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Monday, August 17, 2020

FDA OKs Genentech’s Enspryng for nervous system disorder

The FDA has approved Roche (OTCQX:RHHBY) unit Genentech’s Enspryng (satralizumab-mwge) as the first and only subcutaneous treatment for adults living with anti-aquaporin-4 (AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD), a rare, debilitating autoimmune disorder of the central nervous system that primarily damages the optic nerve(s) and spinal cord.

Enspryng is a humanized monoclonal antibody designed to target and inhibit interleukin-6 (IL-6) receptor activity, which is believed to play a key role in the inflammation associated with NMOSD.

Enspryng will be available in the U.S. in two weeks. It is also approved in Canada, Japan and Switzerland. Applications are under review with numerous regulators, including in the European Union and China.


Sunday, August 16, 2020

Pandemic appears to spare Africa so far; scientists struggle to explain

Although Africa reported its millionth official COVID-19 case last week, it seems to have weathered the pandemic relatively well so far, with fewer than one confirmed case for every thousand people and just 23,000 deaths so far. Yet several antibody surveys suggest far more Africans have been infected with the coronavirus—a discrepancy that is puzzling scientists around the continent. “We do not have an answer,” says immunologist Sophie Uyoga at the Kenya Medical Research Institute–Wellcome Trust Research Programme.

After testing more than 3000 blood donors, Uyoga and colleagues estimated in a preprint last month that one in 20 Kenyans aged 15 to 64—or 1.6 million people—has antibodies to SARS-CoV-2, an indication of past infection. That would put Kenya on a par with Spain in mid-May when that country was descending from its coronavirus peak and had 27,000 official COVID-19 deaths. Kenya’s official toll stood at 100 when the study ended. And Kenya’s hospitals are not reporting huge numbers of people with COVID-19 symptoms.

Other antibody studies in Africa have yielded similarly surprising findings. From a survey of 500 asymptomatic health care workers in Blantyre, Malawi, immunologist Kondwani Jambo of the Malawi–Liverpool Wellcome Trust Clinical Research Programme and colleagues concluded that up to 12.3% of them had been exposed to the coronavirus. Based on those findings and mortality ratios for COVID-19 elsewhere, they estimated that the reported number of deaths in Blantyre at the time, 17, was eight times lower than expected.

Scientists who surveyed about 10,000 people in the northeastern cities of Nampula and Pemba in Mozambique found antibodies to SARS-CoV-2 in 3% to 10% of participants, depending on their occupation; market vendors had the highest rates, followed by health workers. Yet in Nampula, a city of approximately 750,000, a mere 300 infections had been confirmed at the time. Mozambique only has 16 confirmed COVID-19 deaths. Yap Boum, a microbiologist and epidemiologist with Epicentre Africa, the research and training arm of Doctors Without Borders, says he found a high prevalence of SARS-CoV-2 antibodies in people from Cameroon as well, a result that remains unpublished.

So what explains the huge gap between antibody data on the one hand and the official case and death counts on the other? Part of the reason may be that Africa misses many more cases than other parts of the world because it has far less testing capacity. Kenya tests about one in every 10,000 inhabitants daily for active SARS-CoV-2 infections, one-tenth of the rate in Spain or Canada. Nigeria, the continent’s most populous nation, tests one out of every 50,000 people per day. Even many people who die from COVID-19 may not get a proper diagnosis.

But in that case, you would still expect an overall rise in mortality, which Kenya has not seen, says pathologist Anne Barasa of the University of Nairobi who did not participate in the country’s coronavirus antibody study. (In South Africa, by contrast, the number of excess natural deaths reported between 6 May and 28 July exceeded its official COVID-19 death toll by a factor of four to one.) Uyoga cautions that the pandemic has hamstrung Kenya’s mortality surveillance system, however, as fieldworkers have been unable to move around.

Marina Pollán of the Carlos III Health Institute in Madrid, who led Spain’s antibody survey, says Africa’s youthfulness may protect it. Spain’s median age is 45; in Kenya and Malawi, it’s 20 and 18, respectively. Young people around the world are far less likely to get severely ill or die from the virus. And the population in Kenya’s cities, where the pandemic first took hold, skews even younger than the country as a whole, says Thumbi Mwangi, an epidemiologist at the University of Nairobi. The number of severe and fatal cases “may go higher when the disease has moved to the rural areas where we have populations with advanced age,” he says.

Jambo is exploring the hypothesis that Africans have had more exposure to other coronaviruses that cause little more than colds in humans, which may provide some defense against COVID-19. Another possibility is that regular exposure to malaria or other infectious diseases could prime the immune system to fight new pathogens, including SARS-CoV-2, Boum adds. Barasa, on the other hand, suspects genetic factors protect the Kenyan population from severe disease.

More antibody surveys may help fill out the picture. A French-funded study will test thousands for antibodies in Guinea, Senegal, Benin, Ghana, Cameroon, and the Democratic Republic of the Congo; results are expected by October. The studies will ensure good representation across populations, says Jean-François Etard from France’s Research Institute for Development, who is leading the study in Guinea jointly with a local scientist. And 13 labs in 11 African countries are participating in a global SARS-CoV-2 antibody survey coordinated by the World Health Organization.

South Africa, meanwhile, plans to conduct a number of serological studies both in COVID-19 hotspots and the general population, says Lynn Morris, who leads the country’s National Institute for Communicable Diseases. She notes that antibody prevalence found in the study will likely be an underestimate of true infection rates, given that the virus doesn’t induce antibodies in some people and that antibody levels wane over time.

If tens of millions of Africans have already been infected, that raises the question of whether the continent should try for “herd immunity” without a vaccine, Boum says—the controversial idea of letting the virus run its course to allow the population to become immune, perhaps while shielding the most vulnerable. That might be preferable over control measures that cripple economies and could harm public health more in the long run. “Maybe Africa can afford it,” given its apparent low death to infection ratio, Boum says. ”We need to dig into that.” 

But Glenda Gray, president of the South African Medical Research Council, says it could be dangerous to base COVID-19 policies on antibody surveys. It’s not at all clear whether antibodies actually confer immunity, and if so, how long it lasts, Gray notes—in which case, she asks, “What do these numbers really tell us?”


China grants country’s first COVID-19 vaccine patent to CanSino

China’s vaccine specialist CanSino Biologics Inc has won a patent approval from Beijing for its COVID-19 vaccine candidate Ad5-nCOV, state media reported, citing documents from the country’s intellectual property regulator.

It is the first COVID-19 vaccine patent granted by China, state-owned newspaper People’s Daily reported on Sunday.

The paper cited documents published by China’s National Intellectual Property Administration saying that the patent was issued on Aug. 11.

Saudi Arabia said this month it plans to begin Phase III clinical trials for the CanSino vaccine. CanSino has said it is also in talks with Russia, Brazil and Chile to launch Phase III trials in those countries.

CanSino’s Hong Kong shares rose around 14% in Monday’s morning session. Its Shanghai shares rose by 6.6% as of midday.


Health officials hope to avoid ‘twindemic’ as flu season approaches

U.S. health authorities, still grappling with COVID-19, are crossing their collective fingers that the upcoming flu season will be very mild. If not, the healthcare system could be severely tested in a “twindemic” scenario.

The Centers for Disease Control and Prevention (CDC) has ordered an additional 9.3M doses, far beyond its usual purchase of 500K, for uninsured people.

The concern is not confined to America. Global officials are pushing flu shots even before they are available in clinics and doctors’ offices.

Influenza shots are rarely broadly mandated in the U.S., but the University of California system has ordered its 230K employees and 280K students to get vaccinated by November 1.

Last year’s flu season was considered mild but the viral infection still struck 39M – 56M Americans requiring up to 740K hospitalizations. Deaths totaled 24K – 62K.

Experts believe a record 98M flu shots will be given in the U.S. this year, up ~15% from last year.

Selected tickers: Sanofi (NASDAQ:SNY), GlaxoSmithKline (NYSE:GSK), AstraZeneca (NYSE:AZN)


Sanofi to acquire Principia Biopharma

Sanofi (NASDAQ:SNY) and Principia Biopharma (NASDAQ:PRNB) have entered into a definitive agreement under which Sanofi will acquire all of the outstanding shares of Principia for $100/share in cash, representing an aggregate equity value of ~$3.68B, in a cash tender offer.

In 2017, Sanofi collaborated with Principia under which latter granted SNY an exclusive, worldwide license to develop and commercialize BTK inhibitor SAR442168 in multiple sclerosis and other central nervous system diseases.

“Full ownership of our brain-penetrant BTK inhibitor ‘168 removes complexities for this priority development program and simplifies future commercialization,” said Paul Hudson, Sanofi CEO.

The transaction is expected to be completed in Q4.

Sanofi will host a webcast and conference call at 9:00 am ET on August 17.


COVID-19 and Severe Obesity: A Big Problem?



On 11 March 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19) a pandemic. The disease, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now infected nearly 20 million persons worldwide, with a global mortality rate of 3.7%. It is unusual in that symptoms range from none to severe respiratory failure with diffuse lung damage and death. Given these diverse effects, understanding the risks for developing the most severe manifestations was particularly important from the start. Early reports from China and Italy, where the pandemic first took hold, identified a broad range of factors—old age, autoimmune disease, hypertension, and coronary artery disease—as risks for worse outcomes. However, as the pandemic reached the United States, another factor appeared that was particularly common in severely affected patients: obesity. The United States has a 20% rate of severe obesity (body mass index [BMI] >35 kg/m2) and a 10% rate of morbid obesity (BMI >40 kg/m2)—the highest rates in the industrialized world. More than 40% of Americans are considered obese (BMI >30 kg/m2). One possibility was that given this high prevalence, one would expect to find obesity more often in patients with COVID-19 as well. Yet, by early April, research was countering this hypothesis, showing that patients with COVID-19 in the intensive care unit were more likely to be obese than historical ICU patients without COVID-19 (1), and that obese persons who had COVID-19 were more likely to require hospitalization and intensive care unit treatment (2). In contrast to other known risk factors, obesity was very common even in persons younger than 50 years, and this high prevalence predicted a shift in severe COVID-19 disease to younger populations (3).

During the past few months, nearly 300 articles have reported an association between severe obesity and increased morbidity and mortality from COVID-19. Most of the focus is on hospitalized patients and ranges from small single-center studies to large retrospective analyses of thousands of patients (4). They generally cover the period from March 2020, when the pandemic first exploded in New York City, to May 2020, when it had spread to the rest of the United States. The findings are consistent: There is a dose-dependent association of obesity with worse COVID-19 morbidity requiring hospitalization and intensive care and with mortality. This particularly applies to patients younger than 50 to 60 years (5).

In their article, Tartof and colleagues (6) provide an analysis for a large community population: patients in the Kaiser Permanente Southern California system. They retrospectively examined records from 5652 persons with SARS-CoV-2, with the primary outcome being death within 3 weeks of diagnosis. Two thirds of patients were hospitalized, and 43% were ventilated. Patients with BMIs greater than 40 kg/m2 had higher death rates overall, and those with BMIs greater than 45 kg/m2 had a risk ratio of 4.18. Most strikingly, however, those younger than 60 years had increased risk ratios of 12 to 17 versus 1 to 3 if they were older; high BMI increased risk in men more than in women. More important, the obesity risk was adjusted for common comorbidities, including diabetes, hypertension, heart failure, myocardial infarction, and chronic lung or renal disease. The study also took into account when SARS-CoV-2 was detected. Interestingly, with each ensuing week, mortality risk declined substantially. This may reflect the growing social awareness with evolving policies to reduce spread and improve medical practice.

This study follows 2 recent reports in Annals examining a similar question but solely in hospitalized patients. Goyal and colleagues (7) reported on 1687 hospitalized patients in 2 New York City hospitals, finding that those with BMIs greater than 40 kg/m2 were at higher risk for respiratory failure but not death. However, 69% of their cohort had a BMI less than 30 kg/m2, and only 5% had a BMI greater than 40 kg/m2. In a second study, Anderson and colleagues (8) reported on 2466 patients with COVID-19 that had at least 47 days of hospital observation. They found that those younger than 65 years with a BMI greater than 40 kg/m2 had a 2-fold higher risk for intubation; however, BMI was no longer a significant risk factor in older patients.

The consistency of this new study and prior research should put to rest the contention that obesity is common in severe COVID-19 because it is common in the population. Obesity is an important independent risk factor for serious COVID-19 disease. That the risks are higher in younger patients is probably not because obesity is particularly damaging in this age group; it is more likely that other serious comorbidities that evolve later in life take over as dominant risk factors. That males are particularly affected may reflect their greater visceral adiposity over females, given that this fat is notably proinflammatory and contributes to metabolic and vascular disease. As a cardiologist who studies heart failure, I am struck by how many of the mechanisms that are mentioned in reviews of obesity risk and heart disease (9, 10) are also mentioned in reviews of obesity and COVID-19 (9). The top mechanisms include restrictive pulmonary physiology and sleep apnea, diabetes and dyslipidemia, immune dysfunction with depressed anti-inflammatory signaling (for example, adiponectin) and increased proinflammatory signaling (for example, leptin, interleukin-6, and tumor necrosis factor-α), endothelial dysfunction, and renin–angiotensin stimulation that stimulates hypertension and worsens lung inflammation and alveolar damage. Fat deposited in skeletal muscle may be sought after by top-end steakhouses but, in vivo, it compromises muscle metabolic efficiency, nutrient uptake, and performance. Then, there is Newton’s second law: force = mass × acceleration. It requires more muscle force to displace the diaphragm downward when a substantial fat mass lies below it. Abdominal obesity also makes it more difficult to breathe in a prone position that is favored to improve ventilation in patients with COVID-19. Among more specific mechanisms is expression of angiotensin-converting enzyme 2 protein in adipose tissue. This is the docking protein for SARS-CoV-2 to enter a cell, and fat has higher levels than the lungs and so may serve as a viral refuge and replication site, prolonging virus shedding.

Arguably the hardest question to answer is: What is to be done? Severe and morbid obesity is sufficiently common in the United States to have become part of our social fabric. That makes messaging about its health risks difficult but does not change the fact that they are real. The data consistently show major risks at BMIs greater than 35 kg/m2, and at that level, weight reduction is difficult and certainly is not achieved rapidly. Therefore, social distancing; altering behaviors to reduce viral exposure and transmission, such as wearing masks; and instituting policies and health care approaches that recognize the potential effects of obesity should be implemented. These actions should help and are certainly doable.

This article was published at Annals.org on 12 August 2020


High-dose vitamin C infusion for the treatment of critically ill COVID-19

Jing Zhang  Wuhan University Zhongnan Hospital Xin Rao  Wuhan University Zhongnan Hospital Yiming Li  Wuhan University Zhongnan Hospital, et al.


Abstract Background
No specic medication has been proven effective for the treatment of patients with severe coronavirus disease 2019 (COVID-19). Here, we tested whether high-dose vitamin C infusion was effective for severe COVID-19.
Methods
This randomized, controlled clinical trial was performed at 3 hospitals in Hubei, China. Patients with conrmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the ICU were randomly assigned in as 1:1 ratio to either the high-dose intravenous vitamin C (HDIVC) or the placebo. HDIVC group received 12 g of vitamin C/50 ml every 12 hours for 7 days at a rate of 12 ml/hour, and the placebo group received bacteriostatic water for injection in the same way. The primary outcome was invasive mechanical ventilation-free days in 28 days(IMVFD28). Secondary outcomes were 28-day mortality, organ failure, and inammation progression.
Results
Fifty-four critical COVID-19 patients were ultimately recruited. There was no difference in IMVFD28 between two groups. During the 7-day treatment period, patients in the HDIVC group had a steady rise in the PaO2/FiO2 (day 7: 229 vs. 151 mmHg, 95% CI 33 to 122, P = 0.01). Patients with SOFA scores ≥ 3 in the HDIVC group exhibited a signicant reduction in 28-day mortality (P = 0.05) in univariate survival analysis. IL-6 in the VC group was lower than that in the placebo group (19.42 vs. 158.00; 95% CI -301.72 to -29.79; P = 0.04) on day 7.
Conclusion
The addition of HDIVC may provide a protective clinical effect without any adverse events in critically ill patients with COVID-19.
Clinicaltrial.gov identifer: NCT04264533
https://assets.researchsquare.com/files/rs-52778/v1/e3812db9-cb32-4a81-b024-76f54c344112.pdf