COVID-19 Vaccine Development
Sanofi and GlaxoSmithKline (GSK) Collaborate in Adjuvanted Vaccine for Coronavirus (COVID-19)
On 14th April 2020, Sanofi and GSK announced that they have signed a letter of intent for a collaboration focused on development of an adjuvanted vaccine for COVID-19, using innovative technology from both companies.
As part of their partnership, Sanofi will contribute with its S-protein COVID-19 antigen, which is based on recombinant DNA technology. It has been developed as an exact genetic match to proteins found on the surface of the virus, and the DNA sequence encoding this antigen has been combined into the DNA of the baculovirus expression platform, which is the basis of Sanofi’s licensed recombinant influenza product in the United States (US). Development of the recombinant-based COVID-19 vaccine candidate is being supported through funding and a collaboration with the Biomedical Advanced Research and Development Authority (BARDA) in the US.
GSK will provide its tested pandemic adjuvant technology, an adjuvant can be of particular importance in a pandemic situation since it may reduce the amount of vaccine protein required per dose, enabling more vaccine doses to be produced.
Paul Hudson, CEO Sanofi, stated: “As the world faces this unprecedented global health crisis, it is clear that no one company can go it alone. That is why Sanofi is continuing to complement its expertise and resources with our peers, such as GSK, with the goal to create and supply sufficient quantities of vaccines that will help stop this virus.”
Emma Walmsley, CEO GSK, stated: “This collaboration brings two of the world’s largest vaccines companies together. By combining our science and our technologies, we believe we can help accelerate the global effort to develop a vaccine to protect as many people as possible from COVID-19.”
Phase I clinical trials are planned for the second half of 2020 and, if successful and subject to regulatory considerations, aim to complete the development required for a vaccine to be available by the second half of 2021.
CanSinoBIO Advances COVID-19 vaccine into Phase II Clinical Trial
On 9th April 2020, CanSino Biologics Inc. (“CanSinoBIO”) announced that the company and the Chinese Institute of Biotechnology, Academy of Military Medical Sciences plan to start a Phase II clinical trial for Recombinant Novel Coronavirus Disease Vaccine Adenovirus Type 5 Vector (Ad5-nCoV) in China. The decision was made based on the preliminary safety data of the Phase I clinical trial for Ad5-nCoV1.
Ad5-nCoV is a genetically engineered vaccine candidate with the replication-defective adenovirus type 5 as the vector to express severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which intends to be used to prevent the disease caused by COVID-192. In mid-March CanSino Bio started the first-in-human trial of Ad5-nCoV in healthy volunteers in the city of Wuhan, the epicentre of the outbreak. In the Phase I trial, 108 subjects were supposed to be followed for up to six months for analyses of safety as well as T-cell and antibody responses. The study’s primary endpoint was set to look at adverse reactions seven days post injection.
The Phase II trial will also be conducted in Wuhan and will enrol 500 healthy participants, 250 participants will get the middle dose (1×10^11vp of Ad5-nCoV), and the remaining 250 will be split up to receive either the low dose (5×10^10vp of Ad5-nCoV) or placebo3. The randomised study has three primary endpoints, which will examine adverse reactions within the first 14 days of vaccination as well as serum levels of anti-SARS-CoV-2 neutralising antibody and antibody against the coronavirus’s spike protein at day 28. All participants will be followed for up to six months, it is estimated that study will be completed by January 31st 2021.
Xuefeng Yu, Chairman and CEO of CanSinoBIO stated: “Thanks to our collaborators and our diligent team, who worked almost around clock since late January to develop this vaccine candidate with sound scientific data to support IND filing. Having committed to provide unconditional support to fight against the global epidemic, CanSinoBIO is determined to launch our vaccine product candidate as soon as possible with no compromise on quality and safety.”
Viroclinics Xplore Partners with the University of Queensland (UQ) for COVID-19 Vaccine
On 9th April 2020, Dutch firm Viroclinics Xplore announced partnership with the University of Queensland for pre-clinical studies for a COVID-19 vaccine. The studies will assess the candidate’s effectiveness in triggering protection against the coronavirus. Data from these studies should support the human clinical trials planned for later this year.
The vaccine has been developed using UQ’s molecular clamp technology that locks the spike protein into a shape which allows the immune system to be able to recognise and then neutralise the virus.
Vaccine program co-leader, Dr Keith Chappell stated: “These protection studies must be done in specialist biosecurity facilities as they use the live virus, and our long-standing partnership with Viroclinics Xplore gives us the confidence that this can be achieved as quickly as possible. This work will establish a critical package of data that will take us through to human clinical trials in Q3 2020.”
Inovio Pharmaceuticals Initiates Phase I Trial for COVID-19 DNA Vaccine
On 6th April 2020, Inovio Pharmaceuticals announced that the US Food and Drug Administration (FDA) had accepted the company’s Investigational New Drug (IND) application for INO-4800, its DNA vaccine candidate designed to prevent COVID-19 infection, the company has initiated it’s Phase I clinical testing of INO-4800 in healthy volunteers.
The Phase I study of INO-4800 will enrol up to 40 healthy adult volunteers in Philadelphia, PA (at the Perelman School of Medicine at the University of Pennsylvania) and Kansas City, MO (at the Center for Pharmaceutical Research). Participants will be administered with two doses of INO-4800 four weeks apart, initial immune responses and safety data from the study are expected by late summer. Preclinical data, which have been shared with global regulatory authorities and submitted as part of the IND, showed promising immune response results across multiple animal models. Additional preclinical trials, including challenge studies, will take place alongside the Phase I trial.
Dr. J. Joseph Kim, INOVIO’s President and CEO stated: “This is a significant step forward in the global fight against COVID-19. Without a new safe and effective vaccine, the COVID-19 pandemic is likely to continue to threaten lives and livelihoods. It also demonstrates the power of our DNA medicines platform to rapidly develop and advance a vaccine for COVID-19 into Phase 1 clinical testing. Our dedicated team of staff, partners and funders have been mobilized since the genetic sequence of the virus became available in early January and continues to work around the clock to ensure that we are rapidly advancing INO-4800 through this Phase 1 study towards planned efficacy trials.”
COVID-19 Research and Therapeutic Development
AstraZeneca to Initiate Trial of Calquence® for Treatment of Severe COVID-19 Patients
On 14th April 2020, AstraZeneca announced that the company plans to initiate a randomised, global clinical trial to test the effect of Calquence®(acalabrutinib) in the treatment of the exaggerated immune response (cytokine storm) linked with COVID-19 infection in severely ill patients.
The trial was designed based upon scientific evidence supporting the role of the Bruton’s tyrosine kinase (BTK) pathway in the production of inflammatory cytokines and on encouraging early clinical data. Calquence® is a next-generation, highly selective BTK inhibitor currently used to treat certain types of blood cancers. Early clinical data with Calquence® showed that a decrease in inflammation caused by BTK inhibition appears to decrease the severity of COVID-19-induced respiratory distress.
The trial which is called CALAVI will evaluate the efficacy and safety of adding Calquence® to best supportive care (BSC) to reduce mortality and the need for assisted ventilation in patients with life-threatening COVID-19 symptoms. CALAVI is a large, multicentre, global, randomised trial using a two-part patient-centric design developed in record time to accelerate data capture and analysis. Part one evaluates the addition of Calquence® to BSC versus BSC alone in patients hospitalised with COVID-19 who are not in the intensive care unit (ICU). Part two evaluates the addition of Calquence® to BSC in a cohort of patients in the ICU. The primary endpoint measures the use of assisted ventilation or death, enrolment will take place in US and several countries in Europe.
José Baselga, Executive Vice President, Oncology R&D, stated: “With this trial we are responding to the novel insights of the scientific community and hope to demonstrate that adding Calquence® to best supportive care reduces the need to place patients on ventilators and improves their chances of survival. This is the fastest launch of any clinical trial in the history of AstraZeneca.”
Pfizer Identifies Coronavirus Drug Candidate
On 9th April 2020, Pfizer announced the company’s latest therapeutic and development advances in the battle against the COVID-19 pandemic.
Based on results of initial anti-viral compound screening assays, Pfizer identified a lead compound and analogues as potent inhibitors of the SARS-CoV-2 3C-like (3CL) protease. Preliminary data suggested that the lead protease inhibitor shows antiviral activity against SARS-CoV-2. The company will perform pre-clinical confirmatory studies, including anti-viral profiling and assessment of the suitability of the lead molecule for Phase IV administration clinically. Additionally, Pfizer is also planning to conduct a clinical study of the lead candidate in the third quarter of this year.
Pfizer has also announced that the company has entered into a global collaboration agreement with BioNTech SE to co-develop BioNTech’s potential first-in-class, mRNA-based coronavirus vaccine program aimed at preventing COVID-19 infection. The two companies plan to jointly conduct clinical trials for COVID-19 vaccine candidates in the US and Europe across multiple research sites. Clinical trials are expected to start at the end of April 2020, assuming regulatory clearance.
Liverpool School of Tropical Medicine’s Respiratory Infection Clinical Research Group has also partnered with Pfizer for two new studies to supply insights on the interaction between S. pneumoniae and SARS-CoV-2. The SAFER study and the FASTER study will show whether patients infected with the virus have a higher risk of also developing pneumococcal pneumonia and if having both infections leads to more severe disease and poorer outcomes. The SAFER study will enrol 100 healthcare workers at the Royal Liverpool Hospital and examine rates of SARS-CoV-2 acquisition and dynamics of pneumococcal colonization. The FASTER study will recruit 400 patients from the infectious disease ward at the Royal Liverpool Hospital suspected of having coronavirus.
Tiziana Life Sciences Develops Novel Investigational Treatment For Patients Infected with COVID-19
On 9th April 2020, Tiziana Life Sciences, a biotechnology company focused on innovative therapeutics for inflammatory and autoimmune diseases, announced development of an investigational new technology to treat COVID-19 infections, it enables direct delivery of anti-IL-6 receptor (anti-IL-6R) monoclonal antibodies into the lungs using a handheld inhaler or nebulizer. Development of this novel technology is a step forward toward expediting development of TZLS-501, a fully human anti-interleukin-6 receptor (anti-IL6R) monoclonal antibody for treatment of patients infected with coronavirus. According to Tiziana this novel technology could also be applicable for use with other FDA approved monoclonal antibodies (mAbs) and drugs, a provisional patent application for the delivery technology has been submitted.
Early clinical studies conducted by doctors in China suggested that anti-IL6R mAbs may be used in clinical practice for treatment of COVID-19. Consequently, China’s National Health Commission has recommended the use of Roche’s blockbuster drug, Actemra® and Sanofi’s Kevzera® for treatment of patients infected with COVID-19. Excessive production of IL-6 is believed to be associated with the severe lung damage observed in COVID-19 patients, Tiziana believes TZLS-501 (anti-IL6R) combined with their novel inhalation technology may rapidly inhibit inflammation in lungs and in combination with intravenous administration may deplete circulating levels of IL-6 and potentially halt progression of COVID-19-mediated lung damage and death.
Gabriele Cerrone, Chairman of Tiziana Lifesciences stated: “Direct delivery of anti-IL-6R mAb to the lungs using a portable handheld inhaler or nebulizer is a rapid and immediate therapy for children and adults infected with COVID-19. Importantly, this treatment with our fully human anti-IL-6R mAb (TZLS-501) has the potential to be a long-term therapy to halt progression and reduce mortality in patients with COVID-19, as a portion of the population may not opt to utilize a vaccine.”
Novartis and Incyte to Initiate Trial of Jakavi® for Treatment of Severe COVID-19 Patients
On 2nd April 2020, Novartis announced plans to start a Phase III clinical trial in partnership with Incyte to evaluate the use of Jakavi® (ruxolitinib) for treatment of the cytokine storm that can lead to life-threatening respiratory complications in COVID-19 patients.
The trial is based on preliminary reports and pre-clinical data from independent studies and is supported by safety and efficacy data of Jakavi® in conditions like acute graft versus host disease and myeloproliferative neoplasms. The trial will evaluate Jakavi® in combination with standard of care (SoC) therapy combination in comparison with SoC therapy alone, in patients with severe COVID-19 pneumonia as a result of SARS-CoV-2 infection.
Jakavi® is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases, approved by the European Commission (EC) for the treatment of adults with polycythemia vera (PV) and symptoms caused by primary myelofibrosis (MF), post-polycythemia vera MF, or post-essential thrombocythemia MF.
John Tsai, Head Global Drug Development and Chief Medical Officer, Novartis stated: “Novartis is taking a number of steps to address the urgent needs arising from the COVID-19 pandemic, including the evaluation of our existing therapies to assess if any can be utilized beyond their approved indications. The potential that Jakavi® could lead to faster recovery times for COVID-19 patients with fewer requiring intensive care and mechanical ventilation is encouraging and absolutely merits further investigation. We now are moving rapidly to finalize the study plan and then to enrol eligible patients, as well as put in place a process to provide access for patients unable to participate in the trial.”
FDA and EC approvals
FDA Approves Tukysa First New Drug Under International Collaboration, Treatment Option for Patients with HER2-Positive Metastatic Breast Cancer
On 17th April 2020, the FDA announced that as part of Project Orbis, the agency had granted approval to Seattle Genetics Inc. of Tukysa (tucatinib) in combination with chemotherapy (trastuzumab and capecitabine) for the treatment of adult patients with advanced forms of HER2-positive breast cancer that can’t be removed with surgery, or has spread to other parts of the body and who have received one or more prior treatments. The regulatory agency partnered with the Australian Therapeutic Goods Administration (TGA), Health Canada, Health Sciences Authority (HSA, Singapore) and Swissmedic (SMC, Switzerland) on this review. Project Orbis involves a collaborative review to identify any regulatory divergence across the agencies. While the FDA has approved Tukysa, the application is still under review at the other regulatory bodies.
Collaboration alongside international regulators may enable patients to receive earlier access to products where there may be significant delays in regulatory submissions. Early availability of new therapies and adoption as standard of care around the world may have an impact on the increasingly international conduct of cancer clinical trials, with the potential for faster development of anticancer products.
Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research stated: “The FDA’s Project Orbis provides a framework for concurrent submission and review of oncology drug applications among the FDA’s international collaborators. We are pleased to work with our Singapore and Switzerland colleagues for the first time, and to continue working alongside our Australian and Canadian colleagues as we facilitate new treatment options for patients – like today’s first new molecular entity under Project Orbis. This approval represents an additional targeted treatment option for patients with HER2-positive breast cancer. The clinical trial supporting this approval enrolled and specifically studied patients with active brain metastases in addition to the overall population enrolled, which also demonstrated benefit in this subgroup.”
Tukysa is a kinase approved for treatment after patients have taken one or more anti-HER2-based regimens in the metastatic setting. FDA approval was based on the results of a clinical trial enrolling 612 patients who had HER2-positive advanced unresectable or metastatic breast cancer and had prior treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1). The primary endpoint was progression-free survival (PFS), or the amount of time when there was no growth of the tumor. The median PFS in patients who received Tukysa, trastuzumab, and capecitabine was 7.8 months compared to 5.6 months in those patients who received placebo, trastuzumab, and capecitabine. The median overall survival in patients who received Tukysa, trastuzumab, and capecitabine was 21.9 months compared to 17.4 months in patients who received placebo, trastuzumab, and capecitabine.
FDA Accepts Priority Review of New Biologics License Application (BLA) for REGN-EB3
On 16th April 2020, Regeneron Pharmaceuticals announced that the FDA had accepted for priority review the BLA of REGN-EB3, an investigational triple antibody treatment for Ebola virus infection. The agency is expected to make a decision by October 25, 2020.
The BLA is supported by data from the randomised, controlled PALM clinical trial conducted in the Democratic Republic of Congo. In August 2019, the trial was stopped early when preliminary results showed that REGN-EB3 crossed the pre-specified superiority threshold for preventing death compared to the control arm, ZMapp. REGN-EB3 demonstrated superior efficacy compared to ZMapp across multiple measures, including reduced mortality and fewer days until the Ebola virus was no longer detected in the bloodstream.
George D. Yancopoulos, M.D., Ph.D., Co-Founder, President and Chief Scientific Officer of Regeneron stated :”Developed using Regeneron’s proprietary VelociSuite® rapid response technologies, REGN-EB3 was shown to save lives in the PALM trial, which evaluated multiple therapies against the current standard of care. Regeneron is now applying this same approach to develop an antibody medicine that can potentially prevent and treat COVID-19, with initial clinical trials expected to begin in June.”
VelociSuite® creates and selects potent fully-human antibodies against a specific biological target, which is particularly critical for addressing new and/or quickly-spreading pathogens such as Ebola and COVID-19. These technologies facilitate the rapid cloning and generation of optimized fully-human antibodies from both VelocImmune® mice and convalescing human volunteers and allow for the rapid escalation of fully-human antibodies into manufacturing-quality cell line production and large-scale bioreactor manufacturing. Once strong antibody candidates are found, Regeneron’s in-house preclinical, clinical and commercial-scale manufacturing capabilities allow for fast scale-up and flexibility to adapt to current need.
FDA Grants Authorisation to Blood Purification Device for COVID-19 Treatment
On 10th April 2020, the FDA issued an emergency use authorization to Terumo BCT Inc. and Marker Therapeutics AG for their Spectra Optia Apheresis System and Depuro D2000 Adsorption Cartridge devices , a blood purification system to treat patients 18 years of age or older infected with COVID-19 admitted to the ICU with confirmed or imminent respiratory failure. The blood purification system works by reducing the amount of cytokines and other inflammatory mediators in the bloodstream that control a cell’s immune response by filtering the blood and returning the filtered blood to the patient. The proteins that are removed can be associated with the cytokine storm that occurs in some COVID-19 patients.
FDA Commissioner Stephen M. Hahn, M.D. stated: “We continue to work across all sectors to expedite the development of numerous innovative potential preventive and treatment approaches by both facilitating emergency access for patients, to the extent we can, and supporting the evaluation of potential therapies. With today’s authorization of a blood purification device, we are expediting the availability of a treatment option for patients in the ICU to help reduce the severity of the disease. Our staff will continue our around the clock review of all medical products to expedite the availability of treatments to help fight this devastating disease.”
FDA Approves BRAFTOVI® in Combination with Cetuximab for Treatment of Adult Patients with Metastatic Colorectal Cancer
On 9th April 2020, Pfizer announced that the FDA had approved BRAFTOVI® (encorafenib) in combination with cetuximab (marketed as ERBITUX®) for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAFV600E mutation. Approval by the FDA is supported by results from the BEACON CRC trial, a Phase III trial conducted to specifically study patients with previously treated metastatic CRC with a BRAFV600E mutation. BRAF mutations are estimated to occur in up to 15% of people with metastatic CRC and represent a poor prognosis.
BRAFTOVI® in combination with cetuximab was evaluated in the randomised, active-controlled, open-label, multicentre, Phase III BEACON CRC trial. Eligible patients were required to have BRAFV600E mutant metastatic CRC, as detected by an FDA-approved test, with disease progression after one or two prior regimens. The results showed that patients treated with BRAFTOVI® plus cetuximab had a median overall survival (OS) of 8.4 months (95% CI: 7.5, 11.0) compared with 5.4 months (95% CI: 4.8, 6.6) for Control (irinotecan with cetuximab or FOLFIRI® with cetuximab) (95% CI: 0.45, 0.79). There was also an improved objective response rate (ORR) of 20% (95% CI: 13%, 29%) compared with 2% (95% CI: 0%, 7%) for Control and median progression-free survival was 4.2 months with BRAFTOVI plus cetuximab
Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development stated: “We are pleased by the FDA’s approval of BRAFTOVI® in combination with cetuximab, as we are committed to developing targeted medicines that can help people living with certain mutation-driven cancers. We are grateful to the patients and study investigators who participated in the Phase 3 BEACON CRC trial and are proud to now be able to offer a targeted treatment option for people with BRAFV600E-mutant metastatic CRC who have received prior therapy. Looking ahead, we’re committed to continuing to investigate this treatment regimen across earlier lines of therapy.”
European Commission (EC) Approves Nilemdo® Tablet for the Treatment of Hypercholesterolemia and Mixed Dyslipidemia
On 6th April 2020, Esperion announced that the EC had granted its approval to Nilemdo® (bempedoic acid) tablet for use in adults with primary hypercholesterolaemia or mixed dyslipidaemia as an adjunt to diet. Nilemdo® is an oral, once-daily, non-statin LDL-cholesterol (LDL-C) lowering medicine by inhibition of cholesterol synthesis in the liver. Daiichi Sankyo Europe has licensed exclusive commercialization rights to Nilemdo® and Nustendi® (bempedoic acid and ezetimibe) tablet in the European Economic Area and Switzerland from Esperion.
Tim M. Mayleben, president and chief executive officer of Esperion stated: “Millions of patients across the European Economic Area have needed a new daily, non-statin pill to help them achieve their LDL-C goals. For those who require additional non-statin lowering of their bad cholesterol, Nilemdo® will fit easily into their daily routines whether that is with their statin or without because they are statin intolerant. Esperion is committed to finding new ways to affordably manage lipids and won’t stop until everyone can achieve their goals.”
The approval by EC is supported by a Phase III LDL-C lowering program conducted in more than 3600 patients. Results of the program showed that Nilemdo® provides additional LDL-C lowering of up to 28 percent compared to placebo when added onto other lipid-lowering therapies, it also reduced non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and total cholesterol. Notably, the pharmacology section of the Nilemdo® label highlights that among the subset of patients with diabetes (n=1,134), lower levels of hemoglobin A1c (HbA1c) were observed as compared to placebo.
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