Phase IIa Study Research Articles

Translational pharmacology of TD139, an inhaled small molecule galectin‐3 (Gal‐3) inhibitor for the treatment of idiopathic pulmonary fibrosis (IPF)

IntroductionGal‐3 is a pro‐fibrotic β‐galactoside‐binding lectin highly expressed in the lungs of IPF patients 1. TD139 is an inhaled, small molecule Gal‐3 inhibitor in development for IPF[2]. In this study the translational pharmacology of TD139 from pre‐clinical to clinical studies are presented.MethodsTD139 was evaluated in pre‐clinical studies investigating Gal‐3 in vitro and in vivo in naïve and bleomycin‐treated mice (male C57/Bl6 mice) 1, 2. A randomized, double‐blind, multi‐centre, placebo‐controlled, phase IIa study was completed to assess safety, tolerability, and PK/PD of TD139 in 24 patients with IPF. Inhaled TD139 was delivered at 0.3 mg, 3 mg or 10 mg QD to IPF patients (8 patients/cohort, 5:3 ratio (active:placebo)) for 14 days. Patients underwent bronchoalveolar lavage (BAL) prior to dosing and after 14 days. TD139 drug concentration was measured in the BAL fluid, BAL macrophages and plasma. Gal‐3 expression on BAL macrophages was measured by flow cytometry and systemic biomarkers of Gal‐3 inhibition and fibrosis measured in plasma.ResultsTD139 demonstrated high affinity (KD = 2.1 ± 0.1 nM (mean ± SD, n=4)) in vitro and reduced Gal‐3 expression ex vivo on IPF macrophages (IC50 = 361 ± 108 nM (mean ± SD, n=3 patients)). TD139 in vivo attenuated mechanistic PD (BAL Gal‐3) and fibrotic endpoints (total lung collagen/histology) in bleomycin‐treated mice with duration driven by lung retention. Clinically, inhaled TD139 was well tolerated at all doses with concentrations in BAL macrophages >567‐fold higher than systemic exposure. Gal‐3 expression on BAL macrophages was significantly lower in the 3 mg (% change −52.52%, 95% CI −85.43% to −4.74%, P=0.023) and 10 mg (% change −78.60%, 95% CI −110.48% to −29.78%, P<0.0001) dose groups compared to placebo, with a concentration‐dependent inhibition. Reduced Gal‐3 expression on BAL macrophages was associated with lower plasma biomarkers relevant to IPF pathobiology (PAI‐1, YKL‐40 and PDGF‐BB).ConclusionTD139 is safe and well tolerated in man and demonstrates low systemic exposure coupled with high lung concentrations resulting in suppression of Gal‐3 on BAL macrophages and decreased plasma biomarkers associated with IPF progression. Pre‐clinical in vitro and in vivo studies have shown to be clinically translatable. This study supported the progression of TD139 into a phase IIb IPF study 3.Support or Funding InformationAll studies were funded by Galecto Biotech AB.

NP213 (Novexatin®): A unique therapy candidate for onychomycosis with a differentiated safety and efficacy profile.

NP213 (Novexatin®) is a novel antifungal peptide specifically designed for the topical treatment of onychomycosis. NP213 was designed using host defense peptides (HDP), essential components of the innate immune response to infection, as a template. NP213 is a water-soluble cyclic fungicidal peptide that effectively penetrates human nail. NP213 demonstrated a promising preclinical and clinical safety profile, with no evidence of systemic exposure following topical application to the skin and nails. NP213 was efficacious in two phase IIa human trials with 43.3% of patients having no fungi detectable by culture of fragments from NP213-treated nails after 180 days in the first study and likewise 56.5% of patients were culture negative for dermatophytes after 360 days in the second phase IIa study. In both trials, NP213 was applied daily for only 28 days in marked contrast to other topical onychomycosis treatments that require application for up to 52 weeks. Patient reported outcomes from the phase IIa studies were positive with participants recording an improved appearance of their nails after only 14 days of application. All fungi identified in these studies were Trichophyton spp. NP213 (Novexatin®) is a promising, highly differentiated peptide-based candidate for the topical treatment of onychomycosis, addressing the infectious cause and cosmetic issues of this very common condition.

Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: results from MyPathway, a phase IIa multiple basket study

Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab+ trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab+ trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab+ trastuzumab, n= 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n= 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n= 1/1, PFS 18.5 months), and high TMB (atezolizumab, n= 1/1, PFS 5.5+ months). No unexpected toxicity occurred. Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.

Editorial introductions

Editorial introductions

A Multi-Center Phase IIA Trial to Assess the Safety and Efficacy of BL-8040 (a CXCR4 Inhibitor) in Combination with Pembrolizumab and Chemotherapy in Patients with Metastatic Pancreatic Adenocarcinoma (PDAC)

Abstract Background Current treatment options for PDAC are limited. While PD-1/PD-L1 antagonists have shown promising results in other cancer types, this approach has been ineffective in PDAC. In Cohort 1 of the COMBAT study, the dual combination of BL-8040 (a CXCR4 inhibitor) and Pembrolizumab was safe and showed a promising 7.5 mo OS in 2L patients. BL-8040 modified the TME by promoting infiltration of effector T cells and decreasing immune suppressor cells. Based on these encouraging results, as well as preclinical data supporting the combination of BL-8040, Pembrolizumab and chemotherapy, the study was expanded to include a combination arm (Cohort 2) composed of BL-8040, Pembrolizumab and chemotherapy (Onivyde/5-FU/LV). Here we report the preliminary safety and efficacy of BL-8040 in this expansion cohort. Methods Phase IIa study, Cohort 2, treatment regimen consists of 5 days BL-8040 priming monotherapy followed by combination treatment of Onivyde/5-FU/LV every 2 weeks, Pembrolizumab every 3 weeks and BL-8040 twice a week. Eligibility criteria includes metastatic PDAC subjects with measurable disease by RECIST1.1 that have progressed following first-line treatment with gemcitabine-based chemotherapy. Results This is a snapshot of Cohort 2 of the COMBAT study. As of September 2019, 22 patients have been enrolled, of which 15 are evaluable (i.e. received at least 1 dose of combination and have post-baseline CT). Median age 68, ECOG≤1 and 60% males. 15 SAEs were reported by 10 patients. 2 subjects were discontinued due to SAEs. Best Response by RECISTv1.1 for the evaluable population showed 4 partial response (PR) and 8 stable disease (SD) patients, a total of 12 subjects with disease control (DC) out of 15. Median PFS and OS were not reached. Notably all patients with PR and SD had an initial increase in CA 19-9 followed by a decrease. Tumor shrinkage began during the transient increase of CA 19-9. Conclusion Preliminary data from the ongoing COMBAT study Cohort 2 with the triple combination of BL-8040, Pembrolizumab and chemo, show promising ORR (4/15) and DC (12/15) results. Median PFS and OS have not yet been reached. Clinical trial identification NCT02826486. Legal entity responsible for the study The authors. Funding Biolinerx. Disclosure M. Hidalgo: Full / Part-time employment: Beth Israel Deaconess Medical Center; Full / Part-time employment: Harvard Medical School; Full / Part-time employment: Weill Cornell Medical College. V. Semenisty: Full / Part-time employment: Rambam Health Care Campus. B. Bockorny: Full / Part-time employment: Beth Israel Deaconess Medical Center; Research grant / Funding (institution): NanoView Biosciences. E. Borazanci: Full / Part-time employment: Honor-Health/TGen. D.D. von Hoff: Full / Part-time employment: Honor-Health/TGen. J. Feliu: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Seriver. M. Ponz Sarvise: Full / Part-time employment: Clinica Universidad de Navarra. D. Gutierrez Abad: Full / Part-time employment: Grupo Oncologia Fuenlabrada. A. Peled: Full / Part-time employment: Goldyne Savad Institute of Gene Therapy; Leadership role: Biokine Therapeutics Ltd. O. Bohana-Kashtan: Full / Part-time employment: Biolinerx. Y. Gozlan: Full / Part-time employment: Biolinerx. E. Sorani: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Biolinerx. M. Chaney: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. S. Kadosh: Full / Part-time employment: StatExcellence. A.V. Vainstein: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Biolinerx. T. Macarulla: Full / Part-time employment: Vall d´Hebron University Hospital.

A Phase Ib, Open-Label, Randomized Study to Assess Safety and Preliminary Efficacy of Tafasitamab (MOR208) or Tafasitamab + Lenalidomide in Addition to R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma: The First-Mind Trial

A Phase Ib, Open-Label, Randomized Study to Assess Safety and Preliminary Efficacy of Tafasitamab (MOR208) or Tafasitamab + Lenalidomide in Addition to R-CHOP in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma: The First-Mind Trial

Clinical Efficacy of L-Annamycin, a Liposomal Formulated Non-Cross-Resistant and Non-Cardiotoxic Anthracycline in Relapsed/Refractory AML Patients

Introduction: An anthracycline combined with cytarabine remains the backbone for induction therapy in the treatment of AML. De novo and acquired multidrug resistance (MDR) limits efficacy of clinically used anthracyclines. L-Annamycin, a novel anthracycline formulated in multilamellar liposomes, has been shown to overcome MDR in preclinical in vitro and in vivo doxorubicin resistant models as well as in clinical studies. Furthermore, preclinical toxicology studies comparing L-Annamycin to doxorubicin determined that the drug displayed dramatically reduced cardiotoxicity. These promising properties justified initiation of Phase I/II clinical trials in both the US and Europe using L-Annamycin for the treatment of R/R AML. Aims: The aim of the Phase I component is to determine the recommended Phase 2 dose (RP2D) of L-Annamycin for the treatment of R/R AML. The expansion Phase IIa studies are designed to assess L-Annamycin efficacy leading to a Phase II registration study for accelerated approval. Methods: The Phase I component is a standard 3+3 design to determine the RP2D. An additional 21 patients expansion phase will be enrolled at the RP2D to confirm efficacy. A DMC will monitor all data and decide if the study should continue and if any changes to the protocol are needed. Cardiotoxicity is being closely studied with stress 2-D echocardiography and biomarkers such as troponin. Results: This study is ongoing in both Europe and the USA. Even at a relatively low starting dose, two patients had sufficient response from a single 3-day course of L-Annamycin to qualify for a potentially curative bone marrow transplant. In total, 11 patients have completed at least one course of L-Annamycin with no signs of cardiotoxicity. Adverse events included one instance of Grade 2 mucositis, which resolved quickly. Summary/Conclusion: Despite progress in the treatment of AML most patients will relapse and die from refractory disease. Properties of L-Annamycin, including the ability to overcome MDR, a critical mechanism of resistance, and the lack of cardiac toxicity, are highly promising and fully justify a Phase II clinical study designed to demonstrate L-Annamycin efficacy in all patients with R/R AML agnostic of mutational status. Disclosures Shepard: Moleculin Biotech Inc: Employment, Equity Ownership. Silberman:Trovagene: Consultancy; Moleculin Biotech: Employment. Priebe:MOLECULIN BIOTECH INC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Emerging Insights in the Treatment of Psoriasis and Psoriatic Arthritis

Guselkumab is a monoclonal antibody targeting IL-23 that is approved for the treatment of patients with moderate-to-severe plaque psoriasis. Two of the posters reviewed in this article provide new insights into the clinical efficacy of guselkumab in patients with plaque psoriasis from the VOYAGE trials, firstly among those previously failing to respond to adalimumab and secondly in the setting of drug withdrawal and subsequent retreatment. In addition, data from a study reporting 56-week results from a Phase IIa study exploring the efficacy and safety of guselkumab in patients with psoriatic arthritis (PsA) are reviewed. The article concludes with a summary of the results of a survey highlighting the potential importance of evaluating gastrointestinal (GI) signs and symptoms during the management of patients with psoriasis.

1479. Clinical Efficacy and Safety Analysis Evaluating Oral Gepotidacin (GSK2140944) from a Phase IIa Study in the Treatment of Uncomplicated Urinary Tract Infections

BackgroundUrinary tract infections (UTIs) are very common, with approximately 11% of women >18 years of age experiencing at least 1 episode of acute cystitis per year. Multidrug resistance, typically associated with nosocomial infections, has now emerged at the community level making treatment options for UTIs more difficult. Gepotidacin (GEP), a first-in-class, novel triazaacenaphthylene antibacterial has demonstrated in vitro activity against uropathogens including E. coli and provides high and sustained urine concentrations. It selectively inhibits bacterial DNA replication through a unique mechanism not utilized by any currently approved antibacterial. GEP presents an opportunity to address an unmet medical need and warrants study as a potential new and effective oral treatment for acute cystitis.MethodsThis Phase IIa single-center study was designed primarily to evaluate plasma and urine pharmacokinetics (PK) of gepotidacin in female participants with acute cystitis. Safety data and clinical and microbiological efficacy of gepotidacin were also assessed as secondary and exploratory endpoints. All participants received oral gepotidacin 1,500 mg BID for 5 days (total of 10 doses) during clinic confinement. Pretreatment and posttreatment PK collections were performed together with safety, efficacy, microbiological, and exploratory assessments throughout the study.ResultsSummary of Exploratory Endpoints (ITT Population). Clinical Efficacy: All subjects had significant improvement of clinical symptoms (dysuria, frequency, urgency, lower abdominal pain) within 24 to 48 hours of treatment. Most subjects, (20/22; 90.9%) achieved symptom resolution at test of cure (ToC) and follow-up (F/U). Microbiological eradication was achieved independent of baseline CFU’s (see microbiology abstract). Safety Endpoint: Most common AEs involved the GI tract (diarrhea (18/22 [82%] and nausea 17/22 [77%]). Per investigator observation, tolerance to nausea was observed with repeat dosing. No withdrawal due to AE. There were no clinically relevant trends in safety laboratories, ECG, or vital signs.ConclusionThis first report of efficacy and safety in the treatment of acute cystitis supports further study of the clinical use of GEP in this indication.Disclosures All authors: No reported disclosures.

1480. Plasma and Urine Pharmacokinetic Analysis of Gepotidacin (GSK2140944) Following BID Oral Dosing in a Phase IIa Study for Treatment of Uncomplicated Urinary Tract Infections

BackgroundUncomplicated urinary tract infections (uUTIs) are very common, with approximately 11% of women >18 years of age experiencing at least 1 episode of acute cystitis per year [Foxman, 2000]. Multidrug resistance has now emerged at the community level and has made treatment approaches for UTIs more difficult [Hooton, 2012; Flamm, 2014; Sanchez, 2016]. Gepotidacin (GEP), a first-in-class, novel triazaacenaphthylene antibacterial has demonstrated in vitro activity against uropathogens, including E. coli. With its unique ability to selectively inhibit bacterial DNA replication by a means not utilized by any currently approved human therapeutic agent, GEP warrants further study as a potential opportunity to address an unmet medical need by providing a new and effective oral treatment option for acute cystitis.MethodsAll participants received oral GEP 1500 mg BID for 5 days (total of 10 doses) and PK sampling was performed on Days 1–5.ResultsGEP was rapidly absorbed with median Tmax values of 1.50 to 1.92 hours. Steady-state was attained by Day 3 with moderate accumulation in plasma following BID dosing (1.4 fold), which is consistent with an effective elimination half-life of 6.6 hours. Steady-state urine trough levels were high and remained above an MIC of 4 µg/mL over 12 hours. Approximately 20% of the dose was excreted in urine over the 12-hour dosing interval on Day 1, which increased to 31% on Day 4. Urinary AUC24hr (11945 µg hours/mL) was higher than the free plasma AUC24hr (39.4 µg hours/mL). Slightly higher GEP plasma and urine exposures were observed in uUTI patients compared with Phase I healthy subjects.ConclusionOral dosing of 1500 mg BID produces urine GEP exposures that exceed free plasma exposures by ~300-fold. Urine concentrations were also higher than the GEP MIC90 values for common UTI pathogens, such as E. coli (MIC90 = 4 µg/mL), suggesting that GEP warrants further clinical study for the treatment of uUTI. Disclosures All authors: No reported disclosures.

713 A Randomized, Multicenter, Double-Blind, Placebo-Controlled Study of a Targeted Release Oral Cyclosporine Formulation in the Treatment of Mild to Moderate Ulcerative Colitis: Influence of Immunosuppressants at Baseline

INTRODUCTION: Patients (pts) with ulcerative colitis (UC) who have failed immunosuppressants (IM) and biologics have demonstrated poorer response to subsequent therapies. 1 Cyclosporine (CsA) could be an alternative option since it has similar efficacy and safety to infliximab for severe UC, 2 but its use is limited due to concerns regarding systemic toxicity. ST-0529 is a novel oral formulation of CsA that delivers the drug directly to the colon, allowing for precise targeting of the diseased tissue while potentially limiting the risk of systemic toxicity. METHODS: A phase IIa study was conducted in a total of 118 subjects with baseline Disease Activity Index (DAI) < 6 (mild UC) or ≥6 (moderate UC), randomized 1:1 to receive 75 mg ST-0529 once daily (n = 53) or placebo (n = 65) for 4 weeks. The primary endpoint was the induction of clinical remission (DAI score ≤2, with no individual score >1 and rectal bleeding subscore of 0 or 1). The secondary endpoints were safety and tolerability, mucosal healing, clinical response, and histological healing. 3,4 Post-hoc subgroup analysis was conducted in 93 subjects with moderate UC, of whom 75 received at baseline 5-ASA alone or in combination (n = 51, with/without steroids; n = 24, with/without IM) to evaluate the impact of them on clinical improvement (DAI reduction ≥3) and composite subscores (rectal bleeding and stool frequency with or without mucosal appearance evaluation). RESULTS: Table 1 shows the influence of baseline medications on the improvement of DAI scores in subjects with moderate UC, and Tables 2 and 3, the impact of IM on the analyzed parameters. Safety was balanced for the overall population. CONCLUSION: This analysis showed that clinical improvement and composite subscores were influenced by baseline medication in pts with moderate UC. The poorer response in the IM treated group was potentially a function of severity or refractory disease and/or concomitant use of UC medication (prednisone < 10 mg/day, 5-ASAs or purine analogues) at baseline. Concomitant UC medications were not restricted at study entry as long as pts maintained stable dosing regimens throughout. These preliminary data support further investigation of ST-0529 usage as a twice daily treatment for the induction and maintenance of remission in UC pts with moderate disease, which will be the focus of the phase IIb trial.

5234KAND567, the first selective small molecule CX3CR1 antagonist in clinical development, mediates anti-inflammatory cardioprotective effects in rodent models of atherosclerosis and myocardial infarction

Abstract Background Fractalkine is a chemokine that mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and monocytes and has been implicated in the inflammation-driven pathology of cardiovascular disease. More specifically, fractalkine signaling has been proposed to contribute to increased infarct size and enhanced atherosclerotic plaque vulnerability in patients and experimental models. Blocking fractalkine/CX3CR1 signaling is suggested as a promising anti-inflammatory strategy for the treatment of both acute and chronic cardiovascular disease. KAND567 is a small molecule, selective, non-competitive, allosteric antagonist of the fractalkine receptor CX3CR1, that is under preparation for a clinical phase IIa study in AMI patients. Purpose To explore the therapeutic effects of the short and long term administration of KAND567 in experimental rodent models of acute myocardial infarction and atherosclerosis, respectively. Methods Myocardial infarction was induced in Wistar rats (N=6–8 per group) by ligation of the left anterior descending (LAD) coronary artery for 30 minutes followed by 2 h of reperfusion. The drug or vehicle infusion started either 5 min before or 30 min after start of reperfusion and continued during the remainder of the experiment. Hearts were collected and subjected to triphenyl tetrazolium chlorine (TTC) staining and the infarction area/area at risk of the left ventricle was determined by planimetry and compared against vehicle group. Atherosclerosis-prone LDL-receptor deficient mice on a high-cholesterol diet, (N=15–25 per group) were treated with KAND567 for 15–23 weeks. Atherosclerotic plaque development in the thoracic arch was determined by ultrasound imaging and histology. Immunohistochemistry was used to follow changes in the cellular composition in the atherosclerotic lesions. Results In the acute myocardial infarction study, the infusion of KAND567 before the start of reperfusion significantly reduced infarcted/risk area (by up to 50%) as compared to the vehicle group. However, the infusion had no effect on the infarct size when administration was initiated 30 min after start of reperfusion. In the atherogenesis study, oral treatment with KAND567 significantly reduced vascular macrophage infiltration by 50% and reduced intima media thickness. Furthermore, reduced plaque volume and a more stable plaque phenotype was noted following treatment with KAND567. KAND567 experimental results Conclusion Specific inhibition of fractalkine-driven inflammation by KAND567 provides cardioprotective, anti-atherosclerotic and plaque stabilizing effects via mechanisms related to immune cell infiltration, in rodent models. Further studies should be initiated to test if KAND567 is a potential candidate drug, targeting the excessive inflammatory injury associated with ischemia/reperfusion in myocardial infarction and providing plaque stabilization by reducing inflammatory risk for recurrent coronary events.

870P - A phase IIa study of radium-223 dichloride (Ra-223) alone or in combination with abiraterone acetate or enzalutamide in metastatic castration-resistant prostate cancer (mCRPC)

870P - A phase IIa study of radium-223 dichloride (Ra-223) alone or in combination with abiraterone acetate or enzalutamide in metastatic castration-resistant prostate cancer (mCRPC)

87Effects of the chymase inhibitor fulacimstat on adverse cardiac remodelling after acute myocardial infarction - Results of the CHIARA MIA 2 trial

Abstract Introduction Adverse cardiac remodelling represents the most important risk factor for the development of heart failure (HF) after myocardial infarction (MI). Chymase is a protease that generates locally pro-fibrotic factors such as angiotensin II, TGFβ, and matrixmetallproteases that contribute to tissue remodelling. Purpose This phase IIa study examined the effects of the chymase inhibitor fulacimstat on functional parameters of adverse cardiac remodelling after acute MI. Methods A double-blind, multinational, randomized, placebo-controlled study was performed in patients after first STEMI who were treated with primary percutaneous coronary intervention within 24h of symptom onset. To enrich for patients at risk of adverse remodelling, main inclusion criteria were a left-ventricular ejection fraction (LVEF)≤45% and an infarct size>10% on day 5 to 9 post MI as measured by cardiac MRI. On day 6 to 12 post MI, patients were randomized to treatment with either 25 mg fulacimstat (n=54) or placebo (n=53) twice daily on top of standard of care. The changes in LVEF, LVEDVI, and LVESVI from baseline to 6 months of treatment were analyzed by a central blinded cardiac MRI core laboratory. Results Fulacimstat was safe and well tolerated, 64.8% of patients treated with fulacimstat and 75.5% of patients treated with placebo reported treatment emergent adverse events. Fulacimstat achieved exposures that were approximately 10-fold higher than those predicted to be required for minimal therapeutic activity. After six months of treatment, there were no effects of fulacimstat compared to placebo on the changes in LVEF, LVEDVI, and LVESVI (see Table). Analysis of primary efficacy parameters Parameter Placebo Fulacimstat p-value LVEF (%) baseline 37.2±6.1 39.1±5.5 0.15 6 months 41.2±8.4 42.6±8.4 0.45 delta 4.0±5.0 3.5±5.4 0.69 LVEDVI (mL/m2) baseline 80.0±17.1 77.4±18.2 0.51 6 months 85.1±19.1 84.7±23.4 0.94 delta 5.1±18.9 7.3±13.3 0.54 LVESVI (mL/m2) baseline 50.5±13.0 47.3±12.3 0.26 6 months 51.1±16.9 49.6±18.1 0.71 delta 0.6±14.8 2.3±11.2 0.56 Data are given as mean ± standard deviation. Conclusion Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on adverse cardiac remodelling in the experimental setting of this study. Acknowledgement/Funding The study was funded by its sponsor BAYER AG

A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study

BackgroundClaudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells. Patients and methodsPatients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile. ResultsFrom September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent. ConclusionsZolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials. ClinicalTrials.gov numberNCT01197885.

Pharmacokinetic profile, safety, and tolerability of clascoterone topical cream 1% in subjects with moderate-to-severe acne vulgaris: An open-label phase IIa study

Pharmacokinetic profile, safety, and tolerability of clascoterone topical cream 1% in subjects with moderate-to-severe acne vulgaris: An open-label phase IIa study

Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD

BackgroundCHF6001 is a novel inhaled phosphodiesterase-4 inhibitor. This Phase IIa study assessed the effects of CHF6001 on markers of inflammation in induced sputum and blood in patients with chronic obstructive pulmonary disease (COPD).MethodsThis was a multicentre, three-period (each 32 days), three-way, placebo-controlled, double-blind, complete-block crossover study. Eligible patients had COPD, chronic bronchitis, and were receiving inhaled triple therapy for ≥2 months. Patients received CHF6001 800 or 1600 μg, or matching placebo twice daily via multi-dose dry-powder inhaler (NEXThaler). Induced sputum was collected pre-dose on Day 1, and post-dose on Days 20, 26 and 32. Blood was sampled pre-dose on Day 1, and pre- and post-dose on Day 32.ResultsOf 61 randomised patients, 54 (88.5%) completed the study. There were no significant differences between groups for overall sputum cell count, or absolute numbers of neutrophils, eosinophils or lymphocytes. CHF6001 800 μg significantly decreased the absolute number and percentage of macrophages vs placebo.In sputum, compared with placebo both CHF6001 doses significantly decreased leukotriene B4, C-X-C motif chemokine ligand 8, macrophage inflammatory protein 1β, matrix metalloproteinase 9, and tumour necrosis factor α (TNFα). In blood, both CHF6001 doses significantly decreased serum surfactant protein D vs placebo. CHF6001 1600 μg significantly decreased TNFα ex-vivo (after incubation with lipopolysaccharide).ConclusionThe data from this study show that CHF6001 inhaled twice daily has anti-inflammatory effects in the lungs of patients with COPD already treated with triple inhaled therapy.Trial registrationThe study is registered on ClinicalTrials.gov (NCT03004417).

Uridine Cytidine Kinase 2 as a Potential Biomarker for Treatment with RX-3117 in Pancreatic Cancer.

The novel cytidine analog RX-3117, which is activated by uridine-cytidine kinase 2 (UCK2), shows encouraging activity in pancreatic and bladder cancer Phase IIa studies. In this study we highlight the potential role of UCK2 as a biomarker for selecting patients for RX-3117 treatment. The online genomics analysis and visualization platform, R2, developed by the Oncogenomics department at the AMC (Amsterdam, The Netherlands) was used for in silico UCK2-mRNA correlation with overall survival of pancreatic cancer patients, while UCK2 protein expression was evaluated by immunohistochemistry on pancreatic tumor formalin-fixed-paraffin-embedded sections from independent pancreatic cancer patients. mRNA expression was also determined for SUIT-2, PANC-1 and PDAC-3. Lastly, the drug sensitivity to RX-3117 was investigated using the Sulforhodamine-B cytotoxicity assay. The in silico data showed that a high UCK2-mRNA expression was correlated with a shorter overall survival in pancreatic cancer patients. Moreover, UCK2 protein expression was high in 21/25 patients, showing a significantly shorter mean. Overall Survival (8.4 versus 34.3 months, p=0.045). Sensitivity to RX-3117 varied between 0.6 and 11 μM. Pancreatic cancer cells are sensitive to pharmacologically achievable RX-3117 concentrations and UCK2 might be exploited as a biomarker for patient treatment selection.

Efficacy and Safety of Udenafil for the Treatment of Pulmonary Arterial Hypertension: a Placebo-controlled, Double-blind, Phase IIb Clinical Trial

PurposeUdenafil is an oral phosphodiesterase-5 inhibitor approved for the treatment of erectile dysfunction. In a multicenter, placebo-controlled, randomized Phase IIa study, the reduction of pulmonary vascular resistance index was greater with a 50-mg baseline dose of udenafil than with the 100-mg dose, the cardiac index did not decrease at most points, and the safety was excellent, suggesting that 50-mg udenafil could be used in a Phase IIb trial. MethodsIn this 16-week, double-blind, placebo-controlled study, 63 patients with pulmonary arterial hypertension were randomized to receive 50-mg udenafil or a placebo BID. The primary efficacy end point was the 6-min walking distance. The secondary efficacy end points were the Borg dyspnea score and time to clinical worsening. Patients who completed the 16-week study could participate in a long-term extension study. Findings: In terms of the difference between the baseline and 16-week 6-min walking distance in both groups, the mean placebo-corrected treatment effect was 25 (58) m (P = 0.0873). Among the patients with a history of endothelin receptor antagonist therapy, the treatment effect at week 16 between the udenafil and placebo groups was 34 (60) m (P = 0.0460). However, there were no significant differences in the Borg dyspnea score and time to clinical worsening between groups. The safety profile and adverse effects of udenafil were similar to those of typical phosphodiesterase-5 inhibitors seen in previous studies. ImplicationsUdenafil has a favorable safety profile and improves exercise capacity in patients with pulmonary arterial hypertension. ClinicalTrials.gov identifier: NCT01553721.

PF277 ALICE: AN AML STUDY WITH LSD1 INHIBITION IN COMBINATION WITH AZACITIDINE IN THE ELDERLY

Background:Acute Myeloid Leukaemia (AML) is primarily a disease of older people and its incidence is rising. Survival rates decrease with age as does the achievement of complete remission (CR) with current chemotherapy, for which there is no consensus for optimal re‐therapy. Azacitidine is approved for AML with 20–30% blasts. Lysine‐specific demethylase (LSD1) has been shown to be a partner in some gene transformations in AML and helps sustain the oncogenic process. Iadademstat (ORY‐1001) is a highly potent and selective LSD1 inhibitor that has been shown to be effective in preclinical models (both alone or in combination with other compounds, including Azacitidine); and remarkably safe in a phase I study, where it also demonstrated preliminary anti‐leukaemic activity as monotherapy. Iadademstat in combination with azacitidine may thus offer a novel treatment option for a patient group with limited current options.Aims:To assess safety, tolerability and dose finding of iadademstat in combination with azacitidine, and to measure the clinical activity such as time to response (TTR), duration of response (DOR) and objective response (OR) of this combination in older patients who are not eligible to be treated with intensive chemotherapy. Other assessments include haematological improvement and overall survival, along with PK/PD measures (including a set of 6 blood biomarkers).Methods:This is a two‐stage phase II multicentre open‐label study of safety, tolerability, dose‐finding and efficacy of iadademstat in combination with azacitidine in elderly patients. The dose finding stage will dose 12–18 patients with a starting dose of iadademstat of 90 μg/m2/d. Depending on the DLTs observed, iadademstat may be escalated or de‐escalated. Once the Recommended Phase II Dose (RP2D) is identified, an expansion cohort of 18 patients will be enrolled and treated with iadademstat combined with azacitidine. In all cases patients to be recruited correspond to subjects ≥ 60 years of age with AML according to World Health Organization (WHO) classification, who are considered by the investigator to be ineligible for intensive chemotherapy regimen at that time or have refused standard chemotherapy, and which may not have received prior treatment for AML other than Hydroxyurea.Results:The patient assessments of all the enrolled study subjects will be presented as per May 2019 cut‐off, with particular emphasis on available preliminary efficacy outcomes. Current recruitment rate suggests that the available data will include the safety data after the first‐cycle of treatment of the first 8–10 participants. Moreover, preliminary efficacy data of all subjects in any of the cycles will be also presented.Summary/Conclusion:This first combination Phase IIa study with iadademstat aims to further extend the safety and efficacy of iadademstat in the oncology field; in this case, in older unfit leukemic patients as a first line treatment, providing initial support for the effect of its holistic unique MoA, which has been recently related to the potentiation of several other approaches, including immune‐oncology therapies in solid tumors.