written by reader Biosimilars: What Are They, and Why On Earth Should We Care?

Doc Gumshoe takes a look at "biologic generics"

By Michael Jorrin, "Doc Gumshoe", October 20, 2014

[Michael Jorrin, who we like to call “Doc Gumshoe”, is a medical writer who shares his thoughts with us once or twice a month. He does not usually recommend or discuss investments, and, as with all of our contributors, his words are his own and he chooses his own topics.]

To start us off, three quick answers to the second part of that question:

  • One, for people with any of a number of truly serious diseases, the availability of biosimilars may make the difference between getting appropriate treatment and not being able to afford it.
  • Two, for the health-care system and the economy as a whole, biosimilars could result in billions in savings, which would likely affect our individual financial well-being.
  • And, three, the implications for the pharmaceutical industry, both positive and negative, are huge. Some pharmas will clearly take a hit, while others will reap significant profits.

We’ll circle back to the economic implications of biosimilars later on, but to put the matter in perspective, consider for a moment just how big a slice of the total global drug market biosimilars could command.

The total global market for all drugs is currently in the neighborhood of a trillion dollars – that’s a $1 with 12 zeroes after it. Of that total, biologics account for about $200 billion. According to some analysts, within about 5 years biosimilars will account for as much as half – $100 billion – of that amount. Somewhere around 700 biosimilars are now at some point in the planning stages, and more than 200 pharmaceutical companies or medical centers are working on biosimilars. The biosimilar tide is rising, and it’s more than a groundswell.

What are biosimilars, anyway?

From the name we can tell that biosimilars are similar to something – the question is, what? We need to start out with a bit of background on biologic agents or drugs, as they are called.

The biologic category covers a multitude of substances, whose common feature is that they originate in a natural process of some kind. It would be far too simple to try to draw a strict distinction between “made in a lab” and “made by a living organism,” because many biologics are both – they are made in a lab by living organisms. Many substances used in medicine – e.g., insulin, hormones such as estrogen and growth factor, immunoglobulins, and other blood products such as clotting factors – are biologics. However, in the pharmaceutical industry, the term “biologics” is employed to refer to man-made agents that are created by adapting or engineering a living source, such as cells from a living organism, to generate a substance with specific, desired characteristics. These biologics cannot be synthesized from chemicals, as non-biologic drugs are.

Two common classes of pharmaceutical biologics are monoclonal antibodies, often abbreviated as mAbs, and receptor blockers, whose names typically end in “cept.” Monoclonal antibodies are frequently based on the action of physiologic antibodies that the organism generates to fight potentially harmful substances, while receptor blockers guard against those substances by occupying the receptor for those substances and preventing the harmful substance from interacting with the receptor.

Examples of widely-used biologics include drugs used in many diseases and conditions, e.g.:

  • Epogen (erythropoietin) from Amgen (AMGN): stimulates cells in the bone marrow that generate red blood cells (erythrocytes). This biologic is a recombinant protein that mimics physiologic erythropoietin; it is also sold as Procrit, from Janssen. This biologic is legitimately used to treat anemia arising from any of a number of medical conditions, and somewhat less legitimately to enhance sports performance, since boosting the number of red blood cells increases oxygen availability. In case you don’t remember, this was Lance Armstrong’s performance booster of choice.
  • Herceptin (trastuzumab) from Genentech/Roche (RHHBY): an antagonist to the HER2/neu gene that accelerates and aggravates breast cancer; it is also used in some gastric cancers. Trastuzumab is a humanized monoclonal antibody, meaning that it is closely similar to antibodies formed in the human body in response to the HER2 gene.
  • Orencia (abatacept) from Bristol-Myers Squibb (BMY): a T-cell receptor blocker used to treat rheumatoid arthritis; T-cells are among the many auto-immune agents that can attack host tissues. Abatacept is an engineered fusion protein that mimics cytotoxic T-lymphocyte 4 (CTLA-4), a protein that regulates the activity of T-cells. Deficiencies in this protein have been linked to a number of autoimmune diseases besides rheumatoid arthritis.
  • Remicade (infliximab) from Janssen (JNJ): a monoclonal antibody to tumor necrosis factor alpha (TNFα), a cytokine that is active in controlling some malignancies, but can also attack the surfaces of our joints and trigger inflammation in various parts of the body. Infliximab is used to treat rheumatoid arthritis and some other autoimmune diseases.
  • Rituxan (rituximab) from Genentech / Biogen Idec (BIIB): also a monoclonal antibody, which binds to CD20 cells on the surface of B-cells which have become malignant. When rituximab binds to those CD20 cells, natural killer cells in the body have a much higher chance of eliminating the malignant B-cells. Rituximab is primarily used to treat a form of cancer known as non-Hodgkin’s lymphoma.
  • Stelara (ustekinumab) from Janssen: a monoclonal antibody against two interleukins – IL-12 and IL-23 which are active in the pathogenesis of psoriasis, another disease which is now understood to be autoimmune. Mild cases of psoriasis are often treated by addressing the skin symptoms alone, but clinicians are now (mostly!) aware that in more severe cases, they have to be on the lookout for the systemic complications, which can include fairly severe rheumatoid arthritis.

How some biologics work

An example of such interactions, employed by many drugs used to treat rheumatoid arthritis (RA), are the strategies to prevent damage from TNFα. This is a molecule of a class called cytokines, which is involved in autoimmune regulation and in the process of eradicating cancer cells. However, in people with RA, TNFα also erodes the surfaces of the joints; this is one of the fundamental disease processes in RA, and a number of biologics aim to deter this process.

The organism, in its normal process of attempting to maintain health, develops antibodies both to invaders perceived as harmful and to substances developed in the body that have the capacity to become harmful. The cytokine family, an enormous group of proteins that we generate for a vast array of purposes, includes a number of troublesome members. We might call them “black sheep cytokines,” and our ever-watchful physiologic systems detect them and create antibodies to keep them in line. When these antibodies fail to perform, however, we get sick.

Synthesized biologic antibodies use recombinant DNA technology to copy these physiologic antibodies and use them to combat those diseases. The process of identifying which specific antibody combats the disease-causing substance is complex. When it is successful, it results in the creation of an antibody that antagonizes the single specific culprit, while not interfering with other necessary physiologic processes.

Another strategy for preventing or minimizing the damage from a harmful substance such as TNFα is to create an agent that precisely fits into the receptor for the substance, thus blocking the receptor and preventing TNFα from interacting with it. We could think of it as putting a blank key into a lock. The grooves in the key permit it to fit neatly into the lock, but the profile of the key does not allow it to turn the lock. However, while the blank key is in the lock, the key that would otherwise work can’t be inserted, and the lock stays locked. Receptor blockers do exactly that; the receptor blocker itself is inactive, but it effectively prevents the rogue cytokine from reaching its target.

A risk that attaches to many biologics is that antagonizing or blocking the activity of a physiologic substance, only some of whose effects may be harmful, may indeed result in serious adverse effects. Taking tumor necrosis factor as an example, that particular substance is a causative agent in some diseases, but also helps combat some infections. TNFα inhibitors, whether antibodies or receptor blockers, are generally considered safe, but they are linked with some significant risks, among them the reactivation of tuberculosis in persons who have been previously exposed, and also triggering episodes of Herpes zoster. In spite of the name, inhibiting TNFα is not associated with increases in cancers, perhaps because the activity of this cytokine has more to do with disposal of already killed tumors than with actually killing tumors.

Biologics versus biosimilars: the approval process

One reason that biologics are so expensive is that the development of the original agent is highly complex. As we’ve said, they’re painstakingly created to mimic exceedingly complex molecules; this is contrast to many of the most widely-used small-molecule drugs, many of which were discovered by accident or by simple trial-and-error methods (i.e., keep trying the chemicals in your library of 40,000 chemicals until you find one that works in a Petri dish). This doesn’t work for biologics for the simple reason that there aren’t any biologics hanging around in your library, just waiting to be tried out. So the candidate biologics are essentially grown, evolving from some natural substrate. Fo