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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.

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.

Photo by Fusion Medical Animation on Unsplash

FDA approves isatuximab-irfc for multiple myeloma

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On March 2, 2020, the U.S. Food and Drug Administration (FDA) approved Sarclisa (isatuximab-irfc), in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. FDA granted isatuximab Orphan Drug designation for multiple myeloma. Developed by Sanofi, isatuximab (SAR650984) is a chimeric IgG1 antibody directed against CD38 expressed on malignant plasma cells. The antibody acts through a combination of mechanisms, which may depend on the expression level of the target.

The approval was based on the results of the Phase 3 ICARIA-MM study (NCT02990338) demonstrating a statistically significant improvement in progression-free survival (PFS). This study included 307 patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. Patients who received Sarclisa in combination with pomalidomide and low-dose dexamethasone showed improvement in PFS, with a 40% reduction in the risk of disease progression or death compared to patients who received pomalidomide and dexamethasone. These patients also had an overall response rate of 60.4%. Patients who only received pomalidomide and low-dose dexamethasone had an overall response rate of 35.3%.

The European Medicines Agency is currently evaluating a marketing authorization application for isatuximab for the treatment of relapsed/refractory multiple myeloma.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format. Information about other antibody therapeutics that may enter regulatory review in 2020 can be found in ‘Antibodies to watch in 2020’.

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