Royalty: R&D Funding Collaboration With Merck on Schizophrenia Med

 Royalty Pharma plc (Nasdaq: RPRX) today announced that it has entered into an agreement with Merck, known as MSD outside the United States and Canada, to co-fund the development of MK-8189, an investigational oral PDE10A inhibitor currently being evaluated in a Phase 2b study for the treatment of schizophrenia.

Under the agreement Royalty Pharma will provide $50 million upfront to Merck to support ongoing development of MK-8189. Following Merck’s decision to proceed with Phase 3, Royalty Pharma has the option to provide an additional $375 million to co-fund the pivotal clinical development program. Royalty Pharma will be eligible for milestone payments associated with certain regulatory approvals for MK-8189 as well as royalties on annual worldwide sales of any approved product.

https://finance.yahoo.com/news/royalty-pharma-announces-r-d-110000586.html

Blood Leukocyte Counts in Alzheimer Disease

 Jiao Luo, MPH^1,2,3; Jesper Qvist Thomassen, PhD¹; Børge G. Nordestgaard, MD, DMSc^4,5,6; et al

doi:10.1001/jamanetworkopen.2022.35648

Key Points

Question  What is the relevance of types of blood leukocytes in Alzheimer disease (AD)?

Findings  In this cohort study of 101 582 individuals in the Danish general population, low baseline blood monocyte counts were associated with increased AD risk. In a mendelian randomization framework using the most powerful genomic data sets, genetically determined low monocyte counts were also associated with increased AD risk, an association independent of other types of blood leukocytes.

Meaning  The findings of this study suggest that the observational and genetic association observed between low monocyte counts and increased risk of AD highlights a possible role of the innate immune system in AD pathogenesis.

Abstract

Importance  Emerging evidence implicates a role for neuroinflammation in Alzheimer disease (AD) pathogenesis, predominantly involving the innate immune system. Blood leukocyte counts are easily accessible markers of immune function; however, their association with the risk of AD is unknown.

Objective  To investigate the observational and genetic associations between types of blood leukocytes and risk of AD.

Design, Setting, and Participants  In a cohort study comprising observational and genetic analyses, the Copenhagen General Population Study prospective cohort (n = 101 582) was used for the observational analyses. For the genetic studies, nonlinearity was first evaluated for the association between leukocyte cell counts and AD risk using individual-level data from the UK Biobank (n = 365 913). Subsequently, a 2-sample mendelian randomization framework was applied using genetic instruments for blood leukocyte counts (n = 563 085); for AD, the European Alzheimer & Dementia Biobank was used, including 85 934 individuals with AD and 401 577 controls and the International Genomics of Alzheimer’s Project, including 21 982 individuals with AD and 41 944 controls.

Exposures  Observational and genetically determined types of blood leukocyte counts.

Main Outcomes and Measures  Hazard ratios (HRs) and 95% CIs for AD of cell count percentile groups in observational studies and odds ratios (ORs) and 95% CIs for AD per 1 SD genetically determined cell counts.

Results  This cohort study included 101 582 participants (55 891 [55.0%] women) with a median age of 58 years (IQR, 48-67 years); of these, 1588 individuals developed AD. Multivariable-adjusted HRs for participants in the less than 5th vs the 25th to 75th (reference) percentile group were 1.24 (95% CI, 0.99-1.54) for blood monocytes and 1.25 for blood eosinophils (95% CI, 1.05-1.50). For participants in the greater than 95th vs the 25th to 75th percentile group, the HR was 1.30 (95% CI, 1.06-1.61) for blood neutrophils. Genetically, no evidence favored possible nonlinear associations. The ORs for AD per 1-SD decrease in genetically determined blood monocytes were 1.04 (95% CI, 1.00-1.10) in the European Alzheimer & Dementia Biobank consortium and 1.09 (95% CI, 1.01-1.17) in the International Genomics of Alzheimer’s Project consortium. Using mendelian randomization, sensitivity analyses and multivariable analysis showed similar results.

Conclusions and Relevance  The findings of this study suggest that low blood monocyte counts are associated with increased AD risk. These findings highlight a potential role of the innate immune system in AD pathogenesis.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797072

Association of Midlife Inflammatory Markers With Cognitive Performance

  

View ORCID ProfileTeemu Kipinoinen,  View ORCID ProfileSini Toppala,  View ORCID ProfileJuha O. Rinne,  View ORCID ProfileMatti H. Viitanen,  View ORCID ProfileAntti M Jula,  View ORCID ProfileLaura L Ekblad

DOI: https://doi.org/10.1212/WNL.0000000000201116

Abstract

Background and objectives: Chronic low-grade inflammation, commonly associated with cardiovascular diseases and risk factors, has been associated inconclusively with cognitive decline and dementia. The aim of our study was to evaluate whether low-grade inflammation, measured in midlife, is associated with a decline in cognitive performance after a 10-year follow-up. We hypothesized that low-grade inflammation, estimated by interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) and high-sensitivity CRP (hs-CRP), is a predictor of cognitive decline in the general population.

Methods: This prospective cohort study is based on a Finnish nationwide, population-based Health 2000Examination Survey, its supplemental examinations in 2000-2001 and the follow-up Health 2011Survey. Cognitive performance at baseline and at follow-up was assessed with categorical verbal fluency (VF), Word-list learning (WLL) and word-list delayed recall (WLDR). Baseline low-grade inflammation was measured with IL-6, TNF-α and hs-CRP in 2001. Associations between low-grade inflammation and cognitive performance were analyzed with multivariable linear models adjusted for age, sex, education, APOEε4 genotype, type 2 diabetes, hypertension, hypercholesterolemia, body mass index, depressive symptoms, smoking, and baseline cognition.

Results: 915 participants aged 45 to 74 years (median age 54, 55% women) were included in the analysis. Both higher IL-6 and TNF-α at baseline predicted poorer performance in VF and WLL at 10-year follow-up (VF: IL-6 β: -1.14, p=0.003, TNF-α β: -1.78, p=0.008; WLL: IL-6 β: -0.61, p=0.007, TNF-α β: -0.86, p=0.03). Elevated IL-6 also predicted a greater decline in VF and WLL after a 10-year follow-up (VF: β: -0.81, p=0.01; WLL: β: -0.53, p=0.008). Baseline TNF-α did not predict cognitive decline and hs-CRP did not predict cognitive performance or decline after 10-years.

Discussion: Our results suggest that low-grade inflammation in midlife is an independent risk factor of poorer cognitive performance later in life. Of the studied markers IL-6 and TNF-α seem to be stronger predictors for cognitive performance and decline than hs-CRP.

https://n.neurology.org/content/early/2022/10/04/WNL.0000000000201116

Blood Pressure in Migraine Patients Treated With Monoclonal Anti-CGRP (receptor) Antibodies

  

View ORCID ProfileSimone de Vries Lentsch,  View ORCID ProfileBritt Willemijn Heleen van der Arend,  View ORCID ProfileAntoinette Maassen van den Brink,  View ORCID ProfileGisela M. Terwindt

DOI: https://doi.org/10.1212/WNL.0000000000201008

Abstract

Background and Objectives: Anti-CGRP (receptor) antibodies are approved as preventive treatment for migraine. Recent concerns have been raised after a retrospective analysis of post-marketing case reports of elevated BP associated with erenumab. In this prospective follow-up study we aimed to assess the safety regarding blood pressure (BP) in a real world setting.

Methods: All people with migraine that were treated with erenumab and fremanezumab at the Leiden Headache Center between January 2019 and January 2021 were included. BP measurements were collected from baseline (T0) until 12 months follow-up, with a three-month interval (T1–T4). Mixed linear models were fitted with time as a fixed effect and the patient as a random effect.

Results: Both systolic and diastolic BP were increased at all time points T1-T4 compared to T0 (p<0.001). The maximum estimated increase in mean systolic BP was 5.2 mmHg (95% CI: 3.1-7.5). The maximum estimated increase in mean diastolic BP was 3.5 mmHg (95% CI: 2.0-4.9). In the erenumab group (n = 109), both systolic and diastolic BP were increased all time points compared to T0 (all p<0.001). For fremanezumab (n = 87), systolic but not diastolic BP was increased compared to T0 at T1 (p=0.006) and T2 (p=0.004). Four patients (3.7%) with normal BP at T0 required antihypertensive treatment after erenumab was started.

Discussion: The mean systolic and diastolic BP increased after anti-CGRP (receptor) antibodies were started. The majority of patients remained within the normal blood pressure limits, but some patients required antihypertensive treatment. Physicians should be aware that people with migraine may be at risk to develop hypertension when treated with anti-CGRP (receptor) antibodies and this should be added to (inter)national treatment guidelines.

Classification of Evidence: This study provides Class III evidence that anti-CGRP (receptor) antibodies increase blood pressure when used to treat patients with migraine.

https://n.neurology.org/content/early/2022/10/04/WNL.0000000000201008

Hyperbaric Oxygen Therapy for Long COVID?

 In the quest for treatments for people struggling with long COVID, some researchers have evaluated hyperbaric oxygen therapy (HBOT), but the science is far from settled, and questions remain about its feasibility.

Some small studies have shown a possible benefit for select patients suffering from fatigue related to long COVID. But HBOT -- which is more commonly used for wound care or decompression sickness -- might not be a suitable option for most patients, said Monica Verduzco-Gutierrez, MD, of the Long School of Medicine at UT Health San Antonio in Texas.

"Once we know a little bit more about the mechanism of what's happening [with long COVID], then we can really get targeted therapies," Verduzco-Gutierrez told MedPage Today. "Is it endothelial dysfunction and hyperperfusion to the brain? Yes, that's probably one mechanism, and that's where maybe something like hyperbaric [oxygen therapy] could help in that case. Is it immune system dysfunction? ... In that case, hyperbaric treatment wouldn't be something that was helpful."

The research to date on HBOT for long COVID is very limited, but it suggests that the treatment can improve fatigue and cognitive outcomes.

In one randomized, sham-controlled, double-blind trial of HBOT published in Scientific Reports this summer, Shai Efrati, MD, of Tel-Aviv University in Israel, and colleagues showed that there was a significant group-by-time interaction in global cognitive function, attention, and executive function with HBOT in patients with long COVID symptoms for at least 3 months after confirmed SARS-CoV-2 infection. They also found that patients in the treatment group had significant improvements in sleeping scores and psychological symptoms.

"Results indicate that HBOT can induce neuroplasticity and improve cognitive, psychiatric, fatigue, sleep and pain symptoms of patients suffering from post-COVID-19 condition," Efrati and team wrote.

Another study, published last year in Clinical Medicine, showed that 10 long COVID patients who underwent 10 sessions of HBOT over a 12-day period experienced statistically significant improvements in fatigue, global cognition, and executive function.

Tim Robbins, PhD, of the University of Warwick in Coventry, England, and colleagues noted that the results were promising, but the analysis was only an initial evaluation of the treatment. However, "the effect size measures calculated are large, suggesting a substantial improvement and, thus, there is a small likelihood these results are due to chance despite the small initial sample size."

Even so, the reality is that HBOT is suitable for only a small number of patients, said Verduzco-Gutierrez. She pointed out that even if a patient was interested in trying this option, it is off-label and therefore would have a high out-of-pocket cost.

"Right now, [HBOT] for the most part is approved for wound care reasons or for the bends, and otherwise it's not something that is accessible to someone. It could be $10,000 to $12,000 out-of-pocket," she explained.

She suggested that the best approach for patients would be to find an ongoing trial using HBOT for long COVID to alleviate the cost burden, but even then the opportunities are limited.

Still, Verduzco-Gutierrez said there is always utility in casting a wide net, especially when it comes to looking for solutions for patients with long COVID.

"If someone's willing to put financial resources into studying this, then I think we can learn something from it," she noted. "On a global level, could it help a lot of patients? Probably not, in its current state."

https://www.medpagetoday.com/special-reports/features/101181

Adding Antibiotic to Brain Stim Bolstered Effects in Major Depression

 Adding D-cycloserine to the mix may enhance the benefits of intermittent theta-burst stimulation (iTBS) for those with major depressive disorder, a randomized trial showed.

Among 50 patients, those who took the antibiotic during the first 2 weeks of a 4-week course of iTBS had greater improvements in depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) compared with those receiving iTBS plus placebo (mean difference -6.15, 95% CI -2.43 to -9.88), reported Alexander McGirr, MD, PhD, of the University of Calgary in Canada, and colleagues.

Patients in the D-cycloserine group also saw a higher clinical response rate at 4 weeks than the iTBS group (73.9% vs 29.3%; OR 6.88, 95% CI 1.91-24.77, P=0.003), as well as a higher clinical remission rate (39.1% vs 4.2%; OR 14.78, 95% CI 1.68-129.52, P=0.01), the group wrote in JAMA Psychiatry.

Furthermore, those receiving the antibiotic had lower Clinical Global Impression (CGI)-severity scores and higher CGI-improvement scores, as well as improved self-reported anxiety symptoms.

"One notable feature of the course of improvement is a larger treatment effect after 4 weeks than after 2 weeks of treatment, despite the adjuvant being present for the first 2 weeks," McGirr and team wrote. "We speculate that despite ongoing iTBS, this reflects an erosion of the placebo effect, as 15 of 25 participants (60%) in the iTBS plus placebo group plateaued or had a worsening MADRS score compared with 9 of 25 participants (36%) in the iTBS plus DCS [D-cycloserine] group."

The authors noted that D-cycloserine, an NMDA-receptor partial-agonist often used to treat urinary tract infections, has previously been studied for other psychiatric conditions like anxiety, obsessive-compulsive disorder, and trauma. "Despite inconsistent results across studies, DCS is associated with a small but statistically significant efficacy signal in meta-analyses for these conditions," they wrote, pointing out that a weak dose might have been to blame for previous null results.

Another recent randomized trial looking at the same course of iTBS (20 sessions with the same stimulator), but without adjunctive therapy, flopped in a trial of 37 adults with type I or type II bipolar disorder experiencing an acute major depressive episode.

This single-site, double-blind study, conducted from November 2019 through December 2020, randomized 25 participants with major depressive disorder to each group, the majority of whom were women with a mean age of 41. Twenty percent of the placebo group and 32% of the D-cycloserine group had previously attempted suicide.

Inclusion criteria included a major depressive episode with a score of 18 or more on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or less, and normal blood work.

iTBS was delivered via MagVenture's MagPro X100 stimulator and a COOL-B70 coil. The stimulation was targeted at the left dorsolateral prefrontal cortex with the Beam F3 method, and consisted of 600 pulses per session delivered in 20 trains of triplets at 50 Hz repeated at 5 Hz -- 2 seconds on, 8 seconds off -- at 80% resting motor threshold. Participants received daily treatments Monday through Friday for a total of 20 sessions over the 4-week trial.

Those in the D-cycloserine group were given 100 mg for the first 2 weeks of iTBS, followed by iTBS alone for weeks 3 and 4.

While there were no serious adverse events reported, more people in the D-cycloserine group experienced headaches during the first 2 weeks (92% vs 76% with placebo). This subsided during the next 2 weeks of the trial for both groups (52.1% vs 57.1%).

McGirr and team noted that their study was small and conducted at a single site, so "replication in a larger multisite study is required, as is additional investigation into intersectional approaches with other dosing regimens and precision medicine targeting approaches."

Disclosures

The study was supported in part by the 2018 Young Investigator Award from the Brain and Behavior Research Foundation and the Campus Alberta Innovates Program Chair in Neurostimulation.

McGirr and co-authors reported relationships with the Canadian Institutes of Health Research Canada Graduate Scholarship Masters Award and MCGRx Corp.

Primary Source

JAMA Psychiatry

Source Reference: Cole J, et al "Efficacy of adjunctive D-cycloserine to intermittent theta-burst stimulation for major depressive disorder" JAMA Psychiatry 2022; DOI: 10.1001/jamapsychiatry.2022.3255.

https://www.medpagetoday.com/psychiatry/depression/101180

Bright Health Drops Individual Insurance Business

 

• Reaffirms previous 2022 Adjusted EBITDA guidance at midpoint and accelerates Adjusted EBITDA profitability to 2023, a year earlier than previously anticipated

• Will no longer offer Individual and Family Plan products through Bright HealthCare in 2023, or Medicare Advantage products outside of California and Florida

• Raises $175 million of committed convertible preferred equity capital to fully fund business to profitability

• Expects to deliver a $3 billion Net Revenue balanced business in 2023 through its risk-bearing care delivery and Medicare Advantage businesses

https://finance.yahoo.com/news/bright-health-group-further-focus-110000854.html