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Coronavirus in the crosshairs, Part 9: Anti-SARS-CoV-2 biologics entering clinical study

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Antibody therapeutics have been developed for a wide variety of diseases, but starting in 2016 the biopharmaceutical industry increasingly focused on the clinical development of antibodies for cancer. [1] Antibody therapeutics for infectious diseases were historically a minor component of the commercial clinical pipeline, [2] comprising only ~5% of the total number in the pipeline at the end of 2019. Companies saw opportunities in a few niche applications, although approval success rates for anti-infective antibodies are the same, if not better, than those for all antibody therapeutics. Prior to 2020, research and development of anti-infective antibodies tended to be the purview of academic, government and non-profit organizations.

The global pandemic caused by SARS-CoV-2 substantially altered plans laid for 2020. Many commercial, as well as non-commercial, organizations with the capacity to generate recombinant protein-based, antigen-binding molecules have very definitely seen an opportunity in the development of anti-SARS-CoV-2 interventions. Most are monoclonal antibodies (mAbs), but other protein types are included, such as a designed ankyrin repeat protein (DARPin®) and Fc fusion proteins.

Anti-SARS-CoV-2 biologics development

The Antibody Society, in collaboration with the Chinese Antibody Society, is tracking over 100 recombinant protein-based COVID-19 interventions in preclinical and clinical development. Data are collected from the public domain, and therefore likely represent only a portion of the ongoing efforts. Of the programs and molecules we are tracking, all of the interventions that specifically target the virus are currently in preclinical development. Discovery of these interventions involves three main approaches:

  • In vitro library screening;
  • Screening B cells from convalescent patients; or
  • Immunization of animals with SARS-CoV-2 antigens.

Using these approaches, numerous organizations have reported finding 1,000s of antibodies that target SARS-CoV-2 during their screening campaigns. However, to advance into clinical studies, the molecules must also be shown to:

  • Neutralize SARS-CoV-2 in in vitro assays;
  • Provide protection in small animal (e.g., Syrian hamster, cynomolgus macaque) models of COVID-19;
  • Possess suitable developability, which may require protein engineering to improve biophysical properties (e.g., increasing half-life, reducing the potential for immunogenicity);
  • Express from cell lines at sufficiently high levels to enable manufacturing [3] of clinical-grade drug substance that can be formulated into the drug product.

As of the end of May 2020, more than 15 organizations have announced that their anti-SARS-CoV-2 molecules may enter clinical study during June to December 2020. The abundance of potential clinical candidates has enabled some organizations, including Eli Lilly and Company, Sorrento Therapeutics, Vir Biotechnology, Vanderbilt University Medical Center and Yumab, to engage in multiple partnerships, thereby allowing rapid development of multiple assets. Achieving organizational goals to initiate clinical study, however, depends on the successful completion of myriad activities, including regulatory affairs.

Clinical entry anticipated during June – December 2020

Note: Information below is based on press releases or other public disclosures as of May 22, 2020, and is subject to change at any time. Details (e.g., drug code) for the specific molecules entering clinical studies may not be publicly available at this time. The organizations’ plans to start first-in-human studies are subject to review by regulatory authorities.

Regeneron Pharmaceuticals

  • REGN-COV2, a cocktail of antibodies designed to prevent and treat the SARS-CoV-2 virus, is expected to enter clinical study in June 2020.
  • Large-scale manufacturing is anticipated by August 2020.

Celltrion

Eli Lilly and Company, with partners

  • Eli Lilly and Company partnered with AbCellera with the aim of using AbCellera’s antibody discovery platform to identify anti-SARS-CoV-2 antibodies from B cells derived from convalescent patients. Lilly will independently fund and lead clinical development and testing of antibody therapeutics discovered through this partnership. Their goal is to begin clinical trials in July 2020.
  • Eli Lilly and Company partnered with Junshi Biosciences to co-develop therapeutic antibodies for the potential prevention and treatment of COVID-19. Multiple neutralizing antibodies have been engineered, and the companies anticipate moving to first-in-human clinical trials in Q2 2020.  One asset due to progress to clinical studies may be JS016, a recombinant human monoclonal neutralizing antibody that is specific to the SARS-CoV-2 surface spike protein receptor binding domain. Junshi Biosciences developed JS016 jointly with the Institute of Microbiology, Chinese Academy of Science.

Vir Biotechnology, Inc. / Humabs Biomed SA, with partners

  • VIR-7831 and VIR-7832 have demonstrated high affinity for the SARS-CoV-2 spike protein and are highly potent in neutralizing SARS-CoV-2 in live virus-cellular assays. In collaboration with GlaxoSmithKline plc., Vir plans to proceed directly into a Phase 2 clinical trial in July-September 2020.
  • Vir Biotechnology also has partnership agreements involving antibody engineering and manufacturing with Xencor, Biogen, WuXi Biologics, and Samsung Biologics.

Sorrento Therapeutics, with partners

  • COVI-GUARD (STI-1499) is an anti-SARS-CoV-2 antibody that has shown 100% inhibition of the virus in laboratory tests. The antibody is potentially both a preventative and a treatment, and may be evaluated as monotherapy and as one component of COVI-SHIELD (see below). Sorrento anticipates moving STI-1499 into first-in-human clinical trials as monotherapy in July 2020.
  • COVI-SHIELD is a cocktail of three antibodies that together would recognize three unique regions of the SARS-CoV-2 Spike protein. The leading antibody, STI-1499, came from the company’s extensive library. Sorrento and Mount Sinai Health System are jointly developing this asset. Sorrento expects to commence Phase 1 trials in Q3 2020.
  • Sorrento is also developing other potential antiviral therapies against coronaviruses, including COVIDTRAP (STI-4398) and ACE-MAB (STI-4920, CMAB020). Specific information about the dates of first-in-human clinical trials has not been divulged. COVIDTRAP (STI-4398) is a proprietary angiotensin-converting enzyme 2 (ACE2)-Fc fusion protein. ACE-MAB (STI-4920, CMAB020) is a proprietary bispecific fusion protein composed of a human antibody that targets the spike protein of SARS-CoV-2 with high affinity fused to a truncated ACE2 protein that binds to a different epitope of the spike protein. Sorrento Therapeutics, Inc. entered into an exclusive license agreement with Mabpharm Limited for the clinical development and commercialization of ACE-MAB for the potential treatment of COVID-19.

AstraZeneca, with partners

  • In addition to applying their own substantial resources to the problem, AstraZeneca is also working with numerous partners (Vanderbilt University Medical Center, Chinese Academy of Sciences, United States Army Medical Research Institute of Infectious Diseases and the University of Maryland School of Medicine) to develop anti-SARS-CoV-2 antibodies. AstraZeneca is using all three potential sources for antibodies (i.e., in vitro libraries, patient B cells, immunized humanized mice), with the spike protein on the SARS-CoV-2 virus as the primary target being explored. AstraZeneca is aiming for clinical evaluation in July-September 2020.

Vanderbilt University Medical Center, with partners

SAB Biotherapeutics

  • SAB-185 is a transgenic cow-derived human polyclonal antibody therapy that is more consistent and easier to scale up than convalescent plasma.  SAB immunizes the cows every 28 days, and plasma can be collected from each animal three times a month for a monthly total of about 35-45 L. A clinical candidate may be ready as early as Summer 2020.

Yumab, with partners

  • Using antibody libraries, Yumab and its Corona Antibody Team (CORAT) partners have identified human monoclonal antibodies with neutralizing activity against patient-derived coronavirus. CORAT is a consortium of academic and industrial organizations. Initiation of clinical studies is anticipated in H2 2020.
  • YUMAB has also identified neutralizing human anti-SARS-CoV-2 antibodies as part of a partnership with Boehringer Ingelheim. Clinical study of a product candidate may be initiated by Fall 2020.

Brii Biosciences, with partners  

  • Brii Bioscience is using its expertise in infectious diseases to develop highly potent, neutralizing antibodies from convalesced patients that were identified by researchers at Tsinghua University, and 3rd People’s Hospital of Shenzhen. First-in-human clinical trials are planned for Q3 2020.

Molecular Partners

  • Molecular Partners is developing a trispecific designed ankyrin repeat protein (DARPin®) that  targets 3 parts of the spike protein of virus. Half-life extension will be provided via inclusion of a DARPin® domain that binds to human serum albumin. Two candidates shown to neutralize the virus have been identified and will be evaluated in vivo studies. Molecular Partners is preparing for initiation of clinical studies in H2 2020.

Systimmune, Inc.

  • SI-F019 is composed of ACE2 fused to an immunoglobulin Fc that has been engineered to eliminate effector functions. It mimics the naturally occurring human ACE2 protein target of SARS-CoV-2, but has a bivalent architecture and extended half-life. Systimmune aims to initiate a clinical trial with study sites in the US and China by December 2020.

Neurimmune AG and Ethris GmbH

  • As part of Neurimmune’s collaboration with Ethris, Neurimmune is identifying human anti-SARS-CoV-2 antibodies from B cells of recovered COVID-19 patients using its Reverse Translational Medicine platform. Using Ethris’ novel nucleic acid therapy platform, potent neutralizing antibodies will be translated into therapeutic SNIM®RNA product candidates for inhalation. The companies anticipate that the first product candidate may begin clinical testing in Q4 2020.

Upcoming in “Coronavirus in the crosshairs”

The Antibody Society’s ongoing collaboration with the Chinese Antibody Society is designed to provide data, analysis and commentary relating to COVID-19 interventions to the scientific community. We will continue to track and report on the progress of these and other anti-SARS-CoV-2 interventions. In addition, future installments of the series will discuss challenges of antibody manufacturing and vaccine development.

The following people contributed content included in this installment of “Coronavirus in the crosshairs” :

  • Janice M. Reichert (The Antibody Society)
  • Cong Yao (Chinese Antibody Society)
  • Zhidan Tu (Chinese Antibody Society)
  • Lei Huang (Chinese Antibody Society)
  • Liang Siwu (Chinese Antibody Society)
  • Yanhua Xu (Chinese Antibody Society)

References

  1. Kaplon H & Reichert JM. Antibodies to watch in 2019. mAbs;11:219-238 (2019). doi: 10.1080/19420862.2018.1556465.
  2. Reichert JM & Dewitz MC. Anti-infective monoclonal antibodies: perils and promise of development. Nat. Rev. Drug Discov. 5, 191–195 (2006).
  3. Kelley B. Developing therapeutic monoclonal antibodies at pandemic pace. Nat. Biotchnol. 38; 540–545 (2020).

Coronavirus in the crosshairs, Part 8: FDA’s Emergency Use Authorization of Therapeutics

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During public health emergencies, the U.S. Food and Drug Administration (FDA) can allow use of unapproved medical products or unapproved uses of approved medical products to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by threat agents, such as SARS-CoV-2, when there are no adequate, approved, and available alternatives. On March 27, 2020, the Secretary of the Department of Health and Human Services declared that circumstances exist justifying the authorization of emergency use of drugs and biologics during the COVID-19 outbreak, which gave FDA the authority to issue Emergency Use Authorizations (EUA).

It is important to note that FDA’s allowance of an emergency investigational new drug application or compassionate use of a COVID-19 intervention is not equivalent to FDA issuing an EUA, and EUA issuance is not equivalent to FDA approval.

Letters of authorization issued for therapeutics

To date (May 12, 2020), although over 90 EUAs have been issued for diagnostic tests of various types, only 3 EUAs have been issued for therapeutics:

  • Fresenius Propoven 2% emulsion to maintain sedation via continuous infusion in patients greater than 16 years old who require mechanical ventilation in an Intensive Care Unit setting during the COVID-19 pandemic. The EUA was issued to Fresenius Kabi USA, LLC on May 8, 2020.
  • Remdesivir to treat adults and children with suspected or laboratory confirmed COVID-19 and severe disease defined as SpO2 ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation. The EUA was issued to Gilead Sciences, Inc. on May 1, 2020.
  • Chloroquine phosphate and hydroxychloroquine sulfate supplied from the Strategic National Stockpile for treatment of COVID-19. The EUA was issued to the Biomedical Advanced Research and Development Authority on March 28, 2020.

Limitations to the scope and duration of the authorizations, as well as specific conditions that apply, are detailed in FDA’s letters of authorization.

Possible biologic candidates for EUAs in 2020

Infection with SARS-CoV-2 leads to multiple pathologies, including inflammation, respiratory distress and abnormal coagulation.  Existing biological therapies that might ameliorate symptoms, such as monoclonal antibodies (mAbs) that target inflammatory cytokines and proteins involved in clotting, have thus been re-purposed as possible COVID-19 interventions.

Although FDA has not yet issued an EUA for a biologic COVID-19 therapeutic, numerous candidates are in late-stage clinical studies that might yield results that warrant such an authorization in 2020. Of these, 5 (Sarilumab, Emapalumab, Tocilizumab, Siltuximab and Ravulizumab) are already approved as treatments for other diseases, and thus may be available for broad distribution if the sponsoring company chooses to pursue an EUA for COVID-19 and FDA issues the authorization. The logistics of large-scale manufacturing and broad distribution of other candidates may be challenging for the sponsoring companies.

Details of 10 possible biologic candidates for EUAs in 2020 are listed here in chronological order according to the estimated primary completion dates of the relevant studies:

July – August 2020

  • Sarilumab (Kevara®; Sanofi, Regeneron), a human IgG1 mAb targeting the interleukin-6 receptor (IL-6R), is approved for rheumatoid arthritis in adults. Sanofi and Regeneron are sponsoring an adaptive Phase 3, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of sarilumab for hospitalized patients with COVID-19 (NCT04327388). The primary outcome measure of the study is time to improvement of 2 points in clinical status assessment from baseline to Day 29 using the 7-point ordinal scale, and the estimated primary completion date is July 2020.
  • Emapalumab (Gamifant®; Swedish Orphan Biovitrum) is a human IgG1 mAb targeting interferon gamma  approved for treatment of pediatric (newborn and older) and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance to conventional HLH therapy. Sponsored by Swedish Orphan Biovitrum, NCT04324021 is a Phase 2/3, randomized, open-label, parallel group, 3-arm, multicenter study investigating the efficacy and safety of intravenous administrations of emapalumab and anakinra (IL-1R antagonist) versus standard of care in reducing hyper-inflammation and respiratory distress in patients with SARS-CoV-2 infection. The primary outcome measure is treatment success, defined as the proportion of patients not requiring invasive mechanical ventilation or extracorporeal membrane oxygenation, up to Day 15. The estimated primary completion date of this study is July 2020.
  • Tocilizumab (Actemra®; Hoffmann-LaRoche), a humanized IG1 mAb targeting IL-6R, is approved for rheumatoid arthritis in adults, juvenile rheumatoid arthritis, as well as treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome in patients two years of age and older. Clinicaltrials.gov currently lists 42 studies of tocilizumab in COVID-19 patients, with 12 of these Phase 3 studies. Only one Phase 3 study sponsored by the drug’s co-developer, Hoffmann-LaRoche, is now recruiting patients. The NCT04320615 Phase 3 study is evaluating the safety and efficacy of tocilizumab in patients with severe COVID-19 pneumonia. The primary outcome measure is clinical status assessed using a 7-category ordinal scale, and the estimated primary completion date of this study is August 31, 2020.

September – October 2020

  • Lenzilumab (Humanigen, Inc.) is a Humaneered® mAb targeting granulocyte-macrophage colony-stimulating factor. Humanigen, Inc. is sponsoring the NCT04351152 Phase 3 randomized, placebo-controlled study of lenzilumab in hospitalized patients with COVID-19 pneumonia. The primary outcome measure is the incidence of invasive mechanical ventilation and/or mortality up to 28 days. the estimated primary completion date of this study is September 2020.
  • Siltuximab (SYLVANT®; EUSA Pharma, BeiGene, Ltd.) is an anti-Il-6 chimeric IgG1 mAb marketed for treatment of patients with multicentric Castleman’s disease. University Hospital, Ghent is sponsoring the NCT04330638 Phase 3 study  evaluating siltuximab, anakinra and tocilizumab in improving oxygenation and the short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure and systemic cytokine release syndrome. The primary outcome measure is time to clinical improvement evaluated up to Day 15. The estimated primary completion date of this study is September 2020. Preliminary results of a compassionate-use program (SISCO study; NCT04322188) sponsored by the Papa Giovanni XXIII Hospital have been reported. EUSA Pharma has exclusive rights to SYLVANT® globally. EUSA Pharma has granted BeiGene, Ltd., exclusive development and commercialization rights to SYLVANT® in Greater China.
  • Olokizumab and RPH-104 (R-Pharm International, LLC, Cromos Pharma) are being evaluated in a Phase 2/3 study of COVID-19 patients. Olokizumab is a humanized anti-Il-6 mAb and RPH-104 is a fusion protein that selectively binds and inactivates IL-1ß. R-Pharm International is sponsoring the NCT04380519 international, multicenter, randomized, double-blind, adaptive placebo-controlled study of the efficacy and safety of a single administration of olokizumab and RPH-104 with standard therapy in patients with severe SARS-CoV-2 infection. The primary outcome measure is the proportion of patients that responded to the study therapy in each of the treatment groups at Day 15. The estimated primary completion date of this study is October 15, 2020.
  • IFX-1 (InflaRx GmbH) is an IgG4 mAb targeting complement 5a, which is a component of the complement system that can trigger inflammation. InflaRx GmbH is sponsoring a pragmatic adaptive open label, randomized Phase 2/3 multicenter study of IFX-1 in patients with severe COVID-19 pneumonia (NCT04333420). The primary outcome measure is the relative change (%) from baseline in Oxygenation Index (PaO2 / FiO2) to Day 5. The estimated primary completion date of this study is October 31, 2020.

November – December 2020

  • Ravulizumab (ULTOMIRIS®, Alexion Pharmaceuticals) is a humanized IgG2/4 mAb targeting C5 that is approved for treatment of adult patients with paroxysmal nocturnal hemoglobinuria. Due to start in May 2020, NCT04369469 is a Phase 3 open-label, randomized, controlled study to evaluate the efficacy and safety of intravenously administered ravulizumab compared with best supportive care in patients with COVID-19 severe pneumonia, acute lung injury, or acute respiratory distress syndrome. The primary outcome measure is survival based on all-cause mortality at Day 29, and the estimated primary completion date of this study is November 2020.
  • Leronlimab (CytoDyn, Inc.) is an anti-CCR5 IgG4 mAb undergoing evaluation in two Phase 2 studies of COVID-19 patients. The NCT04343651 study to evaluate the efficacy and safety of leronlimab for mild to moderate COVID-19 and the NCT04347239 study to evaluate the efficacy and safety of leronlimab for patients with severe or critical COVID-19 have estimated primary completion dates of December 4 and December 31, 2020, respectively. Based on results from 10 critical COVID-19 patients who received leronlimab, disrupting the CCL5-CCR5 axis leads to rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia.

Biologic candidates targeting SARS-CoV-2

In addition to re-purposing existing biologics for use as treatments for the symptoms of COVID-19, the global biopharmaceutical industry, as well as government, academic and non-profit organizations, are developing therapies that target SARS-CoV-2. Of the biologic candidates that target the virus, the ones most likely to be considered for EUAs in 2020 are those composed of plasma from convalescent patients. SARS-CoV-2- neutralizing antibodies in the plasma are expected to protect patients, and potentially uninfected people such as medical personnel, from the effects of the virus.

The plasma-based products could serve as a critical component of medical care until recombinant anti-viral biologics are available. The first recombinant anti-SARS-CoV-2 antibodies are expected to enter clinical study as early as June 2020. The Antibody Society, in partnership with the Chinese Antibody Society, is maintaining a list of ~60 recombinant biologics that target SARS-CoV-2, including antibodies, a DARPin®, and fusion proteins. We will report on the progress of these candidates in upcoming installments of “Coronavirus in the crosshairs”.

Coronavirus in the crosshairs, Part 4: Antibody therapeutics

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The Antibody Society’s series “Coronavirus in the crosshairs” examines the ongoing discovery and development of COVID-19 interventions for broad use, including small molecule and biologic drugs, and vaccines. Parts 1 and 2 examined re-purposed small molecule and biologic drugs and new vaccines, respectively, while Part 3 focused on COVID-19 convalescent plasma treatments in development. The specific content of the posts is prioritized based on when the interventions might be available to either patients or healthy people, including health care workers. Re-purposed small molecule and biologic drugs are likely to be available first, followed by new vaccines and drugs.

In Part 4 of the series, we provide additional details about re-purposed biologics, such as monoclonal antibodies (mAbs) that are marketed or in clinical studies for other indications, that might ameliorate COVID-19 symptoms and that are already in clinicals studies of COVID-19 patients. We also discuss anti-SARS-CoV-2 antibodies that are in preclinical development and may enter clinical study by the end of 2020.

As mentioned in Part 3, there is no current evidence from randomized controlled trials to recommend any specific anti-SARS-CoV-2 treatment for patients with suspected or confirmed SARS-CoV-2 infection. Therefore, clinical studies must be done to determine the safety and efficacy of the agents when administered to COVID-19 patients.

Re-purposed mAbs in clinical studies

To date, nearly 100 mAb therapeutics are approved and currently marketed in at least one country. A number of these products have mechanisms of action that are relevant to COVID-19, although they are not anti- SARS-CoV-2 agents. Zhou et al. have shown that SARS-CoV-2 infection leads to activation of CD4+ T lymphocytes, which become pathogenic T helper (Th) 1 cells and generate cytokines such as Granulocyte-macrophage colony-stimulating factor, GM-CSF. This environment induces CD14+CD16+ monocytes with high expression of IL-6, which accelerates inflammation. Moreover, Chen et al. reported that IL-6 levels were significantly elevated in critically ill COVID-19 patients, and the extremely high IL-6 level was closely correlated with the incidence of RNAemia. Taken together, these results suggest that mAbs targeting interleukin 6 receptor (IL-6R), IL-6 or GM-CSF, may potentially limit SARS-CoV-2-related immunopathology, and thereby provide more time for anti-viral agents to work.

Anti-IL-6R mAbs tocilizumab (Actemra®) and sarilumab (Kevara®).

Tocilizumab was first approved in Japan in 2005, and it is currently marketed for rheumatoid arthritis in adults, juvenile rheumatoid arthritis, as well as treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome (CRS) in patients two years of age and older. Since severe or life-threatening cytokine release is part of the pathology of COVID-19, tocilizumab may help ameliorate symptoms of the disease. As listed on clinicaltrials.gov on March 27, 2020, 3 clinical studies of tocilizumab are recruiting COVID-19 patients and 2 additional studies are not yet recruiting patients:

  • Started on February 20, 2020, NCT04306705 is a retrospective study evaluating safety and efficacy of tocilizumab compared to continuous renal replacement therapy in controlling CRS triggered by COVID-19. The study site is Tongji Hospital, Wuhan, Hubei, China. The estimated enrollment is 120 patients and the estimated primary completion date is May 30, 2020.
  • Started on March 8, 2020, NCT04310228 is multicenter, randomized and controlled clinical trial evaluating favipiravir combined with tocilizumab in the treatment of COVID-19. The study sites are in China. The estimated enrollment is 150 patients and the estimated primary completion date is in May 2020.
  • Started on March 19, 2020, NCT04317092 is a Phase 2 study of tocilizumab in COVID-19 pneumonia. The study sites are in Italy. The estimated enrollment is 330 patients and the estimated primary completion date is in December 2020.
  • Due to start in March, NCT04315480 is a Phase 2 study of tocilizumab (RoActemra) as early treatment of patients affected by SARS-CoV2 infection with severe multifocal interstitial pneumonia. Patients will receive a single intravenous administration of 8 mg/kg tocilizumab. The study site is in Italy. The estimated enrollment is 30 patients and the estimated primary completion date is April 2020.
  • Due to start on April 3, 2020, NCT04320615 is a Phase 3 study randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and efficacy of tocilizumab in patients with severe COVID-19 pneumonia. The study sites are not yet listed. The estimated enrollment is 330 patients and the estimated primary completion date is August 31, 2021.

Sarilumab was first approved in the US in 2017, and it is currently marketed for rheumatoid arthritis in adults. As of March 27, 2020, one clinical trial of sarilumab in COVID-19 that is recruiting patients is listed on clinicaltrials.gov and 2 studies are listed as not yet recruiting:

  • Started on March 16, 2020, the Phase 2/3 NCT04315298 study is evaluating the efficacy and safety of sarilumab in hospitalized patients with COVID-19. The study site is in New York City. The estimated enrollment is 400 patients and the estimated primary completion date is March 2021.
  • Due to start in March 2020, the NCT04321993 Phase 2 study will evaluate sarilumab or small molecules as treatment of moderate to severe COVID-19 in hospitalized patients. The study includes 4 arms: 1) Lopinavir/ritonavir; 2) Hydroxychloroquine sulfate; 3) Baricitinib; and 4) Sarilumab (200 mg subcutaneous injection once). The study sites are not yet listed; the study sponsors are based in Canada. The estimated enrollment is 1000 patients and the estimated primary completion date is February 2021.
  • Due to start March 26, 2020, the Phase 2/3 NCT04324073 study will assess an intravenous dose of 400 mg of sarilumab in a 1 hour-infusion vs the best standard of care. The study site is in Paris, France. The estimated enrollment is 180 patients and the estimated primary completion date is March 2021.

In addition, tocilizumab and sarilumab will be tested head-to-head in a Phase 2 study in COVID-19 patients that is not yet recruiting.

  • Due to start on March 25, 2020, NCT04322773 is a an open-label, multicenter sequential and cluster randomized Phase 2 study of the effectiveness of interleukin-6 receptor inhibitors in the management of patients with severe SARS-CoV-2 pneumonia. The study has 3 arms: 1) single dose treatment with tocilizumab 400 mg intravenously; 2) single dose treatment with tocilizumab 2 x 162 mg subcutaneously; and 3) single dose treatment with sarilumab 1 x 200 mg subcutaneously. The study site is in Copenhagen, Denmark. The estimated enrollment is 200 patients and the estimated primary completion date is June 1, 2021.

Anti-IL-6 siltuximab (SYLVANT®)

Siltuximab was first approved in the US in 2014, and it is currently marketed for treatment of patients with multicentric Castleman’s disease. As of March 27, 2020, one clinical trial of siltuximab in COVID-19 is listed on clinicaltrials.gov:

Started on March 19, 2020, NCT04322188 is an observational case-control study of the use of siltuximab in patients diagnosed with COVID-19 infection who have developed serious respiratory complications. Patients in Cohort A and Cohort B are treated with siltuximab in a non-ICU and ICU setting, respectively. Each patient will have a matched control receiving standard treatment without siltuximab. The study site is in Italy. The estimated enrollment is 50 patients and the estimated primary completion date is May 19, 2020.

Anti-GM-CSF mAbs

No anti-GM-CSF mAbs have been approved, but 7 investigational mAbs with potentially relevant mechanisms of action are in clinical studies. Five target GM-CSF (TJ003234, Gimsilumab, Lenzilumab, Otilimab and Namilumab), 1 targets the GM-CSF receptor (Mavrilimumab) and 1 targets beta common receptor for GM-CSF, IL-3, IL-5 (CSL311). To date, companies developing TJ003234, Gimsilumab, and Lenzilumab have indicated that they plan on starting clinical studies of COVID-19 patients.

  • On March 13, 2020, I-Mab Biopharma announced that it is initiating the development of TJM2 (TJ003234) to treat cytokine storm associated with severe and critical illness caused by COVID-19. Discovered by I-Mab, TJM2’s development will start following the FDA’s acceptance of I-Mab’s Investigational New Drug application. Study sites will initially be in the US, with possible expansion into other hardest-hit countries. TJM2 was previously evaluated in a Phase 1 study of healthy adults.
  • On March 18, 2020, Roivant Sciences announced that it has engaged with regulators in the United States, Europe, and Asia to rapidly advance the clinical development of gimsilumab for the treatment of acute respiratory distress syndrome associated with SARS-CoV-2 infection. Gimsilumab has been tested two clinical studies, including a 4-week Phase 1 study of a subcutaneous formulation in healthy volunteers.
  • On March 27, 2020, Humanigen, Inc., announced that the company has submitted an initial protocol synopsis to the FDA in support of the company’s plans to initiate a multi-center, US, Phase 3 study in COVID-19 patients. Humanigen has already conducted two Phase 1 and two Phase 2 studies, including in patients with severe respiratory conditions.

Novel anti-SARS-CoV-2 antibodies in preclinical development

Numerous organizations and groups have announced plans or progress in developing anti-SARS-CoV-2 antibody therapeutics. The race will go to the swift, in this case organizations that are:

  • Already experienced in anti-infective antibody discovery;
  • Adept at antibody design, engineering and selection;
  • Able to manufacture antibodies; and
  • Experienced in regulatory affairs.

If any of these elements are missing, then the organization must be able to quickly contract the work or engage a collaborator or partner with the missing expertise.

It must be noted, however, that a single product is unlikely to meet the currently very substantial medical need, and not all product candidates will be successful in clinical studies. Therefore, many initiatives aimed at developing investigational antibodies are needed.

The development of anti-SARS-CoV-2 antibody therapeutics involves the following major steps:

  • Initiation of the discovery process using, e.g., transgenic mouse, display technology or human B cell from COVID-19 patient;
  • Identification and characterization of suitable antibodies via in vitro methods;
  • Non-clinical assessment via in vivo methods;
  • Manufacturing of material suitable for administration to humans;
  • Demonstration of safety and efficacy in humans.

Due to the severity of the pandemic, the pace of the process, which typically is quite slow, has been substantially accelerated.

As of March 27, 2020, early progress on multiple anti-SARS-CoV-2 antibody discovery programs had already been announced. For example:

  • Shanghai Junshi Biosciences Ltd. and the Institute of Microbiology of the Chinese Academy of Sciences are developing neutralizing antibodies derived from patients who recovered from COVID-19 as a potential treatment for COVID-19. The program will progress to clinical trials soon. According to a March 24, 2020 announcement, they have obtained neutralizing antibodies that can effectively block viral invasion in laboratory assays, conducted animal experiments, and are now verifying the preclinical toxicology and in vivo activity of the antibodies. An investigational new drug application, needed to initiate clinical studies, is in preparation.
  • Mabpharm Limited has generated a mAb-based fusion protein (CMAB020, STI-4920, ACE-MAB) that binds to the spike protein of the SARS-CoV-2 virus. Designed as a bispecific molecule, ACE-MAB has two functional arms: 1) a human antibody that targets the spike protein of SARS-CoV-2 with high affinity and 2) a truncated ACE2 protein that binds to a different epitope of the spike protein. ACE-MAB is in the cGMP cell line development stage by Mabpharm Limited, and could be ready for large-scale production for human clinical trials and commercialization upon receipt of requisite regulatory approvals. Mabpharma and Sorrento Therapeutics, Inc. have partnered in the development of ACE-MAB.
  • Vir Biotechnology, Inc., working with partners Xencor, Biogen and WuXi, has identified multiple human monoclonal antibody (mAb) development candidates that neutralize SARS-CoV-2. Two candidates will progress into human testing as soon as possible, with Phase 1/2 clinical testing planned for summer 2020.
  • Regeneron Pharmaceuticals has isolated virus-neutralizing, human antibodies from transgenic VelocImmune® mice, and antibodies from COVID-19 patients. From this large pool of candidates, Regeneron will select the top two antibodies for a ‘cocktail’ treatment based on potency and binding ability to the SARS-CoV-2 spike protein, as well as other desirable qualities. Regeneron aims to have an anti-SARS-CoV-2 antibody treatment ready for human testing by early summer.
  • James Crowe, MD, director of the Vanderbilt Vaccine Center announced that Vanderbilt University Medical Center, in collaboration with academic, governmental and corporate partners already have discovered SARS-CoV-2 antibodies. The collaborators aim to have antibodies for human clinical trials by summer 2020.
  • Distributed Bio has identified thousands of anti-SARS-CoV-19 antibodies, and their scientists are currently working on  engineering, selection, screening and production of candidates.
  • Specifica has used its Generation 3 platform to select hundreds of antibodies against the SARS-CoV-2 spike protein, which are undergoing testing for neutralization.
  • YUMAB has identified antibodies that were proven to inhibit infection and lyse of live cells, and plans to initiate clinical studies after regulatory permission has been granted.
  • AbCellera has identified over 500 unique human antibody sequences derived from the immune cells of COVID-19 patients. AbCellera and Eli Lilly and Company have partnered to co-develop antibody products for the treatment and prevention of COVID-19.
  • Celltrion has identified a library of antibodies sourced from the blood of recovered COVID-19 patients in Korea. These antibodies are undergoing further screening to identify those that are most effective in neutralizing SARS-CoV-2. Selected candidates will form the basis of anti-viral treatment to be tested in preclinical and clinical trials in the third quarter of 2020. Celltrion also plans to develop a ‘super antibody’ that can attach and neutralize all kinds of coronavirus-related strains, enabling further protection against unforeseen or unexpected mutations.
  • Utrecht University, Erasmus Medical Center and Harbor BioMed have developed a human antibody, 47D11, that targets the a conserved epitope on the viral spike receptor binding domain and can inhibit SARS-CoV-2. Data show that 47D11 neutralizes SARS-CoV and SARS-CoV-2 through a yet unknown mechanism that is different from receptor binding interference.
  • The lab of Xavier Saelens (VIB-UGent Center for Medical Biotechnology), in cooperation with the labs of Jason McLellan (University of Texas at Austin, US) and Markus Hoffmann and Stefan Pöhlmann (German Primate Center – Leibniz Institute for Primate Research, Göttingen, Germany) have discovered a unique antibody that is capable of binding SARS-CoV-2 and neutralizing a lab variant of the virus.

Other groups are also working on discovery initiatives. For example, the international research Corona Antibody Team, which includes the Technical University Braunschweig and European colleagues, is developing antibody-based therapies that target SARS-CoV-2. Details about additional biopharmaceutical product candidates in development for COVID-19 may be found here.

The Antibody Society will continue to monitor anti-SARS-CoV-2 antibody development, and report on progress with these and other COVID-19 interventions in the next installment of “Conronavirus in the crosshairs”.

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Coronavirus in the crosshairs, Part 3: Antibodies from human plasma

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Antibodies have extraordinary potential as agents for the treatment of COVID-19 or possible prevention of infection by SARS-CoV-2, the coronavirus that causes the disease. Anti-SARS-CoV-2 antibodies can neutralize the virus, and antibodies that target inflammatory factors such as cytokines can ameliorate symptoms of COVID-19.

The Antibody Society’s series “Coronavirus in the crosshairs” examines the discovery and development of all types of interventions for COVID-19.  In Part 3 of the series, we focus on the use of natural antibodies, i.e., anti-SARS-CoV-2 polyclonal antibodies found in convalescent plasma, in treating COVID-19. In the current emergency when time is of the essence, medical professionals are applying the century-old knowledge that antibody-rich plasma derived from blood donated by people who have recovered from a disease may aid other patients. The efficacy of convalescent plasma was studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic. [1, and references therein]

There is, however, no current evidence from randomized controlled trials to recommend any specific anti-SARS-CoV-2 treatment for patients with suspected or confirmed SARS-CoV-2 infection.[2] Anti-SARS-CoV-2 blood products are thus considered investigational drugs that require clinical study and approval by regulatory agencies before they can be administered broadly to treat COVID-19 patients or potentially prevent disease in healthy people, such as health care workers.

FDA response to the need for COVID-19 convalescent plasma

To address the short-term need for treatments, the US Food and Drug Administration (FDA) is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through emergency Investigational New Drug Applications that will enable administration to a single patient. Highly time sensitive requests will receive a response from FDA within 4 to 8 hours.[3]

In the longer-term, FDA is working with other agencies, such as the National Institutes of Health and the Centers for Disease Control and Prevention, to develop master protocols for use by multiple investigators in order to coordinate the collection and use of COVID-19 convalescent plasma.[3]

Ongoing clinical studies of convalescent plasma

Medical professionals in countries greatly affected by COVID-19, such as China and Italy, are evaluating plasma-based treatments for COVID-19. Clinicaltrials.gov lists several clinical studies evaluating the use of convalescent plasma:

  • NCT04292340. In this observational study recruiting patients at the Shanghai Public Health Clinical Center, the investigators collected the clinical information and clinical outcomes of the COVID-19 patients using anti-2019-nCoV inactivated convalescent plasma. The study objective is to evaluate the efficacy and safety of anti-2019-nCoV inactivated convalescent plasma in the treatment of COVID-19 pneumonia. Primary outcome measures are the virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 1, 3 and 7, and the patient outcome at 4 weeks. The actual study start date is February 1, 2020 and the estimated primary completion date is July 31, 2020.
  • NCT04321421. In this study being conducted in Italy, 49 participants are administered plasma from donors recovered from COVID-19 as therapy at day 1 and, based on clinical response, on day 3 and 5., The dose, 250-300 mL of convalescent plasma, was selected based on published literature for this type of therapy. The primary outcome measure is death from any cause within 7 days. The actual study start date is March 17, 2020 and the estimated primary completion date is May 31, 2020.

Similar trials are listed on the Chinese clinical trials registry, e.g.,

  • ChiCTR2000030841, Exploratory study for immunoglobulin from cured COVID-19 patients in the treatment of acute severe novel coronavirus (COVID-19); study registered March 15, 2020.
  • ChiCTR2000030929, A randomized, double-blind, parallel-controlled trial to evaluate the efficacy and safety of anti-SARS-CoV-2 virus inactivated plasma in the treatment of severe novel coronavirus pneumonia (COVID-19); study registered March 17, 2020.

New plasma-derived COVID-10 product candidates in development

On March 4, 2020, Takeda Pharmaceutical Company Limited announced that they are initiating development of an anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG) to treat high-risk individuals with COVID-19. Referred to as TAK-888, Takeda plans initially to produce the plasma-derived anti-SARS-CoV-2 polyclonal H-IG in a segregated area within its manufacturing facility in Georgia.

On March 11, 2020, Emergent BioSolutions Inc. announced that it has initiated development of two product candidates for the treatment and prevention of coronavirus disease (COVID-19). COVID-HIG, manufactured from human plasma with antibodies to SARS-CoV-2, will be developed as a potential treatment for severe hospitalized patients as well as protection for at-risk individuals. In parallel, COVID-EIG, manufactured from plasma of immunized horses with antibodies to SARS-CoV-2, will be developed as a potential treatment for severe hospitalized patients. Emergent has initiated plasma collection efforts for both human and equine platforms with a goal of manufacturing clinical material within the next four to five months in anticipation of beginning a clinical study as early as the third quarter of 2020.

Upcoming “Coronavirus in the crosshairs” posts

In Part 4 of “Coronavirus in the crosshairs”, we will discuss recombinant antibodies that may ameliorate symptoms of COVID-19, and examine ongoing efforts to discover and develop recombinant anti-SARS-CoV-2 antibodies.

1. Chen et al. Convalescent plasma as a potential therapy for COVID-19. The Lancet. February 27, 2020. DOI:https://doi.org/10.1016/S1473-3099(20)30141-9
2. World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected. Interim guidance. 28 January 2020.
3. US Food and Drug Administration. Investigational COVID-19 Convalescent Plasma – Emergency INDs. March 24, 2020.

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FDA issues guidance on conducting clinical trials during the COVID-19 pandemic

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In these challenging times, the biopharmaceutical industry, government agencies, as well as academic and non-profit organizations, are working toward the development of antibody therapeutics and vaccines for the treatment and prevention of infection by SARS-CoV-2, the virus that causes COVID-19. The Antibody Society is currently compiling information on these efforts, which will soon be posted on our website and distributed via email to our members. Many existing antiviral treatments are also being re-purposed in the fight against the virus.

The Society is an authoritative source of information on antibody therapeutics in the clinical pipeline. The COVID-19 pandemic, however, may delay ongoing clinical studies that are evaluating the safety and efficacy of therapeutics for other diseases. In a March 18, 2020 press release, the U.S. Food and Drug Administration (FDA) notes that challenges may arise from quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, or other considerations if site personnel or trial subjects become infected with SARS-CoV-2. These challenges may lead to difficulties in conducting the clinical trials. Protocol modifications may be required, and there may be unavoidable protocol deviations due to COVID-19.

Information about FDA’s guidance for industry, investigators and institutional review boards conducting clinical trials during the coronavirus (COVID-19) pandemic can be found here.

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