Efficacy and safety of piclidenoson in plaque psoriasis: Results from a randomized phase 3 clinical trial (COMFORT-1).

OBJECTIVE: A3 adenosine receptor (A3AR) is overexpressed in the skin and peripheral blood mononuclear cells of psoriasis patients. We investigated the efficacy/safety of piclidenoson (CF101), an orally bioavailable A3AR agonist that inhibits IL-17 and IL-23 production in keratinocytes, in moderate-to-severe plaque psoriasis. METHODS: The randomized, placebo- and active-controlled, double-blind phase 3 COMFORT-1 trial randomized patients (3:3:3:2) to piclidenoson 2 mg BID, piclidenoson 3 mg BID, apremilast 30 mg BID or placebo. At Week 16, patients in the placebo arm were re-randomized (1:1:1) to piclidenoson 2 mg BID, piclidenoson 3 mg BID or apremilast 30 mg BID. The primary end point was the proportion of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI) from baseline (PASI-75) at Week 16 versus placebo. RESULTS: A total of 529 patients were randomized and received ≥1 dose of study medication (safety population). The efficacy analysis population for the primary end point included 426 patients (piclidenoson 2 mg BID, 127; piclidenoson 3 mg BID, 103; apremilast, 118; placebo, 78). Piclidenoson at 2 and 3 mg BID exhibited similar efficacy. The primary end point was met with the 3 mg BID dose: PASI 75 rate of 9.7% versus 2.6% for piclidenoson versus placebo, p = 0.037. The PASI responses with piclidenoson continued to increase throughout the study period in a linear manner. At week 32, analysis in the per-protocol population showed that a greater proportion of patients in the piclidenoson 3 mg BID arm (51/88, 58.0%) achieved improvement from baseline in Psoriasis Disability Index (PDI) compared to apremilast (59/108, 55.1%), and the test for noninferiority trended towards significance (p = 0.072). The safety/tolerability profile of piclidenoson was excellent and superior to apremilast. CONCLUSIONS: Piclidenoson demonstrated efficacy responses that increased over time alongside a favourable safety profile. These findings support its continued clinical development as a psoriasis treatment (ClinicalTrials.gov identifier: NCT03168256).

Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults.

BACKGROUND: Neurodegenerative diseases are devastating conditions that most commonly affect individuals 65 years and older. Currently there are no effective treatments or cures for neurodegenerative diseases, and therapeutics that selectively target the underlying causes of these diseases are needed. Epichaperomes play a major role in the maintenance and progression of neuronal pathology. Inhibiting epichaperomes induces degradation of disease associated proteins and is a promising therapeutic approach to treat neurodegenerative diseases, in particular Alzheimer's Disease and amyotrophic lateral sclerosis. OBJECTIVES: This Phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics, and bioavailability of icapamespib, a purine scaffold inhibitor of epichaperomes that is specific to epichaperomes, in healthy subjects. DESIGN: Double-blind, placebo-controlled dose escalating single ascending dose and multiple ascending doses and an unblinded two-period cross-over bioavailability study design. SETTING: Single site in the United States. PARTICIPANTS: Healthy men or women of 18 to 60 years of age, inclusive, for Part 1 (single ascending dose), ≥ 60 years of age for Part 2 (multiple ascending dose), or 18 to 49 years of age for Part 3 (bioavailability). TREATMENT: In the single ascending dose group, oral single doses (10, 20, and 30 mg icapamespib or placebo) were administered to healthy non-elderly subjects. In the multiple ascending dose group, multiple doses (20 and 30 mg icapamespib once daily for 7 days or placebo) were administered to healthy elderly subjects. In the bioavailability group, the bioavailability of once daily oral icapamespib solution and tablet was assessed in healthy non elderly subjects. MEASUREMENTS: Safety was evaluated based on assessments of treatment-emergent adverse events, physical examinations, clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital signs, and 12-lead electrocardiograms. Icapamespib concentration was evaluated in plasma and cerebrospinal fluid, the latter in Part 2 (multiple ascending dose) only. RESULTS: Forty-eight subjects in total were randomized and assessed for tolerability, pharmacokinetics, and bioavailability parameters as follows: 24 subjects in Part 1 (single ascending dose) with PU-AD 10 mg (n = 6), 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 6); 16 subjects in Part 2 (multiple ascending dose) with icapamespib 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 4); and 8 subjects in Part 3 (bioavailability) crossed-over between icapamespib 30 mg (tablet) and icapamespib 30 mg (oral solution). Single doses of icapamespib up to 30 mg and multiple doses of icapamespib up to 30 mg for 7 days were generally safe and well tolerated in healthy non-elderly and elderly subjects. Treatment-emergent adverse events were mild, with headache being the most common treatment-emergent adverse event. Mean icapamespib exposure (area under the curve) was dose-proportional over the dose range tested. The median time to maximum observed plasma concentration ranged from 1.00 to 2.00 h across single ascending dose, multiple ascending dose, and bioavailability groups; icapamespib exposure was 50% higher in elderly subjects compared with non-elderly subjects but was well tolerated. CONCLUSIONS: The study provides clinical evidence of the safety of icapamespib in healthy non elderly and elderly subjects and supports the advancement of icapamespib to Phase 2 evaluation in Alzheimer's Disease and other neurodegenerative diseases.

Predictors of suicide attempts in patients with borderline personality disorder over 16 years of prospective follow-up.

BACKGROUND: It is clinically important to understand the factors that increase the likelihood of the frequent and recurrent suicide attempts seen in those with borderline personality disorder (BPD). Although several studies have examined this subject in a cross-sectional manner, the aim of this study was to determine the most clinically relevant baseline and time-varying predictors of suicide attempts over 16 years of prospective follow-up among patients with BPD. METHOD: Two-hundred and ninety in-patients meeting Revised Diagnostic Interview for Borderlines (DIB-R) and DSM-III-R criteria for BPD were assessed during their index admission using a series of semistructured interviews and self-report measures. These subjects were then reassessed using the same instruments every 2 years. The generalized estimating equations (GEE) approach was used to model the odds of suicide attempts in longitudinal analyses, controlling for assessment period, yielding an odds ratio (OR) and 95% confidence interval (CI) for each predictor. RESULTS: Nineteen variables were found to be significant bivariate predictors of suicide attempts. Eight of these, seven of which were time-varying, remained significant in multivariate analyses: diagnosis of major depressive disorder (MDD), substance use disorder (SUD), post-traumatic stress disorder (PTSD), presence of self-harm, adult sexual assault, having a caretaker who has completed suicide, affective instability, and more severe dissociation. CONCLUSIONS: The results of this study suggest that prediction of suicide attempts among borderline patients is complex, involving co-occurring disorders, co-occurring symptoms of BPD (self-harm, affective reactivity and dissociation), adult adversity, and a family history of completed suicide.

Treatment of plaque-type psoriasis with oral CF101: data from an exploratory randomized phase 2 clinical trial.

AIMS: CF101 demonstrated a marked anti-inflammatory effect in Phase 2 studies conducted in patients with rheumatoid arthritis and dry eye syndrome. The aim of this study was to evaluate the safety and efficacy of CF101 for the treatment of patients with moderate to severe plaque-type psoriasis. MATERIALS AND METHODS: This was a phase 2, multicentre, randomized, double-blind, dose-ranging, placebo-controlled study. Seventy five patients with moderate to severe plaque-type psoriasis were enrolled, randomized and treated with CF101 (1, 2, or 4 mg) or placebo administered orally twice daily for 12 weeks. Safety and change from base line of Psoriasis Area and Severity Index (PASI) score and physician's global assessment (PGA) score over 12 weeks. RESULTS: In the 2 mg CF101-treated group, a progressive improvement in the mean change from baseline in the PASI score vs. placebo throughout the study period was observed, with a statistically significant difference on weeks 8 and 12 (P = 0.047; P = 0.031, respectively). In this group, 35.3% of the patients achieved PASI ≥ 50 response, and 23.5% of the patients achieved a PGA score of 0 or 1. CF101 was safe and well tolerated. CONCLUSIONS: CF101 was well tolerated and demonstrated clear evidence of efficacy in patients with moderate to severe plaque psoriasis.

Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men.

OBJECTIVES: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF 101, an A3 adenosine receptor (A3AR) agonist, in healthy men. METHODS: One single and 1 repeated dose, parallel-group, ascending dose, double-blind and placebo-controlled study in normal volunteers. In the single dose study, n = 15 subjects received 1, 5 or 10 mg oral CF101; in each group 1 subject received placebo, the remainder active CF101. In the repeat-dose study, n = 28 subjects received repeated 12-hourly oral doses of CF 101 (2, 3, 4 or 5 mg) for 7 days, in each group 2 subjects received placebo, the remainder active CF101. TEST MATERIALS: Single-dose study: CF101 in 30% Cremophor RH40. Multiple-dose sudy: CF101 in 0.5% methylcellulose suspension. Both studies: the corresponding vehicles were used as placebos. Galenicals were prepared remotely from the clinical study site to ensure double-blind nature of the study. RESULTS TOLERABILITY: Single doses up to 5 mg CF101 were safe and well-tolerated. However, the single dose of 10 mg CF101 was associated with flushing, tachycardia, nausea and vomiting, which were viewed as dose-limiting in normal volunteers. Single doses of CF101 (as well as the first of the multiple doses) were associated with increases in heart rate (8 - 24 beats/min after 5 mg and 18 - 55 beats/min after 10 mg). Multiple doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. However, the 5 mg multiple-dose group reported headache, drowsiness, hot flushes and dizziness on standing; this declined with dosing duration and was not dose-limiting in this study. Adverse events were commonest near t(max). RESULTS PHARMACOKINETICS: For oral CF101, the t(max) was always 1 - 2 h post-dose and t 1/2 about 9 h, in both the single- and multiple-dose studies. For a single 5 mg dose (mean +/- SD) C(max) = 81.6 +/- 23.6 ng/ml in the single dose study, and 63.6 +/- 22.0 ng/ml after the first of the multiple doses; AUC if was 904.0 +/- 221.9 ng.h/ml and 596.1 +/- 196.6 ng.h/ml for the 2 studies, respectively. After 7 days of multiple dosing there was little change, and AUC(0-24h) = 601.0 +/- 163.6 ng.h/ml. These pharmacokinetic parameters were linearly proportional to dose in the other treatment groups. RESULTS PHARMACODYNAMICS: Increases in heart rate were related to plasma concentration and evident only in the upper range of concentrations observed. There were no changes on ECG monitoring beyond sinus tachycardia, and, in particular, no evidence of PR prolongation in any subject (n = 43). In comparison with single doses, this response was almost absent after 7 days of dosing. Leucocytosis (increases up to about 1.5 x 10(9)/l after 5 and 10 mg) was similarly transient and reversible after multiple dosing. CONCLUSIONS: Single oral doses up to 5 mg CF101 and repeated doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. Multiple-dose CF101 pharmacokinetics were unchanged and predictable from single-dose estimates, and were linearly proportional to dose. Increases in heart rate and neutrophil count were reversible during multiple dosing and were not dose-limiting in the repeat dose study. CF101 warrants further study for its efficacy in treating human disease.

Safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men.

AIMS: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men. METHODS: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses. MATERIALS: A6 for subcutaneous injection in phosphate buffer, pH 5.6-6.0. Phosphate-buffered saline was used as placebo. RESULTS: All dose regimens of A6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454-10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300 mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was 94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger production of anti-A6 IgG antibodies within 14 days of the first dose. CONCLUSION: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. A6 did not trigger an early immunogenic response.

Pilot trial of cyclosporine 1% ophthalmic ointment in the treatment of keratoconjunctivitis sicca.

This trial was a randomized, double-masked, crossover study during which patients with keratoconjunctivitis sicca underwent 6 weeks of treatment with either cyclosporine 1% ophthalmic ointment or placebo followed by 6 weeks of the alternative treatment. Washout periods using only unpreserved artificial tears preceded both treatment cycles. Twenty-five patients completed the first treatment period, but only eight met entry criteria for period II. Cyclosporine ointment was associated with initial mild to moderate redness, itching, and burning that returned to baseline levels within 1-2 weeks. Rose Bengal results and results of four subjective (patient diary) efficacy parameters favored cyclosporine: foreign body sensation, overall symptoms, hours of symptom control per day, and overall effectiveness. No systemic adverse events or laboratory abnormalities occurred. We conclude that (a) the crossover design is inappropriate for studying this disease; (b) mild to moderate itching, redness, and burning occur initially with cyclosporine administration, although tolerance quickly develops; (c) cyclosporine appears to benefit the ocular surface in keratoconjunctivitis sicca; and (d) further trials in this syndrome are warranted.

Safety and tolerability of two percent cyclosporine (Sandimmune) ophthalmic ointment in normal volunteers.

Thirty-six healthy male volunteers were enrolled in two sequential double-masked, placebo-controlled trials with the objective of assessing the safety and local tolerability of 2% cyclosporine ophthalmic ointment. Subjects were randomly assigned to active or placebo groups and dosed once, twice, or thrice daily for 14 days. Safety and tolerability were assessed through patient interviews, ophthalmologic examinations, routine laboratory testing, and blood cyclosporine assays. Relative to placebo, cyclosporine ointment was associated with higher frequencies of ocular burning, tearing, redness, itching, and headache. These intolerances were dose-related and reported predominantly in the TID group; QD and BID cyclosporine ophthalmic ointment were better tolerated than the placebo control. Symptoms were usually mild, were reported only once beyond Day 2 in the QD-BID groups, and never required interruption of the study. Transitory, asymptomatic, and unexplained elevations of serum transaminases were seen in five subjects in the first study, but were not confirmed in the second and are not felt to be drug-related. Cyclosporine blood levels were uniformly below the limits of detection. We conclude that the tolerability profile of 2% cyclosporine ointment, dosed once or twice daily in normal volunteers, is acceptable and supportive of trials in patient populations.

Multiple-dose pharmacokinetics and safety of oral amifloxacin in healthy volunteers.

The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections.

Preliminary study of the pharmacokinetics of oral amifloxacin in elderly subjects.

Amifloxacin pharmacokinetics after a single oral dose in healthy elderly subjects were determined. Five males and five females aged 65 to 79 years and having creatinine clearances of 39.3 to 87.2 ml/h per kg of body weight were given a 200-mg amifloxacin caplet following an overnight fast. Mean (standard deviation) pharmacokinetic parameters for amifloxacin were as follows: maximum observed concentration in plasma, 1.13 (0.48) and 1.95 (0.52) micrograms/ml; half-life, 5.37 (0.96) and 4.47 (0.87) h; total plasma clearance (unadjusted for fraction absorbed), 259 (53) and 199 (55) ml/h per kg; renal clearance, 113 (20) and 86 (26) ml/h per kg; Varea/F (Varea is volume of distribution; F is fraction absorbed), 2.05 (0.75) and 1.28 (0.39) liter/kg; and amifloxacin excreted in the urine, 42.5% (14.5%) and 42.8% (10.6%) for males and females, respectively. There were no statistically significant differences in pharmacokinetic parameters between sexes that could not be attributed to differences in body weight. Except for a modest 23% reduction in renal clearance and the suggestion of reduced bioavailability, mean values of pharmacokinetic parameters for elderly male subjects were similar to those previously determined for younger male volunteers. Therefore, a modification in amifloxacin dosage regimen based solely on age may not be necessary.

Randomized, controlled trial of a 10-day course of amifloxacin versus trimethoprim-sulfamethoxazole in the treatment of acute, uncomplicated urinary tract infection. Amifloxacin Multi-Center Trial Group.

We conducted a randomized controlled trial of orally administered amifloxacin versus trimethoprimsulfamethoxazole (TMP-SMX) as treatments of acute uncomplicated urinary tract infection in women. Amifloxacin at a dosage of 200 mg twice a day appeared as safe and effective as TMP-SMX, but amifloxacin at 400 mg twice a day tended to cause adverse events more frequently than did TMP-SMX.

Polyarteritis nodosa associated with ulcerative colitis.

Three months after colectomy for severe ulcerative colitis, an 18-year-old male presented with a multisystem illness characterized by fever, arthralgias, hypertension, and declining renal function. A diagnosis of polyarteritis nodosa was made histologically and confirmed angiographically. Clinical and pathological findings suggest that the patient had 2 separate illnesses. Potential implications of this unique association are briefly discussed.

The kidney in progressive systemic sclerosis: a prospective study.

Nine normotensive progressive systemic sclerosis patients with normal renal function underwent renal biopsy. Four specimens had prominent vascular abnormalities, two mild vascular abnormalities, and three were normal. Vascular deposits of C3 were present in all specimens. Plasma renin activity was elevated in three of four patients with prominent vascular abnormalities, one of two patients with mild vascular lesions, and none of two patients with normal biopsies. Plasma renin activity elevation in response to cold pressor testing in the four patients with prominent vascular lesions was 5.6 ng/ml.h compared to 0.55 ng/ml.h in those with mild or no lesions and 0.26 ng/ml.h in six control subjects. These data indicate that renal vascular lesions may be present in normotensive patients. Elevation or a substantial rise in plasma renin activity (1.8 ng/ml.h or greater) in response to cold pressor testing suggests preclinical renal involvement.