By Annemarie Vroom-ten Wolde, Ph. D.
Today there’s no longer a clear difference between “innovative pharma” and “generic pharma,” since everybody will be doing both. Almost all Big Pharma players have plans to enter — or have already entered — the biosimilars market, from innovative player Novartis (with its generics unit Sandoz) to generics player Teva with its “biogenerics” (and acquired innovative biologics). So, the difference between the two industrial sectors is rapidly fading away.
Since Europe’s regulatory agency EMA (European Medicines Agency) released a draft guideline for the development of biosimilar monoclonal antibodies (mAbs) in November 2010, even more companies are considering entering this business.
Until now, the EMA has approved 14 biosimilars in just a few different classes, including growth hormones (rhGHs), erythropoietins (EPOs), and filgrastims (granulocyte colony-stimulating factors, G-CSFs). Though these biosimilars still show a low market penetration in Europe — except in Germany, where a fixed reference price group resulted in a cascade of price reductions — some analysts are optimistic about future chances in the field. “One of the reasons for the slow uptake of biosimilar EPOs and filgrastims in Europe may be that they are presently competing with second-generation products,” comments biosimilars expert Huub Schellekens, M.D., Ph.D., professor of pharmaceutical biotechnology at Utrecht University, the Netherlands.
Some issues still need to be cleared before the EMA-approved biosimilar EPOs, filgrastims, or growth hormones can really penetrate the market, such issues include whether they are “substitutable” or “exchangeable” with their reference originator biologics. Substitution, is in fact, a legal issue. For example, if a physician writes a prescription, the patient often gets something else at the pharmacy, because the insurer or authorities dictate this. Exchangeability, on the other hand, is a medical issue. In practice it means whether a physician can shift a patient’s medication from one product to the other. There are several forms of exchangeability. Schellekens explains, “You should make a sharp definition of the kind of exchangeability you are talking about, since it’s becoming a ’word game’ between the innovative pharmaceutical industry, health insurance companies, and biosimilars manufacturers.”
First, you have exchangeability at population level, which is decided by the regulatory authorities. For example, if the EMA gives an indication when the biosimilar can be prescribed — for example, you can use biosimilar erythropoietin (EPO) for anemia in chronic kidney disease — then it is exchangeable at population level. But this doesn’t mean that this also happens, or is desirable, at patient level.
If a patient is doing well on a specific biotech drug, then the general opinion is that if there’s no urgent reason to change this, the physician should continue to treat him with this product. For example, if a patient comes to the hospital for a week to get another treatment with EPO, it is good clinical practice to give him the same EPO product as he got before.
Another problem influencing this decision is traceability. “If something happens with a product, it’s important that the physician knows which product he gave to his patient. If you look at the legal regulations about this in the various countries, or what the EMA advises about it [for example, that you mustn’t shift a patient to a different biotech drug without consulting a professional healthcare provider] it is purely a matter of traceability, and not of exchangeability, as sometimes the innovative industry tries to make us believe,” Schellekens stresses.
The main question may be why the biosimilars market penetration varies so much from country to country — and why it is still relatively small in Europe. Schellekens says, “The biggest fights are about monoclonal antibodies, which are sold for EUR 50,000 to 100,000 (US $71,500 to $143,000) per patient. If you look at it closely, you will conclude that these biosimilar mAbs may show a much higher uptake than the current biosimilars.”
The first reason for a faster uptake of biosimilar mAbs may be that monoclonals have extremely high margins. Biosimilar mAbs may be a bit cheaper, but they still have very high margins. Second, exchangeability is not a big issue for mAbs if they are given to terminal patients. “This may sound a bit harsh, but terminal cancer patients don’t live very long. So, you won’t get a chance to switch to a different monoclonal in these months, because after a year you have a completely new patient population. And, this means you’ll get a much larger turnover,” Schellekens explains. Third, competition with second-generation mAbs won’t be an issue for biosimilar mAbs since there are no second-generation monoclonals on the market yet. Schellekens adds “This is probably why the innovative original mAbs producers are worried so much about biosimilar mAbs. But, even more important, Europe’s EMA Guideline is very much in favor of biosimilars manufacturers.”
Carsten Brockmeyer, Ph.D., a biosimilar expert and managing director of Brockmeyer Biopharma in Holzkirchen, Germany, is not so optimistic about biosimilar mAbs. “On one side, the EMA draft guideline still leaves some important topics open. I think that, for instance, interchangeability and extrapolation of indications, at least in oncology, are not really covered. On the other side, the EMA draft guideline is very scientific, and provides detailed guidance on in-vitro comparability testing and other development issues. I agree there will be a bright future for biosimilar antibodies, but this may be on a case-by-case basis. The development of a biosimilar antibody will cost US$150 million to $200 million, and will take at least seven to eight years. First movers in this field will have an advantage if they consider all critical steps when entering this pioneering space. This also includes a close observation of the market and innovator environment, since there will always be a risk that the biosimilar becomes obsoleted by a biobetter or a new molecular entity [NME] in a given indication. Without interchangeability, it will always remain an originator-like market.”
Frank Moffatt, Ph.D., an expert in strategic business opportunity analysis of biosimilars and mAbs at Solvias in Basel, Switzerland, is not so optimistic. “In the context of chemistry, manufacturing and controls [CMC] it looks clear to me that analytical comparability for biosimilars is essentially the same exercise as would be performed for, say, a process change [i.e. using a broad set of characterization measurements].”
Moffatt cannot see the bright future for biosimilar mAbs in the short term because of the high cost of entry and lack of interchangeability, which is complex in the EU. ”It could work in favor of a biosimilar producer with a very powerful marketing organization. Then we have other factors, such as immaturity [with scope for biobetters] and competition [for example small molecules that are much cheaper to produce, and perhaps other totally different technologies]. Blockbuster biologics will prove to be irresistible targets with Big Pharma staring over the edge of the patent expiry precipice, but they will not sustain previous levels of innovation-driven growth.”
Ron Rader, a U.S. biopharmaceutical consultant and president of the Biotechnology Information Institute, thinks the future for biosimilar mAbs is bright, but only in the sense that a number of companies are actively developing these products and, in general, do not foresee major technical difficulties in producing them or getting approvals. “If anything, as with other biosimilars, there are already too many biosimilar versions of each product known to be in development, even before one considers biobetters and eventually substitutable biogenerics, both of which could take significant market share from the biosimilars. I think a future major problem will be too many biosimilars [and biobetters and biogenerics] producers, with most not likely to make much, if any, profit,” he concludes.
So, if you want to enter the biosimilar mAbs field, join it fast to stay ahead of all these possible competitors. Payors and patients will really welcome your cheaper monoclonal antibodies.