Standard Safety Assessments Research Articles

Pharmacodynamics, pharmacokinetics and CYP3A4 interaction potential of the selective P2X3 receptor antagonist filapixant: A randomized multiple ascending-dose study in healthy young men.

We report on investigations exploring the P2X3-receptor antagonist filapixant's effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential. In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2weeks. A single dose of midazolam (1mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate -1.1 points, 90% confidence interval [-3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported. Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.

Characterising the blood-stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected with Plasmodium falciparum

With the spread of artemisinin resistance throughout Southeast Asia and now in Africa, the antimalarial drug pyronaridine is likely to become an increasingly important component of new antimalarial drug regimens. However, the antimalarial activity of pyronaridine in humans has not been completely characterised. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in malaria naïve adults. Volunteers were inoculated with Plasmodium falciparum-infected erythrocytes on day 0 and administered different single oral doses of pyronaridine on day 8. Parasitaemia and concentrations of pyronaridine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47 ± 2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n = 4), 540 mg (n = 4) or 720 mg (n = 1) pyronaridine. One participant was withdrawn without receiving pyronaridine. The time to maximum pyronaridine concentration was 1–2 h, the elimination half-life was 8–9 d, and the parasite clearance half-life was approximately 5 h. Parasite regrowth occurred with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters including the minimum inhibitory concentration (5.5 ng/mL) and minimum parasiticidal concentration leading to 90% of maximum effect (MPC90: 8 ng/mL) were derived from the PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations.

Importance of treating acne sequelae in skin of color: 6-month phase IV study of trifarotene with an appropriate skincare routine including UV protection in acne-induced post-inflammatory hyperpigmentation.

Acne-induced hyperpigmentation (AIH) may accompany acne vulgaris (AV) inflammation in all skin phototypes. Trifarotene has shown depigmenting properties in vivo. This study evaluated trifarotene plus skincare because it is increasingly recognized that holistic AV management should include skincare and treatments. This is a phase IV double-blind, parallel-group study of patients (13-35 years) with moderate AV and AIH treated with trifarotene (N = 60) or vehicle (N = 63) plus skincare regimen (moisturizer, cleanser, and sunscreen) for 24 weeks. Assessments included the AIH overall disease severity (ODS) score, post-AV hyperpigmentation index (PAHPI), exit interviews, photography, and acne assessments. Standard safety assessments were included. Trifarotene 50 μg/g cream improved significantly from baseline in ODS score versus vehicle (-1.6 vs. -1.1, P = 0.03) at Week 12, but scores were comparable between groups at Week 24 (primary endpoint). Trifarotene had a better reduction in PAHPI score at Week 24 (-18.9% vs. -11.3% vehicle, P < 0.01). Lesion count reductions were higher with trifarotene at Week 12 versus vehicle (P < 0.001) and at Week 24 (P < 0.05), as were IGA success rates versus vehicle at Weeks 12 (P < 0.05) and 24 (P < 0.05). Patients agreed that the skincare regimen contributed to less irritation, making treatment adherence easier. Photography showed improvements in pigmentation and erythema across all skin types. AEs were more common in the vehicle group versus trifarotene (30.2 vs. 16.7%, respectively). In all skin phototypes, there was more rapid improvement in the ODS and PAHPI scores with trifarotene by Weeks 12 and 24, respectively. The combination of trifarotene and skincare correlated with high patient satisfaction and adherence to the treatment protocol.

Abstract 15201: Obicetrapib as an Adjunct to Stable Statin Therapy Significantly Lowers LDL-C, Non-HDL-C, and Apolipoprotein B in Japanese Patients: Results From the Japan Phase 2 Study

Background: Obicetrapib is a selective CETP inhibitor that has been shown to reduce LDL-C, non-HDL-C, lipoprotein particles, and apolipoproteins when used as monotherapy, and in combination with ezetimibe, on background high-intensity statins. Previous studies of obicetrapib were conducted in predominantly Caucasian participants. There is a lack of clinical experience with obicetrapib when used in combination with stable statin therapy among Asian population. Objectives: This study was designed to fill the gap in clinical experience and to characterize the safety, efficacy profile of obicetrapib within the Asian population. Methods: The Phase 2 study is a trial of Japanese participants who had not achieved treatment goal in accordance with the 2022 Japan Atherosclerosis Society Guidelines and with LDL-C &gt;70 mg/dL or non-HDL-C &gt; 100 mg/dL and TG &lt; 400 mg/dL, while receiving stable statin background therapy. Participants were randomized 1:1:1:1 to obicetrapib 2.5 mg (n=25), obicetrapib 5 mg (n=25), obicetrapib 10 mg (n=26), or placebo (n=26). The primary endpoint was percent change in LDL-C from baseline to week 8. Key secondary endpoints included changes in ApoB, non-HDL-C, and HDL-C. Standard safety assessments were conducted. Results: Obicetrapib produced significant lowering of median LDL-C (45.8%, P&lt;0.0001), ApoB (29.7%, P&lt;0.0001), non-HDL-C (37.0%, P&lt;0.0001) and raising of HDL-C (158.9%, P&lt;0.0001). Placebo demonstrated median change of -0.9%, -0.4%, -0.4% and +5.2% for these parameters respectively. Obicetrapib was well tolerated with similar treatment emergent adverse events compared to placebo. There were no clinically significant changes in laboratory parameters, vital signs, or physical examinations in any treatment group. Conclusions: Similar to previous studies, obicetrapib 2.5 mg, 5 mg, and 10 mg resulted in significant reductions in LDL-C, ApoB, and non-HDL-C in the Asian population. All doses of obicetrapib were safe and well tolerated.

Safety and efficacy of the novel BRAF inhibitor FORE8394 in patients with advanced solid and CNS tumors: Results from a phase 1/2a study.

3006 Background: FORE8394 is an investigational inhibitor (i) of class 1 (V600) and 2 (activating non-V600) BRAF-altered tumors. FORE8394 did not have paradoxical activation of the MAPK pathway in nonclinical studies. Methods: In a phase 1/2a study, patients (pts) aged ≥3 years with BRAF-altered, advanced solid or CNS tumors received FORE8394 (900-3600 mg/day or mg/m2 dosing) with or without a pharmacokinetic booster (cobicistat 150 mg/day). CNS metastases and prior treatment with other BRAFi were allowed. Besides standard safety assessments, skin and eye exams were required. Objective response was assessed by RECIST v1.1 or RANO criteria. Efficacy was evaluated in pts with class 1/2 BRAF alterations and ≥1 post-baseline assessment, with mg/m2 dosing (n=4) reported separately. Results: On 21Nov2022, 110 pts had received ≥1 dose of FORE8394. 85% completed ≥1 4-week cycle. 10 (9%) and 3 (3%) received FORE8394 ≥2 and ≥6 years, respectively; 14 (13%) are ongoing. Pts included 61 (55%) class 1 mutations, 19 (17%) class 2 mutations (excluding fusions), and 17 (15%) BRAF fusions. 64 pts (58%) had ≥2 prior lines of systemic therapy; 28 (25%) received prior MAPKi. Increased ALT (39%), increased AST (35%), fatigue (34%), nausea (27%), diarrhea (22%), and vomiting (20%) were the most frequently reported treatment-emergent adverse events (TEAEs); most were grade (G) 1/2. G3+ TEAEs were reported in 49% (54/110), the most common being increased ALT (9%), increased blood bilirubin (6%), and hyponatremia (5%). Transient G1 pyrexia was observed in 8 (7%) pts. All rashes were G1; none required a dose change. No TEAE of hyperkeratosis, papilloma, uveitis, retinal detachment, or LVEF reduction were reported. 1 pt discontinued due to FORE8394-related TEAE. Antitumor activity was observed in pts with MAPKi-naïve, V600 mutant tumors (excluding colorectal cancer [CRC]), 39% (9/23) having a PR (median duration of response [DoR]: 32 months). In 17 pts with V600 mutated tumors (excluding CRC) treated with prior MAPKi, 3 (18%) had PR and 5 (29%) had SD. In V600 mutated tumors, PRs occurred in 6 (55%) gliomas, 3 (100%) ovarian cancers, and 1 each in CRC (7%), small bowel (50%), papillary thyroid (13%) and anaplastic thyroid (25%) cancers. Of pts with BRAF-fusions, a pt with AGK-BRAF-fused melanoma had CR (DoR 51.8+ months); 46% (6/13) had SD. Of note, 1 child with V600E mutated Langerhans cell histiocytosis had SD with improvement in neurodegenerative changes and a progression-free survival of 55.8+ months. Conclusions: As single agent anticancer therapy, FORE8394 had antitumor activity in various tumors with BRAF alterations, including pts previously treated with MAPKi and pts with BRAF fusions. Durable tolerability was observed, and TEAEs indicative of paradoxical MAPK activation were not observed, consistent with the novel mechanism of action of FORE8394. These results support further evaluation of FORE8394. Clinical trial information: NCT02428712 .

A topical rectal douche product containing Q-Griffithsin does not disrupt the epithelial border or alter CD4+ cell distribution in the human rectal mucosa

To reduce HIV transmission, locally applied pre-exposure prophylaxis (PrEP) products for anorectal use will be important complements to oral and injectable PrEP products already available. It is critical to preserve an intact rectal epithelium and avoid an influx of mucosal HIV target cells with such product use. In this phase 1 clinical trial, we evaluated application of a topical rectal douche product containing Q-Griffithsin (Q-GRFT). Colorectal tissue samples were obtained via sigmoidoscopy at baseline, 1 and 24 h after single-dose exposure in 15 healthy volunteers. In situ staining for epithelial junction markers and CD4+ cells were assessed as an exploratory endpoint. A high-throughput, digitalized in situ imaging analysis workflow was developed to visualize and quantify these HIV susceptibility markers. We observed no significant differences in epithelial distribution of E-cadherin, desmocollin-2, occludin, claudin-1, or zonula occludens-1 when comparing the three timepoints or Q-GRFT versus placebo. There were also no differences in %CD4+ cells within the epithelium or lamina propria in any of these comparisons. In conclusion, the rectal epithelium and CD4+ cell distribution remained unchanged following topical application of Q-GRFT. In situ visualization of HIV susceptibility markers at mucosal sites could be useful to complement standard product safety assessments.

Characterizing the Blood-Stage Antimalarial Activity of Tafenoquine in Healthy Volunteers Experimentally Infected With Plasmodium falciparum.

The long-acting 8-aminoquinoline tafenoquine may be a good candidate for mass drug administration if it exhibits sufficient blood-stage antimalarial activity at doses low enough to be tolerated by glucose 6-phosphate dehydrogenase (G6PD)-deficient individuals. Healthy adults with normal levels of G6PD were inoculated with Plasmodium falciparum 3D7-infected erythrocytes on day 0. Different single oral doses of tafenoquine were administered on day 8. Parasitemia and concentrations of tafenoquine and the 5,6-orthoquinone metabolite in plasma/whole blood/urine were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 48 ± 2. Outcomes were parasite clearance kinetics, pharmacokinetic and pharmacokinetic/pharmacodynamic (PK/PD) parameters from modelling, and dose simulations in a theoretical endemic population. Twelve participants were inoculated and administered 200 mg (n = 3), 300 mg (n = 4), 400 mg (n = 2), or 600 mg (n = 3) tafenoquine. The parasite clearance half-life with 400 mg or 600 mg (5.4 hours and 4.2 hours, respectively) was faster than with 200 mg or 300 mg (11.8 hours and 9.6 hours, respectively). Parasite regrowth occurred after dosing with 200 mg (3/3 participants) and 300 mg (3/4 participants) but not after 400 mg or 600 mg. Simulations using the PK/PD model predicted that 460 mg and 540 mg would clear parasitaemia by a factor of 106 and 109, respectively, in a 60-kg adult. Although a single dose of tafenoquine exhibits potent P. falciparum blood-stage antimalarial activity, the estimated doses to effectively clear asexual parasitemia will require prior screening to exclude G6PD deficiency. Clinical Trials Registration. Australian and New Zealand Clinical Trials Registry (ACTRN12620000995976).

Advancing Health Research Impact through a Systemic Multi-Sectoral Approach: A Protocol for Introducing Reduced-Sodium Salts and Salty Condiments in Vietnam.

Better alignment between health research organisations with the needs (and interests) of key stakeholders in the health policy and research system is critical to improving research impact. The George Institute for Global Health’s ‘Healthier Societies’ program focuses on harnessing the power of governments, markets, and communities to improve population level health equity outcomes and maximise research impact. This protocol outlines a systemic multi-sectoral approach to advance health research impact globally applied to a project to reduce population salt intake in Vietnam by introducing reduced-sodium salts and salty condiments. We defined a systemic multi-sectoral approach to be a strategy that involves engaging with government, market and communities in a deliberate and joined-up way to solve a problem in which they all have a role to play. The project objectives are to: (i) produce reduced-sodium fish sauce products and test consumer acceptability; (ii) investigate the market feasibility of introducing reduced-sodium foods (salt, bot canh and fish sauce) into the Vietnamese market; (iii) estimate the cost-effectiveness of three different government strategies to support the implementation of reduced-sodium products; and (iv) develop an advocacy roadmap to maximise potential research impact. Methods will include standard quality and safety assessments, consumer sensory testing for the locally produced reduced-sodium fish sauces, market feasibility assessment (including collating market data and semi-structured interviews with stakeholders), cost-effectiveness modelling (Markov cohort model), multi-sector stakeholder engagement, and the development of a coordinated advocacy strategy using the Kotter Plus framework. Health research organisations are increasingly seeking ways to achieve greater impact with their research. Through the application of a systemic multi-sectoral approach with governments, markets and communities, this protocol provides an example of how health research projects can achieve such impact.

33317 Study of nemolizumab pharmacokinetics, safety, and efficacy in adolescents with atopic dermatitis

Background: Atopic dermatitis (AD) is common in children, including moderate to severe disease (MTS). Nemolizumab, an interleukin 31 receptor-α (IL31RA) inhibitor, has safety and efficacy in adults with AD. The objective of this study was to evaluate nemolizumab in adolescents. Methods: Open-label 16-week study of nemolizumab in patients aged 12-17 years with MTS AD and associated pruritus with baseline average daily itch-NRS intensity of at least 4. Nemolizumab was administered subcutaneously as a loading dose of 60 mg at baseline, followed by 30 mg every 4 weeks until week 12 with background topical corticosteroid or calcineurin inhibitor treatment. Standard pharmacokinetic (PK), efficacy, and safety assessments performed. Results: 20 patients participated (8M/12F), with a mean age of 14.8 ± 1/6 years. Baseline (BL) mean Eczema Area and Severity Index (EASI) score was 25.2 ± 7.22. Concentrations peaked 1-2 weeks after loading dose, and steady state occurred by week 4. Nemolizumab PK showed linear elimination, a first order absorption, and a mean half-life of 16.7 ± 4.12 days. In population PK analysis, exposures in adolescents were comparable to adults. The main source of PK variability was body weight. There were marked improvements in key AD signs/symptoms (mean EASI decreased 66.5%, itch NRS decreased 43.2%, sleep NRS decreased 53.5%). Adverse events were experienced by 33.3% of subjects (n = 6) and were primarily mild or moderate in severity. Conclusion: Nemolizumab’s PK, safety and efficacy profile was consistent in adolescents and adults patients with MtS AD.

Asivatrep, a TRPV1 antagonist, for the topical treatment of atopic dermatitis: Phase 3, randomized, vehicle-controlled study (CAPTAIN-AD)

Asivatrep is a potent and selective antagonist of transient receptor potential vanilloid subfamily V member 1 (TRPV1), which plays an important role in itch and inflammation in atopic dermatitis (AD). This current study aimed to evaluate the efficacy and safety of asivatrep cream in patients with AD. For this phase 3 double-blind, vehicle-controlled study, patients aged ≥12 years with mild to moderate AD were enrolled and randomly assigned 2:1 to the 1.0% asivatrep or vehicle group for 8 weeks of twice-daily application (n= 240). The primary end point was the proportion of patients with an Investigator's Global Assessment score (IGA) of 0 or 1 at week 8. Standard safety assessments were conducted. At week 8, significantly more patients in the asivatrep group (36.0%) than in the vehicle group (12.8%) had IGA scores of 0 or 1 (P< .001); significantly more had ≥2 points of improvement on the IGA from baseline score (20.3% vs 7.7%; P= .01). The mean percentage reduction in the Eczema Area and Severity Index (EASI) score was 44.3% for the asivatrep group and 21.4% for the vehicle group at week 8 (P< .001). Significantly more asivatrep-treated patients experienced an improvement of at least 50%, 75%, and 90% on the EASI than the vehicle group. The mean± SD change in the pruritus visual analog scale score at week 8 was -2.3± 2.4 for the asivatrep group and -1.5± 2.4 for the vehicle group (P= .02). No significant safety issues were reported. Asivatrep improved clinical signs and symptoms of AD and was well tolerated.

Pharmacokinetics and Bioequivalence of Isavuconazole Administered as Isavuconazonium Sulfate Intravenous Solution via Nasogastric Tube or Orally in Healthy Subjects.

ABSTRACTFor critically ill patients with invasive fungal infections, a nasogastric (NG) tube can be an alternative route for administration of isavuconazonium sulfate (ISAVUSULF). This was a randomized, open-label, 2-period, 2-sequence single-dose crossover study comparing single doses of 372 mg ISAVUSULF intravenous (i.v.) solution via NG tube (test formulation) to 372-mg ISAVUSULF capsules for oral administration (reference formulation) in healthy male and female subjects. A single dose of ISAVUSULF was administered under fasting conditions on day 1 of each period, with a washout of 30 days between periods. Pharmacokinetic (PK) samples were collected predose through day 21. Standard safety and tolerability assessments were conducted in each period. The analysis of variance estimate of the study population demonstrates that the isavuconazole i.v. NG tube administration geometric least-squares (LS) mean values of the observed maximum concentration (Cmax), area under the plasma concentration-time curve (AUC) to the last measurable concentration (AUClast), AUC to time infinity (AUCinf), and AUC from start of dosing to 72 h (AUC72) were 105.3%, 97.6%, 99.3%, and 97.8%, respectively, of the corresponding oral-administration values. The geometric LS mean ratio and 90% confidence intervals for the PK parameters were completely contained within the prespecified limits of 80% to 125%. There were no deaths or serious adverse events that led to the withdrawal of treatment during the study. The study met its primary endpoint of bioequivalence between the two routes of administration. Both routes of administration were well tolerated.

MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

Molecular characterization for food safety assessment of a genetically modified late blight resistant potato: an unusual case

Standard food safety assessments of genetically modified crops require a thorough molecular characterization of the novel DNA as inserted into the plant that is intended for commercialization, as well as a comparison of agronomic and nutritional characteristics of the genetically modified to the non-modified counterpart. These characterization data are used to identify any unintended changes in the inserted DNA or in the modified plant that would require assessment for safety in addition to the assessment of the intended modification. An unusual case of an unintended effect discovered from the molecular characterization of a genetically modified late blight resistant potato developed for growing in Bangladesh and Indonesia is presented here. Not only was a significant portion of the plasmid vector backbone DNA inserted into the plant along with the intended insertion of an R-gene for late blight resistance, but the inserted DNA was split into two separate fragments and inserted into two separate chromosomes. One fragment carries the R-gene and the other fragment carries the NPTII selectable marker gene and the plasmid backbone DNA. The implications of this for the food safety assessment of this late blight resistant potato are considered.

1320. Pharmacokinetics of Isavuconazole Administered as Isavuconazonium Sulfate Intravenous Solution via Nasogastric Tube or Orally in Healthy Volunteers

BackgroundNasogastric (NG) tube feeding is most common in the intensive care unit and is also used for cancer patients who are unable to eat (e.g. patients with mucositis) or do not want to eat due to severe nausea1. For such critically ill patients with invasive fungal infections, administration of isavuconazonium sulfate (ISAVUSULF) via NG tube can be an alternate route of drug administration.MethodsThis was a randomized, open-label, 2-period, 2-sequence single dose crossover study in healthy male and female subjects. Each subject participated in 2 treatment periods separated by a washout of at least 30 days between investigational product administrations in each period. Subjects were administered a single dose of 372 mg ISAVUSULF intravenous (IV) solution via NG tube (test formulation) or 372 mg ISAVUSULF capsules for oral (PO) administration (i.e., PO capsules administered to subjects without NG tube) (reference formulation) under fasting conditions on day 1 of each period. Pharmacokinetic (PK) samples were collected predose on day 1 of each period and at multiple time points postdose through day 21. Standard safety and tolerability assessments were conducted in each period.ResultsEighteen subjects were randomized in this study and 13 provided concentrations in both sequences that were PK evaluable. The analysis of variance estimate (Table 1) of the study population suggests that the isavuconazole IV NG tube administration geometric least-square (LS) mean values of the observed maximum concentration (Cmax), area under the plasma concentration-time curve (AUC) to the last measurable concentration (AUClast), AUC to time infinity (AUCinf), and AUC from start of dosing to 72 hours (AUC72) were 105.3%, 97.6%, 99.3% and 97.8%, respectively, of the corresponding oral administration values. The geometric LS mean ratio and 90% Confidence Intervals for the Cmax, AUClast, AUCinf, and AUC72 are completely contained within the prespecified limits of 80% to 125%. There were no deaths or serious adverse events that led to withdrawal of treatment during the conduct of the study.Table 1 ConclusionThe study met its primary endpoint of bioequivalence between the two routes of administration in this population. Both routes of administration are well tolerated.Reference 1 Disclosures Amit Desai, PhD, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Melanie Helmick, BA, Clinical Research, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Nakyo Heo, PharmD, MS, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Selina Moy, BS, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Stephen Stanhope, PhD, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc) Ronald Goldwater, MDCM, Astellas Pharma Inc. (Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc. Parexel International received fees for research support from Astellas Pharma Global Development Inc.)Parexel International (Employee, Employee of Parexel International) Nancy Martin, MD, PharmD, Astellas Pharma Inc. (Employee, Other Financial or Material Support, This study was initiated and sponsored by Astellas Pharma Global Development Inc)

Design of a Randomized, Controlled Study to Evaluate Reversal of Anticoagulation of Ciraparantag in Healthy Adults: Whole Blood Clotting Time Assessed By Automated and Manual Methods

There is a need for safe and effective reversal agents for patients on chronic anticoagulant therapy in cases such as serious or life-threatening bleeding, urgent or emergency surgery, after major trauma, or in cases of anticoagulant overdose. Ciraparantag, an anticoagulant reversal agent in clinical development, which is believed to bind directly to anticoagulant molecules through non-covalent bonds, with no binding to blood coagulation factors or proteins in the blood. Phase 2 clinical studies have shown that ciraparantag reverses anticoagulation in healthy volunteers treated with edoxaban, enoxaparin, apixaban, or rivaroxaban as assessed by manual whole blood clotting time (WBCT). WBCT is the key pharmacodynamic marker because ciraparantag is cationic and binds to the anionic substances in standard blood collection tubes, and to anionic, colloidal activators used in the traditional coagulation assays such as PT or aPTT. Therefore, such assays are not appropriate markers for measuring ciraparantag's effect. WBCT is a direct measure of the time required for blood clot formation ex vivo and uses blood drawn into reagent-free collection equipment, using only glass as the activating agent. A Phase 2b clinical study is planned to evaluate the efficacy and safety of ciraparantag for reversal of anticoagulation as measured by WBCT using an automated point-of-care (PoC) coagulometer (developed by Perosphere Technologies, Inc.) compared with a manual testing method. This is a randomized, double-blind, placebo-controlled study in healthy adults 18 to 75 years of age who are anticoagulated with apixaban (10 mg PO twice daily) or rivaroxaban (20 mg PO once daily). Subjects who reach steady-state anticoagulation will be stratified into 2 age groups and randomized 2:1 to receive a single IV dose of ciraparantag or placebo, followed by serial WBCT testing and standard safety assessments over 24 hours. The primary efficacy endpoint is based on the extent and timing of reversal of anticoagulation following ciraparantag administration as compared with placebo, based on WBCT measured using the PoC coagulometer. Manual WBCT testing also will be performed at selected timepoints in order to describe the correlation between results obtained with the two methods. The coagulometer is expected to provide greater sensitivity and precision compared to the manual method. Further details of the design of this study will be provided. The results of this study will inform dose selection for the future Phase 3 clinical trial and will provide data on the use of the PoC coagulometer for assessment of ciraparantag for reversal of anticoagulation. Disclosures Villano: Amag Pharmaceuticals, Inc.: Consultancy. Bakhru:Pherosphere Technologies, Inc.: Current Employment. Luo:Amag Pharmaceuticals, Inc.: Current Employment. Freedman:Amag Pharmaceuticals, Inc.: Current Employment. OffLabel Disclosure: Ciraparantag is an investigational drug being evaluated for the reversal of anticoagulation induced by direct oral anticoagulant (DOAC) therapies.

A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD

BackgroundBatefenterol (BAT) is a bi-functional molecule with both muscarinic antagonist and β2-adrenoceptor agonist pharmacology. This Phase II, randomized, placebo-controlled, double-blind study evaluated the safety and tolerability of BAT 300 μg with fluticasone furoate (FF) 100 μg administered via the ELLIPTA inhaler (BAT/FF 300/100).MethodsSubjects with stable chronic obstructive pulmonary disease were randomized 2:1 to receive BAT/FF 300/100 or placebo once daily for 6 weeks. The primary endpoint was change from baseline in 0–4-h weighted mean (WM) heart rate (HR, measured by electrocardiogram [ECG]) on Day 42. Other endpoints included WM and maximum 0–4-h corrected QT interval (ECG on Days 1, 28, and 42), HR measured by Holter monitoring (Day 42), and standard safety assessments. Study protocol was approved by an Investigational Review Board.ResultsSixty-two patients were randomized and received ≥1 dose of study medication (BAT/FF 300/100 n = 42; placebo n = 20). Mean age was 62.5 years (standard deviation [SD] 8.17). Study completion rates were 83% (BAT/FF 300/100) and 100% (placebo). Screening mean (SD) post-bronchodilator percentage-predicted forced expiratory volume in 1 s was 57.57 (11.42) in the BAT/FF 300/100 group and 55.68 (14.03) in the placebo group. BAT/FF 300/100 was non-inferior to placebo for the primary endpoint, treatment difference: − 2.2 beats per minute (bpm), 95% confidence interval [CI]: − 6.2, 1.7). There were no clinically relevant differences between treatment groups in WM or maximum 0–4-h corrected QT interval, or mean HR based on Holter monitoring on Day 42 (BAT/FF 300/100: 76.3 bpm [SD 11.38]; placebo: 84.8 bpm [SD 9.87]). Adverse events (AEs) occurred in 38% (BAT/FF 300/100) and 35% (placebo) of patients. AEs in ≥2 subjects with BAT/FF 300/100 were dysgeusia (10%), diarrhea (7%), nasopharyngitis (7%), and cough (5%). AEs leading to discontinuation occurred in two subjects who received BAT/FF 300/100: post-treatment severe pneumonia (serious AE) and non-serious AEs of moderate vomiting and severe gastroenteritis; both were not considered drug-related. No deaths occurred.ConclusionsSix weeks of BAT/FF 300/100 treatment was non-inferior to placebo for change from baseline in HR, with no new clinically relevant general or cardiovascular safety signals.Trial registrationClinicaltrials.gov: NCT02573870 (submitted October 12, 2015).

Abstract B001: Safety and efficacy of ZW25, a HER2-targeted bispecific antibody, in combination with chemotherapy in patients with locally advanced and/or metastatic HER2-expressing gastroesophageal cancer

Abstract Background: Up to 30% of gastroesophageal adenocarcinoma (GEA) overexpress HER2. ZW25 is a novel bispecific antibody that targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including increased antibody binding density and improved receptor internalization and downregulation relative to trastuzumab. In an ongoing phase 1 trial (ZWI-ZW25-101; NCT02892123), single-agent ZW25 was well tolerated and showed promising anti-tumor activity across HER2-expressing solid tumors. This abstract presents data for GEA patients treated with ZW25 in combination with chemotherapy in Study ZWI-ZW25-101. Methods Eligible patients had HER2-expressing (IHC 3+, IHC 2+/FISH+, or IHC 2+/FISH-) GEA and had disease progression after 1–3 lines of prior chemotherapy for advanced and/or metastatic disease. Fresh or archived tumor tissue was required for central review of HER2 status, although patients could be enrolled based on local results. Patients received ZW25 in combination with paclitaxel or capecitabine. Evaluations included standard safety assessments, tumor re-staging (Q8W by RECIST 1.1), and assessment of peak/trough pharmacokinetic (PK) levels during each cycle. Results To date, 14 patients have been enrolled, with safety and efficacy data available for 11. ZW25 was administered in combination with paclitaxel (n=5) or capecitabine (n=6). The median age was 62 yrs (range, 26-80). The median number of prior anti-cancer regimens was 3 and the median number of prior HER2-targeted therapies was 1. Six patients (55%) were HER2 IHC3+ or IHC2+ and FISH+ per central review. The most common adverse events (AEs) considered related to ZW25 or ZW25 and chemotherapy were diarrhea (n=5; 45%), fatigue (n=3; 27%), and nausea (n=3; 27%); the majority of events were Grade 1 or 2. Grade 3 or higher events considered related to ZW25 or ZW25 and chemotherapy occurred in 3 patients (27%), including fatigue, hypokalemia, and neutropenia (n=1 each). One additional patient experienced a Grade 5 serious adverse event of pneumonitis, reported as related to the combination of ZW25 and paclitaxel. This patient had been previously treated with trastuzumab, cisplatin, and capecitabine; pembrolizumab and margetuximab; and most recently DS8201, and had asymptomatic interstitial lung disease at study entry. A total of 9/11 patients (82%) had measurable disease and 8/9 (89%) were response-evaluable. The objective response rate was 63% (95% CI: 25, 92) (5/8 patients; all partial responses, with 4 confirmed to date) and the disease control rate was 75% (6/8 patients). Responses were seen in patients with FISH+ and FISH- disease, as well as in combination with either paclitaxel or capecitabine. Patients have received between 1 and 12 cycles of treatment and 4 patients remain on treatment. PK data will be presented at the meeting. Conclusions The combination of ZW25 with chemotherapy was generally well tolerated in heavily pre-treated patients with HER2 high- and low-expressing GEA and the preliminary anti-tumor activity is promising. Further evaluation of the safety and efficacy of ZW25 in combination with standard of care chemotherapy regimens has been initiated in frontline GEA (ZW25-201; NCT03929666). Citation Format: Funda Meric-Bernstam, Jorge Chaves, Do-Youn Oh, Jeeyun Lee, Yoon-Koo Kang, Erika Hamilton, Jose Mayordomo, Melody Cobleigh, Christos Vaklavas, Elena Elimova, Jaffer Ajani, Jordi Rodon, Gerry Rowse, Todd Gray, Rose Lai, Diana Hanna. Safety and efficacy of ZW25, a HER2-targeted bispecific antibody, in combination with chemotherapy in patients with locally advanced and/or metastatic HER2-expressing gastroesophageal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B001. doi:10.1158/1535-7163.TARG-19-B001

Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus

Nemolizumab targets the IL-31 receptor α subunit involved in atopic dermatitis (AD) pathogenesis. We sought to evaluate a new dosing strategy of nemolizumab in patients with AD. We performed a 24-week, randomized, double-blind, multicenter study of nemolizumab (10, 30, and 90mg) subcutaneous injections every 4weeks versus placebo, with topical corticosteroids in adults with moderate-to-severe AD, severe pruritus, and inadequate control with topical treatment (n=226). The Eczema Area and Severity Index (EASI), the peak pruritus (PP) numeric rating scale (NRS), and the Investigator's Global Assessment (IGA) were assessed. Standard safety assessments were performed. Nemolizumab improved EASI, IGA, and/or NRS-itch scores, with the 30-mg dose being most effective. Nemolizumab (30mg) reduced EASI scores versus placebo at week 24 (-68.8% vs -52.1%, P=.016); significant differences were observed by week 8 (P≤.01). With significant improvement (P=.028) as early as week 4, IGA 0/1 rates were higher for 30mg of nemolizumab versus placebo at week 16 (33.3% vs 12.3%, P=.008) but not week 24 because of an increased placebo/topical corticosteroid effect (36.8% vs 21.1%, P=.06). PP-NRS scores were improved for 30mg of nemolizumab versus placebo at week 16 (-68.6% vs -34.3%, P<.0001) and week 24 (-67.3% vs -35.8%, P<.0001), with a difference by week 1 (P<.001). NRS response rates (≥4-point decrease) were greater for 30mg of nemolizumab versus placebo at week 16 (P≤.001) and week 24 (P≤.01). Nemolizumab was safe and well tolerated. The most common adverse events were nasopharyngitis and upper respiratory tract infection. Nemolizumab resulted in rapid and sustained improvements in cutaneous signs of inflammation and pruritus in patients with AD, with maximal efficacy observed at 30mg. Nemolizumab had an acceptable safety profile.

Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials

Effective and well tolerated nucleos(t)ide analogue treatment exists for patients with chronic hepatitis B, although treatment is generally anticipated to be life-long, with concomitant costs and treatment-related side-effects. We aimed to characterise the outcomes of patients with persistent viral suppression who discontinued nucleotide analogue use after extended treatment. The primary objective of this prespecified analysis was to evaluate the safety of stopping long-term tenofovir disoproxil fumarate therapy in patients enrolled in two (completed) randomised controlled studies, GS-US-174-0102 (ClinicalTrials.gov, number NCT00117676) and GS-US-174-0103 (ClinicalTrials.gov, number NCT00116805). In those studies, patients who had completed 8 years or more of nucleotide analogue treatment, were hepatitis B surface antigen (HBsAg)-positive with hepatitis B virus (HBV) DNA concentration of less than 29 IU/mL, and were unwilling or unable to continue therapy were required by protocol to enter a 24-week treatment-free follow-up (TFFU) phase. We present data for patients in the TFFU phase who were assessed at baseline and monitored every 4 weeks for changes in qualitative serum HBsAg, HBV DNA, and alanine aminotransferase (ALT) concentrations in addition to standard safety assessments. Of 124 patients who entered the TFFU phase, 54 (44%) patients did not complete 24 weeks of follow-up (median 12 weeks; IQR 0-20). Overall, 32 (26%) patients reported an adverse event. Serious adverse events occurred in five (4%) patients, including elevated ALT concentrations in two patients, hepatic flare in two patients, and increased lipase in one patient. 38 (31%) of patients had grade 3 or higher laboratory abnormalities, the majority of which were ALT elevations (36 patients). Of the 106 hepatitis B e antigen (HBeAg)-negative patients who entered the TFFU phase, 63 (59%) were followed for 24 weeks. HBsAg loss was observed in five (5%) of the 106 HBeAg-negative patients who entered the TFFU phase, and 37 (35%) had both HBV DNA concentrations of less than 2000 IU/mL and ALT concentrations less than the ULN at TFFU week 24. 18 HBeAg-positive patients entered the TFFU phase, of whom seven (39%) were followed up for 24 weeks. Of these seven patients, none had HBsAg loss or HBV DNA of less than 2000 IU/mL and one (14%) had an ALT less than the ULN at week 24. Within 24 weeks of stopping 8 years or more of nucleotide analogue therapy almost a third of patients experienced a grade 3 or higher laboratory abnormality. Although few patients achieved HBsAg loss, a subgroup of HBeAg-negative patients can achieve a low-replicative state within a short duration of follow-up. Gilead Sciences, Inc.

Topical minocycline foam 4%: Results of four phase 1 studies evaluating the potential for phototoxicity, photoallergy, sensitization, and cumulative irritation

FMX101 4% contains 4% micronized minocycline (as an HCl) formulated in a lipophilic foam vehicle for topical administration. FMX101 4% has been shown to be an effective and well-tolerated treatment for moderate-to-severe acne in three Phase 3 pivotal studies, however, skin sensitization and toxicity potential remains to be fully evaluated. Four single-center, randomized, controlled, within-subject comparison studies were conducted to evaluate the potential for phototoxicity, photoallergy, skin sensitization, and cumulative skin irritation with topical administration of FMX101 4% and the corresponding vehicle. Across the four studies, healthy male and non-pregnant female volunteers (age ≥18 years) were randomized to FMX101 4%, vehicle, or other controls. In the phototoxicity study, treated skin was irradiated at 3 and 24 hr post-application, and local tolerability was assessed pre- and post-irradiation. In the photoallergy study, the skin was treated and irradiated (post-24 hr) twice weekly for 3 wk (induction phase), rested for 10–17 d, and naive skin sites were treated and irradiated (challenge phase); skin reactions were assessed after patch removal and post-irradiation. In the sensitization study, the skin was treated for 3 wk (induction phase), then rested for 10–14 d, and naive skin sites were treated for 48 hr (challenge phase); contact sensitization was assessed for both phases. In the cumulative irritation study, treatment and vehicle were applied daily for 21 d; skin irritation was assessed after each application. In all studies, standard safety assessments were conducted. A total of 32, 56, 233, and 42 subjects were enrolled in the phototoxicity, photoallergy, sensitization, and skin irritation studies, respectively. There was no evidence of phototoxicity, photoallergy, skin sensitization, or skin irritation potential with FMX101 4%. Few adverse events, mostly mild to moderate, were reported. In conclusion, FMX101 4% appeared to be well tolerated and non-irritating, and was considered to be non-sensitizing, non-phototoxic, and non-photoallergic.