Top 10 Therapeutics


Pharma

Top 10 Therapeutic Antibodies

Here we provide an overview of the top 10 biologics and key information regards their application, mode of action and biosimilars.

What's in our Ebook?

Mechanism of action

In our Ebook we provide an overview of the mechanism of action of each our the biologics listed and it's affect on inflammation and respose.

Repurposing

In our Ebook we provide an overview of repurposing of each biologic and associated biosimilars.

Sales

Finally, we provide an overview of sales of each biologic, it's manufacturer and the up and coming biosimilars!

What are biologics?

Biological drugs, or biologics, are commonly defined as large, complex, organic molecules (composed of sugars, proteins, or nucleic acids) produced by living organisms (either microorganisms or mammalian cells). Biologics englobe a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins.

In contrast to chemical drugs, whose production processes and structures are relatively well-characterized and uniform, biologics necessitate complex and costly aseptic manufacturing processes and quality controls that are more difficult to scale-up.

The first biologics

The first appearance of biologics on the pharmaceutical market dates back to the 1980s with the development of human growth hormone, insulin and red-blood cell stimulating agents.

Since then, thanks to the advances in genetics, proteomics, cellular biology and biotechnologies that allow researchers to dissect cellular pathways involved in pathological processes, biologics now represent the cutting-edge of biomedical research and the most promising line of treatment in a wide variety of medical indications, including cancers and autoimmune diseases. Noticeably, among the top 10 drugs reported in 2018 by sales, 7 can be considered bona fide biologics.

Overview

Here, we propose an overview of the Top 10 Biologics sold in 2018, based on the financial reports published by pharmaceutical companies in early 2019. Comprehensive information about each drug can be accessed through their full prescribing information.


Humira®

Generic name: Adalimumab5

Manufacturer: AbbVie Inc.

First marketing date (USA): December 2002

Sales in 2018 (USD billions): 19.9366

Product type: Humanized anti-TNF IgG1K monoclonal antibody.

Medical indication(s) (full prescribing information)7:

  • Moderate to severe rheumatoid arthritis in adults
  • Moderate to severe polyarticular juvenile idiopathic arthritis in children over 2 years old.
  • Psoriatic arthritis in adults.
  • Ankylosing spondylitis in adults.
  • Moderate to severe Crohn’s disease in adults.
  • Moderate to severe ulcerative colitis in adults.
  • Moderate to severe chronic plaque psoriasis in adults.
  • Non-infectious intermediate, posterior and pan-uveitis in adults and children over 2 years old.
  • Moderate to severe hidradenitis suppurativa in people 12 years and older.

Mechanism of action: TNFα is a pro-inflammatory cytokine whose levels are found elevated in various chronic inflammatory diseases. Humira® is a TNF inhibitor that specifically binds soluble and membrane-bound TNFα, thereby preventing this pro-inflammatory cytokine from interacting with its p55 and p75 cell surface receptors8. However, the precise mechanism(s) through which Humira® achieves its anti-inflammatory effect in the variety of clinical conditions it is prescribed for remains elusive.

Repurposing: An ongoing clinical trial (NCT03180957) sponsored by the University of Oxford aims at assessing the effect of Humira® in patients suffering from Dupuytren's disease, a painful and disabling condition, affecting roughly 4% of the general UK and US population, where fingers curl irreversibly into the palm9,10. The investigators identified TNFα as a key mediator of the cellular process that initiates and maintains disease progression.

Biosimilars approved in USA11:

  • Amjevita™ (Amgen) – September 2016
  • Cyltezo™ (Boehringer Ingelheim) - August 2017
  • Hyrimoz™ (Sandoz) - October 2018

Keytruda®

Generic name: Pembrolizumab12

Manufacturer: Merck

First marketing date (USA): 2014

Sales in 2018 (USD billions): 7.17113

Product type: Humanized anti-PD-1 IgG4 monoclonal antibody.

Medical indication(s) (full prescribing information)14:

  • Advanced non-small cell lung cancers
  • Melanoma
  • Head and neck squamous cell cancer
  • Classical Hodgkin lymphoma
  • Microsatellite instability-high cancer
  • Advanced urothelial bladder cancer
  • Advanced gastric cancer
  • Advanced cervical cancer
  • Primary mediastinal B-cell lymphoma
  • Advanced hepatocellular carcinoma
  • Advanced Merkel cell carcinoma


    Mechanism of action:
    One of the strategies through which cancer cells evade immune-mediated clearance is by locally creating an anti-inflammatory environment that dampens the anti-tumoral cytotoxic effector functions of lymphocytes. PD-1, a receptor expressed on lymphocytes, naturally serves as an immune checkpoint to limit deleterious immune activation15. Many tumoral cells acquire the ability to express ligands that activate PD-1, thereby preventing effective anti-tumoral immune responses. As an anti-PD-1 antagonist, Keytruda® specifically binds to PD-1 to prevent its activation, which restores the ability of lymphocytes to target and destroy cancer cells16(p1).

    Repurposing: So far, no new indication has been put forward for Keytruda®, although its potential use to prevent the progression of Alzheimer’s disease was mentioned some years back17.


Herceptin®

Biosimilars approved in USA: No biosimilar available yet. Keytruda®’s patent rights are due to expire in 2028. Several pharmaceutical companies are already developing their production pipelines to launch their copy of the drug when the time comes.

Generic name: Trastuzumab18

Manufacturer: Genentech, Roche

First marketing date (USA): September 1998

Sales in 2018 (USD billions): 7.119

Product type: Humanized anti-HER2 IgG1k monoclonal antibody.

Medical indication(s) (full prescribing information)20:

  • HER2-overexpressing breast cancer.
  • HER2-overexpressing gastric or gastroesophageal junction adenocarcinoma.

    Mechanism of action:
    HER2 is a tyrosinase kinase that binds epithelial growth factors. Under physiological conditions, this receptor is expressed at low levels on the surface of epithelial cells, where it plays a central role in controlling normal cellular proliferation. In 20-30% of breast cancers, classified as the HER2-positive subtype, the levels of HER2 proteins are found to be upregulated up to a 100-fold as a result of the HER2 oncogene overexpression or amplification. The over-activation of the HER2 pathway triggers uncontrollable proliferation of epithelial cells and hence tumor formation. Thanks to its ability to bind to the extracellular domain IV of HER2, Herceptin® can potently suppress tumoral cell growth, proliferation and survival through HER2 internalization and degradation, antibody-dependent cellular toxicity, and mostly through the inhibition of the MAPK and PI3K/Akt pathways21.

    Repurposing: No repurposing of Herceptin has been announced so far.

    Biosimilars approved in USA11:

    • Ogivri™ (Mylan GmBH) - December 2017
    • Herzuma™ (Celltrion, Teva) - December 2018
    • Ontruzant® (Samsung Bioepsis): January 2019
    • Trazimera™ (Pfizer) - March 2019

    Generic name: Bevacizumab22

    Manufacturer: Genentech, Roche


Avastin®

First marketing date (USA): February 2004

Sales in 2018 (USD billions): 6.9119

Product type: Humanized anti-VEGF IgG1 monoclonal antibody.

Medical indication(s) (full prescribing information)23:

  • Recurrent glioblastomas
  • Metastatic colorectal cancers
  • Advanced non-squamous non-small cell lung cancers
  • Metastatic renal cell carcinomas
  • Ovarian cancers
  • Advanced cervical cancers

Mechanism of action: VEGF is a growth factor protein that promotes the growth of blood vessels (or angiogenesis) to guaranty adequate blood supply in physiological conditions. Cancer cells have high metabolic demands due to their accelerated proliferation rate, and in many tumors, they upregulate the expression of VEGF to promote tumor angiogenesis. By binding to VEGF and preventing its interaction with its receptors, Avastin® limits tumor angiogenesis, which in turn slows down metastatic tumor growth24,25.

Repurposing: Avastin® has shown promising results for the improvement of cartilage regeneration and the treatment of macular degeneration, but no official repurposing has been announced yet26–28.

Biosimilars approved in USA11: Mvasi™ (Amgen) - September 2017

Generic name: Rituximab29

Manufacturer: Genentech, Roche

First marketing date (USA): 1997

Sales in 2018 (USD billions): 6.919

Product type: Chimeric murine/human anti-CD20 IgG1K monoclonal antibody.

Medical indication(s) (full prescribing information)30:

  • CD20-positive Non-Hodgkin's lymphomas.
  • CD20-positive chronic lymphocytic leukemia.

Opdivo®

  • Moderate to severe rheumatoid arthritis.
  • Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).
  • Moderate to severe pemphigus vulgaris.

Mechanism of action: Rituxan® specifically targets the CD20 antigen expressed at the surface of normal and malignant B lymphocytes. Binding of the antibody on its target triggers B cell death though several possible mechanisms including cell cycle arrest, direct induction of apoptosis, sensitization to cytotoxic drugs, complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity31.

Repurposing: No repurposing of Rituxan® has been announced so far.

Biosimilars approved in USA11: Truxima® (Celltrion) - November 2018

Generic name: Nivolumab32

Manufacturer: Bristol-Myers Squibb

First marketing date (USA): December 2014

Sales in 2018 (USD billions): 6.73533

Product type: Humanized anti-PD-1 IgG4 monoclonal antibody

Medical indication(s) (full prescribing information)34:

  • Advanced lung cancer
  • Melanoma
  • Advanced kidney cancer
  • Head and neck squamous cell cancer
  • Advanced liver cancer
  • Advanced bladder cancer
  • Colorectal cancer
  • Classical Hodgkin lymphoma

Mechanism of action: Similarly, to Keytruda®, Opdivo® acts as an anti-PD-1 antagonist to promote anti-tumor immunity by preventing the activation of the PD-1 inhibitory pathway in T lymphocytes15,35.


Remicade®

Generic name: Infliximab37

Manufacturer: Johnson and Johnson (Janssen Biotech)

First marketing date (USA): August 1998

Sales in 2018 (USD billions): 5.32638

Product type: Chimeric anti-TNFα IgG1 monoclonal antibody

Medical indication(s) (full prescribing information)39:

  • Moderately to severely active Crohn’s disease
  • Moderately to severely active pediatric Crohn’s disease
  • Moderately to severely active ulcerative colitis
  • Moderately to severely active pediatric ulcerative colitis
  • Moderately to severely active rheumatoid arthritis
  • Active psoriatic arthritis
  • Active ankylosing spondylitis
  • Chronic severe plaque psoriasis

Mechanism of action: Remicade® is a TNF inhibitor that can bind soluble and membrane-bound TNFα in order to prevent it from binding to its receptors and activating pro-inflammatory responses40,41.

Repurposing: Remicade® has shown promising clinical results for the improvement of depressive symptoms in treatment-resistant depressive patients with high baseline inflammatory biomarkers (NCT00463580)42. Additional clinical trials are currently being conducted to further confirm and characterize this effect (NCT03004443, NCT03006393, NCT02363738)43–45.

Biosimilars approved in USA11:

  • Inflectra® (Celltrion) - April 2016

Stelara®

  • Renflexis™ (Samsung Bioepis) - May 2017
  • Ixifi™ (Pfizer) - December 2017

Generic name: Ustekinumab46

Manufacturer: Johnson and Johnson (Janssen)

First marketing date (USA): September 2009

Sales in 2018 (USD billions): 5.15638

Product type: Humanized anti-IL-12p40 IgG1K monoclonal antibody.

Medical indication(s) (full prescribing information)47:

  • Moderately to severely active Crohn’s disease
  • Adults with moderate or severe plaque psoriasis
  • Active psoriatic arthritis

Mechanism of action: Stelara® binds to the IL-12p40 subunit that is common to the IL-12 and IL-23 cytokines, preventing them from binding to the IL-12Rβ1 receptor expressed at the surface of NK and T cells. By doing so, Stelara® effectively disrupts both IL-12 and IL-23-mediated cell activation and cytokine production, thereby dampening deleterious inflammatory immune responses48.

Repurposing: Stelara® is undergoing a phase 2 clinical trial in systemic lupus erythematosus where it shows promising clinical improvements in patients (NCT02349061). A second trial for the same indication is currently recruiting patients (NCT03517722)49.

Biosimilars approved in USA: No biosimilar approved yet. Stelara®’s patent rights are due to expire in 2019. Some pharmaceutical companies, such as NeuClone50 and Formycon51, have already announced that they have Stelara® biosimilars in their production pipelines.

Generic name: Etanercept52

Manufacturer: Pfizer, Amgen, Takeda Pharmaceuticals


Enbrel®

First marketing date (USA): 1998

Sales in 2018 (USD billions): 5.01453

Product type: Dimeric fusion protein combining the human TNF receptor extracellular ligand-binding domain to the constant Fc fragment of the human IgG1 antibody.

Medical indication(s) (full prescribing information)54:

  • Moderate to severe rheumatoid arthritis.
  • Moderate to severe polyarticular juvenile idiopathic arthritis.
  • Psoriatic arthritis
  • Ankylosing spondylitis.
  • Chronic moderate to severe plaque psoriasis in adult patients and in children ages 4-17.

Mechanism of action: As a dimeric soluble form of the p75 TNF receptor, Enbrel® is a TNF inhibitor that acts as a decoy receptor to trap soluble TNF molecules, making them unable to bind to their cell-surface receptors and removing them from the circulation. The resulting decrease in TNFα-mediated immune activation reduces inflammatory responses that contribute to the pathology of autoimmune diseases41.

Repurposing: No repurposing of Enbrel® has been announced so far. Biosimilars approved in USA11: Erelzi™ (Sandoz) - 2016

Generic name: Pegfilgrastim55

Manufacturer: Amgen

First marketing date (USA): January 2002

Sales in 2018 (USD billions): 4.47553

Product type: N-terminal PEGylated human G-CSF.


Neulasta®

Medical indication(s) (full prescribing information)56: Neulasta is prescribed to prevent febrile neutropenia and lessen the chance of infection in patients suffering from non-myeloid cancers who are treated with myelosuppressive chemotherapy.

Mechanism of action: G-CSF is an endogenous hematopoietic growth factor that stimulates the proliferation, differentiation, survival, and activity of neutrophils. They are the most abundant white cells in peripheral blood, and play a crucial in mounting effective innate immune responses. A deficiency in neutrophil count (neutropenia) can lead to severe or lethal infection. Neutrophils have a high turn-over rate in the circulation and are constantly being renewed from granulocyte precursors located in the bone marrow. As these precursors need to actively proliferate to deliver new neutrophils, they are highly susceptible to cell death in patients undergoing cytotoxic cancer chemotherapy. As a result, these patients often display febrile neutropenia that put them at high risk of developing severe infections. Being a G-CSF analog, Neulasta® can bind to the G-CSF receptor at the surface of granulocyte precursors to stimulate the release of neutrophils from the bone marrow, accelerate their maturation and enhance their phagocytic activity in order to reduce the neutropenic phase in cancer patients57–59.

Repurposing: No repurposing of Neulasta® has been announced so far.

Biosimilars approved in USA11: Fulphila™ (Mylan GmbH) – June 2018

Medical indication(s) (full prescribing information)56: Neulasta is prescribed to prevent febrile neutropenia and lessen the chance of infection in patients suffering from non-myeloid cancers who are treated with myelosuppressive chemotherapy.

Mechanism of action: G-CSF is an endogenous hematopoietic growth factor that stimulates the proliferation, differentiation, survival, and activity of neutrophils. They are the most abundant white cells in peripheral blood, and play a crucial in mounting effective innate immune responses. A deficiency in neutrophil count (neutropenia) can lead to severe or lethal infection. Neutrophils have a high turn-over rate in the circulation and are constantly being renewed from granulocyte precursors located in the bone marrow. As these precursors need to actively proliferate to deliver new neutrophils, they are highly susceptible to cell death in patients undergoing cytotoxic cancer chemotherapy. As a result, these patients often display febrile neutropenia that put them at high risk of developing severe infections. Being a G-CSF analog, Neulasta® can bind to the G-CSF receptor at the surface of granulocyte precursors to stimulate the release of neutrophils from the bone marrow, accelerate their maturation and enhance their phagocytic activity in order to reduce the neutropenic phase in cancer patients57–59.

Repurposing: No repurposing of Neulasta® has been announced so far.

Biosimilars approved in USA11: Fulphila™ (Mylan GmbH) – June 2018


Conclusion

Despite their clinical efficiency, a redundant criticism of biologics is their ever-increasing cost, which aggravates the financial burden placed on insurance providers and patients, who sometimes can’t comply with their treatment anymore. With some of the patent rights expired or soon-expiring, the increasing availability of biosimilars on the market might alleviate some of that burden and will likely negatively impacts the sales of the afore-mentioned biologics in the coming years.

Footnotes:

Humira® is a registered trademark of AbbVie Biotechnology, Inc.

Amjevita™ is a trademark of Amgen, Inc.

Cyltezo™ is a trademark of Boehringer Ingelheim Pharmaceuticals, Inc.

Hyrimoz™ is a trademark of Sandoz Canada, Inc.

Keytruda® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Herceptin® is a registered trademark of Genentech, Inc.

Ogivri™ is a trademark of Mylan Institutional, Inc.

Herzuma™ is a trademark of Celltrion, Inc.

Ontruzant® is a registered trademark of Samsung Bioepis, Inc.

Trazimera™ is a trademark of Pfizer, Inc.

Avastin® is a registered trademark of Genentech, Inc.

Mvasi is a trademark of Amgen, Inc.

Rituxan® is a registered trademark of Biogen Idec, Inc.

Truxima® is a registered trademark of Celltrion, Inc.

Opdivo is a registered trademark of Bristol-Myers Squibb Company.

Stelara® is a registered trademark of Johnson and Johnson, Inc.

Remicade® is a registered trademark of Janssen Biotech Inc.

Inflectra® is a registered trademark of Hospira UK, a Pfizer company.

Renflexis™ is a trademark of Merck Sharp & Dohme Corp.

Ixifi™ is a trademark of Pfizer, Inc.

Enbrel® is a registered trademark of Amgen, Inc.

Erelzi™ is a trademark of Sandoz Canada, Inc.

Neulasta® is a registered trademark of Amgen, Inc. Fulphila™ is a trademark of Mylan Institutional, Inc.

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