Category Archives: Transhuman News

In adults with active psoriatic arthritis (PsA) and prior inadequate responses to tumor necrosis factor inhibitors (TNFi-IR), guselkumab (Tremfya; Janssen) provided consistent and sustained improvements to minimal disease activity domains.

Janssen announced the results of its phase 3b COSMOS clinical trial evaluating the drugs safety and efficacy in a press release1. The study is 1 of several abstracts the company will be presenting at the 2023 Annual European Congress of Rheumatology (EULAR) meeting in Milan, Italy, this week.

Our continued research underscores Janssens commitment to not only provide therapeutic options for psoriatic disease, but also to better understand and support the pressing needs of the patients we serve, said Terence Rooney, MD, PhD, in the press release. Rooney is vice president, Rheumatology and Maternal-Fetal Immunology Disease area leader for Janssen Research & Development, LLC. Active psoriatic arthritis is a challenging, chronic disease, so these findings have important implications for patients and their providers as they work together to address the full spectrum of disease symptoms, including patient-reported outcomes, with the goal of achieving long-term relief.

Adults who had been diagnosed with active PsA and had a history of inadequate responses to 1 or 2 TNFi-IR (n=189) were eligible for participation in the trial. Researchers measured the efficacy of guselkumab in achieving sustained improvements across all MDA domains for a 48-week period.

Throughout the trial, researchers evaluated disease-specific, physician-reported domains and patient-driven domains, particularly at weeks 24 and 48. These included Health Assessment Questionnaire Disability Index (HAQ-DI), Leeds Enthesitis Index (LEI), patient global assessment (GA), patient pain, Psoriasis Areaand Severity Index (PASI), swollen joint count (SJC), and tender joint count (TJC).

Between week 24 and 48, all domains experienced improvement.

Week 24 Domains:

Week 48 Domains:

These results contradict those of a prior trial stating that a minority of patients with active PsA receiving biologic therapy are able to achieve sustained MDA, according to the press release.

Assessing patient-reported symptoms is a vital part of our research that helps us to address unmet needs and provide treatments that can improve outcomes, said Laura Coates, MD, PhD, in the press release. Coates is a senior clinical research fellow at the University of Oxford. These results advance our understanding of the psoriatic arthritis patient experience and will help healthcare professionals develop individualized treatment plans that can target debilitating symptoms and, ultimately, aim to improve quality of life for people living with psoriatic arthritis.

Reference

Read more:
Janssen Announces Positive Results From Guselkumab Psoriatic ... - Dermatology Times

Early intervention with secukinumab for patients with psoriasis may be helpful for those with the skin disease including those who are bio-nave, according to recent findings.1

There is evidence that the efficacy of secukinumab and the drugs survival may both be strong in those previously non-exposed to biologic treatments.2 That said, real-world research and case series on long-term efficacy and survival of the treatment in nave patients have been limited.

Consequently, this new multicenter study was done to analyze the long-term effectiveness and survival of the drug, and was authored by Francisco Javier Melgosa Ramos, MD, from the Department of Dermatology at the University Hospital Doctor Peset of Valencia in Spain.

Our objective and primary endpoint was to analyze the long-term efficacy and survival of secukinumab for the treatment of psoriasis in a retrospective, multicenter study performed in a Spanish cohort of psoriatic patients nave to biological therapies followed up to 8 years, Ramos and colleagues wrote. Secukinumab safety was evaluated as a secondary endpoint.

The investigators conducted the observational study across 8 Spanish hospitals to investigate the use of secukinumab in patients with psoriasis who had not previously received biological therapy. The team followed a daily practice cohort between January of 2014 and January of 2022, with a minimum follow-up period of 3 months and a maximum of 8 years.

The study participants initially received a weekly dose of 300 mg of secukinumab for 4 weeks, followed by monthly doses. However, some of the participants had their treatment regimen intensified or optimized based on the Physician Global Assessment (PGA) and disease control.

The study collected demographic data, information on previous nonbiological systemic therapies, and various study variables. The clinical response to the treatment was assessed by the research team using the Psoriasis Activity and Severity Index (PASI) throughout the period of their evaluation.

The investigators defined a complete response as reaching an absolute PASI score of 3 in plaque psoriasis or a PGA score of 1 in special localizations. The team also evaluated the safety of secukinumab and recorded any related side effects as a secondary endpoint.

Statistical analyses were done by utilizing the log-rank test to compare secukinumab survival time between different patient groups based on factors such as age, obesity, gender, and presence of psoriatic arthritis. Cox regression models were then utilized to explore the relationship between drug survival and patient characteristics.

The analyses also reported odds ratios (OR), with P < 0.05 being considered statistically significant. IBM SPSS v21.0 was used for the analyses.

The study ended up involving 128 individuals with moderate-to-severe cutaneous psoriasis who had not received biological therapies before. The investigators reported that around 92.2% of participants exhibited classical psoriasis plaques, while involvement in hard-to-treat areas was found to be less common.

It was reported that those included in the study were made up of 65 males and 63 females, with a mean age of 50.9 years. Approximately 47.2% of the participants were found to be obese.

The research team noted that psoriatic arthritis was detected in 18.8% of patients. The treatment response to secukinumab was evaluated at different follow-up periods, with a significant percentage of patients achieving low PASI scores.

The investigators also reported no occurrences of infections, malignancy, inflammatory bowel disease, or major adverse cardiovascular events associated with the treatments administration during the study period. No major differences were observed in terms of efficacy and survival rates based on factors such as BMI, gender, age, or the presence of psoriatic arthritis.

The research team noted that 86.6% - 100% of those ended up with a PASI score of 3 or lower, and 25% - 65.2% reached a PASI score of 0. The overall drug survival rate for secukinumab was also reported to be 81.9% over an average treatment exposure of 147.9 weeks.

To conclude, as observed in our cohort, the high long-term efficacy and survival of secukinumab in bio-nave patients and the low prevalence of arthritis and psoriasis-related comorbidities might suggest that managing severe psoriasis as a systemic disease, introducing advanced treatments early, could potentially modify the march of this disease, but further studies are needed, they wrote.

The rest is here:
Early Intervention with Secukinumab May Be Effective for Patients ... - MD Magazine

In an ex vivo study1, investigators found that vascular endothelial growth factor-a (VEGF-A) downregulates angiogenesis and blood vessel area in skin with psoriasis plaques. Furthermore, this downregulation is more abrupt among patients with psoriasis who have more severe disease or higher levels of VEGF-A.

Researchers sought to examine VEGF-A's impact on blood vessels, the epidermis, and immune cells in skin with and without psoriatic lesions, citing the known role of VEGF-A mediated angiogenesis in the pathogenesis of the disease. The study was the first to objectively examine the role of VEGF-A inhibition and its potential role as a treatment strategy for psoriasis. These data and findingslead researchers to believe that VEGF-A blocking therapy could be beneficial in patients with high levels of VEGF-A in their skin or plasma or with more severe psoriasis.

6 volunteers with psoriasis and 6 without the disease were recruited by researchers. Prospective participants with inflammatory arthropathy or who had used topical treatments (4 weeks prior) or systemic treatments (12 weeks prior) were excluded from participating.

Upon participant enrollment, researchers conducted skin sampling through skin punch biopsies taken from the same body site. In participants with psoriasis, researchers took 2 biopsies from regions of the skin with psoriasis plaques and 2 biopsies from skin without psoriatic lesions. Biopsies, once collected, were incubated and cultured.

Researchers also conducted examinations of histochemistry, immunofluorescence, and quantitative immunohistomorphometry. They also conducted a peripheral blood mononuclear cells culture, VEGF-A level quantification, DNA extraction, genotyping, and a statistical analysis.

In an organ culture, researchers found that the inhibition of VEGF-A with bevacizumab blocked free VEGF-A. At hours 12 and 48, skin incubated with 0.8 mg/mL of bevacizumab had undetectable levels of VEGF-A.

In skin samples with psoriasis plaques, VEGF-A blockade decreased the overall number of blood endothelial cells and blood vessel area. Additionally, VEGF-A inhibition did not significantly change the parameters of epidermal read-outs. Inhibition also had no significant changes on the number of CD4+ cells, CD8+T-cells, or tryptase+-mast cells in skin samples with psoriasis. Researchers were also unable to identify an association between genotype and patient response to anti-VEGF-A treatment.

While levels of VEGF-A plasma levels did not show significant differences between participants with and without psoriasis plaques, patients with more severe psoriasis tended to have higher levels of VEGF-A plasma levels than those with less severe disease.

According to researchers, potential study limitations included the limit number of volunteers and skin samples, as well as the studys ex vivo nature.

This pilot study provides proof-of-principle for the investigation of VEGF-A inhibition as an adjuvant management strategy to selectively target vascular pathology in psoriasis, study authors wrote. This approach could be especially beneficial for patients who have high levels of VEGF-A, offering an opportunity to personalize management and complement current anti-cytokine strategies and other standard-of-care psoriasis therapeutics.

Reference

See the article here:
VEGF-A Inhibition Downregulates Blood Vessel Area in Psoriasis - Dermatology Times

Lynk Pharmaceuticals is running a phase 1b trial, designed to evaluate the safety, tolerability, pharmacokinetic characteristics of an ointment currently named LNK01004. It is targeted at people with mild to moderate plaque psoriasis.

Psoriasis is an immune-mediated, chronic, relapsing, inflammatory skin disease characterized by scaly erythematous or plaque lesions that can be local or widely distributed. Patients often require lifelong treatment to control symptoms and prevent complications from occurring or developing, thereby maintaining their quality of life.

Lynk say its ointment is a topical, skin-restricted soft pan JAK inhibitor intended for the treatment of psoriasis and other related conditions.

A JAK inhibitorinterferes with signals in the body that are thought to cause inflammation. This, in turn, reduces the inflammation that fuels diseases like eczema, psoriatic arthritis, and vitiligo. With less inflammation, the immune system calms down.

The drug is mainly distributed in the skin tissues but has minimal exposure in the blood system thereby avoiding potential safety issues caused by systemic immune suppression due to systemic exposure. As a representative third-generation JAK inhibitor, LNK01004, Lynk says, has the potential to be a first-in-class treatment.

Henry Wu, chief development officer of Lynk Pharmaceuticals, said: The completion of dosing the first cohort of patients with LNK01004 is an important milestone for the development of this compound.

LNK01004 has already shown good efficacy and safety in preclinical animal studies. Its phase I trial in healthy subject was completed earlier this year, and the results showed good safety profile. We look forward to LNK01004's good performance in patient trials.

Zhao-Kui (ZK) Wan, founder and CEO of Lynk Pharmaceuticals, added: As a third generation JAK inhibitor, LNK01004 can effectively inhibit psoriasis-related cytokine-induced JAK/STAT signalling pathways in skin tissues by topical application. Additionally, LNK01004 has the advantage of extremely low exposure in the blood system to potentially avoid safety concerns due to systemic exposure.

Wan said Lynk is committed to developing safer and more efficacious JAK inhibitors and emphasized that the differentiated products are the companys core competitive advantages.

He said: In addition to the highly selective JAK1 inhibitor LNK01001, we have also assembled a promising pipeline consisting of multiple third-generation, tissue-restricted soft pan JAK inhibitors in clinical trials including the GI-restricted LNK01003 for UC which is currently in phase 2a. We sincerely look forward to bringing safer, more efficacious and innovative treatment options to patients.

Continued here:
Scratching the itch, Lynk Pharmaceuticals trialling ointment for ... - OutSourcing-Pharma.com

In a recent study1, tyrosine kinase 2 (TYK2)/janus kinase 1 (JAK1) inhibitor brepocitinib was significantly more efficacious in reducing signs and symptoms of psoriatic arthritis (PsA) than a placebo.

Researchers sought to evaluate the oral drugs safety, efficacy, and dose-response in patients with the condition over a long-term period, citing its current in-development role in treating immunological diseases, including prior research evaluating its use in treating dermatomyositis, lupus, ulcerative colitis, alopecia areata, and hidradenitis suppurativa. Furthermore, they noted prior phase 2a study research demonstrating the drugs involvement in significantly reducing Psoriasis Area and Severity Index (PASI) scores in patients with plaque psoriasis.

The phase 2b study, which was dose-ranging, parallel-treatment group, placebo-controlled, and randomized in nature, involved patient participation across 11 European countries. Participants (n=218) were required to be ages 18 to 75 years old, fulfill the classification criteria for PsA, and have a PsA diagnosis for equal to or greater than 6 months prior to inclusion. Additionally, they were expected to meet the following inclusion criteria:

Patients were excluded from participation if they were breastfeeding; presented with critical laboratory abnormalities; electrocardiogram abnormalities indicative of an underlying heart disease; had a history of any autoimmune rheumatic disease other than PsA, any lymphoproliferative disorder, chronic or recurrent infection, disseminated herpes infection or a recurrent localized dermatomal herpes zoster, infection requiring hospitalization within 6 months of baseline, or pulmonary embolism or recurrent deep vein thrombosis; had non-plaque psoriasis, were pregnant, or demonstrated risk factors for torsade de pointes.

Patients underwent an up to 5-week screening period following by treatment group randomization. Participants were randomly assigned to 1 of 4 groups: brepocitinib 10 mg, brepocitinib 30 mg, brepocitinib 60 mg, or a placebo. During phase 1 of the 52-week double-blind treatment period, the placebo-controlled phase, participants took their assigned dosage from day 1 to week 16.

At week 16, participants receiving 10 mg brepocitinib or the placebo were advanced to a different dosage groupeither the 30 mg or 60 mg brepocitinib groups. This was known as the extended active treatment phase, which lasted from week 17 to week 52. Afterwards, participants underwent a 4-week safety follow-up period.

Researchers defined sufficient progress as a predefined proportion of participants achieving:

Throughout the study, researchers used the above scales to determine efficacy, while also recording data related to treatment-emergent adverse events (TEAEs), study adverse events (SAEs), serious infections, laboratory abnormalities, electrocardiogram findings, and changes in vital signs. In total, 50 participants withdrew from the study or were excluded as a result of AEs or independent withdrawal.

At week 16, 43.3% of participants in the placebo group achieved ACR20, whereas 64.5%, 66.7%, and 74.6% in the brepocitinib 10 mg, 30 mg, and 60 mg groups, respectively, with higher proportions of patients in the brepocitinib 30 mg and 60 mg groups achieving that metric. These higher proportions were also consistent in the brepocitinib 30 mg and 60 mg groups against the placebo with respect to achievements of PASI75/90, ACR50, and baseline change in Health Assessment Questionnaire Disability Index (HAQ-DI). Achievement rates of ACR70, PASDAS, and Minimal Disease Activity (MDA) were also higher among all brepocitinib groups when compared to the placebo.

Participants in the higher brepocitinib dosage groups also more frequently experienced resolutions or greater numerical improvements in enthesitis and dactylitis. In all brepocitinib groups, participants reported improvements in arthritis pain, fatigue, and acute 36-item Short Form Health Survey Version 2 Physical Component Summary (SF-36 PCS) score.

11 TEAEs and SAEs were reported during weeks 16 and 52 of the study, including coronavirus infection, pneumonia, varicella, herpes zoster/varicella, anogenital warts, basal cell carcinoma, and uterine leiomyoma.

Study limitations, as noted by investigators, included restricted geographical location and ethnic/racial makeup containing predominately white participants.

TYK2/JAK1 inhibition with brepocitinib 30 and 60 mg QD significantly improved the signs and symptoms of PsA, study authors wrote. These clinical benefits across multiple domains of PsA disease activity were observed over 16 weeks, with sustained or further improvements in disease measures out to week 52. Overall, the safety profile of brepocitinib was consistent with that previously observed in other brepocitinib clinical trials and with that of approved JAKis, and no new safety signals were identified.

Reference

The rest is here:
Brepocitinib More Efficacious Than Placebo in Long-Term Psoriatic ... - Dermatology Times

A psychosocial intervention and public exhibition improved the overall wellbeing and self image of individuals with birthmarks.

In a recent study,1 researchers sought to determine the impact of a public exhibition and professional photoshoot on the wellbeing of individuals with congenital melanocytic nevi (CMN). Furthermore, they sought to evaluate the exhibitions impact on the public perception of people with birthmarks. They cited a lack of existing studies examining the psychosocial aspects of having a birthmark, including the potential impact of therapeutic interventions.

Study authors described a patient recruitment effort led by Caring Matters Now, a United Kingdom-based charity supporting individuals with CMN, in 2016. Caring Matters Now partnered with a UK-based photographer to take patient portraits. Individuals with extensive and/or visible CMN were eligible for participation, and participation was not limited to geographic location, amassing participants from 5 continents. Prospective participants were required to meet with the photographer virtually and provide written consent.

Before and after photographing participants, researchers asked the 30 participants (or their parents, if under the age of 18) to complete a survey describing their photoshoot experience and behaviors pre and post photoshoot completion. The questionnaire asked participants whether the photoshoot made them feel:

They also asked participants whether they considered what they wore in relation to their CMN, their level of confidence in crowded places, and their level of confidence about showing their CMN.

All photos were publicly displayed in London, UK, for a 10-day duration in March 2019. Members of the public who visited the exhibition were asked to complete a survey; of the more than 8000 visitors, 464 agreed to complete the survey. The survey asked visitors whether the exhibition made them feel:

More than 90% of photoshoot and exhibition participants with CMN responded positively, agreeing or strongly agreeing, with all points of the questionnaire. Furthermore, responses from participants following the photoshoot and exhibition were positive and demonstratedsignificantly increased confidence. 33% of parents representing their older children described the experience as inspiring, while 57% of parents representing their young children described the experience as beautiful.

While only 51% of exhibition visitors described hearing of CMN prior to viewing the photos, more than 85% agreed or strongly agreed with all points of the questionnaire. 74% of attendees were individuals with CMN who described the exhibition as being very helpful in their appreciation and self-perception of their difference.

Study limitations, as noted by study authors, included the studys self-selective nature and a lack of collection of demographic data from exhibition visitors, aside from gender.

In the era of social media, where the negative psychological effects of posting self-photographs are frequently reported, the positive effect of this exhibition on the views of the general public is a perhaps surprising demonstration of the power of this novel approach. In particular, the general public not only looked more positively on the participants with visible difference, but felt better regarding their own appearance, study authors wrote. These data supportthe impression of the UK support group Caring Matters Now Charity, that non-hiding of visible difference on the skin can have beneficial psychological effects. Further studies will be required to assess whether this approach works in the context of other forms of visible difference, and whether the effects can be replicated using the exhibition book.

Reference

Read more here:
For Patients With Birthmarks, Psychosocial Interventions Improved ... - Dermatology Times

Robert Hariri, MD, PhD

Credit: Celularity

Stem cell pioneer Celularity (CELU) shared exciting results from a recent clinical trial investigating the efficacy of CYNK-001, the company's proprietary natural killer cell therapy.

The trial focused on treating patients with relapsed and refractory acute myeloid leukemia (AML) disease, who face low chances of a cure which has led to the development of a reliable gene manufacturing system that adheres to US Food and Drug Administration (FDA) regulations and produces substantial quantities of exceptional cellular products, according to CEO Robert Hariri, MD, PhD.

If you can utilize (these placenta cells) and identify the starting point for producing cell therapy products like T cells, natural killer cells, and even mesenchymal stem cells, it gives you a great deal of flexibility in your therapeutic development strategies, he explained.

The clinical trial demonstrated that treatment with CYNK-001 was well-tolerated by patients and exhibited no associated toxicities, even at the highest doses administered. Remarkably, the grafts showcased measurable graft-versus-leukemia effects without the need for high doses of chemotherapy commonly used in autologous transplants or the risk of graft-versus-host disease (GVHD) typically associated with standard allogeneic transplants.

Weve been grounded in a technology platform that is highly diversified and leverages the unique source material, the postpartum placenta, which we are credited with discovering over 20 years ago, as an ideal source of cells for the emerging therapeutic space, Hariri said in an interview.

Additionally, the companys manufacturing systems and the inclusion of all usable materials left in the organ for the development of cell therapy products are what sets Celularity aside.

"We want to basically combine the natural killer cells from the placenta, which are completely unmodifiedthese are nonengineered natural killer cellsso their natural anticancer activity is supported by lymphodepletion and administration of the supporting cytokine IL2 or IL15, gave us the answers we were looking at," Hariri said.

Read more from the original source:
Robert Hariri, MD: Natural Killer Cell Therapy Shows Remarkable ... - MD Magazine

Toby Maher, MD, PhD

Credit: Twitter

In a recent crossover trial, patients with idiopathic pulmonary fibrosis (IPF) showed reduced cough after treatment with nalbuphine extended-release tablets (NAL ER). The investigators, led by Toby Maher, MD, PhD, Keck School of Medicine, University of Southern California, stated there are currently no cough therapies approved for this population.1

Because IPF is a progressive lung disease that scars the lung tissue, the lung function of these patients is compromised and accompanied by respiratory symptoms, cough is one of the most common.

The study was a randomized, double-blind, placebo-controlled crossover trial that involved a pair of 22-day treatment periods, with a 2-week washout period in between. NAL ER was administered at an initial dose of 27 mg once daily, which was then titrated up to 162 mg twice daily by day 16.

Investigators assessed the percent change from baseline in hourly daytime objective cough frequency, as measured by an electronic cough monitor, for the primary endpoint of the study. Changes in objective 24-hour cough frequency, cough severity, and breathlessness, based on patient-reported outcomes were secondary endpoints.

The analysis included 41 patients with IPF who received at least one dose of study medication after being randomly assigned. During the NAL ER treatment period, the team observed a significant reduction in daytime objective cough frequency, with a 75.1% decrease compared with the placebo treatment period's reduction of 22.6%.

Investigators reported the finding corresponded to a 52.5 percentage point decrease from baseline (P < 0.001) at day 21, when adjusting for placebo effects. The therapy demonstrated a 76.1% decrease (95% CI, 83.1-69.1) in 24-hour objective cough frequency, while the placebo only showed a 25.3% decrease (43.9-6.7), resulting in a 50.8 percentage point placebo-adjusted change.

Common adverse events exhibited with the treatment included nausea, fatigue, constipation, and dizziness, which were more frequent compared with the placebo group and should be considered when evaluating the overall benefit-risk profile of NAL ER in this population, investigators said.

These safety results are similar to those of a trial of low-dose morphine in chronic cough that reported constipation and drowsiness in 40% and 25% of patients, respectively, the research stated.

Based on the short-term crossover trial results, the team suggested that NAL ER shows promise in reducing cough frequency for individuals with IPF. Given the lack of approved therapies targeting this clinical concern, the findings indicated significant development in the field, according to the study.

However, it was acknowledged that further research is needed to contribute to a better understanding of the treatment's overall efficacy, tolerability, and clinical utility in the management of cough in IPF patients.

Particularly, larger and longer trials evaluating the long-term efficacy and safety of the treatment as a cough therapy. Additionally, the impact of the treatment on cough severity and patient-reported outcomes should also be further explored.

Although our trial was not designed to statistically test other outcomes, the data are encouraging enough to merit further assessment in longer and larger clinical studies. Such trials permit weighing the long-term effects on cough against the adverse effects and loss of efficacy due to habituation associated with chronic opiate use, investigators wrote.

Visit link:
Nalbuphine ER Tablets Show Promise as Cough Therapy in ... - MD Magazine

Javed Butler, MD, MPH, MBA

Credit: Boehringer Ingelheim

A post hoc analysis of the phase 3 EMPEROR-Preserved trial suggests empagliflozin treatment in patients with heart failure with preserved ejection fraction (HFpEF) should be independent of diuretic therapy and could reduce the need for diuretics.1

The analysis showed empagliflozin was associated with comparable improvements in time to cardiovascular death (CV death) or hospitalization for heart failure (HHF), first and total HHF, rate of decline in estimated glomerular filtration rate (eGFR), and health status, regardless of baseline diuretic status or dose.

This is in line with findings from heart failure with reduced ejection fraction (HFrEF) patients in the DAPA-HF trial, where baseline diuretic therapy did not modify the benefit of dapagliflozin on these outcomes, wrote the investigative team, led by Javed Butler, MD, MPH, MBA, at the Baylor Scott and White Research Institute.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors primarily act through a diuretic mechanism and their benefit may be attenuated in patients already taking other diuretics. It is possible that the combined use of SGLT2 inhibitors with conventional diuretics may increase the risk of volume depletion events, acute kidney injury, and other adverse effects.2 Butler and colleagues indicated that the use of SGLT2 inhibitors could additionally impact the need for conventional diuretic therapy.

As a result, the post hoc analysis of the EMPEROR-Preserved trial aimed to assess the safety and efficacy of empagliflozin in relation to background diuretic therapy, as well as to study the association of empagliflozin with the use of conventional diuretics over time. The phase 3 trial was conducted from March 2017 - April 2021 and included individuals with New York Heart Association (NYHA) class II to IV heart failure and left ventricular ejection fraction 40%. A total of 5988 patients were enrolled and randomized to receive either empagliflozin (10 mg), or placebo.

Of the enrolled population, 5815 (97.1%) had data on baseline diuretic use and were included in the present analysis. Patients were categorized into the following subgroups according to baseline diuretic therapy: no diuretic use and furosemide-equivalent doses of 40 mg, 40 mg, and 40mg at baseline. The main clinical outcomes of interest were the composite endpoint of the first hospitalization for heart failure (HHF) or cardiovascular death (CV death), and its various components. Data were analyzed from November 2021 to August 2022.

Among the 5815 patients with known baseline diuretic use, 1179 (20.3%) were not taking diuretics, 1725 (29.7%) were taking 40mg, 1772 (30.5%) were taking 40 mg, and 1139 (19.6%) were taking 40 mg of furosemide-equivalent doses.

In the placebo arm, compared with the nondiuretic group, the analysis found the diuretic group had a higher risk of HHF or CV death (hazard ratio [HR], 1.81; 95% CI, 1.38 - 2.39; P <.001), total HHF (HR, 3.21; 95% CI, 2.15 - 4.80; P <.001), first HHF (HR, 2.75; 95% CI, 1.85 - 4.07; P <.001), and all-cause mortality (HR, 1.40; 95% CI, 1.06 - 1.85; P = .02). The results were similar after stratification by diuretic dose, with higher diuretic doses associated with a stepwise increase in these clinical outcomes.

Moreover, the analysis revealed empagliflozin treatment decreased the risk of HHF or CV death, regardless of background diuretic status (HR, 0.81; 95% CI, 0.70 - 0.93 for the diuretic group vs. HR, 0.72; 95% CI, 0.48 - 1.06 for the nondiuretic group; P for interaction = .58). There was no treatment by diuretic status interaction observed for CV death or all-cause death endpoints.

Compared with placebo, empagliflozin was associated with a slower rate of decline in the eGFR regardless of baseline diuretic use or dose. Additionally, the therapy was associated with improved Kansas City Cardiomyopathy Questionnaire 23 (KCCQ) clinical summary scores similarly in both the diuretic and nondiuretic groups at 12-week, 32-week, and 52-week follow-up. Results were consistent when patients were categorized by diuretic dose.

Among those taking diuretics at baseline, empagliflozin was associated with a significantly greater probability of de-escalation (HR, 1.15; 95% CI, 1.02 - 1.30), as well as a decreased likelihood of diuretic dose escalation (HR, 0.74; 95% CI, 0.65 - 0.84; P <.001). However, the analysis showed empagliflozin was associated with a higher incidence of volume depletion events in the diuretic group (7.5 vs. 5.6 events per 100 patient-years; HR, 1.34; 95% CI, 1.13 - 1.59).

The investigative team noted the important clinical implications of the analysis, suggesting SGLT2 inhibitors should not be withheld in patients not taking diuretics due to concerns of destabilizing the euvolemic status. Empagliflozin improved clinical outcomes without increasing volume depletion events in this population.

Butler and colleagues noted that at the time of SGLT2 initiation, most patients with HFpEF would not require a change in diuretic dose. However, they suggested that like every patient with heart failure, physicians should be ready to adjust the diuretic dose according to a patients individual needs.

Doing so will minimize the small risk of volume depletion when SGLT2 inhibitors and loop diuretics are combined, investigators wrote. Patient education, daily weights, and monitoring for volume depletion is advisable. In the longer term, as HF status improves in patients taking empagliflozin, the need for diuretics may be reduced.

References

See the article here:
Benefit of Empagliflozin in HFpEF Consistent Regardless of Diuretic ... - MD Magazine

selectION has reported initial safety results from the single ascending dose (SAD) stage of its ongoing Phase Ib trial of si-544 for the treatment of atopic dermatitis.

si-544 is a selectivity-optimised peptide that blocks the Kv1.3 ion channel and helps in the activation and proliferation of TEM cells.

The placebo-controlled, double-blind, multi-centre study is designed to assess the tolerability, safety, and efficacy signals of the drug candidate in patients with mild to severe atopic dermatitis.

No safety signals or dose limiting toxicities have been observed during the studys first stage.

selectION chief scientific officer and co-founder Andreas Klostermann said: The ion channel Kv1.3 controls the activation and proliferation of auto-reactive effector memory T-cells and has been regarded a key target in T-cell autoimmunity for decades.

So far, it has not been possible to block this ion channel with sufficient selectivity.

The initial analysis of safety and tolerability data from 20 patients confirms that si-544 can be safely administered at dose levels sufficient to achieve virtually full Kv1.3 target engagement.

Based on the initial results, selectION now progresses the multiple ascending dose (MAD) stage of the Phase Ib trial.

Patients in this study will be treated with si-544 for a period of one month and thereafter monitored for three months.

selectION chairman and CEO Antonius Schuh said: The data provide initial clinical validation that we can safely and selectively target autoimmune disease associated chronically activated effector memory T-cells.

We will continue our path to deliver a potent and immune-selective therapy which maintains a patients general immunocompetency, and we believe that si-544 has the potential to significantly improve safety and outcomes for patients suffering from a wide range of autoimmune diseases, including atopic dermatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, and many others.

See the original post here:
selectION reports results from SAD stage of si-544 Phase Ib trial - Clinical Trials Arena