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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).

NIH seeks community input on research approaches and priorities related to SARS-CoV-2 serology

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The National Cancer Institute (NCI) in partnership with the National Institute of Allergy and Infectious Disease is seeking community input on research approaches and priorities related to SARS-CoV-2 serology. In this Request for Information,  NCI seeks comments on any or all of, but not limited to, the following research topics related to serology:

1. Research about the relationship between immunity, recent infection, antibody production, and other immunological markers, including:

  • The role and value of animal models and in vitro assays for determining the relationship between antibody production and immunity to SARS-CoV-2.
  • The types and titers of antibodies that are important for immune protection and the mechanism of such protection.
  • Whether cross-reacting antibodies from prior infection by other coronaviruses confer immunity.
  • Whether antibodies to coronaviridae can cause immunopathogenesis (e.g. ADE).
  • Genetic or other host factors that could predict antibody production and innate or adaptive immunity.
  • Specific virologic factors that mediate the generation of effective host immunity, especially humoral immunity vs. cell-mediated immunity.

2. Clinical utilization of serological testing, including:

  • Design strategies for use in clinical trials and population-based observational studies that are optimal to address the most critical research questions, including biospecimen sampling/biobanking considerations as well as safety and ethical considerations.
  • Characteristics and performance standards needed for serological testing, whether for seroprevalence surveys or point-of-care tests.
  • Approaches to rapidly increase capacity for high-quality serology testing in United States, by leveraging existing infrastructure, especially for underserved communities.
  • How to use and interpret serological testing results safely, effectively, and equitably.

NCI is also specifically interested in the link to cancer across all of these areas, including but not limited to the characteristics of the immune response in patients undergoing treatment and cancer survivors; prediction of susceptibility to infection and outcomes in cancer patients; seroepidemiology in cancer patients.

Your comments could include any of the following:

  • Research approaches for these topics;
  • Innovative strategies to advance research progress;
  • Challenges to progress in these areas;
  • Emerging trends, advances, technologies, analytic strategies, and perspectives that NCI should consider in this planning process;
  • Potential approaches to gauge research progress and success.

Please comment on any other topic that you find relevant. Responses to the notice are due on May 26, 2020. 

NCI has posted a Notice of Intent to Publish a Funding Opportunity Announcement for components of the new Serological Sciences Network on May 15. The RFA is expected to be announced in June with expected application due dates in July. Awards are anticipated to be made in September 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”.

FDA approves sacituzumab govitecan (Trodelvy®) for triple-negative breast cancer

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On April 22, 2020, the US Food and Drug Administration (FDA) granted an accelerated approval to Trodelvy® (sacituzumab govitecan-hziy) for the treatment of patients with metastatic triple-negative breast cancer who received at least two prior treatments for metastatic disease. Sacituzumab govitecan is composed of an anti-TROP-2 humanized IgG1 antibody conjugated to the topoisomerase inhibitor SN38, which is the active metabolite of irinotecan.

The approval was based on the results of a clinical trial of 108 patients with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease. In this study, the overall response rate was 33.3%, with a median duration of response of 7.7 months. Of the patients who responded to treatment, 55.6% maintained their response for 6 or more months and 16.7% maintained their response for 12 or more months.

The accelerated approval program allows FDA to approve drugs for serious conditions to fill an unmet medical need based on a surrogate endpoint, i.e., a result that is reasonably likely to predict a clinical benefit to patients. Additional clinical trials are required to confirm Trodelvy’s clinical benefit, and the FDA can remove the drug from the market if the confirmatory trial does not show that the drug provides clinical benefit.

Antibodies to watch in 2020: Will the pandemic cause delays?

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As regulatory agencies tasked with evaluating and monitoring the development of medicines, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have pivotal roles in the global response to the COVID-19 pandemic. However, these critical activities have been added to an already substantial workload. FDA and EMA are continuing the ongoing marketing application reviews for drugs that are not COVID-19 interventions, and they will need to process new applications submitted throughout 2020. FDA and EMA’s distribution of work is particularly relevant to new antibody therapeutics because a substantial number of license applications for these drugs, none of which relate to COVID-19, are undergoing FDA or EMA review. In a recent statement, FDA offered assurances that their application review teams are focused on their work, but noted that they may not be able to sustain the current level of performance indefinitely.

In total, biologics license applications (BLAs) for 14 new antibody therapeutics (i.e., not previously approved by any agency for any indication) are undergoing FDA review. EMA is reviewing marketing authorization applications (MAAs) for 4 of these 14 antibody therapeutics, and MAAs for 4 antibody therapeutics that are already approved in the US.

New antibody therapeutics undergoing FDA review

The 14 antibody therapeutics undergoing FDA review are treatments for a variety of diseases, including numerous cancers, neuromyelitis optica spectrum disorders, osteoarthritis pain, diabetes, thrombotic microangiopathies, Ebola and HIV infection. The drugs for cancer are:

  • Sacituzumab govitecan, anti-TROP-2 humanized IgG1 antibody-drug conjugate for triple-neg. breast cancer
  • Belantamab mafodotin, anti-B-cell maturation antigen humanized IgG1 antibody-drug conjugate for multiple myeloma
  • Tafasitamab, anti-CD19 humanized IgG1 for diffuse large B-cell lymphoma
  • Naxitamab, anti-GD2 humanized IgG1 for high-risk neuroblastoma and refractory osteomedullary disease
  • Oportuzumab monatox, anti-EpCAM humanized scFv immunotoxin for bladder cancer
  • Margetuximab, anti-HER2 chimeric IgG1 for HER2-positive metastatic breast cancer
  • Dostarlimab, anti-PD-1 humanized IgG4 for endometrial cancer

The drugs for non-cancer indications are:

  • Inebilizumab, anti-CD19 humanized IgG1 for neuromyelitis optica and neuromyelitis optica spectrum disorders
  • Satralizumab, anti-IL-6R humanized IgG2 for neuromyelitis optica spectrum disorders
  • Tanezumab, anti-nerve growth factor humanized IgG2 for pain due to osteoarthritis of the knee or hip
  • Teplizumab, anti-CD3 humanized IgG1 for type 1 diabetes
  • Narsoplimab, anti-MASP-2 human IgG4 for hematopoietic stem cell transplant-associated thrombotic microangiopathies
  • Leronlimab, anti-CCR5 humanized IgG4  for HIV infection
  • REGNEB3, a mixture of 3 human IgG1 targeting the Ebola virus for Ebola disease.

A first review cycle for the BLAs for all 14 should be completed by the end of 2020. Despite the pandemic, 2020 may be a record year for new antibody therapeutics approvals (potentially 17, including the 14 discussed here and the approvals for teprotumumab-trbw (Tepezza®), eptinezumab-jjmr (Vyepti®) and isatuximab-irfc (Sarclisa®) already granted in 2020, or more).

Antibody therapeutics undergoing EMA review

Like FDA, EMA is continuing to process MAAs for antibody therapeutics despite the increase in workload due to COVID-19. EMA provides monthly updates on applications for centralized marketing authorization for human medicines that they have received for evaluation. EMA’s information as of April 6, 2020, indicates that they are evaluating MAAs for 8 antibody therapeutics that, if approved, would be new to the European Union. These 8 are Belantamab mafodotin, Dostarlimab, Satralizumab and Tanezumab, which are also being reviewed by FDA, as well as:

  • Obiltoxaximab (Anthim®), anti-B. anthrasis protective antigen chimeric IgG1 approved by FDA for prevention of inhalational anthrax in 2016
  • Emapalumab (Gamifant®), anti-IFN gamma human IgG1 approved by FDA for primary hemophagocytic lymphohistiocytosis in 2018
  • Moxetumomab pasudotox (Lumoxiti®), anti-CD22 murine IgG1 dsFv immunotoxin approved by FDA for hairy cell leukemia in 2018
  • Crizanlizumab (Adakveo®) anti-P-selectin humanized IgG2 approved by FDA for sickle cell disease in 2019

Other antibodies to watch in 2020

The COVID-19 pandemic might delay the submission of marketing applications for antibody therapeutics that are now in late-stage clinical studies. As documented by Kaplon et al. in ‘Antibodies to watch in 2020’, companies developing 5 antibody therapeutics for cancer (spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) and 5 for non-cancer indications (aducanumab, evinacumab, etrolizumab, sutimlimab, and anifrolumab) had previously announced plans to submit applications to regulatory agencies during 2020. The Antibody Society will continue to monitor the development of these product candidates and report on progress. Discussion of these antibodies can be found in the ‘Antibodies to watch in 2020’ paper.