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Triple-negative Breast Cancer Day, March 3, 2021

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On March 3rd each year, the global community affected by and working to treat triple-negative negative breast cancer (TNBC) comes together to raise awareness of this disease. Like all cancers, breast cancer is heterogenous. The triple-negative form of the disease is characterized by the absence of expression of the estrogen and progesterone receptors and lack of amplification of human epidermal growth factor receptor 2 (HER2) on tumor cells, which makes it particularly difficult to treat. Although only ~10-20% of all breast cancer cases, TNBC is particularly aggressive, and occurs more commonly in women younger than age 40, who are African-American, or who have a BRCA1 mutation. The 5-year survival rate is high (91%) if the disease is localized when first diagnosed, but decreases substantially (to 12%) if the tumor has already metastasized.

Due to the lack, or relatively small number, of relevant receptors, TNBC typically does not respond to hormonal therapeutics or agents targeting HER2. Chemotherapy has been the standard of care, although the benefits of this treatment are limited. Recently, however, three monoclonal antibody (mAb) therapies, atezolizumab (Tecentriq, Genentech Inc.), sacituzumab govitecan-hziy (TrodelvyTM, Immunomedics, Inc.), and pembrolizumab (KEYTRUDA, Merck & Co.) were approved by the US Food and Drug Administration (FDA) for TNBC. In addition, numerous other mAbs are in late-stage clinical study for this disease.

Atezolizumab is a humanized IgG1 mAb targeting programmed cell death protein 1 ligand (PD-L1) that was first approved by FDA for treatment of locally advanced or metastatic urothelial carcinoma in 2016. The Fc domain of atezolizumab was engineered by introducing an Asp to Ala change at position 298 in the CH2 domain of each heavy chain. Due to this alteration, the antibody devoid of N-linked oligosaccharides and does not have effector functions. On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test. Approval was based on the placebo-controlled Phase 3 IMpassion130 (NCT02425891) study of 902 patients with unresectable locally advanced or metastatic TNBC who had not received prior chemotherapy for metastatic disease. In patients whose tumors express PD-L1, median progression-free survival was 7.4 months for patients receiving atezolizumab with paclitaxel protein-bound and 4.8 months for those receiving placebo with paclitaxel protein-bound. The objective response rate in patients with confirmed responses was 53% compared to 33% for the atezolizumab and the placebo-containing arms, respectively. Tecentriq is also approved in the European Union for treatment of TNBC.

Sacituzumab govitecan is an antibody-drug conjugate (ADC) comprising a humanized IgG1k antibody targeting TROP-2 fused to the active metabolite of irinotecan (SN-38). On April 22, 2020, FDA granted Trodelvy® an accelerated approval for adults patients with metastatic TNBC who received at least two therapies for metastatic disease. FDA’s approval was based on findings from the pivotal, single-arm clinical trial IMMU-132-01 (NCT01631552) that enrolled 108 previously treated patients with metastatic TNBC. The overall response rate was 33.3% and the median response duration was 7.7 months. Of the patients with a response to sacituzumab govitecan-hziy, 55.6% maintained their response for 6 or more months and 16.7% maintained their response for 12 or more month.

Pembrolizumab is a humanized IgG4 mAb targeting programmed cell death protein 1 (PD-1) that was first approved by FDA for treatment of melanoma in 2014. On November 13, 2020, FDA granted accelerated approval to pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. FDA’s approval was based on results from the Phase 3 KEYNOTE-355 study (NCT02819518) of patients with locally recurrent unresectable or metastatic TNBC, who had not been previously treated with chemotherapy in the metastatic setting. Median progression-free survival was 9.7 months in the pembrolizumab plus chemotherapy arm and 5.6 months in the placebo arm.

Other ADCs and antibodies that target PD-1 or its ligand (PD-L1) are undergoing evaluation in late-stage clinical study of TNBC patients, including the anti-HER2 ADC trastuzumab deruxtecan (Enhertu); anti-PD-L1 avelumab (Bavencio) and TQB2450; and anti-PD-1 serplulimab and toripalimab. More information about TNBC and antibody therapeutics for this disease can be found in these reviews:

Nagayama A, Vidula N, Ellisen L, Bardia A. Novel antibody-drug conjugates for triple negative breast cancer. Ther Adv Med Oncol. 2020 May 11;12:1758835920915980. doi: 10.1177/1758835920915980.

Won KA, et al. Triple‑negative breast cancer therapy: Current and future perspectives. Int J Oncol. 2020. PMID: 33174058.

Keep up to date on US and EU approvals all year by visiting our website!

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.

Rare Disease Day, February 28, 2021

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On or about the last day of February each year, the rare disease community comes together to raise awareness of these conditions. In the US, any disease affecting fewer than 200,000 people (1 per ~1,650 people) is considered rare, while a disease is defined as rare in Europe when it affects fewer than 1 in 2,000 people. There are more than 7,000 rare diseases, and these collectively affect ~ 25-30 million Americans. Information about specific rare diseases can be found in the National Organization for Rare Disorders’ Rare Disorders Database and the National Institutes of Health’s Genetic and Rare Diseases Information Center.

In the US, the Orphan Drug Act passed by Congress in 1983 incentivizes the development of drugs to treat rare diseases. Similar programs in Europe, Japan, as well as other countries, also allow other regulatory agencies to grant ‘orphan drug’ designations.  Hundreds of drugs have been approved for the treatment of rare diseases, including numerous antibody therapeutics, although substantial medical need still remains. Antibody therapeutics recently approved for rare diseases include:

  • Caplacizumab (Cablivi), a treatment for acquired thrombotic thrombocytopenic purpura, which is a rare blood clotting disorder.
  • Crizanlizumab (Adakveo), indicated to reduce the frequency of vaso-occlusive crisis, which is a painful complication of sickle cell disease that occurs when blood circulation is obstructed by sickled red blood cells.
  • Teprotumumab (Tepezza), indicated for 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.
  • Inebilizumab (Uplizna) and satralizumab (Enspryng), treatments for neuromyelitis optica spectrum disorder, which is a rare autoimmune disorder of the central nervous system that primarily damages the optic nerve(s) and spinal cord, causing blindness, muscle weakness and paralysis.
  • Evinacumab (Evkeeza), a treatment for homozygous familial hypercholesterolemia, which is a genetic condition that causes severely high cholesterol.
  • Ansuvimab (Ebanga) and the triple antibody cocktail of atoltivimab, maftivimab, and odesivimab (Inmazeb) for the treatment for Zaire ebolavirus (Ebolavirus) infection.
  • Naxitamab (DANYELZA®) for the treatment of relapsed or refractory high-risk neuroblastoma in the bone or bone marrow.

More information about these antibody therapeutics, including target, format and year of approval, can be found here.

Other antibody therapeutics for rare diseases are in late-stage clinical studies and may be approved soon, including:

  • Garetosmab, which is undergoing evaluation as a treatment for fibrodysplasia ossificans progressive (FOP), an ultra-rare genetic disorder characterized by the progressive replacement of soft tissue, such as muscles, tendons, and ligaments, by bone, a process known as heterotopic ossification. Regeneron plans regulatory submission(s) for garetosmab for FOP in 2021.
  • Mirvetuximab soravtansine, which is undergoing evaluation as a treatment for ovarian cancer. ImmunoGen anticipates the submission of a biologics license application for accelerated approval of mirvetuximab soravtansine for ovarian cancer during the second half of 2021.
  • KN046, which is undergoing evaluation as a treatment for thymic carcinoma. Alphamab Oncology has announced that the Phase 2 clinical trial (NCT04469725) of KN046 to treat thymic carcinoma will support their plan to submit marketing applications for KN046 to China’s National Medical Products Administration and the US Food and Drug Administration in 2021.

More information about antibody therapeutics in late-stage studies can be found in ‘Antibodies to Watch in 2021‘.

Keep up to date on US and EU approvals all year by visiting our website!

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.

FDA approves Evkeeza (evinacumab-dgnb) for homozygous familial hypercholesterolemia

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On February 11, 2021, the US Food and Drug Administration approved Evkeeza (evinacumab-dgnb) injection as an add-on treatment for patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH), a genetic condition that causes severely high cholesterol. Evkeeza received orphan drug and breakthrough therapy designations for this indication, and the biological license application received a priority review.

Evinacumab is a human IgG4k antibody targeting angiopoietin-like 3 (ANGPTL3), which regulates the metabolism of plasma lipids, including low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, and triglycerides. The antibody was derived from Regeneron’s Velocimmune® technology platform, and includes a stabilizing mutation in the hinge region to minimize half-antibody formation.

Data from the Phase 3 ELIPSE trial (NCT03399786) was used as the basis of regulatory submissions. In this study 65 patients were randomized to receive either IV administration of evinacumab 15 mg/kg every four weeks (n=43) or placebo (n=22), plus other lipid-lowering therapies. The primary endpoint was the percent change from baseline in the LDL cholesterol level at Week 24. At baseline, LDL cholesterol was 260 mg/dL in the evinacumab group and 247 mg/dL in the placebo group. The primary endpoint of the study was met. Relative to baseline, the LDL cholesterol level at Week 24 was reduced by 47.1% in the patients administered evinacumab, but increased 1.9% in the placebo group.

Keep up to date on US and EU approvals all year by visiting our website!

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.

Evinacumab is the first investigational (i.e., not previously approved for any indication) antibody therapeutic to be granted an approval in the EU or US in 2021. There are currently 17 investigational antibody therapeutics in regulatory review in the EU or US.

FDA issues Emergency Use Authorization for bamlanivimab/etesevimab combination

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On February 9, 2021, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for bamlanivimab and etesevimab administered together for the treatment of mild to moderate COVID-19 in adults and pediatric who test positive for SARS-CoV-2 and who are at high risk for progressing to severe COVID-19. Developed by Eli Lilly and Company, bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target overlapping regions of the SARS-CoV-2 spike protein.

The EUA was based on a randomized, double-blind, placebo-controlled clinical trial in 1,035 non-hospitalized adults with mild to moderate COVID-19 symptoms who were at high risk for progressing to severe COVID-19. Of these patients, 518 received a single infusion of bamlanivimab (2.8 g) and etesevimab (2.8 g) together, and 517 received placebo. The primary endpoint was COVID-19 related hospitalizations or death by any cause during 29 days of follow-up.  Hospitalization or death occurred in 11 (2%) patients treated the mAb combination vs. 36 (7%) patients who received placebo. All 10 deaths (2%) occurred in the placebo group.

The authorized dosage of 700 milligrams bamlanivimab and 1400 milligrams etesevimab administered together is based on analyses of available preclinical, clinical, and virologic data, as well as pharmacokinetic and pharmacodynamic modeling, which, in totality, support that the authorized dosage is expected to have a similar clinical and virologic effect to the dose evaluated in the clinical trial. Use of the mAb combination is not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19.

In November 2020, FDA issued an EUA for a single infusion of 700 mg bamlanivimab for the treatment of mild-to-moderate COVID-19 in adult and certain pediatric patients. Since the monotherapy and the combination treatment are expected to benefit patients at high risk of disease progression, both 700 milligrams bamlanivimab alone and the combination of 700 milligrams bamlanivimab and 1,400 milligrams etesevimab administered together will be available under an EUA.

Ultra-fast development of an anti-COVID-19 antibody

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Thursday February 18, 2021 at 8am PT/11am ET/5pm CET

The SARS-CoV-2 pandemic has spread all over the world in the past year and there is still no efficient treatment available for COVID-19, particularly for patients undergoing severe courses, which often lead to fatal consequences. Antiviral drugs such as virus-neutralizing antibody therapeutics are still urgently needed to save millions of lives.
Corat Therapeutics developed a novel SARS-CoV-2 neutralizing, fully human antibody derived from convalescent patients. Ultra-fast development strategies shortened timelines from discovery to GMP manufactured material to less than 8 months. This was possible by parallelizing discovery and development steps, as well as performing crucial steps on risk. First-in-human studies were recently initiated. This webinar gives an overview of the challenges faced during discovery and development of the lead antibody, COR-101.

Speaker: Dr. André Frenzel, YUMAB/CORAT Therapeutics

Click here to register for this free event!