inotersen) is the first and only self-administered, subcutaneous treatment for the polyneuropathy of hereditary ATTR amyloidosis in adults1

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 short, 20-base antisense oligonucleotide with a sequence complementary to part of the TTR mRNA.1,3

  • Translation inhibited

    DNA diagram of the translation process

    The translation process is inhibited, resulting in a reduction of serum TTR protein 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.

In the NEURO-TTR study, TEGSEDI delivered powerful TTR knockdown1,2

Median percent change from baseline in serum TTR over time4

Median serum TTR reduction were 75% to 79% below baseline from week 13 through week 65 of treatment

  • 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 circulating TTR protein levels and reduces formation of TTR amyloid fibril deposits1,2

Study designs

TEGSEDI was studied in the pivotal NEURO-TTR study and open-label extension study2,5

  • NEURO-TTR was the pivotal study to assess TEGSEDI on both neuropathy and QoL2
  • 97% (135/139) of patients who completed NEURO-TTR elected to continue on to the open-label extension study2

Open-label extension study5NEURO-TTR study design2

Neuro-TTR study design placebo vs. TEGSEDI® (inotersen)
Neuro-TTR study design placebo vs. TEGSEDI® (inotersen)


aAs of May 2018, patients in the clinical study had been on treatment for as many as 1885 days.5

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 included5

  • 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
  • Modified body mass index (mBMI) and body mass index (BMI)
  • NIS and modified +7
  • Neuropathy Impairment Score +7 (NIS+7)

Open-label extension study

  • At the conclusion of the study, patients were given the opportunity to enroll in an open-label extension study and continue on treatment with TEGSEDI or switch from placebo—patients were studied for up to ~5 years from start of treatment with TEGSEDI5
  • Enrollment in the open-label extension study was generally limited only to those patients who met eligibility criteria, completed NEURO-TTR, and elected to enroll in the open-label extension study5
  • 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 drug5

PRIMARY OUTCOMES

Patients treated with TEGSEDI showed significant improvement vs placebo1

mNIS+7 results at 66 weeks

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

Line graph of improvement in patients taking TEGSEDI® (inotersen)

37% of patients treated with TEGSEDI saw improvement at 66 weeks vs 19% of patients receiving placebo (P=0.033)1,2,4

mNIS+7 histogram

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

Percentage of patients treated with TEGSEDI that died, 4.5%; percentage of patients receiving placebo that died, 0%; percentage of patients treated with TEGSEDI missing from analysis, 22.3%; percentage of patients receiving placebo missing from analysis, 13.3%.2

Norfolk QoL-DN results at 66 weeks

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

Line graph of Norfolk improvement

49% of patients treated with TEGSEDI saw improvement at 66 weeks vs 23% of patients receiving placebo (P=0.008)1,2

Norfolk QoL-DN histogram

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

Percentage of patients treated with TEGSEDI that died, 4.5%; percentage of patients receiving placebo that died, 0%; percentage of patients treated with TEGSEDI missing from analysis, 22.3%; percentage of patients receiving placebo missing from analysis, 13.3%.2

Patients treated with TEGSEDI experienced similar improvements in mNIS+7 and Norfolk QoL-DN regardless of age, sex, race, region, Neuropathy Impairment Score, Val30Met mutation status, and disease stage1

Open-label extension study

In the open-label extension study, patients treated with TEGSEDI saw sustained improvements in neuropathy and QoL vs placebo1,a

Open-label extension study results

Patients who started TEGSEDI earlier saw greater numerical improvement in neuropathy5

Bar graph of placebo impairment

aPlacebo refers to actual placebo during NEURO-TTR and projected placebo for the open-label extension study.5

bThe 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.

cTrend line of NEURO-TTR placebo data points, with calculated slope extrapolated beyond placebo data collection.5

Patients who started TEGSEDI earlier saw greater numerical improvement in measures of QoL5

Norfolk QoL-DN outcomes in the OLE

aPlacebo refers to actual placebo during NEURO-TTR and projected placebo for the open-label extension study.5

bThe 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.

cTrend line of NEURO-TTR placebo data points, with calculated slope extrapolated beyond placebo data collection.5

  • 97% (135/139) of patients who completed NEURO-TTR elected to continue on to the open-label extension study2

Patients who switched from placebo to TEGSEDI demonstrated improvements in neuropathy and QoL compared with a continued predicted worsening based on natural history5

Tertiary endpoint: SF-36

Tertiary endpoint of NEURO-TTR: As shown by SF-36 PCS score, TEGSEDI halted worsening of health-related QoL compared with placebo5

SF-36 PCS score

More patients on placebo experienced substantial impairment as measured by SF-36 physical functioning item responses9

SF-36 outcomes in the OLE

eFigure shows change from baseline to week 66 in percentage of patients in each treatment group whose item response indicated substantial impairment. Patients were 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.9

In the open-label extension study, patients who continued on treatment with TEGSEDI from NEURO-TTR saw a sustained improvement in SF-36 PCS score vs placebo5,a,b,c

Substantial impairment in PCS score

Abbreviations: PCS, physical component summary; SF-36, Short-Form 36 Health Survey.

aThe pivotal study and open-label extension study used SF-36v2.5

bA greater value indicates a greater QoL.5

cPlacebo refers to actual placebo during NEURO-TTR and projected placebo for the open-label extension study.5

dThe 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.

eTrend line of NEURO-TTR placebo data points, with calculated slope extrapolated beyond placebo data collection.5

  • SF-36 PCS score is a non–disease-specific measure of health-related QoL5
  • The PCS score is a composite score assessing physical functioning, role-physical, bodily pain, and general health9
  • At week 66, the placebo group had experienced clinically significant worsening in mean change from baseline in PCS score5

Secondary endpoints

  • Analysis of secondary endpoints showed a statistically significant difference in favor of TEGSEDI at 66 weeks for the majority of measures. Certain measures such as BMI and mBMI did not show significance5
Quote from Sharell

When Chuck was able to get on TEGSEDI, we started seeing him feel better and we felt that there was hope, not only for him, but for our children and possibly our grandchildren.

Sharell | Caregiver

Quote from Chuck

I decided to take TEGSEDI not just for myself but for my family. I hope that they’ll know what to do with the disease if they experience polyneuropathy caused by hereditary ATTR amyloidosis in the future.

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

Safety

TEGSEDI has a manageable safety profile1

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

TEGSEDI® (inotersen) adverse events chart

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
    • 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 glomerulonephritis1
    • Required platelet and renal monitoring for your patients can be confidently delivered through the TEGSEDI safety program1

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

No new safety signals were identified in the open-label extension study5

  • There were no cases of grade 4 platelet count decrease or glomerulonephritis in the open-label extension study.5
  • 9 fatal adverse events occurred during the open-label extension study; none were considered related to treatment.5
  • Discontinuation because of adverse events occurred in 15 patients (18%) in the TEGSEDI-TEGSEDI group and 4 patients (8%) in the placebo-TEGSEDI group.5
  • 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%), respectively.5

The most common (≥10%) adverse events across both treatment groups were5

  • Nausea
  • Urinary tract infection
  • Vomiting
  • Diarrhea
  • Fatigue
  • Chills
  • Fall
  • Peripheral edema
  • Injection site pain
  • Thrombocytopenia
  • Syncope
  • Injection site erythema

Platelet and renal monitoring were shown to be effective in the open-label extension study5

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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; 2019. 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. Shen X, Corey DR. Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. Nucleic Acids Res. 2018;46(4):1584-1600. doi:10.1093/nar/gkx1239. 4. 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. 5. Data on file. Akcea Therapeutics, Inc. 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. 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.

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