Stuart R. Gallant, MD, PhD
I have a weakness for old Hollywood movies. The movie still that appears above this paragraph depicts John Carradine in the role of the undertaker in the 1976 film The Shootist. It’s a small role, but Carradine absolutely nails it as the scheming foil to John Wayne’s character, the gunslinger J.B. Books.
You might wonder what this has to do about pharmaceuticals. Take a close look at Carradine’s hands. They are gnarled—bent to the outside in the characteristic posture of severe rheumatoid arthritis. His hands must have been quite painful to him.
Fortunately, today we have a range of medications that prevent the damage that this disease does. Many of these medications are biologics that target and disrupt the inflammatory cascade by binding to a signaling molecule tumor necrosis factor (TNF). They have become a mainstay of treatment for inflammatory diseases, including rheumatoid arthritis.
The story of anti-TNF treatments is an interesting case for two reasons. Of course, Remicade, Enbrel, and Humira are some of the most important pharmaceuticals in today’s market from a revenue perspective, but there is another reason. Previously, PharmaTopo has posted on biologics which were relatively straight forward to develop (insulin and Factor VIII begin two prime examples)—”there’s the target, now make a drug to cure the disease.” Medications targeting TNF were different because TNF’s role in the body is so widespread—it is implicated in rheumatoid arthritis, but it also plays a role in uncontrolled bacterial infections (sepsis), and in other disease states (for example, Alzheimer’s, cancer, and inflammatory bowel disease). So, this is a situation in which pharmaceutical companies had a tool—a wrench—but they didn’t necessarily know which nut to turn with their wrench. The search for which nut to turn is an aspect of today’s post.
Signaling in Rheumatoid Arthritis
In 1975, Lloyd Old’s group at Memorial Sloan-Kettering Cancer Center reported discovery of tumor necrosis factor (TNF—their name for the substance) [1]. Of initial interest because of its role in hemorrhagic necrosis of tumors due to endotoxin, over time it was recognized to have a role in many other conditions, including rheumatoid arthritis (RA).
What we now know is that RA is a disease of errant signaling. It starts with both genetic and environmental risk factors which are important but poorly understood. Tobacco smoking is known to be a risk, and certain infectious diseases such as Epstein-Barr virus are thought to play a role as well [2]. A signaling cascade occurs inside of affected joints that includes these three steps:
Genetic and environmental factors lead to local T cell activation within the joints and release of certain cytokines, including TNF-alpha. Secondary signaling follows with simulation of macrophages and fibroblasts which release more proinflammatory molecules (including TNF-alpha). It is this secondary signaling which cause the painful inflammation (joint swelling and pain) and joint destruction.
Antibodies
In the same year that the Old’s lab reported their discovery of TNF, 1975, Georges Köhler and César Milstein made fusions of myeloma cell lines and B cells—these hybridomas allowed the production of monoclonal antibodies. The invention of this technology would eventually allow TNF signaling to be disrupted. Some examples of RA treatments based on antibodies or antibody-like molecules include:
| Drug | FDA Licensure | Target | Delivery |
| Infliximab (Remicade) | Janssen Biotech in August 1998. | Chimaeric (human/mouse) monoclonal antibody which binds TNF-alpha. | IV, every 2 months |
| Etanercept (Enbrel) | Immunex in Nov. 1998. | Two TNF receptors fused to an antibody Fc which functions as a decoy receptor for TNF-alpha. | SC, weekly |
| Adalimumab (Humira) | BASF Pharma/ Abbott Laboratories. Dec. 2002. | Human monoclonal antibody which binds TNF-alpha. | SC, every 2 weeks |
| Certolizumab (Cimzia) | UCB in April 2008. | Pegylated Fab’ fragment which binds TNF-alpha. | SC, every 2 weeks |
| Golimumab (Simponi) | Janssen Biotech in April 2009. | Human monoclonal antibody which binds TNF-alpha. | SC, monthly |
These treatments bind to TNF-alpha so that it cannot bind its receptor initiating signaling. Binding with the drug speeds TNF-alpha clearance from the body. These medications may also be responsible for lysis of TNF-expressing cells in the presence of complement—so besides soaking up TNF, they may also be lowering TNF production. If we think of TNF overexpression as the cause of RA, then anti-TNF antibodies normalize the level of TNF [3], allowing patients to live almost as if they didn’t have RA.
What to Do With an Anti-TNF Drug
With 20/20 hindsight, anti-TNF medications look like a slam dunk as drug development candidates. According to this line of thought, all that was required was: 1st: create an antibody to bind TNF-alpha and 2nd: cure rheumatoid arthritis. But, it wasn’t that simple.
Before treatment of rheumatoid arthritis could be investigated, investigators wanted to look at the role of TNF in bacterial blood infections. From a scientific point of view, this made good sense:
- In the 1980s, when it became possible to manufacture antibodies against TNF, and even today, many people die in the hospital from blood infections. When patients have severe blood infections, they often exhibit a triad of symptoms (rapid breathing, rapid heart rate, and body temperature dysregulation) known among health professionals as “sepsis.” These visible symptoms are the calling card of deadly molecular events taking place within the body of the patient.
- The researchers who discovered TNF in 1975 associated TNF with endotoxin, the bacterial toxin responsible for sepsis [1, 4]. Once it became possible to assay for TNF, it became clear that TNF was elevated during sepsis. Further, it was found that injecting nontoxic levels of endotoxin into the blood of human volunteers increased their TNF levels. And, administration of TNF to volunteers caused symptoms of sepsis (low blood pressure, decreased white blood cell levels, and characteristic findings in lung imaging) [5].
It looked like TNF might be some kind of circuit breaker in the development of sepsis. If elevated levels of TNF could be neutralized (while also providing other supportive medications, like intravenous antibiotics), perhaps many sepsis patients could be saved. Companies like Bayer invested hundreds of millions of dollars in large expensive clinical trials involving thousands of septic hospital patients [6]. Unfortunately, the results were underwhelming—generally patients did not improve with anti-TNF therapy. Researchers were turning the wrong nut with their anti-TNF wrench.
Fortunately, other avenues of TNF research continued. A fruitful collaboration on rheumatoid arthritis arose between the Marc Feldmann laboratory (at Charing Cross Sunley Research Centre and the Kennedy Institute of Rheumatology) and Genentech in the late 1980s. Genentech took the role of a helpful neighbor loaning Feldmann’s researchers a cup of sugar (in this case, not actual sugar, but samples of rabbit anti-TNF antibodies produced at Genentech). Feldmann’s laboratory had been culturing samples of cells taken from the joints of arthritis patients. Testing showed that these cells produced elevated levels of inflammatory markers. Using the anti-TNF antibodies, it was possible to reduce the levels of these inflammatory cytokines. The researchers were able to “cure” rheumatoid arthritis in a test tube.
Now, there was laboratory data that TNF was the “nut” regulating another disease, other than sepsis. A clinical trial using Centocor anti-TNF antibodies (the drug that would ultimately become Infliximab, the first biologic treatment for RA) followed in 1993 [9]. And, interest in anti-TNF medications pivoted from sepsis to RA and other inflammatory conditions, though some substantial investment in sepsis continued into the late 1990s.
Marketing Anti-TNF Medications
Given the time and effort that it took to develop these treatments, the intellectual property history of the anti-TNF medications is complex. Needless to say, each of the anti-TNF medications listed in the table above has its own protective suite of patents. Storz has an excellent 2016 two-part series on these patents [10, 11] which is a little dated by 2022, but definitely worth reading.
Over time, revenue for branded anti-TNF treatment has shifted toward Humira, as seen in the following table:
| Drug | FDA Licensure | Global 2014 (USD B) | Global 2020 (USD B) | % Change |
| Infliximab (Remicade) | 1998 | 10.15 | 4.20 | -59% |
| Etanercept (Enbrel) | 1998 | 9.12 | 6.37 | -30% |
| Adalimumab (Humira) | 2002 | 13.02 | 20.39 | 57% |
| Certolizumab (Cimzia) | 2008 | 0.80 | 1.80 | 126% |
| Golimumab (Simponi) | 2009 | 1.20 | 2.24 | 87% |
| Total | 34.29 | 35.00 | 2% |
A measure of the importance of the anti-TNF category is that the top three of these drugs (Remicade, Enbrel, and Humira) remained in the top twenty pharmaceutical revenue generators as of 2020—two decades after their introduction.
The anti-TNF market is in flux. As biosimilars enter the market, erosion of the revenue share to branded medications is expected—a type of competition that Remicade is already experiencing. It looks like 2023 will be the year that Humira biosimilars finally enter the market. The FDA has approved at least six biosimilars which will launch in 2023 (with their launch dates controlled by legal settlements with Abbvie):
| Drug | Manufacturer | Launch Date |
| Amjetiva | Amgen | January 2023 |
| Hadlima | Samsung Bioepis | June 2023 |
| Cyletzo | Boehringer Ingelheim | July 2023 |
| Hulio | Mylan | July 2023 |
| Hyrimoz | Sandoz | September 2023 |
| Abrilada | Pfizer | November 2023 |
Biosimilar pressure is likely to reduce the cost of these therapies, but the share of the savings that US patients experience is complicated by the US reimbursement system. An interesting study was published in JAMA in 2018 [12]. The authors suggested that the patient’s share of payment for RA therapy on a biosimilar infliximab could be more expensive than the same therapy on Remicade due the vagaries of Medicare reimbursement ($5118 versus $3432 per year according to their calculation):
Final Thoughts
Anti-TNF therapy has been a blessing to many patients with a wide range of inflammatory conditions. However, the risks of taking a medication with such potentially wide-ranging effects are important to consider [13]. No patient should undertake anti-TNF therapy without appropriate screening and monitoring.
[1] Carswell, E.A., et al. “An endotoxin-induced serum factor that causes necrosis of tumors,” Proc. Nat. Acad. Sci. USA 72, pp. 3666-3670 (1975).
[2] Harrison’s Principles of Internal Medicine, 19th Edition (2015).
[3] Zamora-Atenza, C., et al. “Adalimumab regulates intracellular TNFα production in patients with rheumatoid arthritis,” Arthritis Research & Therapy 2014, 16, R153.
[4] Lüderitz, O., et al. “Lipid A: Chemical Structure and Biological Activity,” The Journal of Infectious Diseases 128: S17–S2 (1973).
[5] Bone, R.C. “The Pathogenesis of Sepsis,” Annals of Internal Medicine 115:457-469 (1991).
[6] Abraham, E., et al. “Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group,” Lancet 28:929-33 (1998).
[7] Brennan, F.M, et al. “Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis,” Lancet 2 (8657):244-247 (1989).
[8] Haworth, C., et al. “Expression of granulocytemacrophage colony-stimulating factor (GM-CSF) in rheumatoid arthritis: regulation by tumor necrosis factor-alpha,” Eur. J. Immunol. 21(10):2575-9 (1991).
[9] Elliott, M.J., et al. “Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha,” Arthritis Rheum 36(12):1681-90 (1993).
[10] Storz, U. “Of patents and patent disputes: The TNFα patent files. Part 1: Humira,” Human Antibodies 25, 1-16 (2016/2017).
[11] Storz, U. “Of patents and patent disputes – The TNF patent files. Part 2: Enbrel, Remicade, Cimzia and Simponi,” Human Antibodies 26, 49-61 (2017).
[12] Yazdany, J., et al. “Out-of-Pocket Costs for Infliximab and Its Biosimilar for Rheumatoid Arthritis Under Medicare Part D,” JAMA 320(9):931-933 (2018).
[13] Atzenia, F., et al. “Concerns about the safety of anti-TNF agents when treating rheumatic diseases,” Review Expert Opin Drug Saf 19(6):695-705 (2020).
Disclaimer: PharmaTopoTM provides commentary on topics related to drugs. The content on this website does not constitute technical, medical, legal, or financial advice. Consult an appropriately skilled professional, such as an engineer, doctor, lawyer, or investment counselor, prior to undertaking any action related to the topics discussed on PharmaTopo.com.