Biotherapeutics: the way of the future?

There has been much talk about biotherapeutics as the drugs of the future. But is the small molecule approach really on the way out? A biotherapeutics approach certainly has its advantages in some instances, as Dr. Katherine Call, Global Head of Biotherapeutics Initiative, sanofi-aventis, explains. “A biotherapeutics approach – whether it’s recombinant proteins, antibodies, engineered antibodies or newer developments such as RNAi – allows us to address targets or biology that in some cases may not be as amenable to small molecule approaches. However, small molecule drugs will always have a strong place in addressing diseases.”

Sanofi-aventis has recently made a commitment to increase its proportion of biotech-driven drugs to 20-30 percent and has spent a considerable amount of time and energy building up its biotherapeutics programs and associated capabilities. Call has been leading a global cross-functional Biotherapeutics Initiative team, mandated by senior Discovery Research management, for the past several years. This work first involved assessing the current state of the field, what types of molecules and treatments were being developed by a variety of different biotherapeutics approaches and then formulating and initiating therapeutic programs and building the required capabilities.

Several years ago, after that initial assessment was performed, the company made a decision to get into biotherapeutics internally. It had already been involved in biotherapeutics, for example, with its diabetes insulins franchise and also through external collaborations. With respect to the latter, sanofi-aventis has had a large ongoing collaboration with ImmunoGen for the past five years in the field of oncology, in which there is a joint portfolio of naked and immunoconjugate antibody programs. Sanofi-aventis also has an ongoing collaboration with Regeneron for a vascular endothelial growth factor (VEGF) trap.

“Those two biotherapeutics collaborations have been very productive,” says Call. “They were key entry points into antibody and trap-based biotherapeutics. However, sanofi-aventis decided we also needed to augment our efforts further. As such, we initiated an internal program across a broad array of therapeutic indications. Concomittantly, we assessed how to leverage our strong capabilities, such a protein production for biotherapeutics, as well as strengthen other required capabilities. This was done in a cross-functional initiative that involved researchers from five therapeutic departments, biological sciences, chemical sciences and DMPK-Safety departments, as well as our Partnerships and Alliances and Legal functions. Researchers within the company were very enthusiastic to contribute to biotherapeutics and a number of them had strong prior experience in the field.”

This allowed sanofi-aventis to build up its own internal capabilities as well as more broadly address therapeutic indications that were not encompassed in its initial biotherapeutics collaborations. “We worked to put therapeutic programs in place – everything was very program driven. We had strong participation from groups like internal medicine, which covers inflammation, diseases like asthma, rheumatoid arthritis, pain and chronic obstructive pulmonary disease (COPD); and we developed a number of programs with them and other therapeutic groups. We built up the capabilities we needed to be able to mount competitive programs and to progress them very rapidly as well.”

Internal and external progress

The company’s external collaborations have resulted in some exciting compounds in its biotech pipeline, including the VEGF trap being developed with Regeneron. “It’s quite advanced – phase II – so we’re very excited about that,” says Call. The relationship has led sanofi-aventis to an additional alliance with Regeneron in 2007 that is larger and broader in scope.

“Our collaboration with ImmunoGen on monoclonal antibodies targeted to cancer has been also very fruitful for us. We have two compounds in clinical phase I, and we have advanced several antibodies in this alliance into preclinical; we’ve done both naked as well as immunoconjugate approaches.”

The company’s internal efforts in biologics are more nascent, but Call says it does have a solid, competitive portfolio of early-stage projects in a number of different disease areas – including monoclonal antibodies, engineered antibodies and traps. Furthermore, some of these have progressed to development in a relatively short, rapid time frame. In addition, sanofi-aventis integrated a wholly owned group in the Paris region focused on traps and antibodies to further strengthen internal biotherapeutics expertise and headcount.

The biotherapeutics approach has its advantages, but how easy will it be for companies to expand into this market? According to Call, the challenge will be in progressing to an improved next generation of biologic molecules. “Biotherapeutics is a growing and evolving field and there are a lot of innovative technologies being developed. New and improved immunoconjugate chemistries will be important for oncology. This is an area our chemistry department is working on with ImmunoGen and also independently.”

Call is aiming to be able to better predict and engineer molecules so that the company can decrease the liability of immunogenicity and better tailor the properties of molecules, such as half-life and distribution for better therapeutic molecules. These, she says, are some of the key areas for future biotherapeutic advancements.

Accessing innovation

In terms of accessing innovative technologies, Call keeps a keen eye on what’s happening externally, while at the same time promoting internal innovation. “Much innovation goes on outside of our own walls. Our scientists are very creative, talented and innovative, but biotherapeutics is a large field, so we definitely expect to be accessing external innovations. As part of our Biotherapeutics Initiative, I also lead a cross-functional global team that assesses key technologies, benchmarks, assesses gaps and recommends solutions. For example, sanofi-aventis recently signed a deal with Dyax to gain access to phage display. If we think a biotech company or academic laboratory has a therapeutic molecule, target or method that is important and would benefit our biotherapeutic portfolio, then it makes sense to evaluate it.”

That said, sanofi-aventis has also been innovative internally. While the company’s main goal is advancing products, it also has some novel, innovative methods, for example related to antibody engineering, that facilitate therapeutic program progression. “We also have been leveraging our genomics, informatics and other capabilities to find targets of interest.”

The best molecules

Biotherapeutics is obviously a thriving area, but will it really take over from the more traditional small molecule approach? And which method will ultimately prove more profitable? “The most important thing is addressing the patient’s needs and tailoring the therapy to be effective against the disease that we’re trying to ameliorate. Biotherapeutics and small molecules each have a unique advantages and challenges – it’s a matter of finding the best molecules that provides an advantage in addressing the disease. In some cases, that’s going to be better addressed in the biotherapeutics approach and other cases through a small molecule.

“Take ion channels,” Call continues to say. “They are an important class of targets, but they present challenges. It is often difficult to get small molecules with high specificity. It can also be a challenge to get functional antibodies with desired properties to ion channels, but specificity can be more readily addressed in the isolation and screening. So again, it’s really the disease and the target that you need to think about in making decisions about a biotherapeutic versus small molecule approach.”

As to profitability, Call concludes, if a company can demonstrate that they have a treatment that’s better and provides an advantage, it should have potential to be profitable whether it’s a biologic or a small molecule. Sanofi-aventis’ aim is first-in-class treatments – both small molecule and biologics – that benefit the patient.

About Dr. Katherine M. Call

Dr. Katherine M. Call is globally responsible for the Biotherapeutics Initiative within Discovery Research at sanofi-aventis. She joined the company as Head of Molecular Genomics at the Cambridge Genomics Center (CGC) in 2000, was appointed Global Head, Genomics Technology Transfer/Management in 2001 and promoted to Global Head, Biotherapeutics in 2005. She has been key in establishing and strengthening genomics platforms, primarily through large-scale technology transfer from Millennium.