Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Purpose Pharma International AB, Grev Turegatan 13b, 114 46 Stockholm, Sweden
Pharmacotherapeutic group: Salicylic acid and derivatives.
ATC code: NO2BA11
Diflunisal is a potent stabiliser of tetrameric transthyretin (TTR), which effectively stabilises the tetramer against dissociation to the TTR monomers which are responsible for amyloidosis pathology.
The efficacy and safety of diflunisal was investigated in an international, randomised, double-blind, placebo-controlled clinical trial. N=130 patients were randomised in a 1:1 manner to receive 250 mg 10 diflunisal twice daily (N=64) or matching placebo (N=66) for 2 years. Patients were between 18 and 75 years old, had biopsy-proven amyloid deposition, mutant TTR genopositivity, clinical signs of peripheral or autonomic neuropathy and routinely spent more than 50% of waking hours out of bed or chair (ECOG performance status <3). Exclusions included alternative causes of sensorimotor polyneuropathy, limited survival expectation (<2 years), prior liver transplantation, severe congestive heart failure (class IV NYHA), renal insufficiency (estimated creatinine clearance <30 mL/min) and ongoing anticoagulation. The mutation distribution of the patients studied was V30M (n=71), L58H (n=15), T60A (n=15), S50R (n=4), F64L (n=4), D38A, S77Y, E89Q & V122I (n=2 each), V30G, V32A, K35N, K35T, E42G, F44S, T49P, E54Q, V71A, Y78F, I84N, A97S & I107F (n=1 each).
The primary endpoint, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7). NIS+7 scores range from 0 (no neurologic deficits) to 270 points (no detectable peripheral nerve function).
Patients had a mean age of 60.2 years and a mean NIS+7 score of 55.3 units at baseline. 66.9% of patients were male and 78.5% were white. 122/130 patients (93.8%) had FAP Stage 1 or 2 disease. Baseline characteristics, TTR genotyping, and polyneuropathy staging were similar between treatment groups. Nearly one third (30.8%) of the patients required support when walking and 4 patients in each treatment group were wheelchair-bound (FAP Stage 3). Outcome measures were not statistically different between groups at enrolment.
51.5% of patients discontinued study drug before completing the 2-year period of treatment (42.2% of patients randomised to diflunisal and 60.6% of patients randomised to placebo). Disease progression and orthotopic liver transplantation were the leading reasons for drop out. Analysis indicated that drop out was preceded by significantly worse disease state. Those patients who dropped out after 12 months had significantly higher 12-month NIS+7 score. The ITT analysis is presented below:
Table 2. Results of longitudinal analysis in the ITT population:
| Variable | Baseline score | Mean placebo-subtracted difference at Month 12 (95% CI) | Mean placebo-subtracted difference at Month 24 (95% CI) | |
|---|---|---|---|---|
| Diflunisal | Placebo | |||
| NIS+7 (primary endpoint) | 51.57 | 59.00 | 6.4 (1.2, 11.6) p=0.017 | 18.0 (9.9, 26.2) p<0.001 |
Results were irrespective of gender, geographical region, and disease severity at entry.
The majority of the patients studied (77.7%) had one of the 3 most common single site TTR variants. There are at least 100 other potential single site mutations associated with the potential to cause TTR amyloidosis. Of these, 19 were represented in the trial. The mechanism of action of diflunisal is expected to be translatable to all TTR variants and the results of the trial are expected to be valid regardless of the underlying mutation.
Diflunisal is close to completely absorbed when used in therapeutic doses. Peak plasma concentrations occur within 2 to 3 hours. Food affects the rate of diflunisal absorption but not the extent of absorption.
The degree of protein binding in plasma is high; approximately 98-99% of diflunisal in plasma is bound to proteins.
At the clinical dose of 250 mg twice daily, steady state concentrations of diflunisal in plasma are reached after 4-5 days and the plasma elimination half-life of diflunisal is 8-10 hours. At higher repeated twice daily doses of diflunisal, time to steady state concentrations of diflunisal and plasma elimination half-life are increased dose-proportionately.
No metabolites of diflunisal have been identified in human plasma. Diflunisal is extensively metabolised mainly in the liver by phase 2 conjugation enzymes and its conjugates have been identified in urine.
In humans, diflunisal is mainly metabolised to form two glucuronide conjugates and one sulphate conjugate, which are water soluble and excreted in the urine. Diflunisal is also excreted in smaller amounts in the urine, approximately 5% of dose administered. Age, weight, gender and ethnicity are not expected to have a significant effect on elimination of diflunisal.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential, which is additional to those already mentioned in other sections of this Summary of Product Characteristics. However, based on doses/human equivalent doses, exposures at the No Observed Adverse Effect Levels (NOAEL) in the different studies were only slightly higher or even below those in patients receiving the maximum recommended human dose.
Diflunisal has shown no evidence of effects on fertility in rats but has been shown to increase the length of the gestation period in rats. Diflunisal has shown no evidence of developmental toxicity in mice, rats and cynomolgus monkeys. Severe maternal haemolytic anaemia was uniquely induced in rabbits, resulting in developmental toxicities in foetuses.
Data suggest that diflunisal is more toxic to neonatal rats and dogs than to adult animals.
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