Corbus Pharmaceuticals (United States)

Incretin receptor agonists are now standard of care in treating obesity. Their efficacy and tolerability might be further improved by combining them with compounds that offer orthogonal mechanisms of action. The cannabinoid type 1 receptor (CB1R) is a clinically validated therapeutic target in obesity, and several experimental CB1R inverse agonists have been shown to induce weight loss. This study characterizes a novel CB1R inverse agonist (CRB-913) with similar preclinical potency to rimonabant but markedly reduced brain penetration. CRB-913 was tested as monotherapy and in combination with tirzepatide, semaglutide, or liraglutide in the diet-induced obesity (DIO) mouse model for body weight reduction. CRB-913 demonstrated enhanced plasma exposure (3.8-fold larger area under the curvelast ) and reduced brain levels (9.5-fold lower area under the curvelast ) than rimonabant. CRB-913 monotherapy yielded a dose-dependent decrease in body weight in DIO mice reaching -22% within 18 days. In further DIO studies in combination with tirzepatide, semaglutide, or liraglutide, CRB-913 (2.5 mg/kg) resulted in -32.6%, -28.8%, and -16.8% decreases in body weight on Day 18, respectively, with concomitant improvements in body fat content, liver triglycerides, and liver fat deposits. CRB-913 in combination with incretin analogues could deliver meaningful improvements over current standards of care for obesity and related conditions.

BackgroundInterstitial lung disease (ILD) is one of the major causes of morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). [1] Within IIM, ILD is frequently found in patients with anti-synthetase syndrome (ASyS). Current treatment is based on a combination of high doses of glucocorticoids and other immunosuppressors such as cyclophosphamide, with progression of ILD despite the treatment. One anti-fibrotic drug, nintedanib, has recently been approved for patients with progressive fibrotic ILD.ObjectivesTo explore if within patients with ASyS there is a group with worsening ILD that fits the definition of progressive pulmonary fibrosis (PPF)[2] and thus would be eligible for anti-fibrotic treatment.[3]MethodsA single center based retrospective cohort of patients diagnosed with ASyS, ILD involvement, and positivity for specific autoantibodies anti-Jo1, anti-PL7, anti-PL12, anti-EJ and/or anti-OJ (ASyS-AB) was identified using the Swedish Myositis network register. We selected the latest computed tomography (CT) thoracic scans, pulmonary function tests (PFT) and the development of respiratory symptoms according to clinical records. Patients were evaluated based on the INBUILD study criteria[3] and the international thoracic and respiratory clinical practice guideline (CPG)[2] for the presence of PPF. An experienced thoracic radiologist reviewed the CT scans of those who met the criteria to confirm PPF.ResultsWe identified 147 individuals positive for ASyS-AB; 66 of them were not included due to either a follow-up period of less than one year, lack of data in the national registry or absence of ILD. Finally, a cohort of 81 patients was included, 67.9% women, with a median (Q1,Q3) age at disease onset of 58 (48,67) years (Table 1). The median time from disease onset until assessment for PPF criteria was of 6 years.The most prevalent CT finding amongst all groups was fibrotic changes (n=28) neither fitting the usual interstitial pneumonia (UIP) (n=9) nor the fibrotic non-specific interstitial pneumonia (NSIP) (n=6) criteria; followed by inflammatory NSIP (n= 18). 14.8 percent or 19.8 percent (INBUILD and CPG, retrospectively) of the individuals with any type of lung fibrotic pattern on CT met the definition of PPF.Table 1.Baseline characteristics of patients with anti-synthetase syndrome (ASyS) in the cohortTotalBy antibodyPL7,n=8PL12,n=8Jo1,n=58EJ,n=4OJ,n=3Women, n (%)55 (67.9)6 (75)5 (62.5)40 (69)3 (75)1 (33.3)Median age at disease onset, years (Q1,Q3)58 (48,67)61 (35,68)61 (48,67)56 (47,65)72 (46,76)61 (55,74)Time since disease onset at evaluation, years (Q1,Q3)6 (3,11)10 (3,22)4 (2,5)7 (3,13)2 (2,15)4 (1,7)Patients meeting criteria for progressive fibrosis, n (%)INBUILD criteria12 (14.8)2 (25)1 (12.5)8 (13.8)0 (0)1 (33.3)ATS/ERS/JRS Clinical practice guidelines14 (17.3)3 (37.5)1 (12.5)10 (17.2)0 (0)0 (0)Time since disease onset at evaluation, years (Q1,Q3)10 (5,21)-----ConclusionIn this cross-sectional study, 15% of patients with ASyS fulfilled the definition of progressive fibrosis and thus could be eligible for anti-fibrotic treatment. To our knowledge, this is the first cohort to demonstrate a possible real-life target of anti-fibrotics in IIM-ILD.

BackgroundRetrospective reviews of clinical databases from two sites have identified strong relationships between patient-reported outcomes and skin activity in dermatomyositis (DM), as measured by CDASI-A.1,2 No studies validate these associations in a controlled setting. Additionally, the relationship between the PROMIS-29 Short Form and skin activity in DM has not been assessed. Previous investigations have demonstrated a correlation between IL-31 and itch in DM.3 IFN-β and IFN-γ are known type I and II interferons, which are critical drivers of DM pathogenesis.4ObjectivesTo assess correlations between CDASI-A, quality of life (QoL), and biomarkers of disease activity in a double-blind, randomized, placebo-controlled clinical trial.MethodsData were retrospectively collected from five visits of a Phase 2 trial evaluating Lenabasum, a cannabinoid receptor type 2 agonist. Quality of life assessments extracted from the trial included Patient Global Assessment (PtGA) scores, PROMIS domains, and Skindex domains. Skindex question 10, regarding itch, was included in the analysis as a separate domain. Physician Global Assessment scores were also evaluated. Additionally, biomarkers derived from skin samples via IHC/PCR collected at visits 1 and 6 were assessed for predictors of CDASI-A response and association with disease activity. Analysis used linear mixed effect models to account for within subject-variability and repeated measures, where applicable. Analysis was performed without regard to treatment arm, as our goal was to correlate CDASI, QoL, and biomarkers among all subjects.ResultsData from 22 subjects with DM and a combined total of 110 visits were included. Biopsies were collected from 12 subjects. Improvement in CDASI-A significantly correlated with Skindex-S, Skindex-E, Skindex-F, Skindex-Itch, PtGA global skin, PtGA global skin, PtGA global skin, and PtGA global skin, with p < 0.001. Improvement in PROMIS social role (p = 0.046) correlated with improvement in CDASI-A. Worsening of PROMIS fatigue (p = 0.019) and pain (p < 0.001) correlated with improvement in CDASI-A. Decreases in PGA overall disease, PGA skin activity, and PGA global skin all correlated with improvement of CDASI-A (p < 0.001). Change in IL-31 protein area positively correlated with change in disease activity (p = 0.047). A positive relationship between changes in IFN-β and IFN-γ protein area and disease activity trended towards significance.ConclusionIn accordance with previous investigations from our group, well-established measures of QoL correlated significantly with CDASI-A. These findings support that CDASI-A reflects both clinical and patient-reported aspects of skin disease and is an appropriate outcome in DM clinical trials. Additionally, Skindex and PtGA scores may better relate to skin activity as measured by the CDASI compared to PROMIS domains. IL-31, a cytokine previously associated with itch in DM,3 correlated significantly with CDASI-A in our study. Trends for IFN-β and IFN-γ reduction with disease improvement support their role in the pathogenesis of DM. This study helps define patient-reported outcomes and biomarkers that may be informative in DM trials.

ABSTRACT The author views every symptom, conflict, defense, or unconscious fantasy as a result, in part, of an adaptation. For example, cumulative traumas from childhood aren’t just traumatic, but become part of an individual unconscious fantasy while potentially contributing to a way of living that can lead to certain satisfactions along with crippling inhibitions. Analyzing adaptations, along with the other components that bring patients to our offices, is necessary because of a paradigm change in the goals of psychoanalysis from reconstruction to building more complex representations from simple representations. Further, the analyst’s appreciation for forces that lead to adaptations helps reduce intense super-ego pressures. Clinical examples are presented to demonstrate the author’s perspective.

The multi-systemic, heterogenous nature of diffuse cutaneous systemic sclerosis (dcSSc) presents challenges in designing clinical studies that can demonstrate a treatment effect on overall disease burden. We describe the design of the first Phase 3 study in dcSSc patients where the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score was chosen prospectively as the primary outcome. The CRISS measures key clinical disease parameters and patient-reported outcomes (PROs). RESOLVE-1 is a Phase 3, randomised, double-blind, placebo-controlled trial of dcSSc patients evaluating the efficacy and safety of lenabasum. Patients ≥18 years of age with dc-SSc and disease duration ≤6 years were eligible. Patients could continue stable background therapy for dcSSc, including stable immunosuppressive therapies. They were randomised to lenabasum 5 or 20 mg twice daily or placebo. The primary efficacy outcome was the mean change from baseline to 52 weeks in the ACR CRISS score. The study enrolled 365 patients over 1.5 years at 77 sites in 13 countries in North America, Europe, Israel, and Asia-Pacific, with the last patient first visit on May 1, 2019. RESOLVE-1 is the first Phase 3 interventional study to date in dcSSc to prospectively use the ACR CRISS as the primary efficacy outcome. Eligibility criteria allowed background therapy as might occur in clinical practice. This approach also facilitated timely patient enrolment. RESOLVE-1 provides a novel study design that may be used for future Phase 3 dcSSc studies to assess the holistic efficacy of therapy.

\n Introdução: As diferenças do desenvolvimento sexual (DDS) afetam 1:1000-4500 nascidos vivos e são definidos como alterações nas quais o desenvolvimento cromossômico, gonadal ou genital são atípicos. Os pacientes portadores de DDS 46,XY apresentam um amplo espectro fenotípico e muitos apresentam genitália atípica ao nascimento. A avaliação diagnóstica de um paciente portador de DDS inclui dosagens hormonais, estudos radiológicos, citogenéticos e moleculares. Porém, uma porcentagem significativa de pacientes permanece sem etiologia e são classificados como DDS de causa indeterminada. Este fato sugere que mecanismos epigenéticos, i.e., não restritos ao DNA e, portanto, não contemplados por análises moleculares usuais, como sequenciamento tipo Sanger e Exoma, possam desempenhar um papel no seu desenvolvimento. Objetivos: Para melhor avaliar estes casos sem diagnóstico estabelecido, investigou-se neste projeto o perfil de expressão plasmático de microRNAs (miRNAs), pequenos RNAs não codificantes de proteína, que se ligam por complementariedade a região 3 ?UTR de mRNA alvos, bloqueando a síntese proteica. Metodologia: Após análise in silico e da literatura os miRNAs, miR-200c, miR-210, e referências miR-23a e miR-451 foram selecionados. O RNA foi extraído do plasma de pacientes e controles, após análise de hemólise por absorbância em 414nm, com o kit MagMAX mirVana Total RNA (Thermofisher), a reação de RT-qPCR foi realizada com os kits TaqMan Advanced miRNA cDNA e Advanced miRNA Assay (Thermofisher). Os dados foram analisados por ?Ct e 2-??Ct. Pacientes e controles foram divididos em dois grupos, pré-púberes (de acordo com volume testicular &lt;3ml e nível de Testosterona &lt;30ng/dL) e, pós-púberes. Adicionalmente, os pacientes foram subdivididos em 2 subgrupos de acordo com o Escore de Masculinização da genitália Externa (EMS), em pouco virilizados (PVG, índice &lt;5) e moderadamente virilizados (MVG, índice &gt;5). Para análise de expressão por faixa etária os controles foram agrupados da seguinte maneira: 1-12 anos, 13-20 anos, 21-30 anos, 31-40 anos e 41-55 anos. Resultados: A expressão plasmática de miR-200c foi maior nos grupos de 13-20 a 41-55 anos do que no grupo de 1-12 anos (ANOVA p=0.0067). Adicionalmente, todos os grupos com mais de 13 anos tiveram médias individualmente maiores de miR-200c do que o grupo de 1-12 anos (p&lt;0.05). A análise ANOVA dos grupos pós-púberes PVG, MVG e controles mostrou uma significância estatística p=0.0013, revelando uma expressão diferencial de miR-200c entre esses grupos. Em pós-puberes uma maior média de expressão de miR-200c foi observada em MVG, com pós-teste de Tukey entre MVG e PVG de p=0.01. Pacientes pós-púberes tiveram maior expressão de miR-200c do que os pacientes pré- púberes (p=0.0002). Os pacientes pós-púberes PVG apresentaram valores de expressão de miR- 200c semelhantes aos dos controles e DDS 46,XY pré-púberes. Em relação ao miR-210, a análise ANOVA de pós-púberes PVG, MVG e controles mostrou significância estatística de p=0.005, com MVG e PVG apresentando médias de expressão superiores ao grupo controle (p=0.002). O mesmo padrão foi observado em relação ao grupo pré-púberes (p=0.022). Conclusão: Em vários tecidos, uma alça de retrocontrole negativo, no qual o miR-200c inibe a expressão de ZEB1 foi demonstrado e foi associado à modulação da transição epitelial- mesenquimal (EMT). Níveis elevados de ZEB1 associado a baixos níveis de miR-200c foram observados na pele genital de indivíduos adultos do sexo masculino e de ratos com hipospádia, reforçando um papel potencial do miR-200c no desenvolvimento da hipospádia. Nossas descobertas fornecem novas evidências sobre o miR-200c circulante, que pode representar uma nova estratégia para a pesquisa em DDS 46,XY, e contribuir para uma maior compreensão do processo de desenvolvimento da genitália externa masculina.\n