Postauthorization safety study of betaine anhydrous.

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 µmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

Long-term follow-up of cystinosis patients treated with 0.55% cysteamine hydrochloride.

BACKGROUND/AIMS: Cystinosis is a rare, autosomal recessive disorder causing defective transport of cystine out of lysosomes. Cystadrops (0.55% cysteamine hydrochloride in viscous solution) has been used on a named-patient basis to treat the accumulation of cystine crystals in the cornea in patients with cystinosis. METHODS: Retrospective analysis of the Temporary Authorisation for Use cohort of 130 patients who received Cystadrops between 2013 and 2017 in France. RESULTS: Patients received an average dosage of 3.3 (±0.94) instillations per eye per day. Over the duration of follow-up, of up to 45 months, patients maintained visual acuity scores of 0.0, which approximated normal. Corneal cystine crystal scores tended to decrease over time, stabilising after around 27 months between 1.22 and 1.87. Photophobia decreased within 3 months, stabilising on scores of around 1.5 and 1.7. 47 non-serious adverse reactions were reported, which were generally transient irritation, stinging or blurred vision. Four serious adverse events were reported, including keratitis and corneal ulcer, but these may have been caused by the underlying disease. CONCLUSION: This large safety cohort confirms the efficacy, safety and tolerability of Cystadrops in real-world clinical practice.

Effect of carglumic acid with or without ammonia scavengers on hyperammonaemia in acute decompensation episodes of organic acidurias.

BACKGROUND: Hyperammonaemia is a key sign of decompensation in organic acidurias (OAs) and can contribute to severe neurological complications, thus requiring rapid treatment. METHODS: A post-hoc analysis of two retrospective studies analysed the efficacy of carglumic acid ± ammonia (NH3) scavengers compared with scavengers alone for reducing plasma NH3 levels in patients with OAs and hyperammonaemia (plasma NH3 > 60 µmol/L) during decompensation episodes. NH3 was analysed in 12-h periods at 0-48 h and 24-h periods at 48-120 h. Treatment-emergent adverse events (TEAEs) were recorded. RESULTS: Of 98 episodes, 38 were treated with carglumic acid (34 patients), 33 with NH3 scavengers (22 patients) and 27 with carglumic acid combined with NH3 scavengers (27 patients). Overall, 45% (carglumic acid group), 46% (NH3 scavengers group) and 74% (combination group) of episodes occurred in neonates. Median episode duration was 6 days for the carglumic acid and combination groups, and 9 days for the NH3 scavenger group. Median baseline NH3 level was: 199 µmol/L, carglumic acid; 122 µmol/L, NH3 scavengers; and 271 µmol/L, combination; 13, 30 and 11% of episodes required extracorporeal detoxification (ED), respectively. Data were censored at ED initiation. While baseline NH3 levels were higher in the combination and carglumic acid groups, mean reduction in NH3 levels to 72 h in both groups was greater than the NH3 scavengers' group; reductions were greatest in the combination group. Mean change in plasma NH3 vs baseline in the carglumic acid, NH3 scavengers and combination groups, respectively, was - 13, + 12% and - 27% at 0-12 h (p < 0.05 NH3 scavengers vs combination); - 47, - 22% and - 52% at 12-24 h (not significant); - 44, - 5% and - 61% at 24-48 h; and - 66, - 16% and - 76% at 48-72 h (p < 0.05 carglumic acid/combination groups vs NH3 scavengers for both timepoints). The number of TEAEs was similar between groups and mainly related to the disease/condition. CONCLUSIONS: Carglumic acid is a well-tolerated and efficacious treatment for OA decompensation episodes. When given alone or combined with NH3 scavengers, the reduction in NH3 was greater than with NH3 scavengers alone in the first 72 h.

A New Viscous Cysteamine Eye Drops Treatment for Ophthalmic Cystinosis: An Open-Label Randomized Comparative Phase III Pivotal Study.

Purpose: The purpose of this study was to evaluate the efficacy of new viscous cysteamine hydrochloride (CH) eye drops (vCH 0.55%) compared with standard CH 0.10% drops treatment. Methods: This was an open-label, phase III, randomized, two-arm multicenter trial conducted at two centers in France. Cystinosis patients ≥2 years old were randomized 1:1 to receive eye drops, four times per day for 90 days in both eyes. We compared the superiority in reducing corneal cystine crystal density as assessed by in vivo confocal microscopy (IVCM). We also evaluated photophobia, corneal cystine crystal scores (CCCSs), and cystine crystal depth measured by optical coherence tomography. Safety objectives were to assess adverse events (AEs), local adverse drug reactions, and ocular safety parameters. Results: We included 15 patients with vCH 0.55% and 16 patients with CH 0.10% drops for 90 days. The mean absolute change in IVCM total score at day 90 in the vCH 0.55% drops group (-4.6 ± 3.1) was significantly greater than and superior to the mean absolute change in the CH 0.10% drops group (-0.46 ± 3.38; P < 0.0001). Photophobia, CCCS, and corneal cystine crystal depth were significantly more improved in the vCH 0.55% drops group than in the CH 0.10% group. The most frequent local adverse drug reactions in both groups were stinging, burning, redness, and blurred vision. Conclusions: vCH 0.55% was effective in reducing corneal cystine crystal density and superior to treatment with CH 0.10% drops, which offer advantages over hospital pharmacy formulations and is a more preferable and convenient treatment option.

Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk-benefit profile: a retrospective observational study.

BACKGROUND: Isovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Rapid reduction in plasma ammonia is required to prevent neurological complications. This retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid, a synthetic structural analogue of NAG, for treating hyperammonaemia during OA decompensation. METHODS: Eligible patients had confirmed OA and hyperammonaemia (plasma NH3 > 60 µmol/L) in ≥1 decompensation episode treated with carglumic acid (dose discretionary, mean (SD) first dose 96.3 (73.8) mg/kg). The primary outcome was change in plasma ammonia from baseline to endpoint (last available ammonia measurement at ≤18 hours after the last carglumic acid administration, or on Day 15) for each episode. Secondary outcomes included clinical response and safety. RESULTS: The efficacy population (received ≥1 dose of study drug and had post-baseline measurements) comprised 41 patients (MMA: 21, PA: 16, IVA: 4) with 48 decompensation episodes (MMA: 25, PA: 19, IVA: 4). Mean baseline plasma ammonia concentration was 468.3 (±365.3) µmol/L in neonates (29 episodes) and 171.3 (±75.7) µmol/L in non-neonates (19 episodes). At endpoint the mean plasma NH3 concentration was 60.7 (±36.5) µmol/L in neonates and 55.2 (±21.8) µmol/L in non-neonates. Median time to normalise ammonaemia was 38.4 hours in neonates vs 28.3 hours in non-neonates and was similar between OA subgroups (MMA: 37.5 hours, PA: 36.0 hours, IVA: 40.5 hours). Median time to ammonia normalisation was 1.5 and 1.6 days in patients receiving and not receiving concomitant scavenger therapy, respectively. Although patients receiving carglumic acid with scavengers had a greater reduction in plasma ammonia, the endpoint ammonia levels were similar with or without scavenger therapy. Clinical symptoms improved with therapy. Twenty-five of 57 patients in the safety population (67 episodes) experienced AEs, most of which were not drug-related. Overall, carglumic acid seems to have a good safety profile for treating hyperammonaemia during OA decompensation. CONCLUSION: Carglumic acid when used with or without ammonia scavengers, is an effective treatment for restoration of normal plasma ammonia concentrations in hyperammonaemic episodes in OA patients.