Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: Effects on weight loss and safety in adults with overweight or obesity.

OBJECTIVE: Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. METHODS: Our focus was a 12-week, multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N = 99) received NN1177 (on an escalating dose regimen of 200, 600, 1300, 1900, 2800, 4200 and 6000 µg) or placebo. Two other trials also contributed to the findings reported in this article: a first human dose (FHD)/single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N = 49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1100 µg) or placebo, and a drug-drug interaction, open-label, single-sequence trial in which adults (N = 45) received a 4200-µg dose of NN1177, following administration of a Cooperstown 5 + 1 index cocktail. Safety, tolerability, pharmacokinetic and pharmacodynamic endpoints were assessed. RESULTS: For the FHD/SAD and MAD trials, baseline characteristics were generally balanced across treatment cohorts. The geometric mean half-life of NN1177 at steady state was estimated at between 77 and 111 h, and clinically relevant weight loss was achieved (up to 12.6% at week 12; 4200 µg in the MAD trial). Although NN1177 appeared tolerable across trials, several unexpected treatment-related safety signals were observed; increased heart rate, decreased reticulocyte count, increased markers of inflammation (fibrinogen and C-reactive protein), increased aspartate and alanine aminotransferase, impaired glucose tolerance and reduced blood levels of some amino acids. CONCLUSION: Although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, the observed safety signals precluded further clinical development.

AV-101, a novel inhaled dry-powder formulation of imatinib, in healthy adult participants: a phase 1 single and multiple ascending dose study.

Background: Oral imatinib has been shown to be effective, but poorly tolerated, in patients with advanced pulmonary arterial hypertension (PAH). To maintain efficacy while improving tolerability, AV-101, a dry powder inhaled formulation of imatinib, was developed to deliver imatinib directly to the lungs. Methods: This phase 1, placebo-controlled, randomised single ascending dose (SAD) and multiple ascending dose (MAD) study evaluated the safety/tolerability and pharmacokinetics of AV-101 in healthy adults. The SAD study included five AV-101 cohorts (1 mg, 3 mg, 10 mg, 30 mg, 90 mg) and placebo, and a single-dose oral imatinib 400-mg cohort. The MAD study included three AV-101 cohorts (10 mg, 30 mg, 90 mg) and placebo; dosing occurred twice daily for 7 days. Results: 82 participants (SAD n=48, MAD n=34) were enrolled. For the SAD study, peak plasma concentrations of imatinib occurred within 3 h of dosing with lower systemic exposure compared to oral imatinib (p<0.001). For the MAD study, systemic exposure of imatinib was higher after multiple doses of AV-101 compared to a single dose, but steady-state plasma concentrations were lower for the highest AV-101 cohort (90 mg) compared to simulated steady-state oral imatinib at day 7 (p=0.0002). Across AV-101 MAD dose cohorts, the most common treatment-emergent adverse events were cough (n=7, 27%) and headache (n=4, 15%). Conclusions: AV-101 was well tolerated in healthy adults, and targeted doses of AV-101 significantly reduced the systemic exposure of imatinib compared with oral imatinib. An ongoing phase 2b/phase 3 study (IMPAHCT; clinicaltrials.gov identifier NCT05036135) will evaluate the safety/tolerability and clinical benefit of AV-101 for PAH.

Pharmacokinetics and Safety of Vibegron 75 mg Administered as an Intact or Crushed Tablet in Healthy Adults.

Oral pharmacotherapy for overactive bladder, a condition that increases with age, includes anticholinergics and ß3 -adrenergic receptor agonists. Older adults, including those with dysphagia, may have difficulty swallowing tablets. In this phase 1 study in healthy adults, we assessed the pharmacokinetic profile of the ß3 -adrenergic receptor agonist vibegron administered as a single 75-mg dose as an intact tablet versus crushed and mixed with applesauce. Additional end points included safety (assessed by adverse events), perception of taste (assessed via questionnaire), and stability over 4 hours after crushing and mixing in applesauce (assessed by chromatography). Overall, 30 participants were randomized, and 29 were included in the pharmacokinetic analysis. Crushing a vibegron tablet and mixing with applesauce decreased vibegron maximum observed plasma concentration and area under the plasma concentration-time curve from time 0 to infinity by ≈30% and ≈10%, respectively; however, these decreases were not considered clinically significant. Treatment-emergent adverse events were reported in 16 (53.3%) participants. Approximately half of participants reported the vibegron and applesauce mixture tasted as expected; of those reporting the taste was different than expected, 50% reported the taste as bitter. The mixture was stable for 4 hours in applesauce. The results of this study showed that crushing and administering vibegron with applesauce may be an appropriate option for patients with overactive bladder and swallowing difficulties.

Anti-KIT monoclonal antibody CDX-0159 induces profound and durable mast cell suppression in a healthy volunteer study.

BACKGROUND: Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC-targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX-0159, an anti-KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers. METHODS: CDX-0159-mediated KIT inhibition was tested in vitro using KIT-expressing immortalized cells and primary human mast cells. CDX-0159 safety and pharmacokinetics were evaluated in a 13-week good laboratory practice (GLP)-compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double-blinded placebo-controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX-0159. RESULTS: CDX-0159 inhibits SCF-dependent KIT activation in vitro. Fc modifications in CDX-0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX-0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX-0159 led to dose-dependent, profound suppression of plasma tryptase, a MC-specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. CONCLUSION: CDX-0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell-driven disorders.

Transition from Syringe to Autoinjector Based on Bridging Pharmacokinetics and Pharmacodynamics of the P2Y12 Receptor Antagonist Selatogrel in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Selatogrel is a potent, reversible, and selective antagonist of the platelet P2Y12 receptor currently developed for the treatment of acute myocardial infarction (AMI). In the completed Phase I/II studies, selatogrel was subcutaneously (s.c.) administered as a lyophilizate-based formulation by syringe by a healthcare professional. In the Phase III study, selatogrel will be self-administered s.c. as a liquid formulation with an autoinjector at the onset of AMI symptoms to shorten treatment delay. This clinical bridging study compared the pharmacokinetics (PK) of selatogrel between the different formulations. METHODS: This was a single-center, randomized, open-label, three-period, cross-over Phase I study in 24 healthy subjects. In each period, a single subcutaneous dose of 16 mg selatogrel was administered as (1) a Phase III liquid formulation by autoinjector (Treatment A), (2) a Phase III liquid formulation by prefilled syringe (Treatment B), or (3) a Phase I/II reconstituted lyophilizate-based formulation by syringe (Treatment C). PK parameters including area under the plasma concentration-time curve from zero to infinity (AUC0-∞), maximum plasma concentration (Cmax), time to reach Cmax(tmax), and terminal half-life (t1/2) were determined using noncompartmental analysis. Pharmacodynamic (PD) parameters were estimated using PK/PD modeling, including the time of first occurrence of inhibition of platelet aggregation (IPA) ≥ 80% (tonset), duration of IPA above 80% (tduration), and responder rate defined as the percentage of subjects with tonset ≤ 30 min and tduration ≥ 3 h. Safety and tolerability were also assessed. RESULTS: Comparing Treatment A to Treatment C, the exposure (AUC0-∞) was bioequivalent with a geometric mean ratio (GMR) (90% confidence interval) of 0.95 (0.92-0.97) within the bioequivalence range (0.80-1.25). Absorption following Treatment A was slightly slower with a tmax occurring approximately 30 min later and a 20% lower Cmax. The autoinjector itself had no impact on the PK of selatogrel, as similar values of Cmax and AUC0-∞ were determined after administration as a Phase III liquid formulation by autoinjector or by prefilled syringe (i.e., GMR [90% confidence interval] of 1.06 [0.97-1.15] and 0.99 [0.96-1.03] for Cmax and AUC0-∞, respectively). PK/PD modeling predicted that the median tonset will occur slightly later for Treatment A (7.2 min) compared to Treatment C (4.2  min), while no relevant differences in tduration and responder rate were estimated between the two treatments. Selatogrel was safe and well tolerated following all three treatments. CONCLUSIONS: PK and simulated PD effects of selatogrel were similar across treatments. CLINICAL TRIAL REGISTRATION: NCT04557280.

Thorough QT Study To Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for Gonorrhea, on Cardiac Repolarization in Healthy Adults.

Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae. To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin at 2 g (therapeutic), zoliflodacin at 4 g (supratherapeutic), placebo, and moxifloxacin at 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia's formula (QTcF). At each time point up to 24 h after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1 to 4 h after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, electrocardiogram (ECG) morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well tolerated. These findings suggest that zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT03613649.).

A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Oral Doses of V-7404 in Healthy Adult Volunteers.

V-7404, a direct-acting enterovirus (EV) 3C protease inhibitor, is being developed as a treatment option for serious EV infections, including infections in immunodeficient people excreting vaccine-derived polioviruses. V-7404 may be combined with pocapavir (V-073), a capsid inhibitor, to treat these infections. A phase 1 single ascending dose (SAD; n = 36) and multiple ascending dose (MAD; n = 40) study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of V-7404 in healthy adult volunteers following oral doses starting at 200 mg and escalating to 2,000 mg once daily (QD) and 2,000 mg twice daily (BID). Adverse events (AEs), vital signs, electrocardiographic findings, physical examinations, clinical laboratory values, and PK of blood samples were assessed. No notable differences in demographic and baseline characteristics were observed across the dose cohorts. A total of 35/36 participants (97.2%) completed the SAD study (1 withdrew in the placebo group), and 37/41 participants (90.2%) completed the MAD study (1 withdrew from the 2,000 mg QD and 3 withdrew from the 2,000 mg BID cohorts). No serious AEs or deaths were reported. Treatment-emergent AEs were mild or moderate in severity. Oral doses of V-7404 in all cohorts were readily absorbed and showed no significant accumulation. PK exposure increased in an approximately dose-proportional manner and appeared to be independent of time. Overall, V-7404 was well tolerated and exhibited an acceptable safety and PK profile, supporting further clinical investigation of V-7404 for the treatment of serious EV infections.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial.

BACKGROUND: Cagrilintide, a long-acting amylin analogue, and semaglutide 2·4 mg, a glucagon-like peptide-1 analogue, are both being investigated as options for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of this drug combination. METHODS: In this randomised, placebo-controlled, multiple-ascending dose, phase 1b trial, individuals aged 18-55 years with a body-mass index 27·0-39·9 kg/m2 and who were otherwise healthy were recruited from a single centre in the USA. The trial included six sequential overlapping cohorts, and in each cohort eligible participants were randomly assigned (3:1) to once-weekly subcutaneous cagrilintide (0·16, 0·30, 0·60, 1·2, 2·4, or 4·5 mg) or matched placebo, in combination with once-weekly subcutaneous semaglutide 2·4 mg, without lifestyle interventions. In each cohort, the doses of cagrilintide and semaglutide were co-escalated in 4-week intervals to the desired dose over 16 weeks, participants were treated at the target dose for 4 weeks, and then followed up for 5 weeks. Participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was number of treatment-emergent adverse events from baseline to end of follow-up. Secondary pharmacokinetic endpoints assessed from day of last dose (week 19) to end of treatment (week 20) were area under the plasma concentration-time curve from 0 to 168 h (AUC0-168 h) and maximum concentration [Cmax] of cagrilintide and semaglutide; exploratory pharmacokinetic endpoints were half-life, time to Cmax [tmax], plasma clearance, and volume of distribution of cagrilintide and semaglutide; and exploratory pharmacodynamic endpoints were changes in bodyweight, glycaemic parameters, and hormones. Safety, pharmacokinetic, and pharmacodynamic endpoints were assessed in all participants who were exposed to at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03600480, and is now complete. FINDINGS: Between July 25, 2018, and Dec 17, 2019, 285 individuals were screened and 96 were randomly assigned to cagrilintide (0·16-2·4 mg group n=12; 4·5 mg group n=11) or placebo (n=24), in combination with semaglutide 2·4 mg, of whom 95 were exposed to treatment (one patient in 0·60 mg cagrilintide group was not exposed) and included in the safety and full analysis datasets. The mean age was 40·6 years (SD 9·2), 56 (59%) of 95 participants were men and 51 (54%) were Black or African American. Of 566 adverse events reported in 92 participants (69 [97%] of 71 participants assigned to 0·16-4·5 mg cagrilintide and 23 [96%] of 24 assigned to placebo), 207 (37%) were gastrointestinal disorders. Most adverse events were mild to moderate in severity and the proportion of participants with one or more adverse event was similar across treatment groups. Exposure was proportional to cagrilintide dose and did not affect semaglutide exposure or elimination. AUC0-168 h ranged from 926 nmol × h/L to 24 271 nmol × h/L, and Cmax ranged from 6·14 nmol/L to 170 nmol/L with cagrilintide 0·16-4·5 mg. AUC0-168 h ranged from 12 757 nmol × h/L to 15 305 nmol × h/L, and Cmax ranged from 96·4 nmol/L to 120 nmol/L with semaglutide 2·4 mg. Cagrilintide 0·16-4·5 mg had a half-life of 159-195 h, with a median tmax of 24-72 h. Semaglutide 2·4 mg had a half-life of 145-165 h, with a median tmax of 12-24 h. Plasma clearance and volume of distribution for both cagrilintide and semaglutide were similar across treatment groups. At week 20, mean percentage bodyweight reductions were greater with cagrilintide 1·2 and 2·4 mg than with placebo (15·7% [SE 1·6] for cagrilintide 1·2 mg and 17·1% [1·5] for cagrilintide 2·4 mg vs 9·8% [1·2] for pooled placebo cohorts 1-5; estimated treatment difference of -6·0% [95% CI -9·9 to -2·0] for cagrilintide 1·2 mg and -7·4% [-11·2 to -3·5] for cagrilintide 2·4 mg vs pooled placebo), and with cagrilintide 4·5 mg than with matched placebo (15·4% [1·3] vs 8·0% [2·2]; estimated treatment difference -7·4% [-12·8 to -2·1]), all in combination with semaglutide 2·4 mg. Glycaemic parameters improved in all treatment groups, independently of cagrilintide dose. Changes in hormones were similar across treatment groups. INTERPRETATION: Concomitant treatment with cagrilintide and semaglutide 2·4 mg was well tolerated with an acceptable safety profile. Future larger and longer trials are needed to fully assess the efficacy and safety of this treatment combination. FUNDING: Novo Nordisk A/S.

A randomized, double-blind, placebo-controlled, single and multiple ascending dose Phase 1 study to determine the safety, pharmacokinetics and food and faecal microbiome effects of ibezapolstat administered orally to healthy subjects.

BACKGROUND: Clostridioides difficile infection is the most common cause of healthcare-associated infections in the USA, with limited treatment options. Ibezapolstat is a novel DNA polymerase IIIC inhibitor with in vitro activity against C. difficile. OBJECTIVES AND METHODS: Randomized, double-blind, placebo-controlled study to assess the safety, tolerability and pharmacokinetics of ibezapolstat in healthy volunteers. Microbiome changes associated with ibezapolstat were compared with vancomycin over a 10 day course using shotgun metagenomics. RESULTS: A total of 62 subjects aged 31 ± 7 years (45% female; average BMI: 25 ± 3 kg/m2) were randomized. Ibezapolstat was well tolerated with a safety signal similar to placebo. Ibezapolstat had minimal systemic absorption with the majority of plasma concentrations less than 1 µg/mL. In the multiday, ascending dose study, ibezapolstat concentrations of 2000 µg/g of stool were observed by Day 2 and for the remainder of the dosing time period. In the multiday, multiple-dose arm, baseline microbiota was comparable between subjects that received ibezapolstat compared with vancomycin. At Day 10 of dosing, differential abundance analysis and ß-diversity demonstrated a distinct difference between the microbiome in subjects given vancomycin compared with either dose of ibezapolstat (P = 0.006). α-Diversity changes were characterized as an increase in the Actinobacteria phylum in subjects that received ibezapolstat and an increase in Proteobacteria in subjects given vancomycin. CONCLUSIONS: Ibezapolstat was shown to be safe and well tolerated, with minimal systemic exposure, high stool concentrations and a distinct microbiome profile compared with oral vancomycin. These results support further clinical development of ibezapolstat for patients with C. difficile infection.

Polyvalent Human Immune Globulin: A Prospective, Open-Label Study Assessing Anti-Hepatitis A Virus (HAV) Antibody Levels, Pharmacokinetics, and Safety in HAV-Seronegative Healthy Subjects.

BACKGROUND: Analytical data suggesting that immunoglobulin given intramuscularly (IGIM) may have reduced protection against hepatitis A virus (HAV) infection led to an update in the recommended IGIM dose (0.2 ml/kg). METHODS: This prospective, open-label, single-arm clinical study evaluated whether a single 0.2 ml/kg dose of IGIM provided protective levels of anti-HAV antibodies (≥ 10 mIU/ml for up to 60 days) in HAV-seronegative healthy adults. RESULTS: Of the 28 subjects enrolled and dosed, 26 (93%) completed the study. Mean uncorrected anti-HAV antibody titers peaked at 109 mIU/ml on day 5 and stayed above 10 mIU/ml through day 60 (N = 26). The mean uncorrected anti-HAV antibody titers had a median Tmax of 95.33 h, a mean Cmax of 118 mIU/ml, and a mean observed Thalf of 63.3 days; baseline-corrected titers had a median Tmax of 95.33 h, a mean Cmax of 114 mIU/ml, and a mean observed Thalf of 47.1 days (N = 27). All subjects (28/28) experienced at least 1 treatment-emergent adverse event (TEAE), with a total of 83 TEAEs reported; none was serious, and 96% (80/83) resolved without sequelae. Most (63%) events judged definitely and possibly related to study treatment involved localized pain due to intramuscular injections. There were no serious adverse events and no deaths or discontinuations due to TEAEs. CONCLUSIONS: A single 0.2 ml/kg dose of IGIM provided protective anti-HAV levels for at least 60 days, with acceptable safety and tolerability profiles in healthy subjects. Uncorrected and baseline-corrected pharmacokinetic findings were similar and consistent with the corresponding sampling points in previous research. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT03351933.

Effect of Food on the Pharmacokinetics of Quizartinib.

Quizartinib is an oral, highly potent, and selective type II FMS-like tyrosine kinase 3 inhibitor in development for acute myeloid leukemia. This parallel-group study evaluated potential food effects on quizartinib absorption in healthy subjects who received a single 30-mg dose after overnight fasting (n = 34) or a high-fat, high-calorie meal (n = 30). Blood samples were collected through 504 hours after dosing, and pharmacokinetic parameters calculated were maximum observed concentration (Cmax ) and area under plasma concentration-time curve from time 0 to last quantifiable concentration (AUClast ) and from time 0 to infinity (AUCinf ). Mean quizartinib pharmacokinetic profiles were similar under fasted and fed conditions. The geometric least squares means ratios (%) for fed/fasted and associated 90% confidence intervals (CIs) for Cmax , AUClast , and AUCinf were 91.58 (82.15-102.08), 105.39 (90.79-122.35), and 108.39 (91.54-128.34), respectively. The 90%CI for the ratio fell within the 80% to 125% limits for Cmax and AUClast , with 90%CI for AUCinf slightly outside the limits (ie, 128%). Food delayed quizartinib time to Cmax by 2 hours. All adverse events were either mild or moderate; no discontinuations due to adverse events occurred. Based on these results, quizartinib can be administered without regard to food.

Persistence of Immune Responses Through 36 Months in Healthy Adults After Vaccination With a Novel Staphylococcus aureus 4-Antigen Vaccine (SA4Ag).

BACKGROUND: Staphylococcus aureus causes serious health care- and community-associated disease, requiring improved preventive measures such as vaccines. The investigational S. aureus 4-antigen vaccine (SA4Ag), comprising capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to CRM197, recombinant mutant clumping factor A (rmClfA), and recombinant manganese transporter protein C (rP305A or rMntC), was well tolerated, inducing robust functional immune responses to all 4 antigens through 12 months postvaccination. This is a serological extension study through 36 months postvaccination. METHODS: In 2 previous studies, healthy adults received SA4Ag, SA3Ag (without rMntC), or placebo; serology was also assessed at ~24 and ~36 months postvaccination. Functional immune responses (antibody responses that facilitate killing of S. aureus or neutralize S. aureus virulence mechanisms) were assessed with opsonophagocytic activity killing assays (CP5 or CP8) and a fibrinogen-binding inhibition assay (ClfA). A competitive Luminex immunoassay assessed ClfA and rMntC responses. Adverse events within 48 hours of blood draw were recorded. RESULTS: Four hundred forty subjects (18-64 years old, 255; 65-85 years old, 185) were enrolled. At 24 and 36 months postvaccination, subjects receiving SA4Ag had substantially higher geometric mean titers (GMTs) for CP5, CP8, and ClfA vs baseline; geometric mean fold rises (GMFRs) from baseline to month 36 were 2.7-8.1. For rMntC, 36-month GMTs declined from peak levels but remained above baseline for all SA4Ag groups; GMFRs from baseline to month 36 were 1.8 and 1.5 in the younger and older cohorts, respectively. CONCLUSIONS: Persistent functional immune responses to S. aureus antigens were observed through 36 months in healthy adults. CLINICALTRIALSGOV: NCT01643941 and NCT01364571.

Effects of CYP3A inhibitors on the pharmacokinetics of quizartinib, a potent and selective FLT3 inhibitor, and its active metabolite.

AIMS: Quizartinib is an oral, highly potent and selective next-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor under investigation in patients with FLT3-internal tandem duplication-mutated acute myeloid leukaemia. This drug-drug interaction study assessed the pharmacokinetics (PK) of quizartinib when coadministered with strong or moderate cytochrome P450 3A (CYP3A) inhibitors. METHODS: In this parallel-group study, subjects were randomised to receive: (i) quizartinib + ketoconazole; (ii) quizartinib + fluconazole; or (iii) quizartinib alone. On Days 1-28, subjects received ketoconazole 200 mg or fluconazole 200 mg twice daily, and on Day 8, all subjects received a single 30-mg quizartinib dose. Blood samples were collected for PK analyses, steady-state PK parameters were simulated by superpositioning, and safety was assessed. RESULTS: Ninety-three healthy subjects were randomised; 86 completed the study. When administered with ketoconazole, geometric mean ratios (90% confidence interval) for quizartinib maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity were 117% (105%, 130%) and 194% (169%, 223%), respectively, vs quizartinib alone. Steady-state PK simulation demonstrated ~2-fold increase of both steady-state Cmax and AUC from time 0 to the end of the dosing interval when quizartinib was administered with ketoconazole due to accumulation of quizartinib at steady state. When administered with fluconazole, geometric mean ratios (90% confidence interval) for quizartinib Cmax and AUC from time 0 extrapolated to infinity were 111% (100%, 124%) and 120% (104%, 138%), respectively, vs quizartinib alone. Overall, 5.4% of subjects experienced quizartinib-related adverse events; no serious adverse events or deaths occurred. CONCLUSIONS: These results suggest reducing the dose of quizartinib when coadministered with a strong CYP3A inhibitor, but not with a moderate or weak CYP3A inhibitor. This dose reduction was implemented in phase 3 evaluation of quizartinib.

A First-in-Human Study To Assess the Safety and Pharmacokinetics of LYS228, a Novel Intravenous Monobactam Antibiotic in Healthy Volunteers.

Infections caused by antibiotic-resistant Gram-negative bacteria expressing extended-spectrum ß-lactamases and carbapenemases are a growing global problem resulting in increased morbidity and mortality with limited treatment options. LYS228 is a novel intravenous monobactam antibiotic targeting penicillin binding protein 3 with potent activity against Enterobacteriaceae, including multidrug-resistant clinical isolates expressing serine and metallo-ß-lactamases. In this study, we evaluated the safety, tolerability, and pharmacokinetics of single and multiple intravenous doses of LYS228 in healthy volunteers. LYS228 was safe: no serious adverse events were reported. Adverse events, with the exception of catheter-related events, occurred sporadically, with similar incidences between LYS228 and placebo groups. No apparent adverse event-dose relationship was identified. LYS228 was not associated with any clinically significant dose-related hematologic, hepatic, or renal laboratory abnormalities. The most frequently observed adverse events were local injection site reactions, noted in 91.7% and 75.0% of subjects administered multiple doses of LYS228 and placebo, respectively. LYS228 demonstrated pharmacokinetic properties consistent with those of other ß-lactam antibiotics, with systemic exposures slightly greater than dose proportional, short terminal half-lives (between 1.0 and 1.6 h) with no significant accumulation, and rapid clearance predominantly through urinary excretion.

Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects.

BACKGROUND: Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. SUBJECTS AND METHODS: In this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd. RESULTS: Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration-time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ETB receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure-response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. CONCLUSION: Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.

A Phase I, Randomized, Crossover, Open-label Study of the Pharmacokinetics of Solriamfetol (JZP-110) in Healthy Adult Subjects With and Without Food.

PURPOSE: Solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, is currently being evaluated for the reduction of sleepiness and improvement of wakefulness in patients with narcolepsy and obstructive sleep apnea. The purpose of this study was to evaluate the effect of food on the pharmacokinetic (PK) parameters and bioavailability of solriamfetol at the highest intended therapeutic dose in healthy adults and to characterize its renal excretion under fasting conditions. METHODS: In this open-label, randomized, crossover study, healthy adult subjects received a single 300-mg dose of solriamfetol in a fasted condition (10 h) and in a fed condition (30 min after the start of a standardized high-fat, high-calorie breakfast), with at least a 7-day washout period between doses. Blood samples for PK analyses were collected during both conditions at prespecified time points. Urine samples were collected up to 48 h postdose in the fasted condition. Samples were analyzed for solriamfetol (plasma and urine) and N-acetyl solriamfetol (urine) by using validated LC-MS/MS bioanalytical methods. The effect of food on solriamfetol relative bioavailability was examined by comparing the 90% confidence intervals (CIs) of the fed/fasted ratios of natural log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞ with the prespecified range of 80%-125%. Safety and tolerability were also assessed. FINDINGS: A total of 32 subjects were enrolled (50% female; 53.1% black, 46.9% white; mean age, 35.6 years), and 31 were included in the PK analyses. Solriamfetol was rapidly absorbed in both conditions. The 90% CIs for the fed/fasted geometric mean ratios were 89.2-98.8 for Cmax (ratio of 93.9%) and 93.8-101.5 for AUC0-∞ (ratio of 97.6%), indicating the absence of a food effect. In the fasted condition, 89.8% of solriamfetol was recovered in urine as unchanged drug over 48 h; 1.1% was excreted as a minor metabolite, N-acetyl solriamfetol. A total of 55 adverse events (AEs), all mild, were reported by 18 subjects (56.3%). The frequency and type of AEs were similar in the 2 conditions; the most common AEs (insomnia, headache, hypervigilance, decreased appetite, and nausea) were all mild in severity and resolved without treatment. IMPLICATIONS: Solriamfetol relative bioavailability was bioequivalent in the fed and fasted conditions, showing that solriamfetol can be taken without regard to meals; furthermore, tolerability was similar in both conditions. Renal excretion of unchanged drug is the primary route of elimination.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Concomitant Multiple Dose Administration of Verinurad (RDEA3170) and Allopurinol in Adult Male Subjects With Gout.

Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of hyperuricemia and gout. This phase 1b, multiple-dose, drug-drug interaction study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of verinurad in combination with allopurinol. Adult males with gout were randomized to receive once-daily oral doses of allopurinol 300 mg or verinurad 10 mg alone for 7 days, allopurinol 300 mg + verinurad 10 mg on days 8 to 14, and the alternative single agent on days 15 to 21. Colchicine 0.6 mg was taken prophylactically for gout flares. Plasma/serum and urine samples were assayed for verinurad, allopurinol, oxypurinol (allopurinol active metabolite), colchicine (plasma only), and uric acid. Safety was assessed by adverse events (AEs) and laboratory tests. Verinurad plasma exposure was unaffected by allopurinol. Verinurad increased the maximum observed plasma concentration (Cmax ) for allopurinol by 33%; the area under the plasma concentration-time curve (AUC) was unaffected. Oxypurinol Cmax and AUC were reduced 32% and 38%, respectively, by verinurad. Colchicine plasma exposure was unaltered by verinurad. The maximum decrease in serum urate was greater with verinurad + allopurinol (65%) than with verinurad (51%) or allopurinol (43%) alone. Compared with the baseline rate, the maximum rate of uric acid excreted in urine was +56% with verinurad, -46% with allopurinol, and unchanged with verinurad + allopurinol. No serious AEs, discontinuations due to AEs, or clinically significant laboratory abnormalities were noted. Despite decreased systemic exposure of allopurinol and oxypurinol in the presence of verinurad, the combination resulted in greater serum urate reduction compared with either drug alone and was well tolerated at the studied doses.

A phase 1 study to evaluate the safety and pharmacokinetics of MEDI8852, an anti-influenza A monoclonal antibody, in healthy adult volunteers.

MEDI8852 is an IgG1 kappa monoclonal antibody that is being developed to treat patients hospitalized with influenza A. We evaluated the safety and tolerability, pharmacokinetics, and anti-drug antibodies (ADA) of a single intravenous dose of MEDI8852 in healthy adult volunteers (NCT02350751). Forty subjects were randomized to receive either MEDI8852 (250, 750, 1,500, or 3000 mg) (n = 32) or placebo (n = 8) on day 1. Dose escalation was based on cumulative safety data through day 8. Subjects were followed through day 101 for safety, pharmacokinetics, and ADA. Treatment-emergent adverse events (TEAEs) were comparable (37.5%; 37.5%); all TEAEs were mild (grade 1) or moderate (grade 2) in severity. The most frequently reported TEAEs were headache (9.4%, 12.5%) and hypoglycemia (12.5%, 12.5%); all subjects with hypoglycemia were asymptomatic and did not require treatment. No subjects discontinued the study due to a TEAE. Mean area under the curve from time 0 to last sampling time point, area under the curve from time 0 to infinity, and observed maximum concentration for MEDI8852 were dose proportional. The terminal half-life ranged from 19.4 to 22.6 days. No ADAs were detected. A population pharmacokinetic model demonstrated good concentration separation between the 750- and 3000-mg dose groups.

Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults.

Prevention of respiratory syncytial virus (RSV) illness in infants is a major public health priority, but there is no approved vaccine. Palivizumab is a monoclonal antibody that provides RSV prophylaxis but requires 5 monthly injections and is approved only for infants who experience the greatest morbidity and mortality from RSV. Thus, there remains a significant unmet medical need for prevention of RSV disease in healthy infants. MEDI8897 is a recombinant human RSV monoclonal antibody with a modified Fc region that extends its half-life and is being developed as RSV prophylaxis for all infants. In this phase 1, first-in-human, placebo-controlled study, 136 healthy adults were randomized to receive a single dose of MEDI8897 (n = 102) or placebo (n = 34) in 1 of 5 cohorts (300, 1,000, or 3,000 mg intravenously or 100 or 300 mg intramuscularly [i.m.]) and were monitored for 360 days. The mean half-life of MEDI8897 was 85 to 117 days across dose groups, and bioavailability after 300-mg i.m. dose administration was 77%. Time to maximum concentration following i.m. dosing was 5 to 9 days. Antidrug antibody (ADA) responses were detected in a similar proportion of placebo (15.2%) and MEDI8897 (13.7%) recipients. The safety profile of MEDI8897 was similar to that of the placebo. These results support clinical studies of the i.m. administration of a single dose of MEDI8897 in the target population of infants to provide protection for the duration of the RSV season. (This study has been registered at ClinicalTrials.gov under identifier NCT02114268.).

Safety, tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): Results from a first-in-human randomised, placebo-controlled phase 1/2 study.

BACKGROUND: A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. METHODS: In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18-64years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA). RESULTS: A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11-15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported. CONCLUSIONS: Single-dose vaccination of SA4Ag in healthy adults aged 18-64years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. TRIAL REGISTRATION NUMBER: NCT01364571.