Treatment of pemphigus vulgaris and foliaceus with efgartigimod, a neonatal Fc receptor inhibitor: a phase II multicentre, open-label feasibility trial.

BACKGROUND: Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. OBJECTIVES: To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. METHODS: Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg-1 intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). RESULTS: Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg-1 and 13 of 15 (87%) patients receiving 25 mg kg-1 , with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26 mg kg-1 per day (range 0·06-0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2-41 weeks. CONCLUSIONS: Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus.

The disability assessment for dementia scale: a 12-month study of functional ability in mild to moderate severity Alzheimer disease.

The Disability Assessment for Dementia (DAD) scale was developed and validated as a measure of functional ability in dementia. DAD results have been reported in Alzheimer disease (AD) randomized, controlled treatment trials of up to 6 months, but results beyond 6 months have yet to be described. SAB INT 12 was a randomized, double-blind, placebo-controlled, parallel-group study in mild to moderate AD that included DAD assessments at baseline, month 6, and month 12. One hundred forty-four patients with AD in the placebo arm of SAB INT 12 were followed up for 12 months. DAD scores were obtained at baseline (mean DAD = 70.1, SD = 22.2), 6 months (mean DAD = 63.7, SD = 25.2), and 12 months (mean DAD = 59.3, SD = 28.9). The rate of decline was consistent across the domains of basic activities of daily living (ADLs) and instrumental ADLs, as well as the scoring of initiation, planning, and organization. The decline in DAD total scores in mild to moderate AD averages about one point per month, which equates to the loss of one item on the DAD scale every 2 months.

APOE genotype: no influence on galantamine treatment efficacy nor on rate of decline in Alzheimer's disease.

Apolipoprotein E (APOE) has been extensively demonstrated to be a genetic risk factor for Alzheimer's disease (AD). Associations of APOE genotype have been reported with age at AD onset, rate of decline, and responsiveness to therapy. This study aimed to test these hypotheses in a large study population of AD patients. APOE genotype was determined from 1,528 Caucasian subjects, diagnosed by NINCDS/ADRDA criteria as probable AD patients, enrolled in four international placebo-controlled clinical trials of 3--12 months duration, designed to evaluate efficacy of treatment with galantamine or sabeluzole. In addition to patient demographics and baseline scores for Mini Mental State Examination, scores on the Disability Assessment for Dementia (DAD) and the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) were recorded at the start, during, and at the end of the study. APOE epsilon 4 homozygotes had a significantly lower age at disease onset compared to patients with other APOE genotypes. The epsilon 4 allele was significantly over-represented in females compared to males, and in the group of subjects with an AD family history. Based on longitudinal data of 504 placebo-treated AD patients, the linear annual rate of change in score was 5 points on the ADAS-cog scale and 11 on the DAD scale. The epsilon 4 allele copy number did not influence these rates of decline. Sabeluzole treatment was not effective in the overall group compared to the placebo-treated group, nor in any subgroup stratified by epsilon 4 allele count. Galantamine produced cognitive and functional improvement that were not affected by epsilon 4 allele count. In conclusion, our data confirm a strong association between epsilon 4 homozygotes and age at onset of AD but do not support an effect of epsilon 4 allele copy number on rate of cognitive and functional decline nor on the efficacy of galantamine in patients with AD.

Galantamine: additional benefits to patients with Alzheimer's disease.

Galantamine, a novel treatment for Alzheimer's disease (AD), has a dual mechanism of action, combining allosteric modulation of nicotinic acetylcholine receptors with reversible, competitive inhibition of acetylcholinesterase. In the Phase III clinical trial programme, over 3,000 patients with mild-to-moderate AD were enrolled in one of five randomized, controlled, double-blind studies. Using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) to assess memory and other cognitive functions, galantamine was found to be significantly superior to placebo in all five studies at doses of 16, 24 and 32 mg/day. In all studies, galantamine-treated patients maintained their cognitive function, whereas the placebo-treated patients experienced a significant deterioration in ADAS-cog scores. The 32-mg/day dose was not associated with any additional cognitive benefit. Pooled data from two 6-month studies (n = 1,269), which were of identical design, show that the therapeutic benefits of galantamine are sustained for the duration of treatment. The treatment effect (galantamine-placebo difference on ADAS-cog) for the pooled data was approximately 4 points. Clinical benefit was seen in all levels of disease severity, with a 7-point advantage over placebo on ADAS-cog for patients with moderately severe disease. Galantamine was well tolerated, with most patients completing the 6-month studies. The long-term effects of galantamine have been evaluated in a 12-month study. Patients who completed one of the pivotal 6-month studies (n = 353) were entered into a 6-month open-label extension. Cognitive and daily function were maintained throughout the 12 months in patients who received galantamine 24 mg/day. This sustained level of benefit may reflect galantamine's dual effect on the cholinergic system. Data from a 5-month, placebo-controlled study have also shown that galantamine produces significant benefits on behavioural symptoms. The persistence and range of therapeutic effects produced by galantamine suggest that it may provide additional benefits for patients with AD.

New trends in the treatment of allergic conjunctivitis.

Histamine is the key mediator producing itching, redness and chemosis in allergic conjunctivitis. Histamine levels in tears are increased ten-fold in patients with this allergic condition. Levocabastine is a newly synthesized histamine H1 antagonist which has been formulated as both eye drops and nasal spray. In well established assays of antihistamine activity, levocabastine was found to be the most potent antihistamine compound available, being 15,000 times more potent than chlorpheniramine. Ocular provocation studies in man have shown that levocabastine protects against the symptoms of allergen-induced conjunctivitis. Ophthalmological examinations, including slit lamp and ophthalmoscopy showed no adverse effects. Data from therapeutic studies are available for more than 1700 patients with allergic conjunctivitis treated for 2-16 weeks. One drop of levocabastine (0.5 mg/ml) per eye given two to four times daily provided significantly better symptom control than placebo, with good to excellent results in 71% of patients on levocabastine compared to 55% on placebo (p < 0.001). Levocabastine has a fast onset of action. In one study 94% of patients experienced symptom relief within 15 minutes after the first instillation. The effects observed with levocabastine were at least as good as those with ocular cromoglycate or oral terfenadine. The incidence of adverse experiences was not different from placebo. Levocabastine promises to be a valuable treatment for patients with allergic conjunctivitis.