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

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

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

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

FDA response to the need for COVID-19 convalescent plasma

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

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

Ongoing clinical studies of convalescent plasma

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

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

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

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

New plasma-derived COVID-10 product candidates in development

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

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

Upcoming “Coronavirus in the crosshairs” posts

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

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

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FDA 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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FDA approves eptinezumab-jjmr for preventative treatment of migraine

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H. Lundbeck A/S has announced that Vyepti™ (eptinezumab-jjmr) was approved by the U.S. Food and Drug Administration for the preventive treatment of migraine in adults and will be available in April 2020. The recommended dosage is 100 mg as an intravenous infusion over approximately 30 minutes every 3 months; some patients may benefit from a dosage of 300 mg. Lundbeck expects to submit eptinezumab for approval to regulatory authorities in the European Union during 2020, followed by submissions for approval in other regions. Development of eptinezumab was initiated by Alder BioPharmaceuticals, Inc., which was acquired by Lundbeck in October 2019.

Eptinezumab-jjmr is a humanized immunoglobulin G1 (IgG1) monoclonal antibody specific for calcitonin gene-related peptide (CGRP) ligand. It is produced in Pichia pastoris yeast cells by recombinant DNA technology. The safety of VYEPTI was evaluated in over 2000 patients with migraine who received at least one dose of the drug. The approval was supported by positive results from the PROMISE 1 (NCT02559895) and PROMISE 2 (NCT02974153) Phase 3 clinical trials, which investigated eptinezumab for episodic and chronic migraine prevention, respectively. In PROMISE-1, a total of 665 patients were randomized to receive placebo (N=222), 100 mg Vyepti (N=221), or 300 mg Vyepti (N=222) every 3 months for 12 months. Mean migraine frequency at baseline was approximately 8.6 migraine days per month and was similar across treatment groups; mean change from baseline in monthly migraine days (MMD) with Vyepti compared with placebo months 1-3 was -3.9 days for 100 mg (p=0.018), -4.3 days for 300 mg (p<0.001), and -3.2 days for placebo. In PROMISE-2, a total of 1,072 patients were randomized to receive placebo (N=366), 100 mg Vyepti (N=356) or 300 mg Vyepti (N=350) every 3 months for 6 months. Mean migraine frequency at baseline was approximately 16.1 migraine days per month and was similar across treatment groups. Mean change from baseline in MMD compared with placebo months 1-3 was -7.7 days for 100 mg (p<0.001), -8.2 days for 300 mg (p<0.001), and -5.6 days for placebo

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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Two new antibody therapeutics enter regulatory review

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Biologics license applications (BLA) for tanezumab and dostarlimab have been submitted by Pfizer and GlaxoSmithKline, respectively.

Tanezumab is a humanized IgG2 antibody that selectively targets nerve growth factor. It has a novel mechanism compared to opioids and other analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), and, in studies to date, tanezumab has not demonstrated a risk of addiction, misuse or dependence. FDA granted Fast Track designation for tanezumab for the treatment of osteoarthritis pain and chronic lower back pain. During a Q4 earnings conference call on January 28, 2020, Pfizer announced that it completed a marketing application submission for tanezumab in December 2019. This submission was done in close collaboration with the FDA, and it includes the 2.5 mg dose in moderate-to-severe osteoarthritis patients. A decision on the application may occur by the end of 2020. The submission was confirmed by development partner Eli Lilly. Tanezumab is also being evaluated in Phase 3 study of patients with cancer pain due to bone metastasis who are taking background opioid therapy.

Dostarlimab (TSR-042) is a humanized IgG4 antibody that binds with high affinity to the PD-1 receptor and effectively blocks its interaction with the ligands PD-L1 and PD-L2. Dostarlimab is being developed by Tesaro (a division of GlaxoSmithKline) for the treatment of solid tumors, including endometrial cancer that could be classified as microsatellite stable (MSS/75%) or microsatellite instability-high (MSI-H/25%). GlaxoSmithKline’s BLA is for dostarlimab as second-line treatment of recurrent endometrial cancer. Tesaro is also evaluating dostarlimab as a treatment for ovarian cancer in the Phase 3 FIRST study (NCT03602859). This study will compare platinum-based therapy with dostarlimab and niraparib versus standard of care platinum-based therapy as first-line treatment of Stage III or IV non-mucinous epithelial ovarian cancer.

Tanezumab and dostarlimab are now queued for a possible first approval in 2020 along with 13 other antibody therapeutics:

  1. Isatuximab, a humanized IgG1 targeting CD38 for multiple myeloma
  2. Inebilizumab, a humanized IgG1 targeting CD19 for neuromyelitis optica and neuromyelitis optica spectrum disorders
  3. Eptinezumab, a humanized IgG1 targeting CGRP for migraine prevention
  4. Leronlimab, a humanized IgG4 targeting CCR5 for HIV infection
  5. Sacituzumab govitecan, a humanized IgG1 antibody-drug conjugate targeting TROP-2 for  triple-negative breast cancer
  6. Satralizumab, a humanized IgG2 targeting IL-6R for neuromyelitis optica spectrum disorder
  7. Narsoplimab, a human IgG4 targeting MASP-2 for hematopoietic stem cell transplant-associated thrombotic microangiopathies
  8. Tafasitamab, a humanized IgG1 CD19 for diffuse large B-cell lymphoma
  9. REGNEB3, mixture of 3 human IgG1 targeting the Ebola virus for Ebola virus infection
  10. Naxitamab, a humanized IgG1 targeting GD2 for high-risk neuroblastoma and refractory osteomedullary disease
  11. Oportuzumab monatox, a humanized scFv immunotoxin targeting EpCAM for bladder cancer
  12. Belantamab mafodotin, a humanized IgG1 ADC targeting B-cell maturation antigen for multiple myeloma
  13. Margetuximab, a chimeric IgG1  targeting HER2 for HER2+ metastatic breast cancer

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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First approval for teprotumumab-trbw (Tepezza)

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On January 21, 2020, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, which is associated with an outward bulging of the eye that can cause eye pain, double vision, light sensitivity or difficulty closing the eye. Teprotumumab, a human IgG1 antibody targeting insulin growth factor 1 receptor, was granted Fast Track, Breakthrough Therapy and Orphan Drug designations by the FDA. Positive data from both Phase 2 (NCT01868997) and Phase 3 (OPTIC, NCT03298867) studies were reported by Horizon Pharma. In the randomized, placebo-controlled OPTIC study, teprotumumab met the study’s primary endpoint, which was a responder rate of ≥ 2 mm reduction of proptosis (bulging) in the study eye (without deterioration in the fellow eye) at Week 24. Data from the OPTIC study showed that 82.9% of patients receiving teprotumumab were proptosis responders compared to 9.5% of patients receiving placebo at Week 24 (p<0.001). All secondary endpoints in the study were also met.

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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