SAFETY AND PHARMACOKINETICS OF IGPRO20 (SUBCUTANEOUS IMMUNOGLOBULIN) AND IGPRO10 (INTRAVENOUS IMMUNOGLOBULIN) IN ADULTS WITH SYSTEMIC SCLEROSIS (SSC) – RESULTS FROM A PHASE 2 TRIAL

BackgroundSystemic sclerosis (SSc) is a severe, progressive multisystem rheumatic disease with high mortality, but without approved disease-modifying treatment to stop or reverse course of disease. Intravenous immunoglobulin G (IgG) may have a positive impact on SSc based upon available literature reports. However, to date, there have been no clinical trials evaluating subcutaneous IgG (SCIG) in SSc. In particular, the impact of pathologically altered skin in SSc on local safety and pharmacokinetics (PK) of SCIG has not been explored yet.ObjectivesThe primary and secondary objectives of this trial (NCT04137224) included safety, including local infusion safety, and bioavailability of subcutaneous IgG (IgPro20) in adults with diffuse cutaneous SSc (dcSSc).MethodsThis was a randomized, open-label, crossover study. Adult subjects with dcSSc diagnosis within 5 years from first non-Raynaud's phenomenon and modified Rodnan Skin Score of 15-45 at screening were randomized 1:1 to sequence A (IgPro20, 20% normal human subcutaneous immunoglobulin followed by IgPro10, 10% normal human intravenous immunoglobulin) or sequence B (IgPro10 followed by IgPro20). Each subject was to complete two treatment periods (16 weeks each), with up to 40 weeks (including screening) study duration for an individual subject. Doses received were 0.5g/kg/week split over two sessions for IgPro20, and 2g/kg/4 weeks split over 2-5 days for IgPro10. The primary endpoint was safety of IgPro20, described as treatment-emergent adverse events (TEAEs) and changes in clinical observations.Results27 subjects were randomized, with 13 subjects to sequence A and 14 subjects to sequence B. In total, 25 subjects completed the study. Of 27 treated subjects, 107 TEAEs occurred in 22 subjects (81.5%) over the 36-week study period, the majority of which were mild or moderate. The most common TEAEs (>10% of subjects) by preferred term (PT) were headache (12 events occurring in 6 subjects [22.2%]), COVID-19 (3 events occurring in 3 subjects [11.1%]), diarrhoea (3 events occurring in 3 subjects [11.1%]), and vomiting (3 events occurring in 3 subjects [11.1%]).A total of 10 serious AEs (SAEs) were reported in 6 subjects (Viral infection, Chronic gastritis, Vomiting, Dehydration, Upper gastrointestinal haemorrhage, Chest pain, Myocardial infarction, Myocardial ischemia, Breast cancer, Interstitial lung disease). Among these, one subject experienced 2 SAEs (myocardial ischemia & myocardial infarction) and was discontinued from study treatment. None of the SAEs were considered related to study treatment by the investigator, and no deaths were reported.For IgPro20, 14 infusion site reactions (ISRs) occurred in 5 subjects (19.2%), all were mild or moderate in severity. The most common ISRs were infusion site pain and infusion site swelling (3 events in 2 subjects each, 7.7%). In total, 686 IgPro20 infusions were performed, resulting in an overall ISR rate per infusion of 0.02, ie 2 ISRs per 100 infusions. No ISRs were reported for IgPro10.No clinically relevant trends in vital signs, body weight, clinical laboratory tests, electrocardiograms, or pulmonary function tests were observed.PK profiles and bioavailability in dcSSc subjects were similar to those observed in other approved indications such as Primary Immunodeficiency. Population relative bioavailability of IgPro20, based on dose-normalized, baseline-corrected AUC0-tau was 0.761 (90% CI: 0.7033, 0.8232), ie 76.1% compared to IgPro10 (intravenous IgG).ConclusionThe overall safety profiles of IgPro20 and IgPro10 in subjects with dcSSc were consistent with that in approved indications such as CIDP, including a relatively low ISR rate for IgPro20. PK profiles and bioavailability were also similar to other indications. This study indicates that subcutaneous administration of IgPro20 has acceptable safety, bioavailability and PK profiles in patients with dcSSc. AcknowledgementsEditorial assistance was provided by Meridian HealthComms Ltd., funded by CSL Behring.Disclosure of InterestsChristopher P Denton Speakers bureau: Ja ssen, Boehringer Ingelheim, Consultant of: GSK, CSL Behring, Boehringer Ingelheim, Merck, Roche, Sanofi, Grant/research support from: GSK, CSL Behring, Inventiva, Horizon, Otylia Kowal-Bielecka Speakers bureau: Abbvie, Janssen-Cilag, Boehringer Ingelheim, Medac, MSD, Novartis, Pfizer, Sandoz, Consultant of: Boehringer Ingelheim and Novartis, Grant/research support from: Received congress support from Abbvie, Boehringer Ingelheim, and Medac, Susanna Proudman Speakers bureau: Boehringer Ingelheim, Grant/research support from: Janssen, Marzena Olesińska Consultant of: AstraZeneca, Margitta Worm Consultant of: Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, DBV Technologies S.A, Aimmune Therapeutics UK Limited, Regeneron Pharmaceuticals, Inc, Leo Pharma GmbH, Boehringer Ingelheim Pharma GmbH &Co.KG, ALK-Abelló Arzneimittel GmbH, Kymab Limited, Amgen GmbH, Abbvie Deutschland GmbH & Co. KG, Pfizer Pharma GmbH, Mylan Germany GmbH (A Viatris Company), AstraZeneca GmbH, Lilly Deutschland GmbH and GlaxoSmithKline GmbH & Co. KG., Nicoletta Del Papa Speakers bureau: Janssen Cilag, Boehringer Ingelheim., Marco Matucci-Cerinic Speakers bureau: Biogen, Sandoz, Boehringer Ingelheim, Consultant of: CSL Behring, Boehringer Ingelheim, Grant/research support from: MSD, Chemomab, Jana Radewonuk Shareholder of: CSL Behring, Employee of: CSL Behring, Jeanine Jochems Shareholder of: CSL Behring, Employee of: CSL Behring, Amgad Shebl Shareholder of: CSL Behring, Employee of: CSL Behring, Anna Krupa Shareholder of: CSL Behring, Employee of: CSL Behring, Jutta Hofmann Shareholder of: CSL Behring, Employee of: CSL Behring, Maria Gasior Shareholder of: CSL Behring, Employee of: CSL Behring.

Immunotherapy: FAMILIAL CD45RA DEPLETED T CELLS TO TREAT SEVERE REFRACTORY INFECTIONS IN IMMUNOCOMPROMISED PATIENTS

Background & Aim: Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. If available, most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. Methods, Results & Conclusion(s): We have previously demonstrated the safety of adoptive cell therapy for COVID-19 patients with CD45RA negative cells containing SARS-CoV-2-specific T cells from a donor, chosen based on HLA compatibility and cellular response to SARS-CoV-2 peptide pools. After finishing a Phase 2 randomized multicenter clinical trial (RELEASE, NCT04578210), we concluded that the infusion is safe, effective, accelerates lymphocyte recovery and shows hallmarks of an immune response. To use adoptive cell therapy to treat COVID-19 it would be necessary to develop a biobank of living drugs. For that, we examined the immune evolution performing a longitudinal analysis from previously SARS-CoV-2 infected and infection- naive individuals covering 21 months from infection. Cellular responses were maintained over time while humoral responses increased after vaccination but were gradually lost. Therefore, the best donors would be recovered individuals and two months after vaccination. We also evaluated the effect of dexamethasone (current standard of care treatment for COVID-19 and other infections involving lymphopenia) and Interleukin-15 (cytokine involved in T-cell maintenance and survival) on CD45RA negative. Dexamethasone did not alter cell functionality, proliferation or phenotype at a clinical-practice concentration, while interleukin-15 increased the memory T-cell and T-regulatory cell activation state, and interferon gamma release. Furthermore, we applied the adoptive passive transfer of CD45RA negative cells containing pathogen-specific memory T-cells to other infectious diseases characterized by sustained lymphopenia. We infused six immunocompromised patients with Cytomegalovirus, BK virus, Aspergillus, and Epstein-Barr virus lymphoproliferative disease. Patients experienced pathogen clearance, resolution of symptoms and lymphocyte increase. Transient microchimerism was detected in three patients. The use of CD45RA negative cells containing specific memory T cells of a third-party donor for treating severe pathogenic diseases in immunocompromised patients is feasible, safe, and effective, and has an advantage over other cell therapies such as lower costs and a less complex regulatory environment.Copyright © 2023 International Society for Cell & Gene Therapy

Remote mental health care interventions during the COVID-19 pandemic: An umbrella review.

Mitigating the COVID-19 related disruptions in mental health care services is crucial in a time of increased mental health disorders. Numerous reviews have been conducted on the process of implementing technology-based mental health care during the pandemic. The research question of this umbrella review was to examine what the impact of COVID-19 was on access and delivery of mental health services and how mental health services have changed during the pandemic. A systematic search for systematic reviews and meta-analyses was conducted up to August 12, 2022, and 38 systematic reviews were identified. Main disruptions during COVID-19 were reduced access to outpatient mental health care and reduced admissions and earlier discharge from inpatient care. In response, synchronous telemental health tools such as videoconferencing were used to provide remote care similar to pre-COVID care, and to a lesser extent asynchronous virtual mental health tools such as apps. Implementation of synchronous tools were facilitated by time-efficiency and flexibility during the pandemic but there was a lack of accessibility for specific vulnerable populations. Main barriers among practitioners and patients to use digital mental health tools were poor technological literacy, particularly when preexisting inequalities existed, and beliefs about reduced therapeutic alliance particularly in case of severe mental disorders. Absence of organizational support for technological implementation of digital mental health interventions due to inadequate IT infrastructure, lack of funding, as well as lack of privacy and safety, challenged implementation during COVID-19. Reviews were of low to moderate quality, covered heterogeneously designed primary studies and lacked findings of implementation in low- and middle-income countries. These gaps in the evidence were particularly prevalent in studies conducted early in the pandemic. This umbrella review shows that during the COVID-19 pandemic, practitioners and mental health care institutions mainly used synchronous telemental health tools, and to a lesser degree asynchronous tools to enable continued access to mental health care for patients. Numerous barriers to these tools were identified, and call for further improvements. In addition, more high quality research into comparative effectiveness and working mechanisms may improve scalability of mental health care in general and in future infectious disease outbreaks.

A Phase I/II Dose-Escalation Multi-Center Study to Evaluate the Safety of Infusion of Natural Killer Cells or Memory T Cells As Adoptive Therapy in Coronavirus Pneumonia and/or Lymphopenia: (RELEASE NCT04578210)

Background: Adoptive cell immunotherapies for opportunistic virus in immunocompromised patients using haploidentical memory T cells have shown to be safe and effective. Since severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state we have proposed that a similar strategy could be proven to be efficient for COVID-19 patients. This is a study protocol of an open-label, multicenter, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the feasibility, safety, tolerability, and efficacy of the administration of a single dose of allogenic SARS-CoV-2 specific memory CD45RA - T cells and Natural Killer (NK) cells in COVID-19 patients with lymphopenia and pneumonia. The aim of the study is to find efficient treatments for patients with moderate/severe COVID-19. Identification of Specific memory T cells and NK cells: i)Memory T Cells: we first determined the existence of SARS-CoV-2 specific T cells within the CD45RA - T memory cells of the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms without inducing classically T cell alloreactivity. Also, CD45RA - memory T cells confer protection for other pathogens the donors encountered in their life. ii)NK cells: we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2 specific NK population in the blood of convalescent donors, as it has been shown for cytomegalovirus infections. Also, NK cells confer protection for other pathogens the donors encountered in their life. Pilot Phase I- Safety, feasibility, and dose escalation: Between September and November 2020 a phase 1, dose-escalation, single-center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA - memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1x10 5 cells/kg), the next three received the intermediate dose (5x10 5 cells/kg) and the last three received the highest dose (1x10 6 cells/kg) of CD45RA - memory T cells. Clinicaltrials.gov registration: NCT04578210. Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilized post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent SARS-CoV-2 specific CD45RA - memory T cells is feasible and safe. We did not find dose-liming toxicity. The Recommended Phase 2 dose was 1x10 6 CD45RA - T cells. Phase II- Efficacy: Between January 2021 and July 2021 patients have been enrolled based on the matched with the HLA genotype of the convalescent donors and following the protocol inclusion/exclusion criteria. The primary outcome is the incidence of patient recovery at day 14, defined as normalization of fever and oxygen saturation or lymphopenia recovery. Secondary outcomes are the time to normal level of lymphocytes, the proportion of patients showing clinical improvement at day 7, time to first negative SARS-CoV-2 PCR, the incidence of treatment-related adverse events, duration of hospitalization, time to discharge, time to improvement by one category a 7-point ordinal scale or NEWS score, the proportion of patients requiring intensive care unit, and all-cause mortality. In addition, lymphocyte recovery by multiparametric flow cytometry and donor chimerism by real-time PCR in the e perimental arm was monitored weekly during the first month. This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA - memory T cells is safe and feasible. The phase II clinical trial is ongoing to demonstrate efficacy. [Formula presented] Disclosures: Soria: Celgene: Other: Fees;Gilead: Other: Fees;AbbVie: Other: Fees.

Impact of COVID-19 pandemics upon pulmonary hypertension patients: insights from BNP-PL national database

Introduction: COVID-19 pandemic has caused not only an increase in overall and cardiovascular mortality, but also hindered access to health care, diagnosis and treatment of diseases other than coronavirus infection. Aim: Assessment of the impact of the SARS-CoV-2 pandemic on the rate of diagnosis and therapy of pulmonary hypertension (PH) in Poland, along with an analysis of the incidence and course of COVID-19 among patients (pts) diagnosed with PH, treated under the National Health Fund program, registered in the national BNP-PL database. Methods: The records of the complete population of Polish pts treated under the National Drug Program of PH (PAH and CTEPH), registered in the national database of BNP-PL, updated on an ongoing basis by all PH centers, were analyzed. The frequency of SARS-CoV-2 infections, the clinical severity of their course and the mortality were reviewed, taking into account the specific therapies used. The basic clinical characteristics of the group of sick and deceased patients were compared to the remaining patients registered in the BNP-PL database. The rate of increase of new diagnoses ended with inclusion in the Drug Program between March and December 2020, compared to the corresponding periods of the previous year, and the change in the treatment profile were compared. Results: The analysis included 1704 pts (PAH 1134, CTEPH 570). The incidence of SARS-CoV-2 infections was 3.8% (n=65), including PAH 2.7% (n=46) and CTEPH 3,2% (n=18). 32 patients (49%) required hospitalization. Mortality rate was 28% (18/65) - including 7/18 outside of hospital. Those who died due to COVID-19 were older (mean age 68.4±l15.8 vs. 50.8±l18.8 yrs;p<0,001), had higher WHO class and more cardiovascular comorbidities (4±l2,06 vs. 2,66±l1,8;p=0,01) (Table 1). During the pandemic the number of new diagnoses of PH markedly decreased compared to the corresponding period in 2019 (total 150 vs. 203, PAH 90 vs. 123, CTEPH 60 vs. 80, respectively). A significant increase in total mortality was also observed in the PH group (9,72 vs. 5,85%). Moreover, escalation of specific PH therapy decreased significantly (14,7% vs. 21,6%). Incidence of COVID-19 study group was lower than estimated for general Polish adult population (3,8% vs. 6,5%). Conclusions: COVID-19 pandemic deeply influenced the diagnostic and therapeutic process of pulmonary hypertension by reducing the number of new diagnoses, escalation therapy and increased overall mortality in this population. This may be due in part to the conversion of some PAH centers into hospitals treating patients infected with SARS-CoV-2, as well as to patients' fear of admitting to hospital despite clinical deterioration. Pulmonary hypertension is linked to markedly increased mortality in COVID-19, similarly for PAH and CTEPH. Intriguing finding of lower infection rate may be linked to protective lifestyle or specific therapies.

Phase I dose-escalation single centre clinical trial to evaluate the safety of infusion of memory T cells as adoptive therapy in COVID-19 (RELEASE).

BACKGROUND: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy. METHODS: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA- memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA- memory T cells. Clinicaltrials.gov registration: NCT04578210. FINDINGS: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. INTERPRETATION: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA- memory T cells is feasible and safe. FUNDING: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.