Clinical Efficacy Measures Research Articles

CA209-9KY: Phase II Study of IMRT Re-Irradiation and Concurrent/Adjuvant Nivolumab (Nivo) in Patients With Loco Regionally Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma (HNSCC) ― Toxicity and Quality of Life (QoL) Results

CA209-9KY: Phase II Study of IMRT Re-Irradiation and Concurrent/Adjuvant Nivolumab (Nivo) in Patients With Loco Regionally Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma (HNSCC) ― Toxicity and Quality of Life (QoL) Results

Cost per responder for upadacitinib vs abatacept in patients with moderate-to-severe Rheumatoid Arthritis in Italy

Purpose: The objective of this economic evaluation was to compare the cost per responder between upadacitinib and abatacept (intravenous [iv] or subcutaneous [sc]) in patients with moderate-to-severe Rheumatoid Arthritis (RA) in Italy.
 Methods: The clinical efficacy was assessed based on SELECT-CHOICE study results. The clinical efficacy of upadacitinib and abatacept (iv or sc) was measured by Clinical Remission (CR), Low Disease Activity (LDA) and American College of Rheumatology response (ACR20, 50 and 70). The treatment cost was based on the number of administrations dispensed at 12 or 24 weeks. The cost per responder was adopted as a cost-effectiveness indicator.
 Results: Independent of the clinical efficacy measure used and the duration of treatment considered, the cost per responder was consistently lower for upadacitinib compared to abatacept (iv or sc) across all clinical measures. For example, considering the CR at 24 weeks, the cost per responder for upadacitinib was € 9,417 compared to € 17,817 for abatacept sc or to € 23,110 for abatacept iv. The differences in the cost per responder between upadacitinib and abatacept (iv or sc) increased when higher ACR response levels were considered.
 Conclusions: These results suggested that upadacitinib is a cost-effectiveness option compared to abatacept (iv or sc) from the perspective of the Italian National Health Service in patients with moderate-to-severe Rheumatoid Arthritis in Italy.

Timing of dornase alfa inhalation for cystic fibrosis.

Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review. To determine whether the timing of dornase alfa inhalation (in relation to airway clearance techniques or morning versus evening inhalation) has an impact on objective and subjective measures of clinical efficacy in people with cystic fibrosis. Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, thePhysiotherapy Evidence Database (PEDro), clinical trial registries and international cystic fibrosis conference proceedings. Date of the most recent search: 12 October 2020. Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the trial with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed. We assessed the quality of the evidence using GRADE. We identified 115 trial reports representing 55 trials, of which five trials (providing data on 122 participants) met our inclusion criteria. All five trials used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials (98 participants) compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second (very-low quality evidence). Similarly, forced vital capacity (low-quality evidence) and quality of life (very-low quality evidence) were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small trials in children (7 to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant. In one trial (25 participants), morning versus evening inhalation had no impact on lung function or symptoms (low-quality evidence). The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and trials with variable follow-up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alfa inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day.Further research is warranted.

AB005. Assessing meaningful changes in disease activity as clinical trial clinical efficacy measures for cutaneous lupus erythematosus

To date, there are no approved treatments for cutaneous lupus erythematosus (CLE), a disease known to significantly burden a patient’s quality of life (QoL). Clinical trials are important for the advancement of treatments and outcome measures of these trials should reflect clinically meaningful improvement in disease activity and its effect on QoL. Currently, clinical trials use an efficacy measure of ≥50% improvement in disease activity, defined by the Cutaneous Lupus Disease Area and Severity Index activity (CLASI-A) score, in patients with an initial CLASI-A score of ≥10. However, the degree of improvement in disease activity needed to predict a meaningful impact on QoL has not been defined. This is a retrospective study of 126 patients enrolled in a longitudinal research database. Using a linear regression model, we calculated the percent change and difference needed in CLASI-A to have an important impact on QoL, defined as a 9.38-point and a 7.37-point improvement in the Emotions and Symptoms subscales of Skindex-29, respectively. In patients with an initial CLASI-A score ≥8, a decrease by 42.1% and a decrease by 31.0% in disease activity is associated with a meaningful impact in the Emotions and the Symptoms subscales, respectively. Using a CLASI-A score ≥8 for trial entry allows for inclusion of patients with milder disease for whom improvement of CLASI-A by ≥50% has a meaningful impact on QoL, as determined by the Emotions and Symptoms subscales. In patients with moderate to severe initial disease, a respective decrease in activity by seven and five-points is not only clinically significant, but also has a meaningful impact on the Emotions and Symptoms subscales. Our findings establish appropriate trial endpoints by determining clinically significant change in disease activity associated with meaningful changes in patients’ QoL.

Cancer Stem Cell (CSC) Inhibitors in Oncology-A Promise for a Better Therapeutic Outcome: State of the Art and Future Perspectives.

Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal, tumorigenicity, pluripotency, chemoresistance, differentiation, invasive ability, and plasticity, reside in specialized tumor niches and are responsible for tumor maintenance, metastasis, therapy resistance, and tumor relapse. The new-age "hierarchical or CSC" model of tumor heterogeneity is based on the concept of eradicating CSCs to prevent tumor relapse and therapy resistance. Small-molecular entities and biologics acting on various stemness signaling pathways, surface markers, efflux transporters, or components of complex tumor microenvironment are under intense investigation as potential anti-CSC agents. In addition, smart nanotherapeutic tools have proved their utility in achieving CSC targeting. Several CSC inhibitors in clinical development have shown promise, either as mono- or combination therapy, in refractory and difficult-to-treat cancers. Clinical investigations with CSC marker follow-up as a measure of clinical efficacy are needed to turn the "hype" into the "hope" these new-age oncology therapeutics have to offer.

PR001 gene therapy improved phenotypes in models of Parkinson’s disease with GBA1 mutation

AbstractBackgroundMutations in GBA1, which result in deficiency of lysosomal enzyme glucocerebrosidase (GCase), are the most common known genetic cause of Parkinson’s disease (PD). Decreased GCase activity in PD patients with GBA1 mutations (PD‐GBA) causes accumulation of glycolipid substrates, which leads to lysosomal dysfunction and neuroinflammation. With our gene therapy product candidate, PR001, we aim to increase GCase activity in PD‐GBA patients in order to ameliorate the lysosomal dysfunction and slow or stop disease progression.MethodGCase activity and α‐Synuclein levels were assessed following PR001 treatment in vitro in a cell line and in primary rodent neurons. Two mouse models of GCase deficiency that display phenotypic characteristics consistent with PD‐GBA, including decreased GCase activity, glycolipid substrate accumulation, motor behavioral phenotypes, and neuroinflammation, were used to assess the efficacy of PR001 in vivo. Safety endpoints were examined in the two mouse models as well as in nonhuman primates.ResultPR001 treatment in vitro increased GCase activity and decreased α‐Synuclein levels. In PD‐GBA models in vivo, PR001 treatment increased GCase activity, decreased glycolipid substrate accumulation, improved motor abnormalities, and decreased neuroinflammation. These therapeutic benefits were persistent, with lasting effects observed at 6 months post‐treatment. Safety studies demonstrated that PR001 was well tolerated at all doses tested.ConclusionOverall, PR001 displayed efficacy in multiple independent cell and animal models of PD‐GBA and no PR001‐related safety events or adverse findings in mice and nonhuman primates. These findings demonstrate that PR001 is a promising potential gene therapy for PD‐GBA patients. We have recently initiated a Phase 1/2 clinical trial to investigate safety, tolerability, and effects on biomarkers and measures of clinical efficacy.

The quality of life index: a pilot study integrating treatment efficacy and quality of life in oncology

The majority of women diagnosed with breast cancer will experience some form of drug-related toxicity and subsequent impairments in Health-related Quality of Life (HRQoL). Despite this, HRQoL is assessed inconsistently and there is no validated method to integrate HRQoL data into the assessment of therapeutic agents. This proof of concept study utilizes data from the neoadjuvant I-SPY 2 clinical trial to describe the development of the Quality of Life Index (QoLI) measure. The QoLI represents a single composite score that incorporates validated longitudinal measures of clinical efficacy and QoL and one that permits a more comprehensive, direct comparison of individual therapeutic agents. Preliminary data suggest the QoLI is able to distinguish between agents based on their efficacy and toxicity; with further validation, the QoLI has the potential to provide more patient-centered evaluations in clinical trials and help guide treatment decision making in breast cancer and other oncologic diseases.

S0683 Absence of Bowel Urgency Is Associated With Improvements in Clinical Outcomes in Patients With Ulcerative Colitis Receiving Mirikizumab

INTRODUCTION: Bowel urgency is one of the most common yet often overlooked symptoms experienced by patients with UC (1). Mirikizumab (miri), a humanized monoclonal antibody directed against the p19 subunit of IL-23, demonstrated efficacy (2), was well-tolerated, and significantly reduced urgency (3) in a phase 2 randomized clinical trial in patients with ulcerative colitis (UC). Here we show the relationship between patient-reported urgency and improvements in measures of clinical efficacy. METHODS: Patients (N = 249) were randomized 1:1:1:1 to receive intravenous placebo, miri 50mg or 200mg with possibility of exposure-based dose increases, or fixed miri 600 mg every 4 weeks. Patients who achieved clinical response (n = 106) at Week 12 were re-randomized 1:1 to double-blind maintenance treatment with miri 200 mg subcutaneously every 4 or 12 weeks and treated through Week 52. Analyses of the association between urgency and clinical efficacy at Weeks 12 and 52 were conducted by pooling treatment arms in the induction and maintenance periods, respectively. Absence of urgency was defined as reporting no urgency for the three consecutive days prior to each scheduled visit, regardless of urgency status at BL. Patients with missing urgency data were imputed as having experienced urgency at that visit. Clinical efficacy in patients with presence or absence of urgency was compared using logistic regression models adjusting for geographic region, prior biologic experience, age, and sex. RESULTS: As previously reported, miri significantly reduced urgency over 52 weeks of treatment (3). At Week 12 and Week 52, patients with absence of urgency had significantly higher rates of improvement on all clinical outcomes examined (clinical remission, clinical response, stool frequency (SF) remission, rectal bleeding (RB) remission, endoscopic remission, histologic remission, mucosal healing; see Table 1 for definitions and P values) compared to those with presence of urgency. CONCLUSION: Absence of urgency is strongly associated with improved clinical, endoscopic and histologic outcomes. These findings suggest that urgency may be a useful surrogate marker of disease activity and is a distinct symptom that is important to discuss with patients with UC.Table 1

New Electrosurgical Technologies for High Amputations of the Lower Limbs

We present here results obtained using hightech bipolar instruments with an electrosurgical device and a non-linear dynamic feedback system for excision of large tissue blocks. The effectiveness of using bipolar scissors with blades made of nanostructured zirconium dioxide and thermostabilized bipolar forceps was assessed using high amputation of the lower limbs as an example. Significant results were obtained showing that the use of innovatory electrosurgical technologies for transfemoral amputation in patients with terminal-stage peripheral arterial disease increases the typical clinical measures of efficacy by an average of 39%. The results can be taken as the basis for a new method of using electrosurgical technology for high amputations of the lower limbs.

TILT: Time-Lapse Imaging Trial\u2014a pragmatic, multi-centre, three-arm randomised controlled trial to assess the clinical effectiveness and safety of time-lapse imaging in in vitro fertilisation treatment

BackgroundSubfertility is a common problem for which in vitro fertilisation (IVF) treatment is commonly recommended. Success rates following IVF are suboptimal and have remained static over the last few years. This imposes a considerable financial burden on overstretched healthcare resources. Time-lapse imaging (TLI) of developing embryos in IVF treatment is hypothesised to improve the success rates of treatment. This may be either by providing undisturbed culture conditions or by improving the predictive accuracy for optimal embryo selection from a cohort of available embryos. However, the current best evidence for its effectiveness is inconclusive.MethodsThe time-lapse imaging trial is a pragmatic, multi-centre, three-arm parallel-group randomised controlled trial using re-randomisation. The primary objective of the trial is to determine if the use of TLI or undisturbed culture in IVF treatment results in a higher live birth rate when compared to current standard methods of embryo incubation and assessment. Secondary outcomes include measures of clinical efficacy and safety. The trial will randomise 1575 participants to detect an increase in live birth from 26.5 to 35.25%.DiscussionIn the absence of high-quality evidence, there is no current national guidance, recommendation or policy for the use of TLI. The use of TLI is not consistently incorporated into standard IVF care. A large, pragmatic, multi-centre, trial will provide much needed definitive evidence regarding the effectiveness of TLI. If proven to be effective, its incorporation into standard care would translate into significant clinical and economic benefits. If not, it would allow allocation of resources to more effective interventions.Trial registrationISRCTN registry ISRCTN17792989. Prospectively registered on 18 April 2018

Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis

ObjectiveTo characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures.MethodsThe project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment. T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed. Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked.ResultsVariable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types. Evidence of increased Treg competence was observed after each treatment course. CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells. Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk. In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells.ConclusionsLymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments. Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types. Several immune measures were identified as possible biomarkers of lesion activity. Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS.Trial registrationParent trials for this study are registered with ClinicalTrials.gov: CARE-MS II: NCT00548405, CARE-MS II extension: NCT00930553 and ISS: NCT01307332.

Measuring airway clearance outcomes in bronchiectasis: a review.

While airway clearance techniques (ACTs) are recommended for individuals with bronchiectasis, many trials have demonstrated inconsistent benefits or failed to reach their primary outcome. This review determined the most common clinical and patient-reported outcome measures used to evaluate the efficacy of ACTs in bronchiectasis. A literature search of five databases using relevant keywords and filtering for studies published in English, up until the end of August 2019, was completed. Studies included randomised controlled trials, using crossover or any other trial design, and abstracts. Studies were included where the control was placebo, no intervention, standard care, usual care or an active comparator. Adults with bronchiectasis not related to cystic fibrosis were included. Extracted data comprised study authors, design, duration, intervention, outcome measures and results. The search identified 27 published studies and one abstract. The most common clinical outcome measures were sputum volume (n=23), lung function (n=17) and pulse oximetry (n=9). The most common patient-reported outcomes were health-related quality of life (measured with St George's Respiratory Questionnaire, n=4), cough-related quality of life (measured with Leicester Cough Questionnaire, n=4) and dyspnoea (measured with Borg/modified Borg scale, n=8). Sputum volume, lung function, dyspnoea and health- and cough-related quality of life appear to be the most common clinical and patient-reported measures of airway clearance treatment efficacy.

A phase II clinical trial of the phosphatidylserine targeting antibody, bavituximab, in combination with pembrolizumab in patients with advanced hepatocellular carcinoma.

TPS599 Background: Phosphatidylserine (PS) is an immunosuppressive lipid segregated to the inner leaflet of the plasma membrane of normal cells. PS is externalized to the outer leaflet of the plasma membrane on cells that line tumor blood vessels, tumor cells and exosomes in the tumor microenvironment creating a specific target for anticancer treatments. Bavituximab is a PS targeting antibody that binds to PS via β2 glycoprotein-1 (β2GP1), an abundant serum glycoprotein. Bavituximab can modulate the tumor immune microenvironment to promote anti-tumor immune activity. This clinical trial is evaluating the effect of combining bavituxumab and the checkpoint inhibitor pembrolizumab in patients with advanced hepatocellular carcinoma (HCC). Methods: This is a single arm phase 2 clinical trial for patients with histologically confirmed HCC which is not eligible for curative and/or loco-regional therapy. No prior systemic therapy for HCC is allowed. Patients should be > 18 years, have Child-Pugh Score A, ECOG 0-1 and meet the following laboratory criteria: total bilirubin ≤ 2.0, INR ≤ 1.7; Hgb ≥ 8.5 g/dl; AST, ALT ≤5 times ULN; platelet ≥ 50,000/mm3; and albumin ≥ 2.5 g/dl. Major exclusion criteria include thromboembolic event within the last 6 months, clinically evident ascites, GI bleeding within 2 months, uncontrolled hypertension, HIV and autoimmune disease (except DM1, childhood allergies and thyroid abnormalities if adequately controlled. Dosing is as follows: Bavituximab: 3 mg/kg IV weekly, pembrolizumab: 200 mg IV every 3 weeks. The primary objective is to determine the overall response rate (ORR) of therapy. Secondary objectives are to determine the safety, tolerability and other measures of clinical efficacy (overall survival, 6 month PFS, and duration of response). Tumor and blood samples are being collected to assess for pharmacodynamic biomarkers. A minimax two-stage method will be used to analyze ORR after the first 15 patients are accrued. If 3 or more of the first 15 patients have either a complete or partial response, 13 additional patients will be enrolled. ORR will be analyzed by RECIST 1.1 criteria. Clinical trial information: NCT03519997.

832 Pharmacokinetics and Exposure-Response Relationships of Ustekinumab in Patients With Ulcerative Colitis: Results From the UNIFI Induction and Maintenance Studies

INTRODUCTION: Serum concentrations of monoclonal antibody-based biologics have been shown to correlate with their efficacy. PK, exposure-response (ER), and immunogenicity of ustekinumab (UST) were evaluated in UNIFI induction and maintenance studies in UC. Induction results were presented previously. METHODS: PK, immunogenicity, efficacy & safety data were obtained from induction and maintenance Phase 3, double-blind, PBO-controlled trials in adults with moderate-severe UC. Pts (n = 961) in the induction study received a single IV infusion at Wk0 of PBO, UST 130 mg, or UST ∼6 mg/kg UST. Responders to a single IV infusion of UST (n = 523) were randomly assigned to receive SC PBO, UST 90 mg q12w, or UST 90 mg q8w. Blood samples were collected to measure serum UST concentration and antibodies to ustekinumab. Relationships between serum UST concentrations & efficacy measures, and safety outcomes were evaluated. RESULTS: Serum UST concentrations over time were dose proportional, unaffected by concomitant immunosuppressants, & similar between pts who were biologic failures & non-failures. Median peak serum UST concentrations in the induction study were 43.2 μg/mL & 127.0 μg/mL for the 130 mg & ∼6 mg/kg dose groups, respectively. At induction Wk8, median UST concentrations were 2.51 μg/mL & 8.59 μg/mL, respectively. Steady-state was reached by the start of the second SC maintenance dose. Median steady-state trough serum UST concentrations over time in the UST q8w group (2.69 to 3.09 μg/mL) were 3-fold higher than in the q12w group (0.92 to 1.19 μg/mL). Serum UST concentrations were positively associated with response & remission rates (Table 1), and there was an inverse association between serum UST concentrations and CRP and fecal calprotectin levels. No relationship was observed between serum UST concentrations & the incidence of infections, serious infections or SAEs during induction or maintenance. 3.4% of pts receiving UST maintenance had antibodies to UST through 1 year using a drug-tolerant assay vs. 9.1% with PBO; no impact of antibodies on efficacy was observed. CONCLUSION: Serum UST concentrations were approx. dose-proportional. A positive ER of serum UST with clinical efficacy measures and an inverse relationship with inflammatory markers was observed during UST IV induction & SC maintenance. Adverse events including infections did not increase with increased serum UST concentrations. These findings are consistent with those in UST for Crohn’s disease.

170 Forecasting Phase 3 Dose-Response for Abrocitinib, an Oral Janus Kinase 1 Selective Inhibitor, Using Investigator’s Global Assessment and Eczema Area and Severity Index

Abrocitinib is an oral Janus Kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis (AD). To support a phase 3 study design, dose-response modeling and simulation was used to predict the relationship between abrocitinib dose and clinical AD efficacy measures. Investigator’s Global Assessment (IGA) response (clear [0] or almost clear [1] with ≥2-grade improvement from baseline) at week 12 and Eczema Area and Severity Index (EASI) score over time were measured in a phase 2b, randomized, double-blind, proof-of-concept, dose-ranging trial in patients with moderate-to-severe AD (NCT02780167; N=245 IGA records [nonresponder imputation], N=2220 EASI records from 263 patients). IGA response at week 12 was adequately described by an Emax dose-response model (ie, landmark logistic regression). EASI score, from baseline through week 16, was adequately described across time by a linear dose-response model. The final models were used to simulate IGA response rates (as defined above) and EASI75 response rates (≥75% reduction in EASI score from baseline) in 1000 simulated trials with cohorts of 50 patients/dose. Simulations answered the question: what is the median (90% prediction interval) response rate at week 12 expected in a subsequent AD trial? The predicted rates for IGA response were 6% (0-14%), 26% (14-38%), and 38% (26-54%), and for EASI75 response were 21% (12-30%), 50% (38-62%), and 62% (52-74%) for placebo and abrocitinib doses of 100 mg and 200 mg, respectively. Based on these findings, once-daily abrocitinib doses of 100 mg and 200 mg were forecasted to provide clinically meaningful response relative to placebo in the current randomized, double-blind, placebo-controlled phase 3 trial in patients aged ≥12 years with moderate-to-severe AD.

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined. This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n=40) with mild-to-moderate AD. Two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14days. Patients then applied crisaborole (open-label) to all affected areas for 28days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15. Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P<10-15) that was sustained until day 15 (92.90% vs 49.59%, P<10-15). Crisaborole significantly modulated key AD biomarkers versus vehicle, including TH2 and TH17/TH22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function. Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD.

IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis

Hyperactivity of the IL-23/IL-17 axis is central to plaque psoriasis pathogenesis. Secukinumab, a fully human mAb that selectively inhibits IL-17A, is approved for treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. Secukinumab improves the complete spectrum of psoriasis manifestations, with durable clinical responses beyond 5years of treatment. In the feed-forward model of plaque chronicity, IL-17A has been hypothesized as the key driver of pathogenic gene expression by lesional keratinocytes, but invivo evidence in human subjects is lacking. We performed a randomized, double-blind, placebo-controlled study (NCT01537432) of patients receiving secukinumab at the clinically approved dose up to 12weeks. We then correlated plaque and nonlesional skin transcriptomic profiles with histopathologic and clinical measures of efficacy. After 12weeks of treatment, secukinumab reversed plaque histopathology in the majority of patients and modulated thousands of transcripts. Suppression of the IL-23/IL-17 axis by secukinumab was evident at week 1 and continued through week 12, including reductions in levels of the upstream cytokine IL-23, the drug target IL-17A, and downstream targets, including β-defensin 2. Suppression of the IL-23/IL-17 axis by secukinumab at week 4 was associated with clinical and histologic responses at week 12. Secukinumab did not affect exvivo T-cell activation, which is consistent with its favorable long-term safety profile. Our data suggest that IL-17A is the critical node within the multidimensional pathogenic immune circuits that maintain psoriasis plaques and that early reduction of IL-17A-dependent feed-forward transcripts synthesized by hyperplastic keratinocytes favors plaque resolution.

A first-in-human study of KY1044, a fully human anti-ICOS IgG1 antibody as monotherapy and in combination with atezolizumab in patients with selected advanced malignancies.

TPS2644 Background: The Inducible T-cell costimulator (ICOS/CD278) is related to the CD28 superfamily and is induced upon T cell activation. There is a hierarchical order of ICOS expression level, in which highly immunosuppressive TReg (CD4+Foxp3+) present in the tumor microenvironment (TME) are at the top level of expression and CD8 TEff cells are at the bottom level. In addition, ICOS expression on TRegs is higher in the TME than in the blood or spleen. Methods: KY1044, a fully human anti-ICOS IgG1 kappa monoclonal antibody, selectively binds to ICOS with high affinity (which is maintained at intratumoral acidic pH) and has a dual mechanism of action: it promotes the preferential depletion of intratumoral ICOSHigh TRegs resulting in an increase in the TEff:TReg ratio in the TME; and it stimulates ICOSLow TEff cells. Preclinical data demonstrate that KY1044 monotherapy or in combination with anti-PD-L1 is associated with immune cell activation and anti-tumor response. In order to validate the dual mechanism of action in vivo, studies in mice and cynomolgus monkeys were conducted. Firstly, KY1044 injected i.v. at doses up to 100 mg/kg weekly were well tolerated in non-human primates. In addition, pharmacodynamic studies in mice and cynomolgus monkey confirm preferential depletion of ICOSHigh cells. KY1044-CT01 is an open-labelled first in human Phase I/II study assessing the safety, tolerability, PK, PD and anti-tumor activity of KY1044 administered every 3 weeks (Q3W) as an i.v. single agent infusion and in combination with atezolizumab (1200 mg, Q3W IV) in adult patients with advanced/metastatic malignancies. The primary endpoint of the Phase I dose escalations, designed as sequential but overlapping arms of KY1044 monotherapy and combination with atezolizumab, is safety and tolerability. Secondary endpoints are the characterization of pharmacokinetic, pharmacodynamic and efficacy profiles in all patients. In the Phase II part, the primary endpoint is overall response rate (ORR), and the measure of clinical efficacy will be confirmed as per RECIST 1.1. and immune-related (ir)RECIST. An intensive biomarker plan is integral to the study design to underpin the phenotypic and molecular changes in both peripheral blood and tumor. Clinical trial information: NCT03829501.

556 Evaluating important change and clearance of disease activity as clinical efficacy measures for clinical trials in dermatomyositis

556 Evaluating important change and clearance of disease activity as clinical efficacy measures for clinical trials in dermatomyositis

587 Evaluating meaningful change in disease activity as a clinical efficacy measure for clinical trials in cutaneous lupus erythematosus

To date, there are no approved treatments for cutaneous lupus erythematous (CLE), a disease known to significantly burden a patient’s quality of life (QoL). Clinical trials are important for the advancement of treatments and outcome measures of these trials should reflect clinically meaningful improvement in disease activity and its effect on QoL. Currently, clinical trials use an efficacy measure of ≥ 50% improvement in disease activity, defined by the Cutaneous Lupus Disease Area and Severity Index activity (CLASI-A) score, in patients with an initial CLASI-A score of ≥ 10. However, the degree of improvement in disease activity needed to predict a meaningful impact on QoL has not been defined. This is a retrospective study of 126 patients enrolled in a longitudinal research database. Using a linear regression model, we calculated the percent change and difference needed in CLASI-A to have an important impact on QoL, defined as a 9.38-point and a 7.37-point improvement in the Emotions and Symptoms subscales of Skindex-29, respectively. In patients with an initial CLASI-A score ≥ 8, a decrease by 42.1% and a decrease by 31.0% in disease activity is associated with a meaningful impact in the Emotions and the Symptoms subscales, respectively. Using a CLASI-A score ≥ 8 for trial entry allows for inclusion of patients with milder disease for whom improvement of CLASI-A by ≥ 50% has a meaningful impact on QoL, as determined by the Emotions and Symptoms subscales. In patients with moderate to severe initial disease, a respective decrease in activity by at least seven and five-points is not only clinically significant, but also has a meaningful impact on the Emotions and Symptoms subscales. Our findings establish appropriate trial endpoints by determining clinically significant change in disease activity associated with meaningful changes in patients’ QoL.