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Designated COVID-19 Section on the B-T.CR Forum

May 17, 2020 by jpburckert

Sharing is caring. This has become a key phrase during the COVID-19 pandemic. The AIRR Community proudly announces a designated channel in our data discussion forum B-T.CR (www.b-t.cr). This public resource will list all current and upcoming studies with immune repertoire data on COVID-19.

If you happen to stumble upon AIRR-seq or single cell RNA-seq data of COVID-19 research projects, please add them to the list found here!

Filed Under: AIRR Community, Coronavirus, COVID-19 Tagged With: Adaptive Immune Receptor Repertoire Community

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

May 13, 2020 by Janice Reichert

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”.

Filed Under: Antibody therapeutic, Coronavirus, COVID-19 Tagged With: antibody therapeutics, COVID-19, Food and Drug Administration, SARS-CoV-2

Coronavirus in the crosshairs, Part 7: Diagnostic tests

April 28, 2020 by The Antibody Society

Post written by Simon L. Goodman, D.Phil.

With no foreseeable safe or effective therapy or vaccine against SARS-CoV-2, extensive population testing and quarantine are amongst the few scientifically rational means of protecting people and monitoring the pandemic.  To date (April 26, 2020) only 26.6  million tests for infection have been performed worldwide, with 3 million positives reported (1) by 129  of 195 countries.  Cases of infection were confirmed predominantly via nucleic acid amplification tests for viral RNA. Current antibody-based serological tests are qualitative, and poorly validated.  But there is little doubt that during epidemic and endemic infection, testing and obligate retesting will likely involve many 100s of millions of samples.

There are currently no validated US Food and Drug Administration (FDA)-approved diagnostic assays for SARS-CoV-2 or anti-SARS-CoV-2 antibodies in patient samples, but tests can receive  emergency use authorization (EUA) (2).  The lack of certification means that data from these tests is likely to be of lower quality than approved diagnostics, from the point of view of clinical specificity and selectivity.  However, in third-world countries, rapid point-of-care tests must become available as soon as possible.  To add to the difficulties that governments, the public, and healthcare providers face, there is an amoral escalating grey-market in dysfunctional serological home-test-kits (3).

Classes of virus tests

The coronavirus SARS-CoV-2 triggers a lethal and highly infectious disease, COVID-19, so rapid (minutes-to-hour) point-of-care tests are essential to reduce spread and establish the epidemiology of infection.  Classical laboratory culture methods, in any event necessitating rare Biosafety Level-3 facilities, are excluded. The level of anti-SARS-CoV-2 neutralizing antibodies needed for protective immunity, and the degree and duration of protective immunity developed, if any, remain unknown.  And there are no well-validated immunohistochemistry-capable anti-virus antibodies, so interstitial tissue distribution and loading remain unknown.

COVID-19 tests currently come in three classes:

1) Viral RNA amplification tests (Nucleic Acid Amplification Tests; NAAT);
2) Viral antigen tests, which are based on affinity detection methods (VADM); and
3) Serological tests, which detect any SARS-CoV-2-reactive antibodies.

Nasal, laryngeal or sputum swabs are currently accepted for tests 1) and 2), while pin-prick or venous blood is used for test 3). Swabbing is uncomfortable and exposes the sampler to virus, so a preprint suggesting detection in saliva of high viral titers by NAAT is of interest (4).

Tests 1) and 2) identify those who carry virus and may be infectious, even if asymptomatic.  Test 3) identifies people whose immune systems have responded to SARS-CoV-2 exposure, including those who may have active viremia. Only NAATs and a single VADM are quantitative at present.

A 4th class of test is currently unavailable: a commercial test that accurately detects neutralizing anti-SARS-CoV-2 antibodies, would be valuable because it could identify those likely to mount a strong response to a repeated infection.

Only a combination of such tests, including a serological test in particular, will identify the prevalence and exposure of populations to the virus.  However, as described below, current serological tests fall far below diagnostic standards (e.g., > 98% clinical selectivity; > 98% clinical specificity).  At present, only predominantly qualitative VADM and serological tests are available.  Infectivity is related to the amount of virus emitted by infected people, so routine quantitative tests might allow an accurate assessment of the progression of the pandemic.

Viral RNA detection

Automated commercial PCR and quantitative (Q-PCR) systems can rapidly detect and quantify (Q-PCR) SARS-CoV-2 RNA.  However, the high-throughput machinery and expertise needed to perform the test is generally found only in a sophisticated centralized laboratory environment.  Q-PCR laboratory-use only kits from 41 companies have received FDA EUAs, including those from:

  • Hologix (Panther Fusion SARS-CoV-2 Assay);
  • Primerdesign (COVID-19 genesig Real-Time PCR assay),
  • Thermo Fisher (TaqPath COVID-19 Combo Kit),
  • Roche (cobas SARS-CoV-2), and
  • Cepheid (Xpert Xpress SARS-CoV-2 test).

Use of central laboratory facilities leads to slow readouts (1000-20000 samples per day). In the US, 21 laboratories have independently developed SARS-CoV-2 tests that are permitted for EUA usage as high-complexity molecular-based laboratory developed tests.

An exciting development is the use of isothermal amplification (IA) methods, which need less complex machinery and can be very fast (readout in < 15 mins). On March 27, 2020, the FDA issued an EUA for an IA system, ID NOW COVID-19 (Abbott laboratories), for rapid quantitative point-of-care use in SARS-CoV-2 detection.  The system has fast sample analysis time (15 min), but low throughput.

On April 20, 2020, Baek et al. (5) reported a 15 minute, quantitative, one-tube, isothermal reverse transcription-loop-mediated isothermal amplification technique (Q-RT-LAMP) with a visual read out of phenol-red color change, possibly adaptable to microtiter plates.  This could prove valuable in those many COVID-19-plagued countries lacking ready access to Q-RT-PCR technology.

Although NAATs are state-of-the-art diagnostics for SARS-CoV-2 infection, it must be noted that “…a significant portion of patients who otherwise fit the diagnosis based on clinical and chest CT findings, including many hospitalized patients, have tested negative for viral RNA.” (italics added) (6).  This may include victims whose NAAT sinks below the limit of detection of Q-PCR after day 5 post infection (7).

Viral antigen detection

A number of companies provide point-of-care tests for viral antigen. These tests rely on SARS-CoV-2 antigen in patient samples being trapped  by antigen-targeting antibodies on a detectable mobile phase. For a few examples:

  • SD Biosensor’s lateral flow system has a well-documented limit of detection of ~2000 tissue culture infective dose / ml with 0/170 false positives specificity, but only 84% sensitivity over PCR (8) (i.e., resulting in 16% false negatives).
  • Coris BioConcept’s acute-phase screening kit uses immunochromatographic colloidal gold-based dip stick technology (analogous to capture ELISA). With a sensitivity of 5000 pfu /ml, the kit has a high positive predictive value (78-100%), but sensitivity over PCR of < 86%.  Both kits are reported to identify both SAR-CoV-2 and SAR-COV (vs other respiratory viruses and bacteria), and target conserved coronavirus nucleoprotein (9, 10).
  • Bioeasy uses time-resolved fluorescence analysis in a similar assay system, but the sensitivity and selectivity data are not reported (11).  Early phase infection was undetectable in a small sample set of urine and blood by VADM, while it could be identified in respiratory test probes (7).

The Foundation for Innovative New Diagnostics (FIND), a non-government organization, has identified some 10 (poorly validated) antigen tests marketed under the European CE label, and many tests of very dubious provenance are available on the internet.

Detecting anti-viral serological responses

Serological tests rely on detecting blood IgM and IgG antibodies, or mucus IgA and IgG, reacting with SAR-CoV-2.  The FDA has noted that owing to the urgency of the situation, they “… had not reviewed or authorized (or “approved”) … (these tests)… at least not initially, and … (they)… should not be used for diagnosing or excluding active SARS-CoV-2 infection.” (italics added).

To date (April 28, 2020), 7 serological tests from 6 companies have received EUA. These are based on:

  • Lateral flow colloidal gold capture rapid tests (Cellex; AutoBio Diagnostics; Chem-Bio Diagnostic Systems);
  • Classical plate-ELISA based on the viral S1 spike protein (Ortho-Clinical Diagnostics);
  • Dual ELISA for Covid-RBD protein + Spike protein (Mount Sinai Laboratory); or
  • Magnetic bead-based automated ELISA targeting the S1 and S2 spike proteins (DiaSorin).

Many more tests have been developed and marketed in Europe, including:

  • Immunochromatographic (Coris);
  • Lateral flow (Bioeasy; ElabScience; HighPlusTech; Senova; SD sensor; Premier/Hangzou); and
  • Classical plate-ELISA based for detection of anti-Covid-19 IgA and IgG (EuroImmun) (12).

FIND has identified over 60 CE labelled antibody tests (13).  Each provider uses immobilized recombinant SARS-CoV-2 proteins to capture antibodies from blood, which are in turn captured on, or recognized by, “anti-human-IgG” and or “anti-IgM” reagents.  As yet little detail of the validation of the reagents used in the tests has been published.  Whether any tests will ever become FDA-approved diagnostics is still an open question. The sensitivity of these tests is reportedly 1-2 logs below that of viral NAAT, and only the EuroImmun test is semi-quantitative.  For many rapid tests, the specificity and sensitivity has been challenged due to the low sample numbers, biased sampling and questionable reagents (14).

As yet only DiaSorin has claimed that their laboratory-based serological assay, detecting both S1 and S2 spike proteins of SARS-CoV-2, can preferentially detect neutralizing antibodies (15).   If their claim and methodology can be independently confirmed, the use of such an antibody combination in a rapid test kit may be a valuable step towards disease control.

Though many companies are now offering antibody tests, the World Health Organization has yet to recognize a single appropriate serological SARS-CoV-2 assay, none have been validated sufficiently for clinical approval by the FDA, and they remain as laboratory tests.  The quality of the antibodies used is currently unknown, and little data has been published on the conditions used to verify their specificity and selectivity.  As we saw in our recent webcast series, such a lack of validation can cause major problems when antibodies are used as a basis to make life and death decisions. In the case of SARS-CoV-2, properly validated tests are urgently needed.

Deciphering test results

There are 4 clear stages in the progression of SARS-CoV-2 infection, which should have distinct test profiles useful for making decisions on disease spread.

1) The newly infected carry replicating virus, detectable with NAAT.
2) The infected mount a delayed adaptive immune response producing anti-viral IgM 5-10 days after infection.
3) An IgG response begins some 14 days after infection.  This response may or may not produce neutralizing antibodies.
4) “Recovered” patients have a low viral titer, and so are NAAT-negative, and may or may not have detectable, and possibly neutralizing anti-SARS-CoV-2 IgG. 

Thus, people at stage 1 express only viral RNA, while those at stage 2 express viral RNA and anti-SARS-CoV-2 IgM and, later, IgA. At stage 3, the infected may not express viral RNA and may have SARS-CoV-2 IgG, while those at stage 4 may continue to express anti-SARS-CoV-2 IgG.  The duration, strength, and possible neutralizing nature of the primary and any secondary antibody response is currently unknown.

The COVID-19 pandemic has triggered a rapid effective scientific response.  Sadly, this has in general been obscured.  The demand for “tests” has driven a gold-rush – resulting in a morass of point-of-care lateral-flow kits. These frequently use unvalidated polyclonal antibodies. Given the volume of tests to be performed, this will drastically lower the quality of the resulting data.  The Antibody Society welcomes recent ongoing efforts to better define the performance of such kits (16), and we hope for more efforts along these lines in the coming weeks.

References

1.           Foundation for Innovative New Diagnostics. FIND Covid-19 tests. Geneva: FIND; 2020. Available from: https://www.finddx.org/covid-19/test-tracker/.
2.           US Food and Drug Administration. Policy for Diagnostic Tests for Coronavirus Disease-2019 during the Public Health Emergency Washington D.C.: FDA; 2020. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-diagnostic-tests-coronavirus-disease-2019-during-public-health-emergency.
3.           Hahn SM, McMeekin JA. Coronavirus (COVID-19) Update: FDA Alerts Consumers About Unauthorized Fraudulent COVID-19 Test Kits. March 20, 2020. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-alerts-consumers-about-unauthorized-fraudulent-covid-19-test-kits
4.           Wyllie AL, Fournier J, Casanovas-Massana A, Campbell M, Tokuyama M, Vijayakumar P, et al. Saliva is more sensitive for SARS-CoV-2 detection in COVID-19 patients than nasopharyngeal swabs. medRxiv. 2020:2020.04.16.20067835.
5.           Baek YH, Um J, Antigua KJC, Park JH, Kim Y, Oh S, et al. Development of a reverse transcription-loop-mediated isothermal amplification as a rapid early-detection method for novel SARS-CoV-2. Emerg Microbes Infect. 2020:1-31.
6.           Xiao SY, Wu Y, Liu H. Evolving status of the 2019 novel coronavirus infection: Proposal of conventional serologic assays for disease diagnosis and infection monitoring. J Med Virol. 2020;92(5):464-7. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25702
7.           Woelfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Mueller MA, et al. Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. Available from: medRxiv. 2020:2020.03.05.20030502.
8.           SD Biosensor. STANDARD Q COVID-19 Ag 2020. Available from: http://www.sdbiosensor.com/xe/product/7672.
9.           BioConcept C. COVID-19 Ag Respi-Strip [Product insert]. B – 5032 Gembloux, Belgium: Coris BioConcepts; 2020 [updated 8th April 2020]. Available from: https://www.corisbio.com/Products/Human-Field/Covid-19.php.
10.         Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J Microbiol Immunol Infect. 2020. Available from: https://doi.org/10.1016/j.jmii.2020.03.022
11.         Bioeasy. 2019-nCovIgG/IgM GICA rapid test kit 2020. Available from: http://en.bioeasy.com.tr/bioeasy-novel-coronavirus-2019-ncov-test-kits/.
12.         EuroImmun. SARS-CoV-2 test systems from EUROIMMUN [Supplier web site]. Lubeck: EuroImmun; 2020. Available from: https://www.coronavirus-diagnostics.com/.
13.         European Centre for Disease Prevention and Control.  An overview of the rapid test situation for COVID-19 diagnosis in the EU/EEA Stockholm: ECDC; 2020. Available at: https://www.ecdc.europa.eu/sites/default/files/documents/Overview-rapid-test-situation-for-COVID-19-diagnosis-EU-EEA.pdf
14.         Vogel G. First antibody surveys draw fire for quality, bias. Science. 2020;368(6489):350-1. Available at: https://science.sciencemag.org/content/368/6489/350.
15.         Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020;181(2):281-92 e6. Available at: https://www.sciencedirect.com/science/article/pii/S0092867420302622.
16.         Whitman JD, Hyatt J, Mowery CT, Shy BS. Test performance evaluation of SARS-CoV-2 serological assays [Assay analysis Lateral flow tests]. UCSF Harvard consortium: University of California, San Francisco; 2020. Available from: https://covidtestingproject.org/.

Filed Under: Antibody Validation, COVID-19 Tagged With: COVID-19, diagnostics, SARS-CoV-2

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

April 22, 2020 by Janice Reichert

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.

Filed Under: ADC, Approvals, Food and Drug Administration Tagged With: Antibody drug conjugates, Food and Drug Administration, sacituzumab govitecan

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

April 21, 2020 by Janice Reichert

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.

Filed Under: Approvals, European Medicines Agency, Food and Drug Administration Tagged With: approved antibodies, European Medicines Agency, Food and Drug Administration

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