Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Abstract

Introduction: AKCEA-TTR-LRx is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-LRx shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-LRx is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-LRx is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients.

Methods/design: Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-LRx 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-LRx through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-LRx arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire.

Conclusion: NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-LRx to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN.

Trial registration: The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).

Keywords: AKCEA-TTR-Lrx; Antisense oligonucleotide; Clinical trial design; Hereditary transthyretin-mediated amyloid polyneuropathy; Phase 3 clinical trial.

Figures

Fig. 1

ASGPR mediates the uptake of the GalNAc3-conjugated ASO AKCEA-TTR-LRx by hepatocytes, where it binds to the TTR mRNA through Watson–Crick hybridization and prevents production of TTR protein via RNase H1-mediated degradation of the target TTR mRNA. ASGPR asialoglycoprotein receptor, ASO antisense oligonucleotide, DNA deoxyribonucleic acid, mRNA messenger ribonucleic acid, RNase ribonuclease, TTR transthyretin

Fig. 2

NEURO-TTRansform study design. EOT end of treatment, hATTR-PN hereditary transthyretin-mediated amyloid polyneuropathy, SC subcutaneously. aThe screening period is ≤ 6 weeks (or ≤ 10 weeks if genetic testing is required). bConcomitant therapy with tafamidis or off-label use of diflunisal is not allowed. Doxycycline use for the indication of infection (< 15 days) is allowed. cPatients not participating in the open-label extension will enter a 20-week post-treatment evaluation after completing EOT assessments. dPlacebo arm of the NEURO-TTR study (NCT01737398)

Fig. 3

NEURO-TTRansform study endpoints. 10MWT 10-min walk test, COMPASS-31 Composite Autonomic Symptom Score-31, ECHO echocardiogram, EQ-5D-5L 5-level EuroQol 5-dimension, EOT end of treatment, mBMI modified body mass index, mNIS + 7 modified Neuropathy Impairment Score + 7, Norfolk QOL-DN Norfolk Quality of Life Questionnaire—Diabetic Neuropathy, NSC Neuropathy Symptom and Change, NT-proBNP N-terminal pro-brain natriuretic peptide, PCS Physical Component Summary, PND Polyneuropathy Disability Score, R-ODS Rasch-built Overall Disability Score, SC subcutaneously, SF-36 36-Item Short-Form Health Survey, TTR transthyretin. aPercentage change. bThe mNIS + 7 assessment procedure includes: Neuropathy Impairment Score, quantitative sensory testing, heart rate response to deep breathing, and predetermined sensory and nerve conduction testing. Additional clinical evaluations done during mNIS + 7 assessment include: lower limbs function test and NSC. cweeks 35 and 66. dweek 65. eweek 37. fweek 35. gweek 81. hVital signs, body weight, physical examination, clinical laboratory tests, electrocardiogram, use of concomitant medication, thyroid panel, inflammatory panel, coagulation, immunogenicity test

Fig. 4

Key inclusion and exclusion criteria for the NEURO-TTRansform study. ASO antisense oligonucleotide, eGFR estimated glomerular filtration rate, FAP familial amyloid polyneuropathy, hATTR-PN hereditary transthyretin-mediated amyloid polyneuropathy, NIS Neuropathy Impairment Score, NYHA New York Heart Association, siRNA small interfering ribonucleic acid, TTR transthyretin, UPCR urine protein/creatinine ratio. aStage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance). bIn the event of UPCR ≥ 1000 mg/g, eligibility may be confirmed by a repeat random urine test with UPCR < 1000 mg/g or a quantitative total urine protein measurement of < 1000 mg/24 h. cChronic Kidney Disease Epidemiology Collaboration equation 1 formula