IDEA Pharma has worked on positioning a range of blockbuster drugs over the years and you know you’ve been in the game for a long time when you see those drugs now facing generic (in the case of small molecules) or biosimilar (for biologics) competition.

The generics market is pretty well characterized so the key question is whether the period we are entering now will see the biosimilars market come of age.

Most biosimilar interest focuses on the rheumatoid arthritis market – 4 of the world’s 5 top-selling brands major are here and all 4 of them are biologics, with 3 of them (Humira, Enbrel and Remicade) being from the same anti-TNF class (used in various autoimmune diseases, especially rheumatoid arthritis), all of which are facing massive biosimilar pressure. And not just from specialist generics houses, as we shall see.

One biosimilar does have problems, however. Samsung Bioepis’ version of Amgen and Pfizer's Enbrel is going so well post-launch that analysts believe more manufacturing capacity may be needed to cope with demand, and biosimilar production is not a cheap or quick process to upscale.  Being mean, I could point out that they got their forecasts way too low but revenues rising three times faster than initial forecasts is a problem most companies would tolerate!

Europe is the current hotbed for biosimilars with the performance of biosimilars of Johnson & Johnson and Merck & Co's Remicade (infliximab) seemingly having grown the European market by around 10%-20%. Importantly, that suggests price reductions are leading to reduced levels of rationing these medicine by cost-conscious state-funded health systems.

Celltrion and partner Pfizer were first to market with Remicade clones in Europe, launching their Remsima/ Inflectra products last year. Since then, these drugs have captured around 30%-40% of the EU market, which in turn accounts for around a third of global sales. Analysts expects that share to exceed 50% before long. Samsung Bioepis further stirred the waters in the EU last month with the launch of its Flixabi version of Remicade.

Biogen (which operates with a range of partners, including Samsung), becoming the first drug maker to market two anti-TNF biosimilars in the UK earlier this year. Samsung Bioepis looks outside the anti-TNFs and has advanced biosimilar versions of Sanofi's blockbuster insulin Lantus (insulin glargine), AbbVie's anti-TNF treatment Humira (adalimumab), Roche's breast cancer drug Herceptin (trastuzumab) and its multicancer drug Avastin (bevacizumab) -plus it has another 7 molecules in early stages of development. The FDA accepted Samsung Bioepis’ application for the infliximab biosimilar in May.

Outside Europe, interest in launching biosimilars in emerging markets appears to have waned with Celltrion, for example, saying it has no plans in the next four to five years, saying that even in larger markets such as China and India patient spending is too low, the market is too complicated and the authorities' stance on biosimilars too uncertain.

So what is happening in the largest market of them all, the US of A, where the anti-TNF market alone is worth $20 billion a year??

Regulators are moving faster than in the past. Pfizer’s Hospira unit won U.S. FDA approval for its Remicade biosimilar just last month and its launch is imminent. Novartis’ Sandoz gained FDA panel backing for its Enbrel biosimilar, while Amgen got similar backing for its version of AbbVie’s Humira, the dominant drug in the category. Meanwhile, Samsung Bioepis is still awaiting FDA approval for its Remicade version in the U.S. after filing it in May.

Given the stakes involved, the originators of the blockbusters are NOT giving up easily. Patent lawsuits will keep those launches at bay for some time, at least for the Enbrel and Humira biosimilars, but the fights over the patents on Remicade, Enbrel and Humira are all still raging. And though Remicade’s patent case is weak enough to encourage Pfizer to move ahead with an “at risk” launch of its Inflectra biosimilar next month, the outstanding IP protection on the other two brands is likely to give Sandoz and Amgen pause.

Of course, it is possible to launch a biosimilar before an IP battle is resolved but this places the copyists at risk for restitution and damages if the patents stand. Unless and until upcoming court dates and filings offer enough encouragement, the launches are likely to wait.

We have concentrated so far on manufactures and payers, but we’ve left out two major stakeholders, the people who write the prescriptions and the institutions that set the guidelines.

The originators have done a tremendous job of planting this seed of doubt in their minds. Biologics are incredibly complex molecules with huge multi-dimensional protein chains and backbones on which sugars and other subgroups sit, which can in turn affect how the proteins function. How can different microbial batches in different production containers thousands of miles apart produce “identical” molecules? The copyists respond by producing data which show that the original and copies, although not identical, behave very similarly in assays and biological systems, i.e. they hint/ claim they are interchangeable.

However, that lack of FDA guidance on interchangeability (and the absence of such a designation in the EU) has not stopped more than 20 US states from enacting legislation that would prohibit pharmacists from switching patients from a biologic to a non-interchangeable biosimilar without a doctor’s consent.

What has been missing, till now, is a large scale, long term study to compare an original with its biosimilar to see if the patients fare differently. So far, these studies have been small and not carried out within a national framework involving all stakeholders.

This trial - called NOR-SWITCH - presented at the 2016 United European Gastroenterology Week in Vienna, and run in collaboration with the Norwegian health authorities, showed that swapping from Remicade (after at least 6 months stable treatment) to a biosimilar version made by Celltrion posed no problems across 481 patients regardless of the disease for which they were taking the drug (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn's disease or chronic plaque psoriasis).

Worsening of disease after a year was primary measure in the trial, and this occurred in 26.2% of those who remained on Remicade and 29.6% of those who switched to the biosimilar, a difference that did not reach the pre-defined level statistical significance. The incidence of antibody formation and adverse events was also the same.

Norway, it must be said is pro-switching with biosimilars having just about achieved complete market penetration, with 90% or more prescribing rates also seen in Denmark and Finland. Conversely in Sweden - where switching is not endorsed - biosimilars have around a third of the market.

How much influence, however, will the NOR-SWITCH data have on the large health care market globally?

The US Congress started the process for the introduction of biosimilars in the US with the Biologics Price Competition and Innovation Act (BPCIA) but further congressional action is now needed to reinforce the intent of BPCIA and finalise the biosimilar approval process. Presumably whether or not the Democrats can regain control of Congress will have a major bearing on future directions.

The NOR-SWITCH trial is not the end of the interchangeability question but (to misquote Winston Churchill) it may be the end of the beginning. Watching it unfold is going to be fascinating.