COVID-19: Therapeutics, Preventives and Industry Perspectives
Industry Insight Apr 09, 2021
CT-P59 (regdanvimab), a monoclonal antibody directed against COVID-19. Credit: Celltrion.
Technology Networks had the pleasure of speaking with Ki-Sung Kwon, head of the R&D unit at Celltrion to learn more about therapeutic versus preventive strategies against COVID-19. Kwon also discusses the company’s monoclonal antibody-based therapeutic – CT-P59 – that is currently being developed against COVID-19, the impact variants are having on the development of therapeutics in this space and highlights key lessons and scientific innovations within the pharmaceutical industry that have resulted from the pandemic.
Molly Campbell: Can you talk about some of the scientific innovations of 2020 that were delivered by the biotech sector?
Ki-Sung Kwon (KSK): Unprecedented challenges such as the COVID-19 pandemic confront biopharmaceutical companies in their quest to bring innovative new medicines to market and find a way to alleviate this global health crisis and its impact; be it through a vaccine or treatment to prevent or treat patients with COVID-19, diagnostic testing to identify who has already had and recovered from COVID-19, or setting up technology to trace and isolate those who have been diagnosed with COVID-19 to prevent its spread.
The coronavirus pandemic has changed the treatment landscape entirely, with there now being an increased need for treatments that can be administered at home. Celltrion, as a global biopharmaceutical company, explored the development of a subcutaneous (SC) formulation of infliximab, Remsima®SC, as part of extending the treatment longevity of infliximab – allowing for a rapid response with Remsima IV and maintaining the treatment regimen with Remsima SC, as the subcutaneous formulation can be self-administered by patients in the comfort of their own homes. This could reduce a patient’s risk of COVID-19 infection by sparing them their regular hospital visits but also provides patients with a more convenient option, without changing the molecule of their current medications.
LL: Should a greater focus be given to therapeutic strategies against COVID-19 versus preventive?
KSK: The COVID-19 outbreak is an unprecedented crisis affecting the lives of millions worldwide. And while vaccines and antibody treatments are being developed by numerous governments and companies, there has yet to be a set treatment guideline for the disease. Therefore, it is important to investigate all possible options ranging from diagnosis to treatment and prevention.
Celltrion is taking a “total care” approach against COVID-19. For early treatment and prevention, Celltrion is conducting studies on CT-P59, which binds to the spike protein of the virus, neutralizing it. In terms of early detection, Celltrion has also developed an antigen and antibody on-site testing kit for the diagnosis of COVID-19.
MC: Could you tell us more about Celltrion’s monoclonal antibody-based therapeutic CT-P59. Can you discuss the data from the latest studies? What are the next steps for this therapeutic?
KSK: CT-P59 (regdanvimab) is a monoclonal antibody (a recombinant human IgG1 lambda antibody) directed against COVID-19. A monoclonal antibody is a type of protein that has been designed to attach to a specific structure called an antigen. CT-P59 has been designed to attach to the spike protein of SARS-CoV-2, the virus that causes COVID-19. When it attaches to the spike protein, CT-P59 blocks the binding of spike proteins on the surface of SARS-CoV-2 to human cell receptors (ACE2), which prevents the virus from entering the body’s cells.
CT-P59 is targeted to treat mild-to-moderate COVID-19 in adults who have tested positive for SARS-CoV-2 and those who are at high risk of progressing to severe COVID-19 and/or hospitalization. A single vial contains 60 mg/ml and for a single intravenous (IV) infusion, 40 mg/kg is recommended to be administered over 90 minutes.
CT-P59 was identified as a potential treatment for COVID-19 through screening of antibody candidates from recovered patients and selecting those that showed the highest potency in neutralizing SARS-CoV-2. In preclinical studies, the treatment candidate demonstrated a 100-fold reduction in viral load of SARS-CoV-2, as well as a reduction in lung inflammation.
Phase 1 studies in healthy volunteers and patients with mild COVID-19 have now been completed. In the Phase 1.1 study, the safety and tolerability of CT-P59 was evaluated in 32 healthy volunteers at a single site in Korea. Overall, CT-P59 was well tolerated in all enrolled healthy participants.
The 1.2 global study was conducted in Korea and Europe, in patients with mild symptoms of COVID-19 to evaluate the safety, tolerability and antiviral effect of CT-P59. The trial enrolled 18 patients with mild symptoms of SARS-CoV-2 infection; patients were randomized into three cohorts of which 15 received CT-P59 at 20 mg/kg, 40 mg/kg or 80 mg/kg respectively, or matching placebo (3 patients). The results indicate that the patient population treated with CT-P59 experienced about 44% reduced mean clinical recovery time in comparison to the average placebo recovery time. None of the patients treated with CT-P59 required hospitalization or antiviral therapy as a result of COVID-19. No significant treatment-emergent serious adverse events or clinically significant treatment-emergent adverse events were identified at the interim stage.
Part one of the Phase 2/3 study has been completed whilst part two of the Phase 2/3 study is on track and currently enrolling patients. This global pivotal study was conducted to evaluate the efficacy, safety and biology of CT-P59 in patients with mild to moderate symptoms of COVID-19. With this purpose, the study was designed in two parts.
In part one, the trial enrolled 327 patients with mild-to-moderate symptoms of COVID-19 in four countries including Korea and US across three treatment groups (40 mg/kg, 80 mg/kg and placebo), in which approximately 60% of patients with moderate symptoms suffered from COVID-19 related pneumonia. The study demonstrated that at day-28, CT-P59 treated patients presented with a significantly reduced risk of COVID-19 related hospitalization and oxygenation without mortality.
When compared to placebo, CT-P59 (40 mg/kg) treated patients reported reduced progression rates to severe COVID-19 by 54% for mild-to-moderate patients and 68% for moderate patients aged 50 years and over. CT-P59 treatment groups also reported with significantly shortened time to clinical recovery ranging from 3.4 to 6.4 days quicker compared to placebo. A significant reduction of viral load compared to placebo was reported at day-7 in patients treated with CT-P59, with CT-P59 receiving a positive safety profile and no drug-related serious adverse events reported.
CT-P59 received Conditional Marketing Authorization (CMA) this February in Korea, and a CMA application has been submitted to the European Medicines Agency (EMA). Recently, the EMA issued advice on the use of CT-P59 for COVID-19 patients in the European Union as it can be considered a treatment option for patients at high risk of progressing to severe COVID-19, based on a reasonable likelihood that the medicine may provide clinical benefit, and a low likelihood of harm. The EMA has also initiated a rolling review of regdanvimab based on data from animal studies (non-clinical data) and clinical trials, in addition to data on the quality of the medicine. In addition, Celltrion plans on submitting the Emergency Use Authorization (EUA) application to the FDA in the upcoming months.
MC: The emergence of SARS-CoV-2 variants has created concern across the globe. What effect do variants have on the development of therapeutics against COVID-19?
KSK: The COVID-19 therapeutics that are currently in development or have been approved are expected to provide at least some efficacy against new virus variants because these treatments elicit a broad immune response involving a range of antibodies. Therefore, changes or mutations in the virus should not make therapeutics completely ineffective. If any of these therapeutics prove to be less effective against one or more variants, it will be possible to change the composition of the therapeutics to protect against these variants. For instance, the US Food and Drug Administration (FDA) recommends that individual monoclonal antibody products be developed with the expectation that they will be combined with one or more monoclonal antibody products that bind to different epitopes, to minimize the risk of losing activity against emergent variants.
To elicit potent neutralizing antibodies against the new emerging variants and to minimize lead-time for introducing cocktail treatments with CT-P59, Celltrion previously captured a total of 38 potent neutralizing antibodies against SARS-CoV-2 in which antibody candidate No. 32 produced neutralizing titers against new emerging strains in the UK and South Africa. Using an already constructed antibody portfolio and encouraged by confirmed potency against various mutants, Celltrion has commenced the development of a neutralizing antibody cocktail with CT-P59 against new emerging variants of SARS-CoV-2.
We believe it is vital for pharmaceutical companies to continually monitor the COVID-19 environment and assess the neutralization of therapies against a wide array of emerging variants and mutations to end this pandemic.
LL: How has the COVID-19 pandemic impacted the sector, have you seen a shift in the dynamic between drug discovery academics, small biotechs and big pharma?
KSK: The urgency of curbing the COVID-19 pandemic has motivated many investigators globally to identify new drugs and repurpose old ones, so as to target viral proteins as well as some host cell targets essential for viral replication.
All companies looking to address healthcare are up against a new set of challenges – while the pandemic has spurred the adoption of med-innovations and collaboration within the industry to tackle the pandemic, we now need to continue to innovate to further support people globally. While continuing to support the development of treatments to address the pandemic and mutant variants of the virus, Celltrion is striving to support with continued innovation and development of innovative drugs, bio-betters beyond its work in COVID-19. Celltrion is continuing to invest in the development of innovative solutions, such as its subcutaneous formulation of infliximab, to address the increased need for treatments that can be administered at home and its high concentration, low-volume adalimumab biosimilar CT-P17, which should support treatment adherence and enable affordable access to treatment alternatives for patients suffering with chronic inflammatory disease.
LL: The pandemic has highlighted the pharmaceutical industry’s ability to expedite drug discovery efforts and the development and manufacturing of vaccines. What key lessons have been learned along the way? What impact do you think this progress will have in terms of future scientific advancements?
KSK: The pandemic has prompted many regulatory agencies to introduce accelerated reviews of COVID-19 research proposals, consistent with their public health missions and mandates. To ensure that novel treatments and vaccines for COVID-19 are developed as quickly and as efficiently as possible, there is a need for continuous dialogue between developers, regulators and other stakeholders so that there is mutual awareness, agreed analysis of the emerging data and a common understanding of what the data is showing. This would allow for more rapid approval of medicines and faster access for patients to new treatments. Not only for SARS-CoV-2, but this kind of innovation, creativity, and speed could be potentially applied to other chronic, life-threatening, and rare diseases to make drug development more efficient.
Ki-Sung Kwon was speaking with Molly Campbell, Science Writer, and Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.