Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050, Bruxelles, Belgium
Pharmacotherapeutic group: Other nervous system drugs
ATC code: N07XX08
Tafamidis is a selective stabiliser of TTR. Tafamidis binds to TTR at the thyroxine binding sites, stabilising the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process.
Transthyretin amyloidosis is a severely debilitating condition induced by the accumulation of various insoluble fibrillar proteins, or amyloid, within the tissues in amounts sufficient to impair normal function. The dissociation of the transthyretin tetramer to monomers is the rate-limiting step in the pathogenesis of transthyretin amyloidosis. The folded monomers undergo partial denaturation to produce alternatively folded monomeric amyloidogenic intermediates. These intermediates then misassemble into soluble oligomers, profilaments, filaments, and amyloid fibrils. Tafamidis binds with negative cooperativity to the two thyroxine binding sites on the native tetrameric form of transthyretin preventing dissociation into monomers. The inhibition of TTR tetramer dissociation forms the rationale for the use of tafamidis to slow disease progression in stage 1 ATTR-PN patients.
A TTR stabilisation assay was utilised as a pharmacodynamic marker and assessed the stability of the TTR tetramer.
Tafamidis stabilised both the wild-type TTR tetramer and the tetramers of 14 TTR variants tested clinically after once-daily dosing with tafamidis. Tafamidis also stabilised the TTR tetramer for 25 variants tested ex vivo, thus demonstrating TTR stabilisation of 40 amyloidogenic TTR genotypes.
The pivotal study of tafamidis meglumine in stage 1 ATTR-PN patients was an 18-month, multicentre, randomised, double-blind, placebo-controlled study. The study evaluated the safety and efficacy of once-daily 20 mg tafamidis meglumine in 128 patients with ATTR-PN with the V30M mutation and primarily stage 1 disease; 126 of the 128 patients did not routinely require assistance with ambulation. The primary outcome measures were the Neuropathy Impairment Score of the Lower Limb (NIS-LL – a physician assessment of the neurologic exam of the lower limbs) and the Norfolk Quality of Life – Diabetic Neuropathy (Norfolk QOL-DN – a patient reported outcome, total quality of life score [TQOL]). Other outcome measures included composite scores of large nerve fibre (nerve conduction, vibration threshold and heart rate response to deep breathing – HRDB) and small nerve fibre function (heat pain and cooling threshold and HRDB) and nutritional assessments utilizing the modified body mass index (mBMI – BMI multiplied by serum albumin in g/L). Eighty-six of the 91 patients completing the 18 month treatment period subsequently enrolled in an open-label extension study, where they all received once daily 20 mg tafamidis meglumine for an additional 12 months.
Following 18 months of treatment, more tafamidis meglumine-treated patients were NIS-LL Responders (change of less than 2 points on NIS-LL) Outcomes for the pre-specified analyses of the primary endpoints are provided in the following table:
Vyndaqel versus Placebo: NIS-LL and TQOL at Month 18 (Study Fx-005):
| Placebo | Vyndaqel | |
|---|---|---|
| Pre-specified ITT Analysis | N=61 | N=64 |
| NIS-LL Responders (% Patients) | 29.5% | 45.3% |
| Difference (Vyndaqel minus Placebo) | 15.8% | |
| 95% CI of Difference (p-value) | -0.9%, 32.5% (0.068) | |
| TQOL Change from Baseline LSMean (SE) | 7.2 (2.36) | 2.0 (2.31) |
| Difference in LSMeans (SE) | -5.2 (3.31) | |
| 95% CI of Difference (p-value) | -11.8, 1.3 (0.116) | |
| Pre-specified Efficacy Evaluable Analysis | N=42 | N=45 |
| NIS-LL Responders (% Patients) | 38.1% | 60.0% |
| Difference (Vyndaqel minus Placebo) | 21.9% | |
| 95% CI of Difference (p-value) | 1.4%, 42.4% (0.041) | |
| TQOL Change from Baseline LSMean (SE) | 8.9 (3.08) | 0.1 (2.98) |
| Difference in LSMeans (SE) | -8.8 (4.32) | |
| 95% CI of Difference (p-value) | -17.4, -0.2 (0.045) | |
In the pre-specified ITT NIS-LL Responder analysis, patients who discontinued prior to the 18-month time point due to liver transplantation were categorized as non-responders. The pre-specified Efficacy Evaluable analysis used observed data for those patients who completed the 18 month treatment per protocol.
The secondary endpoints demonstrated that tafamidis meglumine treatment resulted in less deterioration of neurologic function and improved nutritional status (mBMI) compared with placebo, as shown in the following table.
Secondary Endpoints Changes from Baseline to Month 18 LSMean (Standard Error) (Intent-to-Treat Population) (Study Fx-005):
| Placebo N=61 | Vyndaqel N=64 | P-value | Vyndaqel % change relative to Placebo | |
|---|---|---|---|---|
| NIS-LL change from BL LSMean (SE) | 5.8 (0.96) | 2.8 (0.95) | 0.027 | -52% |
| Large Fibre change from BL LSMean (SE) | 3.2 (0.63) | 1.5 (0.62) | 0.066 | -53% |
| Small Fibre change from BL LSMean (SE) | 1.6 (0.32) | 0.3 (0.31) | 0.005 | -81% |
| mBMI change from BL LSMean (SE) | -33.8 (11.8) | 39.3 (11.5) | <0.0001 | NA |
mBMI was derived as the product of serum albumin and Body Mass Index.
Based on repeated measures analysis of variance with change from baseline as the dependent variable, an unstructured covariance matrix, treatment, month and treatment-by-month as fixed effects, and subject as a random effect in the model.
NA = not applicable.
In the open-label extension study, the rate of change in the NIS-LL during the 12 months of treatment was similar to that observed in those patients randomised and treated with tafamidis in the previous double blind 18 month period.
Although data are limited, (one open-label study in 21 patients), taking into account the mechanism of action of tafamidis and the results on TTR stabilisation, tafamidis meglumine is expected to be beneficial in patients with stage 1 ATTR-PN due to mutations other than V30M.
The effects of tafamidis have been assessed in a double-blind, placebo-controlled, randomised 3-arm study in 441 patients with wild-type or hereditary transthyretin amyloid cardiomyopathy (ATTR-CM). The primary analysis of pooled tafamidis meglumine (20 mg and 80 mg) versus placebo demonstrated a significant reduction (p=0.0006) in all-cause mortality and frequency of cardiovascular-related hospitalisations.
A supra-therapeutic, single, 400 mg oral dose of tafamidis solution in healthy volunteers demonstrated no prolongation of the QTc interval.
The European Medicines Agency has waived the obligation to submit the results of studies with tafamidis in all subsets of the paediatric population in transthyretin amyloidosis (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
After oral administration of the soft capsule once daily, the maximum peak concentration (Cmax) is achieved within a median time (tmax) of 4 hours after dosing in the fasted state. Concomitant administration of a high fat, high calorie meal altered the rate of absorption, but not the extent of absorption. These results support the administration of tafamidis with or without food.
Tafamidis is highly protein bound (>99%) in plasma. The apparent steady-state volume of distribution is 16 litres.
The extent of tafamidis binding to plasma proteins has been evaluated using animal and human plasma. The affinity of tafamidis for TTR is greater than that for albumin. Therefore, in plasma, tafamidis is likely to bind preferentially to TTR despite the significantly higher concentration of albumin (600 μM) relative to TTR (3.6 μM).
There is no explicit evidence of biliary excretion of tafamidis in humans. Based on preclinical data, it is suggested that tafamidis is metabolised by glucuronidation and excreted via the bile. This route of biotransformation is plausible in humans, as approximately 59% of the total administered dose is recovered in faeces, and approximately 22% recovered in urine. Based on population pharmacokinetic results, the apparent oral clearance of tafamidis meglumine is 0.228 L/h and the population mean half-life is approximately 49 hours.
Exposure from once-daily dosing with tafamidis meglumine increased with increasing dose up to 480 mg single dose and multiple doses up to 80 mg/day. In general, increases were proportional or near proportional to dose and tafamidis clearance was stationary over time.
Pharmacokinetic parameters were similar after single and repeated administration of 20 mg tafamidis meglumine, indicating a lack of induction or inhibition of tafamidis metabolism.
Results of once-daily dosing with 15 mg to 60 mg oral solution tafamidis meglumine for 14 days demonstrated that steady-state was achieved by Day 14.
Pharmacokinetic data indicated decreased systemic exposure (approximately 40%) and increased total clearance (0.52 L/h versus 0.31 L/h) of tafamidis meglumine in patients with moderate hepatic impairment (Child-Pugh Score of 7-9 inclusive) compared to healthy subjects due to a higher unbound fraction of tafamidis. As patients with moderate hepatic impairment have lower TTR levels than healthy subjects, dosage adjustment is not necessary as the stoichiometry of tafamidis with its target protein TTR would be sufficient for stabilisation of the TTR tetramer. The exposure to tafamidis in patients with severe hepatic impairment is unknown.
Tafamidis has not specifically been evaluated in a dedicated study of patients with renal impairment. The influence of creatinine clearance on tafamidis pharmacokinetics was evaluated in a population pharmacokinetic analysis in patients with creatinine clearance greater than 18 mL/min. Pharmacokinetic estimates indicated no difference in apparent oral clearance of tafamidis in patients with creatinine clearance less than 80 mL/min compared to those with creatinine clearance greater than or equal to 80 mL/min. Dosage adjustment in patients with renal impairment is considered not necessary.
Based on population pharmacokinetic results, subjects ≥65 years had an average 15% lower estimate of apparent oral clearance at steady-state compared to subjects less than 65 years old. However, the difference in clearance results in <20% increases in mean Cmax and AUC compared to younger subjects and is not clinically significant.
In vitro data indicated that tafamidis does not significantly inhibit cytochrome P450 enzymes CYP1A2, CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Tafamidis is not expected to cause clinically relevant drug interaction due to induction of CYP1A2, CYP2B6 or CYP3A4.
In vitro studies suggest that it is unlikely tafamidis will cause drug interactions at clinically relevant concentrations with substrates of UDP glucuronosyltransferase (UGT) systemically. Tafamidis may inhibit intestinal activities of UGT1A1.
Tafamidis showed a low potential to inhibit Multi-Drug Resistant Protein (MDR1) (also known as P-glycoprotein; P-gp) systemically and in the gastrointestinal (GI) tract, organic cation transporter 2 (OCT2), multidrug and toxin extrusion transporter 1 (MATE1) and MATE2K, organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 at clinically relevant concentrations.
Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, fertility and early embryonic development, genotoxicity and carcinogenic potential. In repeat-dose toxicity and the carcinogenicity studies, the liver appeared as a target organ for toxicity in the different species tested. Liver effects were seen at exposures approximately ≥2.5-times the human AUC at steady-state at the clinical dose of 20 mg tafamidis meglumine.
In a developmental toxicity study in rabbits, a slight increase in skeletal malformations and variations, abortions in few females, reduced embryo-foetal survival, and reduction in foetal weights were observed at exposures approximately ≥ 7.2 times the human AUC at steady-state at the clinical dose of 20 mg tafamidis meglumine.
In the rat pre- and postnatal development study with tafamidis, decreased pup survival and reduced pup weights were noted following maternal dose administration during pregnancy and lactation at doses of 15 and 30 mg/kg/day. Decreased pup weights in males were associated with delayed sexual maturation (preputial separation) at 15 mg/kg/day. Impaired performance in a water-maze test for learning and memory was observed at 15 mg/kg/day. The NOAEL for viability and growth in the F1 generation offspring following maternal dose administration during pregnancy and lactation with tafamidis was 5 mg/kg/day (human equivalent dose = 0.8 mg/kg/day), a dose approximately 4.6 times the clinical dose of 20 mg tafamidis meglumine.
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