China COVID vaccines: already being distributed; how they work, where are they in trials?

 Chinese authorities have already approved multiple COVID vaccines for emergency use in the country, and nearly a million Chinese have already been vaccinated with one candidate.

Several local governments are already placing orders for domestically developed vaccines, though the Chinese government hasn't confirmed how many people it's aiming to vaccinate as part of emergency approval.

The first international shipments of the vaccine, by private Chinese company Sinovac, have also already arrived in Indonesia this week in preparation for a mass vaccination campaign ahead of expected local approval.

China is developing at least five COVID vaccines from four producers. These vaccines, which have progressed through development very rapidly, are largely based on traditional vaccine manufacturing techniques such as inactivating the virus.

These methods provide some benefits to the vaccines over others. For example, some of the Chinese-developed vaccines can be stored in regular fridges, making distribution much easier. This is in contrast to Pfizer's jab, which must be kept at around -70℃.

Too early to tell if they're safe and effective in the long term

The results of clinical trials of vaccines developed by Chinese-based companies have for the most part been published in leading international journals. These journals are independently reviewed by members of the global scientific community who provide open and critical analysis before acceptance of the work. They're also some of the most trusted medical research journals in the world, a testament to the quality of the science being carried out in China.

The emergency approval for use of a number of the vaccines developed in China has come exceptionally early in the clinical trial process. This is likely to have raised concerns that the correct due diligence for safety isn't being followed. These are, however, exceptional times. It should also be noted the vaccine developed by Pfizer, and granted emergency approval in the United Kingdom, hasn't yet received full regulatory approval with phase 3 clinical trials set to conclude soon.

The early rollout of these vaccines into the general population should really be viewed as an unofficial extension of phase 3 clinical trials, rather than an ultimate seal of approval. People who have been vaccinated should continue to be monitored for adverse events and lasting immune responses. Any subsequent reports of serious adverse events due to vaccination will halt use of that vaccine, but could also erode confidence in vaccination and vaccine uptake internationally.

So who are the companies developing these vaccines in China, and what do we know about them?

Sinovac

Sinovac Life Sciences is a private Chinese company that focuses on research, development and manufacturing of human and animal vaccines. It has developed and commercialised six vaccines for human use, and one for animals.

The company's COVID vaccine, called CoronaVac, is an inactivated vaccine. It has recently been shipped to Indonesia.

It's manufactured by growing the COVID virus in laboratories and treating it with a chemical that inactivates it. The chemical locks the virus in a state where it's unable to replicate, but its structure is maintained, allowing the body to recognise it as foreign and mount an immune response.

It's also delivered with an adjuvant, an immune stimulant that's given to improve the protective response.

Having shown a substantial immune response and minimal safety concerns (mostly mild pain at the injection site) in phase 1 and 2 clinical trials, CoronaVac is now in phase 3 clinical trials.

The phase 3 trials have recruited tens of thousands of participants to test vaccine efficacy and safety, and are taking place in Brazil, Indonesia and Turkey.

Brazilian officials claimed in October that the vaccine is safe, amid phase 3 trials.

However, the death of a phase 3 trial participant in October led Brazilian authorities to temporarily halt the Sinovac trial. Although details of the death were unclear, the trial was quickly resumed with the Brazilian institute involved in the trial confirming the participant's death was unrelated to the vaccine. The outcome of phase 3 trials may be released in a matter of days.

Despite not knowing the results of phase 3 trials, a condition typically required to receive regulatory approval, CoronaVac has been approved for emergency use in China to vaccinate high-risk groups since July 2020.

This emergency approval is likely to have followed positive data from the vaccine's phase 1 and 2 trials.

Sinopharm

Sinopharm is a state-owned Chinese company that researches, develops and distributes vaccines and other pharmaceuticals. It has produced a number of drugs that've been approved by the US Food and Drug Administration, and by EU authorities.

The two COVID-19 vaccines being developed by Sinopharm are both inactivated vaccines. Both follow a similar inactivation process as the Sinovac vaccine, and also use adjuvants to stimulate an immune response.

Both have undergone phase 1 and 2 clinical trials with encouraging results. They produced an effective immune response in participants and reported adverse reactions, including pain at the injection site and fever, were mild and quickly resolved. Certain doses generated SARS-CoV-2 specific antibodies in all phase 1 and 2 trial participants.

Both vaccines are currently in phase 3 trials. Again, despite incomplete clinical trials, both are reported to have been distributed for use by Chinese government officials and health-care workers.

What's more, the United Arab Emirates, a site of ongoing phase 3 trials, granted emergency use for one of Sinopharm's vaccines in September, following testing in 31,000 participants.

Despite this unusual early use of the vaccines, phase 3 testing is still required to determine if it's safe and effective in the long run.

CanSino Biologics

This Chinese company has developed a COVID vaccine based on an adenovirus in partnership with the Chinese Academy of Military Medical Sciences. The adenovirus is unable to cause disease itself, but is used to deliver a coronavirus protein.

Phase 2 clinical trials reported the vaccine to be safe and induce significant immune responses in most participants.

This vaccine was also approved for limited use by the Chinese military in June, around the time of the conclusion of phase 2 trials.

Phase 3 clinical trials, which began in August, are ongoing in countries including Saudi Arabia.

Anhui Zhifei Longcom Biopharmaceutical

Chinese-based company, Anhui Zhifei Longcom, has developed a protein subunit COVID-19 vaccine. Subunit vaccines use a purified piece of the virus, a protein, to trigger an immune response. It has recently started phase 3 clinical trials. There hasn't yet been any announcement or published report of the results of phase 1 and 2 trials.

https://medicalxpress.com/news/2020-12-china-covid-vaccines-trials.html

COVID-19 may also invade central nervous system, cause neurological illness

 COVID-19 is known primarily as a respiratory disease, with symptoms that include cough, shortness of breath, and, in severe cases, acute respiratory distress syndrome and pneumonia. Now, researchers from Cleveland Clinic's Department of Biomedical Engineering note in a recent review that infection with the coronavirus may also affect the central nervous system and cause corresponding neurological disorders, including ischemic stroke, encephalitis, encephalopathy and epileptic seizures.

According to the review—published in Cells and authored by Chaitali Ghosh, Ph.D., and Aneesha Achar—the symptoms of COVID-19-related neurological manifestations include dizziness, headache, a loss of consciousness and ataxia (loss of balance and muscle control).

he coronavirus gains access to the body by attaching to a specific receptor most abundantly found on cells that line many organs and tissues throughout the respiratory system, called the ACE2 (angiotensin-converting enzyme 2) receptor. ACE2 can be found less abundantly on cells in other areas of the body—including the heart, esophagus, kidneys and bladder—which increases the chances of viral infection, including through the central nervous system.

As reported in the review, the coronavirus may enter the central nervous system either through a porous bone in the nasal cavity (which causes the loss of smell and/or taste commonly experienced with COVID-19), or through the body's circulatory system, subsequently crossing the blood-brain barrier.

"Ordinarily, the blood-brain barrier allows nutrients to reach the brain while protecting it from circulating toxins or pathogens that could cause infections," Dr. Ghosh said. "However, the exact mechanisms underlying COVID-19-associated neurological disorders remain unknown. Such viral infectivity could alter blood-brain barrier function, which may influence disease progression."

Cytokine storms: An early warning system

Once in the central nervous system, the virus activates proteins called cytokines (central players in the body's immune response) and initiates a "cytokine storm." This can cause inflammation in the central nervous system and affect blood-brain barrier integrity.

What's more, while cytokine storms are usually associated with severe cases of COVID-19, Dr. Ghosh sounded a note of warning. "Central nervous system disorders can occur in patients who have only mild or moderate COVID disease," Dr. Ghosh said. "In fact, they can also come about even before the patient has any respiratory symptoms."

While there is currently limited evidence on long-term consequences of COVID-19-associated neurodegenerative and inflammation-mediated brain diseases, investigations into whether these comorbidities are risk factors for COVID-19 would be critical to follow.

"I am eager to define and learn more about which signaling pathways are linked to which neurological disorders, and think this will be an exciting new frontier in COVID-19 research," said Dr. Ghosh.

More information: Aneesha Achar et al, COVID-19-Associated Neurological Disorders: The Potential Route of CNS Invasion and Blood-Brain Barrier Relevance, Cells (2020). DOI: 10.3390/cells9112360

https://medicalxpress.com/news/2020-12-covid-invade-central-nervous-neurological.html

Potential weaknesses in SARS-CoV-2 infection revealed

 A single protein that appears necessary for the COVID-19 virus to reproduce and spread to other cells is a potential weakness that could be targeted by future therapies.

The molecule, known as transmembrane protein 41 B (TMEM41B), is believed to help shape the fatty outer membrane that protects the virus' genetic material while it replicates inside an infected cell and before it infects another.

The latest finding comes from a pair of studies led by researchers at NYU Grossman School of Medicine and NYU Langone Health's Perlmutter Cancer Center, and colleagues at Rockefeller University and elsewhere.

Published in the journal Cell online Dec. 8, the studies revealed that TMEM41B was essential for SARS-CoV-2 to replicate. In a series of experiments, researchers compared how the COVID-19 virus reproduces in infected cells to the same processes in two dozen deadly flaviviruses, including those responsible for yellow fever, West Nile, and Zika disease. They also compared how it reproduces in infected cells to three other seasonal coronaviruses known to cause the common cold.

"Together, our studies represent the first evidence of transmembrane protein 41 B as a critical factor for infection by flaviviruses and, remarkably, for coronaviruses, such as SARS-CoV-2, as well," says the studies' co-senior investigator John T. Poirier, Ph.D.

"An important first step in confronting a new contagion like COVID-19 is to map the molecular landscape to see what possible targets you have to fight it," says Poirier, an assistant professor of medicine at NYU Langone Health. "Comparing a newly discovered virus to other known viruses can reveal shared liabilities, which we hope serve as a catalogue of potential vulnerabilities for future outbreaks."

"While inhibiting transmembrane protein 41 B is currently a top contender for future therapies to stop coronavirus infection, our results identified over a hundred other proteins that could also be investigated as potential drug targets," says Poirier, who also serves as director of the Preclinical Therapeutics Program at NYU Langone and Perlmutter Cancer Center.

For the studies, researchers used the gene-editing tool CRISPR to inactivate each of more than 19,000 genes in human cells infected with each virus, including SARS-CoV-2. They then compared the molecular effects of each shutdown on the virus' ability to replicate.

In addition to TMEM41B, some 127 other molecular features were found to be shared among SARS-CoV-2 and other coronaviruses. These included common biological reactions, or pathways, involved in cell growth, cell-to-cell communication, and means by which cells bind to other cells. However, researchers say, TMEM41B was the only molecular feature that stood out among both families of viruses studied.

Interestingly, Poirier notes, mutations, or alterations, in TMEM41B are known to be common in one in five East Asians, but not in Europeans or Africans. He cautions, however, that it is too early to tell if this explains the relatively disproportionate severity of COVID-19 illness among some populations in the United States and elsewhere. Another study finding was that cells with these mutations were more than 50 percent less susceptible to flavivirus infection than those with no gene mutation.

Poirier says more research is needed to determine if TMEM41B mutations directly confer protection against COVID-19 and if East Asians with the mutation are less vulnerable to the disease.

The research team next plans to map out TMEM41B's precise role in SARS-CoV-2 replication so they can start testing treatment candidates that may block it. The team also has plans to study the other common pathways for similar potential drug targets.

Poirier adds that the research team's success in using CRISPR to map the molecular weaknesses in SARS-CoV-2 serves as a model for scientists worldwide for confronting future viral outbreaks.

More information: William M. Schneider et al. Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks, Cell (2020). DOI: 10.1016/j.cell.2020.12.006

H.-Heinrich Hoffmann et al. TMEM41B IS A PAN-FLAVIVIRUS HOST FACTOR, Cell (2020). DOI: 10.1016/j.cell.2020.12.005

https://medicalxpress.com/news/2020-12-reveal-potential-weaknesses-sars-cov-infection.html

What the coming year might hold for biopharma

 Biopharma’s ongoing response to the pandemic will be the dominant theme for the sector and its followers next year. From driving financings, deal-making and of course newsflow, the industry’s role in trying to bring the pandemic to an end looks set to continue to generate a huge amount of attention.

But the business of drug development outside Covid-19 continues apace, and 2021 promises much activity elsewhere. In our latest report, which is free to download, Evaluate Vantage has pulled together data-driven analyses to help identify the drugs, research projects and companies to watch next year.

Covid-19

The first section of the report concerns biopharma’s attempts to halt the pandemic. We take a closer look at the main therapy approaches, from vaccines to antivirals and antibodies and beyond, and highlight what to expect next.

With many of the leading approaches yet to generate late-stage data, robust consensus models have yet to emerge for a large part of the pipeline. Figuring out which companies might benefit financially over the short or long term will remain a big preoccupation for investors in 2021.

At least the impact of global shutdowns is beginning to unravel. An analysis of trial suspensions finds the number shut down due to Covid-19 has dramatically reduced, and hopes are high that the picture will improve further in next year.

Innovation and regulation

Oncology will continue to be a major driver of the sector’s topline growth in 2021. Six of the 10 biggest new sales generators are treatments for various cancers, and three of these are anti-PD(L)1 antibodies. Keytruda is king here, and is forecast to add $2.7bn in new sales in 2021, taking its annual revenues to almost $17bn.

Abbvie’s Humira retains the crown as the biggest-selling drug for now, however. Abbvie is also expected to enjoy the largest top-line growth next year, adding $6bn in new sales, thanks to two very well-received new immunotherapies, Rinvoq and Skyrizi.

Further analyses in the report detail the most costly R&D projects, as computed by Evaluate Omnium’s R&D Costs module. Heading the table is Lilly’s new diabetes project tirzepatide, clinical trials of which are estimated to cost the pharma giant $617m in 2021.The report also details the 10 biggest potential new launches next year, as well as biopharma’s top 10 most highly valued R&D projects. The top three are detailed here.

Money, Markets and M&A

Biopharma was already enjoying a relatively buoyant time before the pandemic hit, and the huge amount of focus that the outbreak bestowed on the drug development sector has generated even more investor interest. Consequently a huge amount of money flowed into the industry in 2020. Whether that continues in 2021 is a burning question.

The fourth quarter has seen some pullbacks in IPOs and venture financings in the final months of 2020, however this was from very high levels. And big drug developers continue to prove themselves motivated buyers, so there are many reasons to believe that on the deal front – both financing and M&A – 2021 should be another good year.

Analyses in this section include M&A premiums and takeout trends, the latest numbers of venture financing and IPOs, and a look at Spacs, a new financing vehicle that industry followers are likely to hear a lot more about in 2021.

For the biggest launches to the top selling drugs, financing and deal making trends and important clinical readouts, download Evaluate Vantage’s free 2021 Preview.

https://www.evaluate.com/vantage/articles/news/corporate-strategy/what-coming-year-might-hold-biopharma

Sonoma Pharma up on Crown Laboratories partnership

 

• Sonoma Pharmaceuticals (NASDAQ:SNOA) +35.3% post-market after announcing a partnership with Crown Laboratories for a license and supply agreement for exclusive rights to sell and market products for the over-the-counter dermatological market in the U.S.
• Under the deal terms, Crown will sell Sonoma's Microcyn technology dermal sprays and gels targeting itch and pain under the Sarna brand.
• Sonoma will continue to sell its prescription strength products, while Crown will distribute an OTC version available without prescription.
• https://seekingalpha.com/news/3643562-sonoma-pharmaplus-35-on-crown-laboratories-partnership

FDA advisory panel endorses Pfizer/BioNTech Covid-19 vaccine

 

A panel of outside experts on Thursday recommended the Food and Drug Administration issue an emergency use authorization to the Covid-19 vaccine being developed by Pfizer and BioNTech, a vaccine that appeared to be highly efficacious in a Phase 3 clinical trial.

The vote came after a long day in which members of the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, discussed a wide range of issues related to the vaccine. Although the FDA does not have to follow the panel’s recommendation, it is widely expected to do so.

The rollout of Covid-19 vaccine could then begin in the United States in a matter of days.

STAT’s coverage of the meeting is below, with updates and analysis posted in reverse chronological order.

5:37 p.m.:After eight-plus hours of data presentations, discussion and debate, today’s Covid vaccine advisory panel finally got down to voting on the penultimate question:

Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its risks for use in individuals 16 years of age and older?

The results:

17 Yes, 4 No, 1 abstention.

And with that, the FDA will very likely grant an emergency use authorization to the Pfizer/BioNTech Covid vaccine within days, if not sooner.

One thing to watch: There was a lot of disagreement among the panel members about whether the data support the inclusion of people 16-17 years of age in the EUA. Will FDA make changes to the EUA to exclude this group?

Pfizer pushes back against “crossover” design for placebo patients

5:05 p.m.: Earlier in the day, there was an enthusiastic presentation of a proposal that tried to allow volunteers who had received placebo to receive the vaccine while minimizing the problems this would present for collecting new data about the vaccine.

The idea, summarized by Helen this morning, is that all volunteers would get two more shots. Those who had received placebo would get the vaccine; those who got the vaccine would get placebo.

But William Gruber, a Pfizer senior vice president, pushed back on this idea. It was, he pointed out, potentially impractical. “44,000 individuals would have to be brought in for two additional visits,” he noted. That means they would need to sign new consent forms. And, if they already suspected they received the vaccine because they noticed aches or chills, they might decide not to come in for those additional visits. Gruber has said previously that he is worried that volunteers will leave the study if they are not offered the vaccine, and that he will not get data from them at all.

In an email earlier today, a Pfizer spokesperson confirmed the company is not currently planning to use the crossover design.

“The participants in our COVID-19 vaccine clinical trial are courageous volunteers who have made a personal and important choice to help make a difference during this pandemic,” Pfizer said in a statement. “We also believe that we have an ethical duty to create a pathway within the study for interested, eligible participants in the placebo group to have access to the vaccine as regulatory authorities make decisions about authorization or approval of the vaccine candidate around the world.”

Pfizer added: “In turn, we have developed a protocol amendment that is subject to input from and alignment with regulatory authorities but is designed so that all interested participants 16 years and older in the placebo group would have the option to receive the vaccine at scheduled timepoints in the study.”

https://www.statnews.com/2020/12/10/tracking-the-fda-advisory-panel-meeting-on-the-pfizer-biontech-covid-19-vaccine/

Pfizer/BioNTech COVID-19 vaccine rollout marred by adverse events

 

• The U.K. has received two reports of anaphylaxis and one report of a possible allergic reaction on the first day of the roll of the COVID-19 vaccine candidate from Pfizer Inc. (PFE) and BioNTech SE (BNTX), the officials there have said.
• The anaphylaxis, an overreaction of the body’s immune system, is described by the country's National Health Service as severe and sometimes life-threatening.
• Later in the day, the country’s regulator advised anyone with a history of anaphylaxis to a vaccine, medicine, or food not to get the vaccine. The late-stage clinical trials of the vaccine had left out people with a history of significant adverse reactions to vaccines or vaccine’s ingredients.
• Ahead of the potential emergency use authorization by the FDA for the vaccine candidate, the issue has surfaced during the ongoing expert panel review, STATNews reports.
• Paul Offit, a panelist as well as a reputed virologist in the panel has raised his concerns, noting ‘tens of millions of Americans will hesitate to get vaccinated due to medical history of severe allergy. Earlier, Associated Press had reported that 70% of the US population would have to be vaccinated to achieve herd immunity for the COVID-19 virus.
• While ruling out any impact on EUA, Offit has said, “this issue is not going to die until we have better data,”
• https://seekingalpha.com/news/3643552-pfizer-biontech-covidminus-19-vaccine-rollout-marred-adverse-events