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Juan Lama
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Phase 2 study expected to enroll 600 participants Finalizing protocol for Phase 3 study, expected to begin in July 2020 Moderna, Inc. , (Nasdaq: MRNA) a clinical stage biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines otday announced that the first participants in each age cohort have been dosed in the Company’s Phase 2 study of its mRNA vaccine candidate (mRNA-1273) against the novel coronavirus (SARS-CoV-2). This Phase 2 study, being conducted by Moderna under its own Investigational New Drug (IND) application, will evaluate the safety, reactogenicity and immunogenicity of two vaccinations of mRNA-1273 given 28 days apart. The Company intends to enroll 600 healthy participants across two cohorts of adults ages 18-55 years (n=300) and older adults ages 55 years and above (n=300). Each participant will be assigned to receive placebo, a 50 μg or a 100 μg dose at both vaccinations. Participants will be followed through 12 months after the second vaccination. Given the 25 μg and 100 μg dose levels in the Phase 1 study showed neutralizing antibody titers at or above convalescent sera and were generally well tolerated, the Company has decided not to pursue the 250 μg dose level in the Phase 2 study. On May 6, the U.S. Food and Drug Administration (FDA) completed its review of the Company’s Investigational New Drug (IND) application for mRNA-1273 and on May 12, the FDA granted it Fast Track designation. On May 18, Moderna announced initial data from the Phase 1 study of mRNA-1273 led by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The NIH will be submitting the Phase 1 data to a peer-reviewed clinical publication. Moderna anticipates collaborating with NIAID to implement the Phase 3 study. The dose for the Phase 3 study is expected to be between 25 µg and 100 µg and expects Phase 3 trial initiation in July, subject to finalization of the clinical trial protocol. Funding from the Biomedical Advanced Research and Development Authority (BARDA), a division of the Office of the Assistant Secretary for Preparedness and Response (ASPR) within the U.S. Department of Health and Human Services (HHS), supported the planning for these studies and will also support the late-stage clinical development programs, as well as the scale-up of mRNA-1273 manufacturing both at the Company’s facilities and that of its strategic collaborator, Lonza Ltd. A summary of the company’s work to date on SARS-CoV-2 can be found here.
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Juan Lama
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Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory- confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/L (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. The criteria for discharge were absence of fever for at least 3 days, substantial improvement in both lungs in chest CT, clinical remission of respiratory symptoms, and two throat-swab samples negative for SARS-CoV-2 RNA obtained at least 24 h apart... For survivors, the median duration of viral shedding was 20·0 days (IQR 17·0–24·0) from illness onset, but the virus was continuously detectable until death in non- survivors (table 2; figure 1). The shortest observed duration of viral shedding among survivors was 8 days, whereas the longest was 37 days. Published March 9, 2020 in The Lancet:
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Juan Lama
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We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission..... Published in New England Journal of Medicine on Feb. 28, 2020: https://www.nejm.org/doi/full/10.1056/NEJMoa2002032
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This Viewpoint discusses the 2 most common categories of testing to diagnose SARS-CoV-2—real-time PCR to identify viral RNA and serological diagnosis of IgG and IgM antibodies to assess immune response—and estimates time intervals for test positivity by specimen source to help clinician. Thus far, the most commonly used and reliable test for diagnosis of COVID-19 has been the RT-PCR test performed using nasopharyngeal swabs or other upper respiratory tract specimens, including throat swab or, more recently, saliva. A variety of RNA gene targets are used by different manufacturers, with most tests targeting 1 or more of the envelope (env), nucleocapsid (N), spike (S), RNA-dependent RNA polymerase (RdRp), and ORF1 genes. The sensitivities of the tests to individual genes are comparable according to comparison studies except the RdRp-SARSr (Charité) primer probe, which has a slightly lower sensitivity likely due to a mismatch in the reverse primer. In most individuals with symptomatic COVID-19 infection, viral RNA in the nasopharyngeal swab as measured by the cycle threshold (Ct) becomes detectable as early as day 1 of symptoms and peaks within the first week of symptom onset. The Ct is the number of replication cycles required to produce a fluorescent signal, with lower Ct values representing higher viral RNA loads. A Ct value less than 40 is clinically reported as PCR positive. This positivity starts to decline by week 3 and subsequently becomes undetectable. However, the Ct values obtained in severely ill hospitalized patients are lower than the Ct values of mild cases, and PCR positivity may persist beyond 3 weeks after illness onset when most mild cases will yield a negative result.However, a “positive” PCR result reflects only the detection of viral RNA and does not necessarily indicate presence of viable virus.... Published in JAMA (May 6, 2020): https://doi.org/10.1001/jama.2020.8259
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Juan Lama
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A mix of legacy drugmakers and small startups have stepped forward with plans to develop vaccines or treatments that target the infection caused by the novel coronavirus. COVID-19, which was first detected in December in Wuhan, China, has sickened more than 100,000 people worldwide and killed at least 3,400. There are no Food and Drug Administration-approved vaccines or therapies for the disease. In the U.S., the companies that are initiating development have received funding from two organizations: the Biomedical Advanced Research and Development Authority (BARDA), which is a division of the Department of Health and Human Services, and the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health. Some companies have received funding from Coalition for Epidemic Preparedness Innovations (CEPI), a global organization based in Oslo. Other companies are funding trials by themselves or through partnerships with other life sciences companies. Here are some of the companies developing treatments or vaccines in the U.S. for COVID-19: Company: Gilead Sciences Type: Treatment Stage: Phase 3 clinical trials Name: remdesivir Background: Gilead is a longtime drug maker that is best known for developing the first major cure for hepatitis-C in Sovaldi, a therapy that changed the standard of care for that disease but also kicked off the national debate about drug pricing. The company has experience developing and marketing HIV drugs, including Truvada for pre-exposure prophylaxis (PrEP), its preventive HIV medicine. Along with U.S. trials, Gilead is conducting a randomized, controlled clinical trial in Wuhan, testing remdesivir as a treatment for mild to moderate forms of pneumonia in people with the virus. The trial was given the go-ahead by China’s Food and Drug Administration in February. Clinical trials: 1. On Feb. 21, the National Institute of Allergy and Infectious Diseases started enrolling patients in a randomized, double-blind, placebo-controlled Phase 3 trial evaluating 394 hospitalized patients with COVID-19 at up to 50 sites worldwide. The trial is expected to conclude April 1, 2023. Sites include the National Institutes of Health in Bethesda, Md., (not recruiting), the University of Nebraska Medical Center in Omaha (recruiting), the University of Texas Medical Branch in Galveston (not recruiting), and Providence Sacred Heart Medical Center in Spokane (recruiting).
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