Category:Biologics

A biologic (or biopharmaceutical) is a medicine derived from a biological source rather than chemically synthesised, or one that is so large and structurally complex that it cannot be characterised by routine chemical analysis. The category encompasses the recombinant proteins (insulin, growth hormone, the interferons, the coagulation factors), the monoclonal antibodies and their derivatives, the fusion proteins, the cellular therapies (chimeric antigen receptor T cells, mesenchymal stromal cells), the gene therapies (the AAV-vectored corrective gene products, the antisense oligonucleotides, the siRNA therapeutics), the vaccines, the blood-derived products (immunoglobulin preparations, coagulation-factor concentrates, albumin), and the biosimilar versions of approved biologic medicines whose patents have expired.

The history of biologic medicine begins, by convention, in the 1980s. The 1982 approval by the U.S. Food and Drug Administration of recombinant human insulin (Humulin, Genentech/Eli Lilly), produced by Escherichia coli engineered to express the human insulin gene, was the first commercial product of the biotechnology industry; it freed diabetes treatment from animal-source insulin (porcine and bovine pancreas extract) and made the supply of insulin essentially unlimited.^[1] The recombinant human growth hormone (Protropin, Genentech 1985) followed and gave the first non-cadaver-derived supply of growth hormone, ending the iatrogenic Creutzfeldt-Jakob outbreak that had followed pituitary-extracted growth hormone of the 1960s and 1970s. The recombinant tissue plasminogen activator (Activase, Genentech 1987) provided the first effective thrombolytic for acute myocardial infarction and acute ischaemic stroke. The recombinant erythropoietin (Epogen, Amgen 1989) was the first biotechnology medicine to surpass a billion dollars in annual sales and is the conventional founding event of the contemporary biotechnology industry.

The monoclonal antibody story is a parallel chapter. The technique for making monoclonal antibodies was developed by Georges Köhler and César Milstein at the Laboratory of Molecular Biology in Cambridge in 1975, by fusion of antibody-producing mouse B-cells with myeloma cells to produce immortal antibody-secreting hybridomas;^[2] Köhler and Milstein shared the 1984 Nobel Prize. The first therapeutic monoclonal antibody, muromonab-CD3 (OKT3), a murine anti-CD3 antibody, was approved in 1986 for prevention of kidney transplant rejection; its murine origin produced human-anti-mouse-antibody (HAMA) response and cytokine-release syndrome on administration. The development of chimeric (Reichmann 1988 at LMB; rituximab 1997), humanised (Winter 1989 at LMB; trastuzumab 1998), and fully human (Lonberg's transgenic mouse 1994; adalimumab 2002) antibodies progressively reduced the immunogenicity, and the contemporary monoclonal-antibody pharmacopoeia now numbers in the hundreds of approved medicines. The classes are listed in detail under monoclonal antibodies.

The cellular and gene therapies are the contemporary frontier. The first approved cellular medicine in oncology was sipuleucel-T (Provenge, Dendreon 2010), an autologous dendritic-cell vaccine for prostate cancer; the chimeric antigen receptor T cell products tisagenlecleucel (Kymriah, Novartis 2017) for paediatric acute lymphoblastic leukemia and axicabtagene ciloleucel (Yescarta, Gilead/Kite 2017) for refractory lymphoma opened the CAR-T era. Approved gene therapies now include voretigene neparvovec (Luxturna, Spark 2017, RPE65-mutation-mediated retinal dystrophy), onasemnogene abeparvovec (Zolgensma, Novartis 2019, spinal muscular atrophy), eladocagene exuparvovec (Upstaza, 2022, AADC deficiency), etranacogene dezaparvovec (Hemgenix, CSL Behring 2022, haemophilia B), valoctocogene roxaparvovec (Roctavian, 2022 Europe, 2023 U.S., haemophilia A), exagamglogene autotemcel (Casgevy, Vertex 2023, the first CRISPR-edited approved medicine, for sickle cell disease and transfusion-dependent beta-thalassemia), and lovotibeglogene autotemcel (Lyfgenia, Bluebird 2023, sickle cell disease). The antisense oligonucleotide nusinersen (Spinraza, Biogen 2016) for spinal muscular atrophy and the small interfering RNA therapeutics patisiran (Onpattro, Alnylam 2018, transthyretin amyloidosis) and inclisiran (Leqvio, Novartis 2021, hypercholesterolemia) represent the related nucleic-acid-based class.

The vaccines, although a long-established category of biologic medicine, deserve specific mention here. The traditional inactivated, attenuated, subunit, conjugate, and toxoid vaccines have been the foundation of public-health practice for over two centuries (Jenner's smallpox cowpox inoculation in 1796 being the conventional founding event). The contemporary additions of the recombinant subunit vaccines (the hepatitis B vaccine, 1986, the first FDA-approved recombinant vaccine; the human papillomavirus vaccines Gardasil and Cervarix), the conjugate polysaccharide vaccines (the Haemophilus influenzae type b vaccine, the pneumococcal conjugate vaccines, the meningococcal conjugate vaccines), the virus-like-particle vaccines (the HPV vaccines, Cervarix and Gardasil), the viral-vectored vaccines (the Ebola Ervebo, the COVID-19 AstraZeneca and Janssen vaccines), and the mRNA vaccines (the COVID-19 Pfizer-BioNTech and Moderna vaccines, approved in late 2020) extend the platform.

The clinical-pharmacology challenges of the biologic category differ substantially from those of small-molecule medicines. Biologics are administered parenterally (subcutaneous, intramuscular, intravenous, intrathecal, intravitreal) because of their oral non-absorption; they are immunogenic to varying degrees (neutralising antibodies that reduce or abolish efficacy on continued exposure; immediate hypersensitivity reactions including anaphylaxis; the cytokine release syndrome characteristic of T-cell-engaging therapies); they have complex pharmacokinetics with non-linear clearance, target-mediated drug disposition, and substantially longer half-lives (weeks to months) than most small molecules; they are temperature-sensitive (the cold-chain requirement for many biologics has shaped both manufacturing and supply); and they are expensive, with annual treatment costs commonly in the tens of thousands of dollars. The introduction of biosimilars (the FDA Purple Book lists more than fifty approved biosimilars across major reference biologics including infliximab, adalimumab, trastuzumab, rituximab, pegfilgrastim, epoetin) has reduced costs but the substitution pattern remains substantially more conservative than that of small-molecule generics.

By structure:

• Recombinant proteins:
  • Hormones: insulin and analogues, growth hormone, parathyroid hormone analogues, follicle-stimulating hormone, recombinant glucagon
  • Coagulation factors: recombinant factors VIII, IX, VIIa, X, XI, XIII; activated protein C
  • Erythropoietic agents (cross-indexed under hematinics): epoetin alfa, darbepoetin alfa, methoxy-PEG-epoetin beta
  • Granulocyte and platelet growth factors: filgrastim, pegfilgrastim, sargramostim, romiplostim
  • Tissue plasminogen activator and recombinant thrombolytics: alteplase, tenecteplase, reteplase
  • Other: pegloticase, palifermin, mecasermin, glucarpidase
• Monoclonal antibodies (cross-indexed; the largest single biologic subclass): the immune-checkpoint inhibitors, the TNF inhibitors, the CD20 antibodies, the IL-pathway antibodies, the receptor-targeted antibodies in oncology, the antibody-drug conjugates, the bispecific T-cell engagers
• Fusion proteins: etanercept, abatacept, belatacept, aflibercept, ziv-aflibercept, romiplostim, dulaglutide, denileukin diftitox
• Vaccines: the inactivated, attenuated, subunit, recombinant, conjugate, virus-like-particle, viral-vectored, and mRNA vaccines (each major class summarised on the immunisation-schedule pages)
• Blood-derived products:
  • Immunoglobulin: intravenous (IVIg) and subcutaneous (SCIg) immunoglobulin preparations, hyperimmune globulins (hepatitis B IG, rabies IG, varicella-zoster IG, tetanus IG, anti-D), C1-esterase inhibitor, alpha-1-antitrypsin
  • Coagulation factor concentrates: prothrombin complex concentrate, fibrinogen concentrate, von Willebrand factor / factor VIII complex
  • Albumin solutions (5% and 25%)
• Cellular medicines:
  • CAR-T: tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, ciltacabtagene autoleucel; the BCMA-targeted myeloma products
  • Mesenchymal stromal cells: remestemcel-L
  • Engineered hematopoietic cells: exa-cel (Casgevy), lovo-cel (Lyfgenia)
• Gene therapies:
  • AAV-vectored: voretigene neparvovec, onasemnogene abeparvovec, eladocagene exuparvovec, etranacogene dezaparvovec, valoctocogene roxaparvovec, fidanacogene elaparvovec, delandistrogene moxeparvovec
  • Antisense oligonucleotides: nusinersen, eteplirsen, golodirsen, viltolarsen, mipomersen (withdrawn), volanesorsen, casimersen
  • siRNA: patisiran, vutrisiran, inclisiran, givosiran, lumasiran, nedosiran
• Biosimilars: the growing list of approved biosimilar versions of reference biologics; major examples include the biosimilars of infliximab (Inflectra, Renflexis, Avsola), adalimumab (Amjevita and others), trastuzumab (Ogivri, Herzuma, Kanjinti, Trazimera, Ontruzant), bevacizumab (Mvasi, Zirabev), rituximab (Truxima, Ruxience, Riabni), pegfilgrastim, and epoetin alfa

The boundary of this category is "medicine of biological origin or large-molecule complexity that cannot be characterised by routine chemical analysis." The peptide medicines synthesised by chemical synthesis (the small peptide hormones in their synthetic form: oxytocin, vasopressin, calcitonin, octreotide, leuprolide and other GnRH analogues) sit at the boundary; they are conventionally classified as biologics when their molecular weight and complexity make a chemistry-based regulatory pathway difficult, and as small-molecule medicines when the chemistry is straightforward. The category here uses the conventional regulatory boundary (FDA's Biologics License Application versus New Drug Application pathway) rather than a molecular-size cutoff. The recombinant proteins are biologics; the wholly synthetic peptides under a New Drug Application are not. The category extends to include the cellular and gene-therapy medicines, which the FDA regulates under its Center for Biologics Evaluation and Research (CBER) rather than under the small-molecule Center for Drug Evaluation and Research (CDER).

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.