Antibodies continue to dominate the biopharma market. Analyzing the strategies employed by successful players in the field could provide invaluable lessons for those hoping to enter it.

By Günter Jagschies

Since the 1990s, antibodies have been the leading category of biotherapeutics – both in terms of the development pipeline and the approved range of biotherapeutics. Because of their unique ability to target almost any disease mechanism we can think of, they have a very wide range of medical indications. Moreover, using an antibody-based therapeutic tends to reduce the risk of side effects, improving patient tolerance.

The wide applicability of antibodies has made them a key driver of revenue growth in the biopharma industry – today, they still represent over 50 percent of its overall revenue. The majority of antibody treatments currently focus on cancer and autoimmune disease, plus a few rare diseases, such as hemophilia A, as well as a handful of infectious diseases. Growth in the cancer and autoimmune categories is likely to continue – there are a large number of patients in need of treatment and many disease mechanisms to which antibodies can be directed. And this is reflected by biopharma’s R&D portfolio.

Graph, APIs introduced between 1982 and 2016 (injectable recombinant biotherapeutics).

Fig 1. APIs introduced between 1982 and 2016 (injectable recombinant biotherapeutics).

Many approved antibodies, such as adalimumab, infliximab, trastuzumab and rituximab, are also the most attractive targets for the biosimilars industry, so I expect to see a great deal of activity in terms of both innovator and “me too” products.

Further potential lies in modifying existing antibodies – or building so-called “artificial antibodies” – to create bispecific antibodies (antibodies with two different specific modes of action). Such advanced antibodies open up exciting possibilities: for example, one arm could get the antibody through the blood-brain barrier and the other could bind to a target inside the brain.

Antibody-drug conjugates (ADCs) are another form of exciting modification. By hooking up what’s sometimes called a “warhead” (a highly toxic chemical) to an antibody, specific cells can be targeted with the killer payload. Here, antibodies act to reduce the action of the toxic agent on non-targeted cells, minimizing side effects

It’s clear then that the antibody is not only versatile in terms of addressing a large variety of different diseases, but it’s also versatile from a “design” perspective, meaning that we can generate even more advanced therapies than the antibodies themselves.

Learn from the best

Humira (adalimumab) consistently tops pharma’s annual best sellers’ chart – and that’s despite being first approved back in 2002. Originally developed by Abbot, Humira is a monoclonal antibody directed against various autoimmune diseases, including rheumatoid arthritis and Crohn’s disease. It generates around $18 billion in annual revenue – a figure that grows year upon year (it is expected to reach sales of $21 billion by 2020). Humira uses the same mechanism of action as some of the older drugs in the same field, but it is a fully human monoclonal antibody (the first approved by the US FDA). It is considered highly effective.

Another blockbuster antibody is Avastin (bevacizumab), which, like Humira, has been pulling in high sales for more than a decade. New blockbuster product launches are rare, but there is still a lot of potential to be found in new antibody therapies. For example, a new generation of antibodies directed against the programmed cell death protein 1 (PD-1) work by interfering with the ability of cancer cells to escape the immune system. These medicines, known as checkpoint inhibitors, are causing a great deal of excitement.

Looking further ahead, some companies are looking at antibodies to tackle high cholesterol; targeting this indication could lead to a new blockbuster as it would apply to a large patient population. The antibody train shows no sign of slowing down just yet…

Graph, Revenue development for selected therapeutic proteins.

Fig 2. Revenue development for selected therapeutic proteins. Data from annual manufacturer reports. Double lines: strongest growing products; dotted lines: products experiencing revenue decline.

Little or large?

Aside from finding a good product for an unmet need, what else are the main players doing to find success with antibodies? Manufacturing capability is a must, but some of the conditions for success are easier to replicate than others. Take Roche, for example, which has a very strong pipeline of antibody products and is leading the way with a new generation of antibodies: how many companies – especially smaller ones – would be able to build such large facilities or to recruit the same number of CDMOs?! Such an approach requires huge amounts of financial muscle and bit of an appetite for risk from relying on the continuation of previous R&D success in an environment where still 80 to 90% of new therapeutic candidate molecules fail in the clinic. It’s not an option for everyone.

Amgen has taken a different path, or rather added a new path to its strategy. Amgen is among the first of the established biopharma companies to challenge their own manufacturing paradigm of constructing large, stainless steel facilities. In recent years, Amgen has focused more on flexible manufacturing approaches using single-use technology. Their new facility in Singapore – constructed in 2014 – was significantly smaller than their other facilities but still has the same productivity. The facility uses mainly single use technology and has been approved for operation by a number of major regulatory authorities, including the FDA and EMA. One of the products that will be produced by the facility is denosumab, which is used in the Amgen products Prolia and XGEVA.

Other companies would do well to take cues from Amgen’s approach; such cutting-edge facilities not only minimize footprint but also capital investment, as you do not require stainless steel equipment and the associated pipework and plumbing. And even with the reduced scale, you can still produce a great quantity of product – enough for a global market. It’s a smart approach that can make decision-making and product production much faster and more nimble.

At GE, we see many of our customers looking to scale down their manufacturing facilities. There is a trend towards smaller, more flexible plants in the several thousand-liter scale rather than sprawling stainless steel plants pumping out tens of thousands of liters. Smaller plants are faster to build and to validate – and can take advantage of a modular approach that allows you to expand once you have a better idea of your product’s success in the market.

Many small and start-up companies are developing new ideas as to how antibodies can be used. In many cases, these companies will go on to be acquired by larger companies with the financial capability to progress their ideas further. But with costs to establish manufacturing capability in suitable existing buildings at not much more than $10-15 M , this strategic opportunity lies within reach even for smaller businesses. Despite steep competition and the need for significant investment, the antibody space is a lucrative opportunity with various therapeutic avenues that can be explored.

 

Günter Jagschies is Senior Director of Strategic Customer Relations, GE Healthcare, Freiburg, Germany.