Evolving landscape in the management of transthyretin amyloidosis

Figures & data

Figure 1. Timeline of access to anti-amyloid therapies for patients with hereditary transthyretin amyloidosis with polyneuropathy. OLE = open-label extension; Ph = phase; Vyndaqel = trade name for tafamidis.

Table I. Key clinical data for novel agents in clinical development of TTR amyloidosis.

Treatment	Study design	Patient population	End-points	Key efficacy data	Key safety data
Tafamidis	•Phase II/III randomized controlled trial (96) •Treatment: Taf 20 mg QD or PBO for 18 months •12-month OLE: remain on Taf or switch to Taf	•Biopsy-confirmed amyloid deposits •Val30Met mutation •Stage I ATTR-FAP •Aged 18–75 years •n = 128 (Taf = 65; PBO = 63)	•Phase II/III co-primary end-points: NIS-LL response (< 2-point decrease); change in TQoL •OLE objectives: long-term safety and efficacy	•NIS-LL responders with Taf vs. PBO: ITT population: 45.3% vs. 29.5% (P = 0.068), EE population: 60.0% vs. 38.1% (P = 0.041) •TQoL change in Taf vs. PBO: ITT population: 2.0 vs. 7.2 (P = 0.116), EE population: 0.1 vs. 8.9 (P = 0.045) •OLE: gradual increases in NIS-LL and muscle weakness to month 30	•Similar incidence of AEs and SAEs (Taf, 9% vs. PBO, 8%) in both treatment arms •Urinary tract infections and diarrhea more common in Taf arm vs. PBO arm •No new safety signals with long-term treatment
	•Open-label, single-arm phase II study (97) •Treatment: Taf 20 mg QD for 12 months	•Biopsy-confirmed TTR amyloidosis •TTR mutation other than Val30Met or Val122Ile •Aged 18–75 years •n = 21	•Primary end-point: TTR stabilization at week 6 compared with baseline	•94.7% achieved TTR stabilization at week 6 •Worsening of neurologic function (NIS score) at month 12 •No clinical worsening of TQoL or mBMI at month 12	•Most common AEs were falls (24%), diarrhea (24%), and extremity pain (19%) •SAEs reported in 4 patients
	•Open-label single-treatment phase II study (98) •Treatment: Taf 20 mg QD for up to 12 months •OLE: treatment to 60 months	•TTR amyloid cardiomyopathy and NYHA classification of I/II •TTR mutation other than Val122Ile •Aged > 40 years • Phase II, n = 35; phase III, n = 31	•Primary end-points: phase II: TTR stabilization at week 6; phase III: long-term safety and efficacy data	•97.1% achieved TTR stabilization at week 6 •Estimated median survival of 48.2 months from first dose of tafamidis •NYHA classification stable to month 3	•SAEs reported in 11% of patients in phase II study and 6% in phase III study; 1 patient discontinued due to SAE
	•Prospective, non-randomized trial (99) •Treatment: Taf 20 mg QD for up to 12 months	•Symptomatic patients with ATTR-FAP •Val30Met mutation •Stage ≥ II: 77% •n = 29	•Primary end-point: disease progression	•93% of patients deteriorated on disability or NIS parameters	•45% reported AEs, all except 1 in the first 6 months •Severe GI toxicities in 3 patients in first 6 months
Diflunisal	•Randomized, double-blind phase III study (52) •Treatment: Dif 250 mg or PBO BID for 2 years	•Biopsy-confirmed amyloid deposits and mutant TTR •Clinically detectable neuropathy •Aged 18–75 •Any disease stage •n = 130 (Dif n = 64; PBO n = 66)	•Primary end-point: change in NIS + 7 at 2 years	•Mean NIS + 7 score increased by 25.0 in PBO group and 8.7 in Dif group •Mean SF-36 physical and mental scores improved in Dif group, deteriorated with PBO •No significant reduction in LV wall thickness or longitudinal strain in patients with cardiac involvement compared with PBO	•AEs in musculoskeletal (8% vs. 19%) and general disorders (7% vs. 19%) categories more frequent in the Dif vs. PBO group •Similar proportion of SAEs in both arms •Discontinuation due to AEs in 4 patients in the Dif arm and 2 in the PBO arm
	•Short-term, single-arm open-label study (100) •Treatment: Dif 250 mg BID	•Biopsy-proven cardiac amyloidosis •mutant ATTR or wt-ATTR disease •n = 13	•Changes in LVEF, LV mass •Changes in hemoglobin, creatinine, mBMI	•No significant change in cardiac structure (LV mass) or function (EF) at mean follow-up of 0.9 years	•Stable hematologic and hemodynamic parameters during treatment •Non-significant 6% decrease in eGFR
Doxycycline plus TUDCA	•Phase II open-label study (101) •Treatment: doxycycline 100 mg BID; TUDCA 250 mg TID	•Symptomatic ATTR-FAP/FAC or SSA •NYHA class ≤ III •Aged ≥ 18 years •Patients with liver transplant were eligible •n = 40	•Primary end-point: response rate (< 2-point increase in NIS-LL in patients with neuropathy; < 30% or < 300 pg/mL increase in NT-proBNP in patients with cardiomyopathy)	•Response rate of 46% (6/13) in patients with neuropathy •Response rate of 75% (18/24) in patients with cardiomyopathy •No significant changes in mBMI or QoL	•Four patients discontinued treatment due to doxycycline-related GI events, and 1 due to rash on limbs •Persistent mild redness of hands and face
ISIS-TTRRx	•Phase I study (102) •Treatment: ISIS-TTRRx 50–400 mg or PBO as single or multiple doses	•Healthy volunteers •Three subjects for each ISIS-TTRRx single-dose cohort •Eight subjects for each ISIS-TTRRx multiple-dose cohort	•Safety, PK, PD	•Dose-dependent reductions in serum TTR with ISIS-TTRRx > 50 mg •Mean reduction of ∼80% by day 22 with ISIS-TTRRx 300 and 400 mg dosing •TTR knockdown evident at ≥ 10 weeks after cessation of ISIS-TTRRx in 200–400 mg groups	•No SAEs reported •Most common AEs were injection-site pain and somnolence with single doses •No significant laboratory abnormalities
Patisiran	•Dose-escalation phase I study (103) •Treatment: single-dose Pat 0.01–0.5 mg/kg or PBO	•Healthy volunteers •n = 17	•Safety, PK, PD	•Dose-dependent reductions in serum TTR with Pat > 0.01 mg/kg •Mean maximal TTR knockdown of ∼90% with single dose of Pat 0.3–0.5 mg/kg •TTR knockdown evident at ≥ 8 after single-dose patisiran at doses ≥ 0.15 mg/kg	•No SAEs reported •Most common AE was skin erythema (Pat, 46%; PBO, 50%) •No significant laboratory abnormalities
	•Open-label dose-escalation phase II study (104) •Treatment: two doses of Pat 0.01–0.3 mg/kg Q4W and 0.3 mg/kg Q3W	•Diagnosis of ATTR amyloidosis. Any TTR mutational status •Co-administration of Dif or Taf permitted •Stage I or II disease •Aged 18–85 years •n = 29	•Safety, PK, PD	•Dose-dependent reductions in serum TTR following two doses of Pat > 0.01 mg/kg •Mean maximal TTR knockdown of ∼85% with two doses of Pat 0.3 mg/kg •TTR knockdown unaffected by concurrent use of Dif or Taf •No accumulation of TTR siRNA after second dose of Pat	•Majority of AEs of mild-to-moderate intensity •SAEs observed in 1 patient at 0.3 mg/kg dose •No significant laboratory abnormalities •Most common AEs were infusion-related reactions (10% overall) •Knockdown of RBP and vitamin A correlated with circulating TTR
	•Phase II OLE study (105) •Pat 0.3 mg/kg Q3W for up to 2 years	•Maintained on study from dose-escalation phase •n = 27	•Safety and tolerability of long-term dosing •Neurologic impairment (mNIS + 7, NIS), cardiac involvement, autonomic symptoms, QoL (EQ-5D), serum TTR levels	•Mean TTR knockdown at 80% level •Knockdown sustained over ∼16 months •Decrease in mNIS + 7 of 2.5 points at 12 months •Minimal changes in EQ-5D scores or clinical assessments at 12 months	•All TEAEs mild to moderate in severity •Infusion-related reactions in ∼18% of patients •SAEs in 3 patients (unrelated to study drug) •No significant laboratory abnormalities
Revusiran	•Phase I dose-escalation study (in preparation) •Treatment: Rev 1.25–10 mg/kg as single or multiple doses	•Healthy volunteers •n = 41	•Safety, PK, PD	•Dose-dependent TTR knockdown with multiple dosing of Rev •Mean maximal TTR knockdown of ∼90% with multiple dosing of Rev 7.5 or 10 mg/kg	•No SAEs observed •No significant laboratory abnormalities •Most common AEs were mild-to-moderate infusion-related reactions (68% in multiple-dose phase)
	•Open-label phase II study (106) •Rev 5 or 7.5 mg/kg, daily × 5, then weekly × 5	•ATTR amyloidosis with cardiomyopathy •Wt- or h-ATTR amyloidosis •n = 26	•Safety, PK, PD	•Serum TTR levels reduced by ∼90% with multiple dosing •TTR reductions similar in patients with wt- or h-ATTR amyloidosis •Clinical measures typically stable to day 90	•All TEAEs of mild intensity •No treatment discontinuations •No significant laboratory abnormalities •Transient injection-site reactions in 23% of patients

AE = adverse event; ATTR = transthyretin (TTR) amyloidosis; BID = twice daily; Dif = diflunisal; EE = efficacy evaluable; EF = ejection fraction; eGFR = estimated glomerular filtration rate; EQ-5D = EuroQol 5-Dimensions questionnaire; FAC = familial amyloidosis with cardiomyopathy; FAP = familial amyloidosis with polyneuropathy; GI = gastrointestinal; h = hereditary; ITT = intent to treat; LV = left ventricular; LVEF = left ventricular ejection fraction; mBMI = modified body mass index; mNIS + 7 = modified NIS plus seven nerve tests; NIS = Neuropathy Impairment Score; NIS + 7 = Neuropathy Impairment Score plus seven nerve tests; NIS-LL = Neuropathy Impairment Score of the Lower Limbs; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; OLE = open-label extension; Pat = patisiran; PBO = placebo; PD = pharmacodynamics; PK = pharmacokinetics; Q3W = every 3 weeks; Q4W = every 4 weeks; QD = once daily; QnW = every n weeks; QoL = quality of life; RBP = retinol binding protein; Rev = revusiran; SAE = serious adverse event; SF-36 = Medical Outcomes Study Short-Form (36-item) Health Survey; siRNA = small interfering RNA; SSA = senile systemic amyloidosis; Taf = tafamidis; TEAE = treatment-emergent adverse event; TID = three times daily; TQoL = Norfolk Quality of Life–Diabetic Neuropathy total; TTR = transthyretin; TUDCA = tauroursodeoxycholic acid; wt = wild type.

Figure 2. Current treatment pathway for patients with ATTR amyloidosis with polyneuropathy. Disease is classified in stages according to Coutinho et al. (51) at initial diagnosis. ^a First-line anti-amyloid therapy is initiated according to stage of the disease and approval of the medicine in the country, in parallel with symptomatic treatment, to prevent disease progression and improve patient quality of life. Currently approved treatments may stabilize disease (liver transplantation (53)), or slow progression of the disease (tafamidis, diflunisal (52,96)); treatment options are very limited for patients with stage II and III. The pathway described is followed irrespective of TTR gene mutation at stage I, and initiation of treatment for non-neurologic symptoms (renal, cardiac) may also need to be considered in affected patients. ^bMostly performed in patients with early-onset FAP with Val30Met mutation. Approval based on pivotal phase II/III study in patients with FAP stage I with Val30Met mutation (96) and an open-label phase II study in patients with FAP stage I with non-Val30Met mutations (97). ^cDiflunisal should be used with caution in patients with a history of gastrointestinal bleeding or ulceration, renal impairment, or heart failure. ^dPreliminary data from a phase II open-label extension study with patisiran, a RNAi investigational agent, demonstrate a mean 2.5-point decrease in mNIS + 7 score; this treatment has the potential to halt progression of neuropathy (105). Of ongoing recruiting trials, none specify the acceptance of patients with late-stage (FAP stage > II) ATTR amyloidosis with polyneuropathy (clinicaltrials.gov, accessed on 15 May 2015). ^eThere are limited published data for diflunisal treatment of patients with FAP stage III (4 patients with PND stage IV received diflunisal in the Diflunisal Trial (52)). ^fLiver transplant is proposed according to eligible criteria (health status, no evolutive cancer, compliance in the anti-rejection treatment). Best outcome recorded for early-onset (≤ 50 years of age) Val30Met patients. ATTR = transthyretin amyloidosis; FAP = familial amyloidosis with polyneuropathy; PND = polyneuropathy disability; TTR = transthyretin.

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