Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant,in patients with severe hemophilia

Essentials

• Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII.
• A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia.
• MarzAA was safe and tolerated at intravenous doses up to 30 μg kg^?1
• Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX.

Summary

Background

Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia.

Objectives

To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non‐bleeding patients with congenital hemophilia A or B with or without inhibitors.

Methods

This international, phase 1, open‐label study (NCT01439971) enrolled males aged 18–64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single‐dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 μg kg^?1). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD.

Results

Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose‐limiting toxicity. No treatment‐emergent severe or serious adverse events occurred. MarzAA showed linear dose–response PK across the 4.5–30 μg kg^?1 dose range, with a terminal half‐life of ? 3.5 h. Dose‐dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses.

Conclusions

MarzAA was tolerated at doses up to 30 μg kg^?1. The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.

     

Recombinant factor VIIa analog (vatreptacog alfa [activated]) for treatment of joint bleeds in hemophilia patients with inhibitors: a randomized controlled trial

Summary. Background: A recombinant factor VIIa analog (NN1731; vatreptacog alfa [activated]) was developed to provide safe, rapid and sustained resolution of bleeds in patients with hemophilia and inhibitors. Patients/Methods: This global, prospective, randomized, double‐blinded, active‐controlled, dose‐escalation trial evaluated and compared one to three doses of vatreptacog alfa at 5, 10, 20, 40, and 80 μg kg^?1 with one to three doses of recombinant FVIIa (rFVIIa) at 90 μg kg^?1 in the treatment of acute joint bleeds in hemophilia patients with inhibitors. The primary endpoint comprised adverse events; secondary endpoints were evaluations of immunogenicity, pharmacokinetics, and efficacy. Results and Conclusions: Overall, 96 joint bleeds in 51 patients (> 12 years of age) were dosed. Vatreptacog alfa was well tolerated, with a low frequency of adverse events. No immunogenic or thrombotic events related to vatreptacog alfa were reported. A high efficacy rate of vatreptacog alfa in controlling acute joint bleeds was observed; 98% of bleeds were controlled within 9 h of the initial dose in a combined evaluation of 20–80 μg kg^?1 vatreptacog alfa. The efficacy rate observed for rFVIIa (90%) is consistent with data from published clinical trials. The trial was not powered to compare efficacy, and further trials are needed to investigate the efficacy of vatreptacog alfa as compared with that of rFVIIa. The trial was registered at ClinicalTrials.gov (Registration Number: NCT00486278).     

Pharmacokinetics,safety, and tolerability of sulcardine sulfate: an open‐label,single‐dose,randomized study in healthy Chinese subjects

Sulcardine sulfate (Sul) is a novel anti‐arrhythmic agent as a potential treatment for atrial fibrillation and ventricular arrhythmias. This study was conducted to investigate the pharmacokinetic profile, safety, and tolerability of Sul in healthy Chinese subjects. In this open‐label, single‐dose, randomized study, 10 healthy subjects were assigned to receive Sul doses of 200, 400, and 800 mg under fasting conditions (Cohorts A, B, and C, respectively) or 400 mg under fed conditions (Cohort D). The study incorporated a crossover design, separated by a seven‐day washout period. Blood samples were collected before treatment and at successive time intervals up to 48 h after treatment. Sul concentrations in plasma samples were determined using a validated LC‐MS/MS method. Tolerability was determined by clinical evaluation and adverse event (AE) monitoring. Pharmacokinetic results demonstrated that C_max and AUC_(0–t) of Sul increased with an increasing dose. The mean t_1/2 values for Cohorts A, B, and C were 16.85, 17.66, and 11.87 h, respectively. No statistically significant differences were observed between men and women for the main pharmacokinetic parameters, with the exception of t_1/2 in Cohorts B and C. No significant differences were observed in the absorption and bioavailability of Sul between the fed and fasted states (P > 0.05). Four subjects reported mild AEs during the study. No serious AEs were reported. Sul was shown to be safe and well tolerated in healthy Chinese subjects. Pharmacokinetics studies demonstrated that Sul has adequate oral absorption and bioavailability properties.     

Bortezomib delays the onset of factor VIII inhibitors in experimental hemophilia A,but fails to eliminate established anti‐factor VIII IgG‐producing cells

Summary. Background: Replacement therapy with exogenous factor VIII to treat hemorrhages induces inhibitory anti‐FVIII antibodies in up to 30% of patients with hemophilia A. Current approaches to eradicate FVIII inhibitors using high‐dose FVIII injection protocols (immune tolerance induction) or anti‐CD20 depleting antibodies (Rituximab) demonstrate limited efficacy; they are extremely expensive and/or require stringent compliance from the patients. Objectives: To investigate whether the proteasome inhibitor bortezomib, which depletes plasmocytes, modulates the anti‐FVIII immune response in FVIII‐deficient mice. Methods and results: Preventive 4‐week treatment of naïve mice with bortezomib at the time of FVIII administration delayed the development of inhibitory anti‐FVIII IgG, and depleted plasma cells as well as different lymphoid cell subsets. Conversely, curative treatment of inhibitor‐positive mice for 10 weeks, along with FVIII administration, failed to eradicate FVIII inhibitors to extents that would be clinically relevant if achieved in patients. Accordingly, bortezomib did not eradicate anti‐FVIII IgG‐secreting plasmocytes that had homed to survival niches in the bone marrow, despite significant elimination of total plasma cells. Conclusions: The data suggest that strategies for the efficient reduction of anti‐FVIII IgG titers in patients with hemophilia A should rely on competition for survival niches for plasmocytes in the bone marrow rather than the mere use of proteasome inhibitors.     

A phase I,randomized, double‐blind,placebo‐controlled,single‐ and multiple dose escalation study evaluating the safety,pharmacokinetics and pharmacodynamics of VX‐128, a highly selective Nav1.8 inhibitor,in healthy adults

Selective inhibition of certain voltage‐gated sodium channels (Na_vs), such as Na_v1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX‐128 is a highly potent and selective Na_v1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX‐128 in healthy subjects in a single‐ and multiple‐ascending dose (MAD) first‐in‐human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX‐128 up to 300 mg were well‐tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX‐128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX‐128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor‐ and pressure pain, which was dose‐dependent for the latter. VX‐128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half‐life of ~80 h at 10 mg q.d., and approximately two‐fold accumulation ratio after 10 and 30 mg q.d. Although VX‐128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Na_v1.8 inhibitors as pain treatments.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selective sodium channel (Na_v) inhibitors have been proposed as an alternative to opioids for pain management. Their potential, however, has yet to be confirmed, as none of the multiple selective Na_v inhibitors that have been investigated for pain management has reached the market.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We investigated the safety, tolerability, and initial analgesic effects of VX‐128, a novel and highly selective Na_v1.8 inhibitor, in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This is the first study to describe clinical data obtained on the highly selective Na_v1.8 inhibitor VX‐128, and the first to report analgesic effects of this selective Na_v inhibitor in humans. VX‐128 administered as a single dose was well‐tolerated, but dose‐limiting skin rashes occurred after multiple doses resulting in a premature study halt. Although the study had a parallel design and was not necessarily powered to detect pharmacodynamic effects, nociceptive test results suggest that VX‐128 leads to dose‐dependent analgesic effects.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our findings substantiate research that is performed on evaluating selective Na_v1.8 inhibitors as treatment for pain, and suggests that the cold pressor‐ and pressure pain models are suitable to evaluate selective Na_v1.8 inhibitors.     

Lack of efficacy of alpha‐lipoic acid in burning mouth syndrome: A double‐blind,randomized, placebo‐controlled study

Background: A systematic review from the Cochrane Collaboration stated that alpha‐lipoic acid (ALA) may help in the management of burning mouth syndrome (BMS). Because all of the data on ALA came from a single group, it has been stressed that its effectiveness should be reproduced in other populations. Aim: A double‐blind, randomized, placebo‐controlled study, including two test groups (Group A and Group B) and one control group (Group C), was carried out to evaluate the efficacy of systemic ALA (400mg) and ALA (400mg) plus vitamins in the treatment of BMS. Methods: Sixty‐six patients (54 females and 12 males) were included in an 8‐week trial. Symptoms were evaluated by using a visual analogue scale (VAS) and the McGill Pain Questionnaire (MPQ) at 0, 2, 4, 8 and 16 weeks. Results: Fifty‐two patients (43 females and 9 males, aged 67.3±11.9 years) completed the study. All three groups had significant reductions in the VAS score and in the mixed affective/evaluative subscale of the MPQ; the responders’ rate (at least 50% improvement in the VAS score) was about 30%. No significant differences were observed among the groups either in the response rate or in the mean latency of the therapeutic effect. Conclusions: The fairly high placebo effect observed is very similar to data obtained from patients affected by atypical facial pain. This study failed to support a role for ALA in the treatment of BMS, and further investigations are needed to identify the cause of BMS in order to develop efficacious therapies.