Tim Mant

DNA vaccination protects against an influenza challenge in a double-blind randomised placebo-controlled phase 1b clinical trial.

BACKGROUNDnWe have developed a Trivalent DNA vaccine for influenza consisting of three plasmids expressing haemagglutinin from different seasonal influenza virus strains delivered using PMED (particle mediated epidermal delivery). We set out to determine whether this vaccine (with and without a molecular adjuvant DNA Encoded Immunostimulator-Labile Toxin (DEI-LT)) could protect subjects from a controlled influenza virus challenge.nnnMETHODSnHealthy adult subjects were screened for susceptibility to infection with influenza A/H3 Panama/2007/99 then vaccinated with 4microg Trivalent influenza DNA vaccine, 2microg Trivalent influenza DNA vaccine plus DEI-LT or placebo. Safety and serological responses to vaccination were assessed and on Day 56 subjects were challenged with A/H3 Panama/2007/99 virus.nnnRESULTSnVaccination with 4microg Trivalent or 2microg Trivalent/DEI-LT was well tolerated and induced antibody responses to two of the three influenza virus vaccine strains. Post challenge, subjects in the 4microg Trivalent group (N=27) showed reductions in disease symptoms and viral shedding compared to placebo (N=27), with an overall vaccine efficacy of 41% (95% confidence interval (CI)=?1.5, 67.7) for Any illness with or without fever and 53% for Upper respiratory tract infection (95% CI=8.0, 77.7).nnnCONCLUSIONnIt was concluded that PMED vaccination with 4microg Trivalent influenza DNA vaccine was safe and elicited immunological responses that protected human subjects from influenza; this is the first report of protection of human subjects from disease by DNA vaccination.

Effect of oral posaconazole on the pharmacokinetics of cyclosporine and tacrolimus.

Study Objective. To analyze the pharmacokinetic properties of the immuno‐suppressants cyclosporine and tacrolimus when either is coadministered with oral posaconazole.

Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A

Current management of hemophilia A includes prophylaxis with factor VIII (FVIII) replacement every 2 to 3 days. BAX 855, Baxaltas pegylated full-length recombinant FVIII (rFVIII), was designed to increase half-life and, thus, reduce the frequency of prophylactic infusions while maintaining hemostatic efficacy. BAX 855 was evaluated in previously treated patients with severe hemophilia A who were aged 12 to 65 years. A phase 1 study compared the pharmacokinetic (PK) profile of BAX 855 with that of licensed rFVIII (Advate). In a pivotal study, the annualized bleeding rate (ABR), PK parameters, and efficacy of bleeding treatment were assessed. In the phase 1 study, the mean half-life (T1/2) and the mean residence time of BAX 855 compared with Advate were 1.4- to 1.5-fold higher. These results were confirmed in the pivotal study. The pivotal study met its primary endpoint: Prophylaxis with BAX 855 resulted in an ABR that was significantly lower than half the ABR of on-demand treatment (P < .0001). The median ABR was 1.9, and 39.6% of compliant subjects had no bleeding episodes during prophylaxis, whereas subjects treated on-demand had a median ABR of 41.5. BAX 855 was also efficacious for the treatment of bleeding episodes, with 95.9% of bleeding episodes treated with 1 to 2 infusions and 96.1% having efficacy ratings of excellent/good. No FVIII inhibitory antibodies or safety signals were identified. These studies provide evidence that BAX 855 was safe and efficacious for on-demand treatment and prophylaxis administered twice weekly in patients with hemophilia A. The trials were registered at www.clinicaltrials.gov as #NCT01736475 and #NCT01599819.

Evaluation of the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy men.

ABSTRACT Objective: Posaconazole is a triazole antifungal agent for the treatment and prophylaxis of invasive fungal infections. This non-randomized, open-label, parallel-group, multiple-dose, drug-interaction study was conducted to evaluate the pharmacokinetics of posaconazole and rifabutin following co-administration to healthy subjects. Methods: Subjects were assigned to treatment groups: Group 1 (posaconazole, 200‑mg tablet once daily for 10 days) or Group 2 (rifabutin, 300‑mg capsule once daily for 17 days [Days –7 to 10] co-administered with posaconazole, 200u2009mg tablet once daily for 10 days [Days 1–10]). Posaconazole was administered after rifabutin steady-state was reached. Individual plasma concentration–time data for posaconazole (Day 10, Groups 1 and 2) and rifabutin (Days –1 and 10, Group 2) were analyzed using model-independent methods. Results: Twenty-four men were enrolled in the study. All subjects in Group 1 completed the study; however, four subjects in Group 2 discontinued because of adverse events. When co-administered with rifabutin, posaconazole maximum plasma concentration (Cmax) and area under the plasma concentration–time curve over the dosing interval (AUC[τ]) were reduced 43% (u2009p = 0.005) and 49% (u2009p = 0.008), respectively. Conversely, rifabutin Cmax and AUC[τ] increased 31% (u2009p = 0.016) and 72% (u2009p < 0.001), respectively, when co-administered with posaconazole. Conclusion: Based on the reduced exposure to posaconazole observed in the limited number of subjects in this study and the increased risk for adverse events associated with elevated rifabutin concentrations, concomitant use of rifabutin and posaconazole should be avoided unless the benefit outweighs the risk.

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

Background Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. Methods In this phase 1 dose‐escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. Results No thromboembolic events were observed during the study. The most common adverse events were mild injection‐site reactions. Plasma levels of fitusiran increased in a dose‐dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose‐dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Conclusions Once‐monthly subcutaneous administration of fitusiran resulted in dose‐dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605.)

Pharmacokinetics and Tolerability of the Novel Oral Prostacyclin IP Receptor Agonist Selexipag.

PurposeTargeting the prostacyclin pathway is an effective treatment option for pulmonary arterial hypertension (PAH). Patients with PAH have a deficiency of prostacyclin and prostacyclin synthase. Selexipag is an orally available and selective prostacyclin receptor (IP receptor) agonist. Selexipag is hydrolyzed to its active metabolite ACT-333679, also a selective and potent agonist at the IP receptor.MethodsIn this phase I study the pharmacokinetics (PK) and tolerability of single and multiple ascending doses of selexipag were investigated in a double-blind, placebo-controlled manner in 64 healthy male subjects. An additional group of 12 subjects received an open-label dose of selexipag 400xa0μg in the fasted condition and after a meal.ResultsMaximum plasma concentrations of selexipag and ACT-333679 were reached within 2.5 and 4xa0h, respectively, with mean half-lives of 0.7–2.3 and 9.4–14.22xa0h. In the presence of food, exposure to ACT-333679 was decreased by 27xa0%. The most frequent adverse event was headache. Selexipag was well tolerated up to a single dose of 400xa0μg and multiple doses of 600xa0μg following an up-titration step. No relevant treatment-related effects on vital signs, clinical laboratory, and electrocardiogram (ECG) parameters were detected.ConclusionSelexipag exhibits a good tolerability profile and PK properties that warrant further investigation.

Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies.

AIMnFostamatinib (R788) is an orally dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of fostamatinib and R406.nnnMETHODnThree clinical studies were conducted in healthy subjects: (A) A single ascending dose study for R406 with doses ranging from 80-600u2009mg, (B) a single- and multiple-dose study of fostamatinib in aqueous suspension, with single doses ranging from 80-400u2009mg and multiple doses at 160u2009mg twice daily and (C) a study comparing suspension and tablet of fostamatinib, with the latter tested in both fed and fasted states.nnnRESULTSnThese studies demonstrated that when administered as a solution, R406 was rapidly absorbed. Increases in exposure were observed with doses up to 400u2009mg. A terminal half-life of 12-21u2009h was observed. Similar R406 exposure could be achieved with fostamatinib suspension and steady-state was achieved after 3-4 days following twice daily administration. Fostamatinib tablet and suspension exhibited similar R406 exposure. Upon co-administration with food, a delay in peak time and lower peak concentrations of R406 were observed but at the same time the overall exposure did not change.nnnCONCLUSIONnFostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK. Solid dosage forms of fostamatinib overcome the challenge of low aqueous solubility of R406. The PK profile of R406 could potentially allow once daily or twice daily oral administration of fostamatinib.

Maximum tolerated dose and pharmacodynamics of eptastigmine in elderly healthy volunteers

Eptastigmine is a new acetylcholinesterase (AChE) inhibitor currently under development for the symptomatic treatment of Alzheimer disease. This study was conducted to establish the maximum tolerated dose and the pharmacodynamics of eptastigmine in nine healthy elderly volunteers. Subjects received single oral doses of 8 mg, 20 mg, 32 mg, and 40 mg eptastigmine and placebo according to a double‐blind, randomized, rising‐dose, five‐way crossover design. Adverse events, blood pressure, heart rate, body temperature, forced expiratory volume, salivary flow, and pupilar activity were closely monitored during treatment. Pharmacodynamic activity of eptastigmine was evaluated with an assay of AChE activity in red blood cells. Eptastigmine doses of 8 mg, 20 mg, and 32 mg were well tolerated. Two of four subjects receiving the 40‐mg dose developed profound AChE inhibition (58–59%) and reported severe adverse events (nausea, vomiting, syncope, and bradycardia), precluding further administration in the remaining subjects. Eptastigmine administration produced a weak effect on supine heart rate, body temperature, and pupil diameter. There were no effects on blood pressure, forced expiratory volume, salivary flow, and near point of focus. Acetylcholinesterase activity was inhibited in a dose‐related fashion according to a sigmoidal (logistic) function. The mean (± SEM) maximum inhibition of AChE activity (Imax) was 14.5 ± 3.3%, 20.4 ± 2.3%, 28.7 ± 2.9%, 45.2 ± 1.3% and 53.6 ± 2.9% after placebo, 8 mg, 20 mg, 32 mg, and 40 mg of eptastigmine, respectively. The theoretical maximum response (Emax) was 72.9%, and the dose that produced half of the maximum response (ED50) was 29.5 mg. At 24 hours, residual AChE inhibition ranged from 9% to 15%, with a half‐life of recovery of the enzyme of approximately 10 hours. The maximum tolerated dose of eptastigmine after single‐dose oral administration in healthy elderly subjects is 32 mg. Single oral doses of eptastigmine produce sustained, dose‐related inhibition of AChE activity. Adverse events are related to the degree of AChE inhibition.

Albuterol HFA is as effective as albuterol CFC in preventing exercise-induced bronchoconstriction

BACKGROUNDnSecondary to the phase-out of chlorofluorocarbons (CFCs), the albuterol (Ventolin, GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom) pressurized metered-dose inhaler (MDI) has been formulated in a non-ozone-depleting propellant, hydrofluoroalkane (HFA) 134a.nnnOBJECTIVEnTo compare the efficacy of albuterol HFA to albuterol CFC and placebo HFA in protecting patients from exercise-induced bronchospasm (EIB).nnnMETHODSnRandomized, double-blind, placebo-controlled, three-way crossover study in patients with documented EIB. Patients (n = 24) aged 18 to 45 years old received albuterol HFA or albuterol CFC, (total dose of 180 microg ex-actuator), or placebo HFA via an MDI, 30 minutes before a standardized exercise challenge. Serial forced expiratory volume in 1 second (FEV1) measurements were made 5 minutes before exercise and 5, 10, 15, 20, 25, 30, and 60 minutes postexercise. The primary outcome measure was the maximum percentage fall in FEV1 over the 60 minutes after exercise.nnnRESULTSnThe adjusted mean maximum percentage falls in FEV1 postexercise for albuterol HFA and CFC groups were 15.4% and 14.9%, respectively. The two formulations were comparable with a treatment difference of -0.5% (P = 0.848; 95% confidence interval, -5.3 to 4.4%). When compared with the fall in FEV1 for placebo (33.7%), both active treatments demonstrated a significantly smaller fall in FEV1 postexercise (P < 0.001). Safety profiles were similar among the three treatment groups.nnnCONCLUSIONSnThe results provide assurance to prescribers that the formulation of albuterol in the non-ozone-depleting propellant HFA 134a has not affected its efficacy in the treatment of EIB in asthmatic patients. Single doses of albuterol HFA and CFC from an MDI are comparable in terms of efficacy and safety on a microgram per microgram basis.

Ipecacuanha‐induced emesis: A human model for testing antiemetic drug activity

In a double‐blind, randomized, parallel‐group study, five groups of 10 healthy men received single 5‐minute infusions of 8 mg, 4 mg, 1 mg, 0.25 mg, or 0.1 mg ondansetron (as hydrochloride dihydrate) 30 minutes before oral administration of 30 ml syrup of ipecacuanha. Emetic episodes and nausea (100 mm visual analog scale) were assessed over an 8‐hour period. There were no emetic episodes after 8 or 4 mg ondansetron. Seven, nine, and 10 subjects vomited after 1 mg, 0.25 mg and 0.1 mg ondansetron, respectively, with median times to onset of 62, 31, and 37 minutes. Median peak nausea scores were 0 mm for both 8 and 4 mg ondansetron and 30, 53, and 26 mm for 1, 0.25, and 0.1 mg ondansetron. Adverse events were mild. This model showed a close correlation with clinically effective doses of ondansetron. It may be successfully and safely used to assess the antiemetic potential of 5‐HT3‐receptor antagonists in healthy subjects.