Coronavirus treatment: Vaccines/drugs in the pipeline for Covid-19

By Praveen Duddu@clinicaltrialsarena

The mysterious coronavirus outbreak in the Chinese city Wuhan, now termed as Covid-19, and its fast spread to many other countries, endangers thousands of lives. The pandemic has catalysed the development of novel coronavirus vaccines across the biotech industry, both by pharmaceutical companies and research organisations such as the National Institutes of Health (NIH), US.

The first Covid-19 vaccine in China is expected to be ready for clinical trials by the end of April, according to Xu Nanping, China’s vice-minister of science and technology. Inovio Pharmaceuticals plans to begin clinical trials on a coronavirus vaccine in April this year.

Health officials from WHO have noted that Gilead’s remdesivir has demonstrated efficacy in treating the coronavirus infection.

Favilavir, the first approved coronavirus drug in China

The National Medical Products Administration of China has approved the use of Favilavir, an anti-viral drug, as a treatment for coronavirus. The drug has reportedly shown efficacy in treating the disease with minimal side effects in a clinical trial involving 70 patients. The clinical trial is being conducted in Shenzhen, Guangdong province.

Pharmaceutical companies involved in developing coronavirus drugs/vaccines

Here is a list of the major coronavirus drugs that pharmaceutical companies across the world are developing that have the potential to become major coronavirus vaccines or antivirals for treating the contagious coronavirus infection.

Novel coronavirus vaccines

Listed below are the coronavirus vaccines in various stages of development, across the world.

Vaccine by Medicago

Medicago is developing drug candidates against COVID-19 after having produced Virus-Like Particles (VLP) of the coronavirus. The company has formed a collaboration with the Laval University’s Infectious Disease Research Centre to develop antibodies against SARS-CoV-2.

The company’s research activities are being partly funded by the Canadian Institutes for Health Research (CIHR).

AT-100 by Airway Therapeutics

Airway Therapeutics is exploring its novel human recombinant protein named AT-100 (rhSP-D) as a treatment for coronavirus. The company has announced a filing with the Respiratory Diseases Branch of the National Institutes of Health to evaluate the drug.

AT-100 has shown efficacy in preclinical studies in reducing inflammation and infection in the lungs, while also generating an immune response against various respiratory diseases.

TZLS-501 by Tiziana Life Sciences

Tiziana Life Sciences is developing its monoclonal antibody named TZLS-501 for the treatment of COVID-19. TZLS-501 is a human anti-interleukin-6 receptor (IL-6R), which helps in preventing lung damage and elevated levels of IL-6.

The drug works by binding to IL-6R and depleting the amount of IL-6 circulating in the body thereby reducing chronic lung inflammation.

OYA1 by OyaGen

OyaGen’s OYA1 has shown strong antiviral efficacy against coronavirus in laboratory essays. It was found to be more effective than chlorpromazine HCl in inhibiting SARS-CoV-2 from replicating in cell culture.

OYA1 was earlier approved as an investigational new drug for treating cancer but abandoned due to lack of efficacy. OyaGen plans to conduct further research on the drug to determine the efficacy in treating coronavirus.

BPI-002 by BeyondSpring

BeyondSpring’s BPI-002 is a small molecule agent indicated for treating various infections including COVID-19. It has the ability to activate CD4+ helper T cells and CD8+ cytotoxic T cells and generating an immune response in the body.

If combined with another COVID-19 vaccine, the drug has the ability to generate long-term protection against viral infections. BeyondSpring has filed US patent protection for the drug for treating viral infections.

Altimmune’s intranasal coronavirus vaccine

An intranasal Covid-19 vaccine is being developed by US-based clinical-stage biopharmaceutical company, Altimmune.

Design and synthesis of the single-dose vaccine have been completed, while animal testing will follow.

The coronavirus vaccine is being developed based on a vaccine technology platform that is similar to NasoVAX, an influenza vaccine developed by Altimmune.

INO-4800 by Inovio Pharmaceuticals and Beijing Advaccine Biotechnology

Inovio Pharmaceuticals has collaborated with Beijing Advaccine Biotechnology Company to advance the development of the former’s vaccine, INO-4800, as a novel coronavirus vaccine. The company has started pre-clinical testing for clinical product manufacturing.

The vaccine development is supported by a $9m grant from the Coalition for Epidemic Preparedness Innovations (CEPI).

Inovio announced an accelerated timeline for the development of the vaccine on 03 March. Preclinical trials are ongoing and the design for human clinical trials have been completed. The company has also prepared 3,000 doses for human clinical trials planned to be conducted across the US, China, and South Korea. Plans for large-scale manufacturing have also been developed.

Human clinical trials in 30 healthy volunteers are expected to commence in April 2020 in the US, followed by China, and South Korea. A phase one clinical trial is planned to be conducted in parallel in China, by Beijing Advaccine. Results from the clinical trials are expected to be available in September 2020.

Inovio aims to produce one million doses of the vaccine by the end of 2020 to perform additional clinical trials or emergency use.

NP-120 (Ifenprodil) by Algernon Pharmaceuticals

Algernon Pharmaceuticals has announced that it is exploring its NP-120 (Ifenprodil) as a potential treatment Covid-19. Ifenprodil is an N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonist sold under the brand name Cerocal. It has demonstrated efficacy in improving survivability in mice infected with H5N1.

APN01 by University of British Columbia and APEIRON Biologics

A drug candidate developed by APEIRON Biologics named APN01 is being tested in China in a phase one pilot trial as a treatment for Covid-19. APN01 is based on research conducted by a professor at the University of British Columbia for treating SARS. The research revealed that the ACE2 protein was the main receptor for the SARS virus.

The clinical trial will test the drug’s efficacy in reducing the viral load in patients. Data from the trial will be used to determine if additional clinical trials are required to be conducted in larger number of patients.

mRNA-1273 vaccine by Moderna and Vaccine Research Center

Moderna and the Vaccine Research Center, a unit of the National Institute of Allergy and Infectious Diseases (NIAID), have collaborated to develop a vaccine for coronavirus. The vaccine targets the Spike (S) protein of the coronavirus.

The first vials of the vaccine have been manufactured at Moderna’s Massachusetts manufacturing plant and shipped to NIAID for phase one clinical trial, which is scheduled to start in April.

Avian Coronavirus Infectious Bronchitis Virus (IBV) vaccine by MIGAL Research Institute

The MIGAL Research Institute in Israel announced that an Infectious Bronchitis Virus (IBV) vaccine developed to treat avian coronavirus has been modified to treat Covid-19. The vaccine has demonstrated efficacy in pre-clinical trials conducted by the Volcani Institute.

The IBV vaccine was developed after four years of research and has high genetic similarity to the human coronavirus. The institute has genetically modified the vaccine to treat Covid-19 and will be available in the oral form.

The institute is currently exploring potential partners for producing the vaccine in the next eight to ten weeks and obtaining the necessary safety approvals for in-vivo testing.

TNX-1800 by Tonix Pharmaceuticals

Tonix Pharmaceuticals has partnered with Southern Research, a non-profit research organisation, to develop a coronavirus vaccine named TNX-1800. The vaccine is a modified horsepox virus developed using Tonix’s proprietary horsepox vaccine platform.

TNX-1800 is designed to express a protein derived from the virus that causes the coronavirus infection. Southern Research will be responsible for evaluating the efficacy of the vaccine, under the partnership.

Brilacidin by Innovation Pharmaceuticals

Innovation Pharmaceuticals announced that it is evaluating Brilacidin, a defensin mimetic drug candidate, as a potential treatment for coronavirus. Brilacidin has shown antibacterial, anti-inflammatory and immunomodulatory properties in several clinical trials.

The company is planning to explore research collaborations and seek federal grants to develop the coronavirus drug. It is already investigating the drug for inflammatory bowel disease and oral mucositis in cancer patients.

Innovation has signed two material transfer agreements with a university in the US and 12 biocontainment labs in the US for evaluation of Brilacidin as a treatment for Covid-19. One of the biocontainment labs is scheduled to commence testing of the drug in the third week of March.

Recombinant subunit vaccine by Clover Biopharmaceuticals

Clover Biopharmaceuticals is developing a recombinant subunit vaccine using its patented Trimer-Tag© technology. The company is developing the vaccine based on the trimeric S protein (S-Trimer) of the Covid-19 coronavirus, which is responsible for binding with the host cell and causing a viral infection.

Using Trimer-Tag© technology, Clover successfully produced the subunit vaccine in a mammalian cell-culture based expression system on 10 February. The company also identified antigen-specific antibody in the serum of fully recovered patients who were previously infected by the virus.

A highly purified form of the S-Trimer vaccine is expected to be available in six to eight weeks for performing pre-clinical studies. The company is equipped with in-house cGMP biomanufacturing capabilities to scale-up production if the vaccine is proven to be successful.

Clover is also collaborating with GSK to develop a vaccine using the latter’s pandemic adjuvant system.

Vaxart’s coronavirus vaccine

Vaxart is developing an oral recombinant vaccine in tablet formulation using its proprietary oral vaccine platform, VAAST.

The company plans to develop vaccines based on the published genome of 2019-nCOV to be tested in pre-clinical models for mucosal and systemic immune responses.

CytoDyn-leronlimab

CytoDyn is examining leronlimab (PRO 140), a CCR5 antagonist, as a potential coronavirus drug.

The drug is already being investigated in phase two clinical trials as a treatment for HIV and has been awarded fast-track approval status by the United States Food and Drug Administration.

Linear DNA Vaccine by Applied DNA Sciences and Takis Biotech

Applied DNA Sciences’ subsidiary LineaRx and Takis Biotech formed a joint venture on 07 February to develop a linear DNA vaccine as a treatment for coronavirus. The JV will use Polymerase Chain Reaction (PCR)-based DNA manufacturing technology to develop the vaccine.

The PCR technology offers several advantages including high purity, increased production speed, and absence of antibiotics and bacterial contaminants. Further, the vaccine gene developed through this technology can be effective without being inserted into the patient’s genome.

The design for four DNA vaccine candidates is expected to be produced using the PCR technology for carrying out animal testing. The design of one of the vaccine candidates is based on the entire spike gene of the coronavirus, while the remaining are designed based on the antigenic portions of the protein.

BXT-25 by BIOXYTRAN to treat late-stage acute respiratory distress syndrome (ARDS)

BIOXYTRAN announced that it is exploring partners to develop its lead drug candidate, BX-25, as a treatment for Acute Respiratory Distress Syndrome (ARDS) in late-stage patients infected with the coronavirus. The diffusion of oxygen to the blood is comprised in patients suffering from ARDS leading to fluid build-up in the lungs.

BX-25 is designed to be 5,000 times smaller than blood cells and efficiently transport oxygen through the body for a period of nine hours before being processed by the liver. The drug can help in supplying oxygen to the vital organs and enable the patient to recover and survive.

MERS CoV vaccines for coronavirus

Novavax’s MERS coronavirus vaccine candidate

Novavax developed a novel Middle East Respiratory Syndrome (MERS) coronavirus vaccine candidate in 2013, post the identification of the first MERS coronavirus ((MERS-CoV) in Saudi Arabia in 2012. It is a crucial target for coronavirus vaccine development by the Coalition for Epidemic Preparedness Innovations (CEPI) and is a priority disease for the World Health Organisation (WHO).

The candidate is designed to primarily bind to the major surface S-protein and developed using the company’s recombinant nanoparticle vaccine technology. Tested along with the Novavax’s proprietary adjuvant Matrix-M™, it inhibited infection by inducing immune responses in the laboratory studies.

Novavax has received $4m in funding from CEPI to advance the development of the vaccine. The company has produced several nanoparticle vaccine candidates for testing in animal models and aims to carry out human trials in 2020.

The MERS coronavirus is related to the severe acute respiratory syndrome (SARS) coronavirus, for which the company had previously developed a recombinant nanoparticle vaccine candidate.

Inovio Pharma’s INO-4700

The investigational DNA immunotherapy, INO-4700 (GLS-5300) is being developed by Inovio in partnership with GeneOne Life Science. It is delivered as vaccine intramuscularly, using the Cellectra® delivery device.

The company has received a $5m grant from the Bill and Mellinda Gates foundation to accelerate the development of the Cellectra® delivery device.

The vaccine was well-tolerated and demonstrated high immune responses against the MERS-CoV in 94% of patients in the early-stage clinical trial in July 2019.

It also generated broad-based T cell responses in 88% of the subjects.

“Research organisations such as the National Institutes of Health (NIH), US are also developing a vaccine for the coronavirus.”

Coronavirus drugs

The novel coronavirus drugs in various stages of development globally are listed below.

Remdesivir (GS-5734) by Gilead Sciences

An ebola drug developed by Gilead Sciences that was found to be ineffective is now being tested in two phase III randomised clinical trials in Asian countries.

The trials are being performed on 761 patients in a randomised, placebo-controlled, double-blind study at multiple hospitals in Wuhan, the epicentre of the novel coronavirus outbreak. The results from the trials are expected to be available over the next few weeks.

According to a report by The New England Journal of Medicine (NEJM), remdesivir, when administered to a coronavirus patient in the US, appeared to have improved the clinical condition.

The University of Nebraska Medical Center is also carrying out clinical trials to test the safety and efficacy of the drug. The first patient to be administered the drug is an evacuee from the Diamond Princess cruise ship.

Actemra by Roche to treat coronavirus-related complications

China approved the use of Roche’s Actemra for the treatment of severe complications related to coronavirus. Drugs like Actemra have the ability to prevent cytokine storms or overreaction of the immune system, which is considered as the main reason behind organ failure leading to death in some coronavirus patients.

Actemra is also being evaluated in a clinical trial in China, which is expected to enroll 188 coronavirus patients. The clinical trial is expected to be conducted until May 10.

Biocryst Pharma’s Galidesivir, a potential antiviral for coronavirus treatment

The antiviral drug Galidesivir (BCX4430) has shown broad-spectrum activity against a wide range of pathogens including coronavirus. It is a nucleoside RNA polymerase inhibitor that disrupts the process of viral replication.

The drug has already shown survival benefits in patients against deadly viruses such as Ebola, Zika, Marburg, and Yellow fever.

Galidesivir is currently in advanced development stage under the Animal Rule to combat multiple potential viral threats including coronaviruses, flaviviruses filoviruses, paramyxoviruses, togaviruses, bunyaviruses, and arenaviruses.

Regeneron’s REGN3048-3051 and Kevzara

Discovered by Regeneron, the combination of neutralising monoclonal antibodies REGN3048 and REGN3051 is being studied against coronavirus infection in a first-in-human clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). The safety and tolerability of the drug will be studied in 48 patients.

Both the antibodies bind to S-protein of MERS coronavirus. The intravenous administration of the drug in the mouse model of MERS resulted in the high-level neutralisation of the MERS coronavirus in circulating blood with reduced viral loads in the lungs.

Regeneron has partnered with Sanofi to evaluated Kevzara, a fully-human monoclonal antibody, in a phase two/three clinical trial in patients with severe COVID-19 infection. Kevzara is approved for the treatment of rheumatoid arthritis and is known to block the interleukin-6 (IL-6) pathway, which causes an overactive inflammatory response in the lungs of Covid-19 patients.

Other companies developing coronavirus vaccines/drugs

Companies such as Inovio Pharmaceuticals, Moderna, and Novavax have been reported to be developing coronavirus vaccines. A total of 30 therapies are planned to be tested, including few traditional medicines for coronavirus treatment by Chinese scientists. Chloroquine phosphate has shown efficacy in treating symptoms of the disease, among the 30 therapies. Patients administered with the drug achieved a better drop in fever and shorter recovery time in clinical trials being conducted in hospitals in the Guangdong province and Hunan province.

Predictive Oncology

Predictive Oncology has launched an AI Platform for the discovery and development of vaccines against coronavirus. The company has signed an agreement with InventaBioTech to acquire Soluble Therapeutics, which provides it with access to the HSCTM Technology.

Predictive will use the HSCTM Technology along with its predictive modeling platform to deploy an AI discovery platform that can screen the ideal combination of additives and excipients for protein formulations.

Emergent BioSolutions

Emergent BioSolutions is developing two plasma-derived product candidates or hyperimmunes using its hyperimmune platforms for the treatment of coronavirus. The hyperimmune platforms have been used previously for the development of several approved products including vaccines for smallpox, botulism, and anthrax.

The hyperimmunes are polyclonal antibodies derived from plasma, which are capable of generating an immune response and protecting against infection. Product candidate derived from human plasma is named COVID-HIG, while COVID-EIG is derived from equine plasma. Both will be explored for the treatment of patients with a severe case of infection.

Integral Molecular

Integral Molecular has launched a vaccine programme using its two technology platforms including Shotgun Mutagenesis Epitope Mapping and the Membrane Proteome Array. The technologies will help in understanding the human immune response to the coronavirus and isolate the cellular receptors that enable the virus to spread quickly.

The Shotgun technology helps in identifying more than 1,000 binding sites for antibodies, while the Membrane Proteome Array technology is capable of identifying the receptors through which viruses infect cells.

CEL-SCI

CEL-SCI is developing immunotherapy against Covid-19 using its proprietary LEAPS peptide technology, which utilises conserved areas of the coronavirus proteins to generate T-cell responses and reduce viral load. The technology can also be used to develop immunotherapeutic peptides with both antiviral and anti-inflammatory properties.

The peptides developed using this technology can help in reducing tissue damage from inflammation caused due to lung infection, which is a major cause of mortality in elderly patients.

AJ Vaccines

AJ Vaccines has launched the development of a vaccine against Covid-19. The company will use the latest technology to develop antigens that can mimic the native structures of the virus. The vaccine will be capable of inducing a strong immune response in the body thereby protecting against the infection.

Takeda Pharmaceutical Company

Takeda Pharmaceutical Company has announced plans to develop a plasma-derived therapy against coronavirus. The anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG) therapy will be designed to treat high-risk patients. The H-IG therapy includes concentrated pathogen-specific antibodies derived from plasma of recovered patients. These antibodies have the potential to generate an immune response when injected into a new patient.

Heat Biologics

Heat Biologics has announced plans to develop a vaccine to treat or prevent coronavirus infection using its proprietary gp96 vaccine platform. The technology is capable of reprogramming live cells to produce antigens that can bind to the gp96 protein and generate an immune response against those antigens.

Pfizer

Pfizer announced that it has identified certain under development antiviral compounds that may be effective in treating coronavirus. The company is planning to partner with a third party to screen and identify potential compounds by the end of March and begin testing in April.

Mateon Therapeutics

Mateon Therapeutics has launched an antiviral response programme to develop coronavirus treatments using its therapeutic and artificial intelligence (AI) platforms. It has also established a division, which will adopt a multi-modal approach to developing Covid-19 treatments as well as other future zootonic outbreaks.

Hong Kong University of Science and Technology

The Hong Kong University of Science and Technology has identified several vaccine targets, which can be developed as a treatment for coronavirus. Researchers at the university have identified B-cell and T-cell epitopes, which are capable of generating an immune response against the SARS virus and a similar response against the coronavirus.

Some of the epitopes identified may be capable of generating an immune response specifically against Covid-19.

Vaccine by Generex

Generex has announced that it is developing a COVID-19 vaccine following a contract from a Chinese consortium comprising of China Technology Exchange, Beijing Zhonghua Investment Fund Management, Biology Institute of Shandong Academy of Sciences and Sinotek-Advocates International Industry Development.

The company will utilise its Ii-Key immune system activation technology to produce a Covid-19 peptide for human clinical trials.

Generex will receive an upfront payment of $1m to commence the groundwork for the vaccine development and $5m licensing fee for its Ii-Key technology. It is also eligible to receive a 20% royalty on every dose of vaccine produced under the contract.

Coronavirus drugs by Columbia University

Researchers at Columbia University have been awarded a $2.1m grant by the Jack Ma Foundation to develop a coronavirus cure. Four different teams at the university will adopt various approaches towards the development of a vaccine against coronavirus.

Vaccine by Tulane University

Tulane University has launched a research programme to identify a potential medicine for coronavirus in the form of a vaccine. The university will utilise a grant from the Brown Foundation to carry out the research activities.

Coronavirus vaccine by ImmunoPrecise Antibodies

ImmunoPrecise Antibodies has launched a vaccine and therapeutic antibody programme to develop a vaccine as well as antibodies against Covid-19. The company will use its B Cell Select™ and DeepDisplay™ discovery platforms to therapeutic compounds against the coronavirus.

The company has updated its research efforts and noted that it will be using the PolyTope mAb TherapyTM and EVQLV’s artificial intelligence platforms develop a COVID-19 therapy.

Serum Institute of India

Serum Institute of India (SII) is collaborating with Codagenix, a US-based biopharmaceutical company, to develop a coronavirus cure using a vaccine strain similar to the original virus. The vaccine is currently in the pre-clinical testing phase, while human trials are expected to commence in the next six months. SII is expected to launch the vaccine in the market by early 2022.

Southwest Research Institute

Southwest Research Institute is using its virtual screening called Rhodium to identify potential drug candidates for treating coronavirus from more than two million drug compounds. The most promising compounds will be identified for further development.

Zydus Cadila

Zydus Cadila announced the launch of an accelerated research programme to develop a vaccine for Covid-19 using two novel approaches. The first approach includes the development of a DNA vaccine against the viral membrane protein of the virus, while a live attenuated recombinant measles virus (rMV) vectored vaccine will be developed in the second approach. The rMV-based vaccine works by inducing specific neutralising antibodies, which will provide protection from the coronavirus infection.

NanoViricides

NanoViricides, a clinical-stage company, is working on developing a treatment for nCoV-2019 using its nanoviricide® technology. The company’s technology is used to develop ligands that can bind to the virus in the same way as a cognate receptor and attack various points of the virus.

Vir Biotechnology

Vir Biotechnology, a clinical-stage immunology company, announced on 12 February that it has identified two monoclonal antibodies that can bind to the virus that causes Covid-19. The antibodies target the spike (S) protein of the virus by entering through the cellular receptor ACE2.

The company has formed a partnership with WuXi Biologics on 25 February to commercialise the antibodies identified to treat coronavirus. If approved, Wuxi will have the rights to market the therapies in China, while Vir will retain the marketing rights in other countries.

Vir has also partnered with Alnylam Pharmaceuticals to identify siRNA candidates targeting SARS-CoV-2. It has formed another partnership with Biogen for cell line and process development and manufacturing of the antibodies.

HIV drugs for coronavirus treatment

Abbvie’s HIV protease inhibitor, lopinavir is being studied along with ritonavir for the treatment of MERS and SARS coronaviruses. The repurposed drug is already approved for the treatment of HIV infection under the trade name Kaletra®.

The combination is listed in the WHO list of essential medicines. Lopinavir is believed to act on the intracellular processes of coronavirus replication and demonstrated reduced mortality in the non-human primates (NHP) model of the MERS.

Lopinavir/ritonavir in combination with ribavirin showed reduced fatality rate and milder disease course during an open clinical trial in patients in the 2003 SARS outbreak.

Cipla is also reportedly planning to repurpose its HIV drug LOPIMUNE, which is a combination of protease inhibitors Lopinavir and Ritonavir, for the treatment of coronavirus.

A licensed generic of Kaletra®, LOPIMUNE is currently available in packs of 60 tablets each, containing 200mg of Lopinavir and 50mg of Ritonavir.

Janssen Pharmaceutical Companies, a subsidiary of Johnson & Johnson, donated its PREZCOBIX® HIV medication (darunavir/cobicistat) for use in research activities aimed at finding a treatment for Covid-19.

Darunavir is a protease inhibitor marketed by Janssen. Anecdotal reports suggest darunavir as potentially having antiviral activity against Covid-19. It is, however, currently approved only for use with a boosting agent, and in combination with other antiretrovirals, for the treatment of HIV-1.

Janssen has no in vitro or clinical data to support the use of darunavir as a treatment for Covid-19. The drug is in the process of being evaluated in vitro for any potential activity against the coronavirus.

Further, Janssen has partnered with the Biomedical Advanced Research and Development Authority (BARDA) to expedite the development of a Covid-19 treatment.

The Coronavirus outbreak

The contagious coronavirus outbreak at the end of 2019, which the WHO named as Covid-19 (formerly 2019-nCoV), led to a medical emergency across the world.

Similar infections are caused by human alpha and beta coronaviruses such as 229E, NL63, OC43 and HKU1.