EDP-235, A Potent and Once-daily Oral Antiviral, Demonstrates Excellent Penetration into Macrophages and Monocytes, with the Potential for Mitigation of Cytokine Storm in High-Risk COVID-19 Patients

Background. Macrophages, including lung alveolar macrophages (AM), and monocytes are the first lines of defense against SARS-CoV-2. Several reports have suggested that SARS-CoV-2 can hijack AM and monocytes for replication and viral spread, which may, in turn, drive the cytokine storm associated with severe COVID-19. Herein, we describe one of many advantageous features that EDP-235, a novel and potent SARS-CoV-2 3C-like protease (3CLpro) inhibitor under development as a once-daily oral antiviral therapy for COVID-19, displays - excellent penetration into macrophages and monocytes. Methods. Intracellular uptake of EDP-235 was tested side-by-side with nirmatrelvir in rat lung AM, human monocytes and human macrophages. To determine the in vivo drug distribution into lung AM, rats were dosed orally with 25 mg/kg of EDP-235 or nirmatrelvir and plasma andAMdrug levels were analyzed by LC/MS/MS. Results. The ratios of intracellular to extracellular concentrations of EDP-235 in rat lung AM, human monocytes and human macrophages were 22.8, 22.7 and 30.5, respectively. In contrast, nirmatrelvir had ratios of 1.2 to 1.5 in these cells. Consistent with the in vitro observations, EDP-235 showed favorable rat AM penetration with an AUC0-24 ratio of 28.4 (AM over plasma), and nirmatrelvir had much less rat AM penetration with an AUC0-24 ratio of 0.5 (AM over plasma). EDP-235 had respective AUC0-24 values of 9.6 and 271.9 h*mug/mL in rat plasma and AM, while the AUC0-24 values of nirmatrelvir in rat plasma and AM were 2.7 and 1.2 h*mug/mL, respectively. Conclusion. EDP-235, a novel and potent SARS-CoV-2 3CL protease inhibitor, demonstrated excellent penetration into monocytes and macrophages, including lung AM. EDP-235 has the potential to eliminate the viral replication of SARS-CoV-2 in these critical immune cells, thus mitigating macrophage-mediated cytokine storm in high-risk COVID-19 patients. Clinical trials with EDP-235 for COVID-19 treatment and prevention are ongoing.

INNOVATIVE USE OF TELEHEALTH TO MANAGE COVID-19 INFECTED OUTPATIENTS BY A VETERANS HEALTH CARE CENTER

STATEMENT OF PROBLEM/QUESTION: In the spring of 2020 during the initial outbreak of COVID-19, the Rocky Mountain Regional VA (RMR) was tasked with ensuring the health of infected veterans. The RMR COVID-19 Telehealth Clinic was developed to support veterans in the community diagnosed with COVID-19, identify those with clinical deterioration requiring a higher level of care, and encourage appropriate isolation protocols. DESCRIPTION OF PROGRAM/INTERVENTION: Patients were stratified by risk factors (obesity, CHF, DM, cancer, CAD, HTN, age > 64) and clinical status into 3 tiers, with high-risk (Tier 3) receiving daily telehealth, moderate-risk (Tier 2) telehealth every other day, and low-risk (Tier 1) telehealth every three or more days. Providing care seven days a week, Tier 1 veterans were contacted by nurses and advanced practitioners, while Tier 2 and 3 veterans were managed predominantly by resident physicians and attendings, who provided clinical care for exacerbations of chronic disease as well as comprehensive care of COVID-19 infection. Hypoxic patients were provided oxygen and closely monitored with pulse oximeters. MEASURES OF SUCCESS: Between April 13 to October 5, 2020, 351 veterans testing positive for COVID-19 were followed. Thirty-eight were excluded (26 were outside study dates, 7 covid negative, 5 never received care). Charts for the remaining 313 patients were retrospectively evaluated for demographic data, comorbid conditions, duration of follow-up, and interventions provided, including prescribing and managing medications, referrals for emergency services, and escalating tiers. FINDINGS TO DATE: Of the cohort, 88% were male, 43% obese, 34% over age 64, 40% HTN, and 27% DM. Veterans were followed for 10.4 days on average. Approximately 54% were assigned to Tier 1, 29% to Tier 2, and 16% to Tier 3. Medications were prescribed for 45% and 27% of Tier 3 and Tier 2 patients respectively, and emergency care was advised for 22% and 20% of Tier 3 and Tier 2 veterans. Of Tier 1 patients, medications were ordered on 5%, emergency care recommended for 3%, and only 7% were escalated to Tier 2. Of the five deaths that occurred, two were directly attributed to COVID-19. KEY LESSONS FOR DISSEMINATION: A dedicated telehealth clinic for veterans with Covid-19 appropriately identified patients into low, moderate, and high-risk categories based on risk factor assessment. Low-risk patients were safely followed with intermittent telehealth emphasizing self-care and isolation, avoiding unnecessary Emergency Department visits. More frequent monitoring of symptoms and pulse oximetry in moderate to high-risk patients facilitated identification of patients with clinical deterioration requiring emergency evaluation and avoiding admissions for at-risk clinically stable patients. Tiered management resulted in judicious utilization of health care resources during a critical time marked by scarcity of hospital beds and personal protective equipment.

eP520: Screening results in 186 any-health-status adults in primary care clinics receiving clinical NGS for 431 health risk and recessive genes

Introduction: The ACMG has recommended returning clinically relevant results for certain genes when identified in research or as secondary findings in diagnostic testing. Research studies have shown that genomic population screening detects patients with previously unrecognized and often actionable health risks or genetic conditions, with acceptably low levels of harm. Cascade testing of relatives at risk is enabled. Screening for recessive disorder carrier status with gene sequencing panels is common in clinical practice. Preventative screenings routinely occur in primary care settings. The cost of reliably sequencing of many genes in a clinically reliable fashion is approaching levels where offering genomic screening tests may be contemplated for entire populations, and the results used for preventative health purposes, including clinical correlation, early screening, and education. In anticipation of universal genome sequence-based screening, integrated with existing health risk screenings, we piloted a novel implementation of clinical genomic population screening in primary care, mostly family medicine clinics. Screening involved clinical sequencing and reporting of 431 genes where variants are associated with personal health risks or recessive disease carrier status. Methods: Interested primary care providers (PCPs) in two Family Medicine practice systems were invited to participate and given onboarding education. Adult patients with any health status were introduced to The Genomic DNA Test and provided test information by their PCPs in the context of preventative health assessment. Patient education materials included paper, online, and video information, a ‘hotline,’ and optional free genetic counseling. Patients completing a bespoke, health system-approved, written clinical consent provided blood or occasionally saliva samples that were NGS sequenced according to validated procedures in a commercial CLIA-certified genetic testing laboratory. Laboratory reports were returned to the PCP and patient after a local genetics professional added a 1-to-3-page messaging document, the Genomic Medicine Action Plan (GMAP). The PDF-format reports and GMAP were placed in the patient’s electronic health record. Only pathogenic (P) and likely pathogenic (LP) variants were reported. Variant classification was according to Sherloc, the performing laboratory’s system. Patients or providers could request free post-test genetic counseling locally, and the performing lab offered free family member testing and limited-cost partner testing for health risk panel genes and recessive disorder panel genes, respectively. Patients with health risk results were defined as being heterozygous for a P/LP variant for a dominant condition or for a recessive condition where some heterozygotes are symptomatic or co-dominant, hemizygous for a P/LP variant for an X-linked recessive condition, or bi-allelic and plausibly in trans for an autosomal (or X-linked in a female) recessive condition. Many such conditions that are common have reduced or low penetrance, and were characterized as increased risk compared to those not having those variants. When increased risk was identified, the GMAP recommended appropriate medical responses and/or patient education. As part of quality assessment of the pilot, the frequencies of reported results and certain events are monitored. Results: Between November 2019 and October 2021, 186 patients with a median age of 58 years were tested by 20 PCPs at no cost to patients or insurance. Testing volumes declined during the COVID-19 pandemic and when other health system events made high demands on PCPs and their staff. Only 13.3% of patients had no reportable variants in any of the 431 genes. Eighty point nine percent were carriers for at least one recessive disease. The most common recessive genes showing carrier status were HFE, SERPINA1, GALT, CFTR, BTD, F5, DHCR7, PC, GAA, GJB2, PMM2, PAH, and PKHD1. Twenty-six percent had at least one potential health risk result identified, 20% if the common thrombophilias are excluded. The most common category was hereditary cancer risk (7.5%), followed by F5, F2, and SERPINC1 thrombophilia variants (6.5%), hereditary hemochromatosis 1 (HFE) (4.3%), cardiovascular disorders, mostly cardiomyopathies (3.8%), alpha-1-antitrypsin deficiency or other pulmonary disorder (3.8%), familial Mediterranean fever heterozygotes (1.6%), G6PD deficiency (1.1%), and lipid disorder (0.5%). Two patients had health risks in two areas, and two in three areas. Interestingly, BRCA1 and BRCA2 variants were only identified in males. Thirteen patients, about 7%, had an amended report issued during the period. This happened when an unreported variant of uncertain significance was reclassified as LP or P, or when LP became P, and the performing laboratory issued an amended report. Surprisingly few patients took advantage of the free genetic counseling. No patient adverse events were reported by the participating PCPs despite ongoing outreach, nor by patients. Conclusion: Genomic population health screening can be successfully implemented in primary care settings with use of limited but essential genetic professional assistance, after careful planning and input from other medical specialties. A significant proportion of adults not selected for health status harbors germline genetic variants associated with increased health risk. In the absence of a culture where routine genomic screening is expected and where patient genomic competency is high, PCP capacity limits are a barrier to universality. Inclusion of genes for both health risk results with variable degrees of penetrance and for recessive carrier status, and multiple simultaneous results, dictates careful messaging of the implications, while doing so in a primary care setting begs a concise and efficient process. Rates of carrier detection were in-line with predictions based on general population frequencies. Rates of health risk detections were higher than earlier research programs because a larger number of genes with a much broader scope of health risk was included, including disorders with low penetrance yet meaningful clinical relevance and carefully-designed care pathways meant to optimize care while avoiding unnecessary additional testing. We conclude that genomic population health screening of primary care patients where large numbers of genes are clinically sequenced is feasible in a real-world health system, and that value exists for some tested patients now. Research to overcome certain technical limitations of current clinical genomic testing methods and to better stratify risk level in the context of incomplete penetrance should enhance the value of universally-offered genomic population health screening in the future.

Clinical genomic population health testing for 431 genes implemented through family medicine practices: the Vermont experience

Integration of genomics into health practice depends on successful implementation in non-research settings. We describe a medical home-centered implementation at the intersection of genomic medicine and population health in the UVM Health Network. In this clinical implementation, the hospital laboratory orchestrates a collaboration involving primary care providers (PCPs), patient and family advisors, health system administrators, clinical genetics services, oncologists and cardiologists, Vermont’s accountable care organization, and a commercial CLIA genomic testing laboratory. Phenotypically unselected adult primary care patients are offered “The Genomic DNATest” at no cost as part of their regular care. Testing is introduced by primary care providers and their staff using a brief animated video and printed decision aids with graded detail. Question resolution and pre- and post-test genetic counseling is offered at no cost using telephone, video, or in-person visits, and is coordinated bya single phone and email contact point, the Genomic Medicine Resource Center. 431 genes are sequenced for germline health risk and recessive carrier variants;only pathogenic and likely-pathogenic variants are reported. New reports are issued when reported and unreported variants are later reclassified. Test reports are reviewed by a clinical geneticist and genetic counselor. Two brief "action plans" are developed with PCP and patient focus in a single messaging document. This is prepended to the lab reports before release to the PCP, who reviews and then conveys them to the patient. PCPs and their staff receive initial training on the test and process and are invited to participate in an online community with monthly video case discussions. Among the first 72 patients tested, 17% had a health risk identified. This included dominantly inherited disorders and bi-allelic or hemizygous variants for common recessive disorders. Care pathways created in advance using multi-disciplinary expertise were activated for those. Free testing for blood relatives was made available. 76% of tested patients had at least one heterozygous recessive disease variant identified, and low-cost partner testingwas made available. Frequency of positive test results was in line with population frequency predictions. Pre- and post-test genetic counseling uptakewas lower than expected. This raised the question of unmet informational needs. A 2-page anonymous process quality survey mailed twice to the first 61 tested patients had a 31% return rate. Key findings included (1) pre-test engagement methods and decision aids were helpful;(2) the testing decision was influenced equally by value for the individual’s health, for their family’s health, and for researchers;(3) emotions during the ∼4-week time to results were neutral or excited, with none experiencing anxious feelings, and none reported the wait time as too long;(4) 21% reported contacting the Genomic Medicine Resource Center;(5) 16% reported referral to a specialist due to their result;(6) about half reported sharing the results with family members, but none reported any family members getting tested;(7) none indicated they were dissatisfied with the testing and result process, and only one responded they would not recommend others get the test;and (8) all agreed or somewhat agreed that the PCPs officewas the right place to do this testing.While this implementation was designed with scalability and a low management profile in mind, several systems-level barriers were encountered that contributed to lower engagement efforts and slower expansion than planned. This included lack of institutional information technology resources to surmount paper-based systems for requisitions, sample-routing, and consent forms;dependency of the patient engagement process during PCP visits on rooming and nursing staff during times of staffing shortages;susceptibility to practice model disruptions and priorities caused by the Covid-19 pandemic;and PCP time distraction resulting from user interface and polic changes in our EHR during the pilot. These barriers are targets for study and continuous process improvement activities. In summary, an example of clinical genomic population health testing using a medical-home focus has been successfully implemented in a non-research setting, supported by multi-disciplinary collaboration. This implementation depends on minimal staff, avoids financial barriers to access and genetic counseling, and offers a short, defined, test turnaround time as compared to similar biobank-based research programs. Tested patients find the program satisfactory, and meaningful test results are at least as common as in existing population health risk screening archetypes.

Implementing and adapting FEV1-indicated exacerbation signal algorithms through quality improvement

Background: In an attempt to standardize the definition, recognition, and treatment of lung function decline, the CF Learning Network (CFLN) developed an FEV1-indicated exacerbation signal (FIES). Cincinnati Children's Hospital (CCHMC) CF center is one site of a network-wide innovation laboratory (iLab), with a goal to increase the percentage of patients assessed for an exacerbation signal by implementing a series of interventions through quality improvement (QI). CF centers, including our own, have a strong and successful history of using QI to improve outcomes. Prior to this initiative, infrastructure, communication and tools were already in place to recognize lung function decline, using different definitions. Interventions: QI methodology was used to plan all processes and goals, including key driver diagrams (KDD), failure modes and effects analysis (FMEA) and process maps with all stakeholders, including physicians, nurses, patients and families. Early education sessions for team members and our parent/patient advisory group were held to discuss the project and changes in our definitions of lung function decline, which was then communicated with all CF patients and families. In order to provide a uniform transition to the new definitions of lung function decline, databases and reports were created and communicated with team members. Utilizing several plan-do-study-act (PDSA) cycles, these data were added to reports, communications and pre-visit planning in the most useful and efficient ways. Several PDSA cycles were then implemented to determine how to assure real time recognition of an FIES during clinic, including adding pre-calculated FIES thresholds and care-algorithms to day-of-clinic worksheets. After ramping center-wide, we adapted to the new definitions and abandoned the prior definitions and are tracking progress in run charts. During the initial months of the COVID-19 pandemic, this project was briefly paused. Once our PFT lab re-opened, we needed to repeat some early PDSA-cycles to account for our new clinical setting. As PFT availability remained variable across patients and CF centers, the CFLN adapted this project by adding a symptom-indicated exacerbation score (SIES). With this new information, we revisited and addended prior KDDs, FMEAs and process maps to incorporate SIES into the FIES algorithms. Several SIES intervention PDSA cycles are currently underway. Outcomes: New outcome-definitions and treatment algorithms can be successfully integrated into clinical systems through quality improvement. FIES definitions have been incorporated in all CCHMC CF reports, and are used in communication, pre-visit planning, and point-of-care decision making. Our algorithms and processes have been addended to incorporate the SIES when PFTs are not available. Standardizing home exacerbation signals is also underway, in addition to comparing clinical outcomes to FIES/SIES algorithm use.

Developing communication tools for CF patients during a pandemic

Background: At the onset of the COVID-19 pandemic, the CF Center at Cincinnati Children's Hospital Medical Center (CCHMC) was forced to shutter operations as usual and find new ways to communicate with the 235 pediatric patients and their families. In-person appointments and direct communication were decreased to minimize possible exposure to COVID-19. Information had to be shared in varying ways to answer questions for fearful patients and caregivers, as well as provide tools to empower them at home. Method: A virtual town hall was held in April 2020 that featured three providers who discussed information about COVID-19, how it affected both the inpatient and outpatient settings for our patients with CF, methods to cope with the stresses of living through a pandemic, followed by a Q&A with the webinar participants. A second virtual town hall was held in May to continue communication with patients and families regarding the effects of COVID-19 on current practices at CCHMC. A link to a recording of the town halls was emailed to all families and recordings and pertinent information were also posted on the CCHMC COVID-19 website. Another town hall is scheduled for June 2, 2020, and the CF Center anticipates holding these at least once a month moving forward. Just prior to the pandemic outbreak, the CF Center at CCHMC created a Pulmonary Exacerbation Scoring (PES) tool which enabled patients and caregivers to provide an objective score to signs and symptoms of a CF exacerbation. This tool is individualized for each patient, contains a list of each person's home maintenance respiratory medications, and helps families identify their child's baseline to know when symptoms increase. The PES tool was emailed to each patient/caregiver to empower and encourage them to continue care at home during this pandemic. A video, created by a parent partner, was included in the email to explain how to utilize the PES tool. Two social workers initiated patient-family communication by sending out an email of resources (CF-specific, med/food delivery, rent/mortgage/ food/utilities aid, etc) available to our patients in our tri-state region. Following this, several CF care members created and distributed informative videos concerning their respective fields. Our school liaison specialist offered tips to set up the caregivers for success with remote learning. The psychologist proffered two videos: one video was a COVID-19 specific video to address fear and anxiety, while the second video addressed mental health resources offered through CCHMC. Our physical therapist presented different ways patients and families can engage in activities while also under quarantine. Outcome: To date there have been 236 views of all recordings distributed. Families prior to the CF town hall webinar expressed concerns regarding COVID-19 and its effects on operations, but once the town hall was complete, felt that their concerns had been addressed. Verbatim feedback after the town halls included: “Great job everyone! This was really great! Dr. Chris did such a great job answering questions that I have nothing else!” and “This is truly an unbelievable time for all of us and all of you at Cincinnati Children's. I fully trust all of your decisions.”.