Realizing the Promise of Biologics
Biologics-based medicines are benefiting more patients with unmet medical needs than ever before. While they have their own challenges, these targeted therapies offer tremendous opportunities to take personalized healthcare to new heights.
The future of biologics and its growing potential to benefit patients with unmet medical needs has perhaps never been more promising. This was not always a given.
A mere twenty-five years ago, the future of the biologics industry as we now know it today seemed to be over even before it began. A now-infamous1 phase 3 clinical trial of a monoclonal antibody (mAb) in development for the treatment of gram-negative sepsis had just been halted following patient deaths. It was a bleak moment, both for many families and in the short history of biologics. However, against the backdrop of such serious concerns, the industry learned significant lessons that have profoundly changed the ways in which we approach development, testing, and regulation of biologic drugs.
Those lessons have now informed a multibillion-dollar biologics industry in which 7 of the top ten best-selling medicines globally are biologics—including a medicine developed by the very company whose phase 3 study had been halted. The list of medicines that impacts so many patient lives includes Humira—not merely the best-selling biologic, but the best-selling drug worldwide (originally developed through a partnership of Cambridge Antibody Technology, now part of MedImmune, and BASF).
What’s more, the most successful biologic drugs on the market today cross a variety of therapy areas, treating such devastating diseases as multiple sclerosis, Crohn’s disease, asthma, psoriatic arthritis, rheumatoid arthritis, chronic pain and cancer; hundreds more are in pre-clinical or clinical development. The biopharmaceutical industry has stepped up its already-robust efforts to develop new and better biologics to address a multitude of still-unmet needs. At AstraZeneca, for example, biologics now represent 50 percent of our overall pipeline, up from 5 percent just 10 years ago.
In an industry that inherently exists on the premise of risk and reward, there’s no question that salvaging biologics’ early legacy and getting us to where we are now was in large part due to the perseverance of researchers. They recognized the failures of biologic drug development for what they were: a mandate to do better; to scrutinize and follow the science; and to design safe, effective—and groundbreaking—medicines with the potential to vastly improve, and even save, lives.
Biologics versus small-molecule drugs
What is unique about biologics—and why they are so important to the future of medicine on a global scale—is their ability to interact with challenging therapeutic targets; something that has eluded the more traditional and familiar small-molecule drugs. Also unique is the composition of biologic drugs. These are very large molecules derived from living cells and produced using recombinant DNA technology; they are typically composed of thousands of atoms. Small molecules are synthetically produced through a more predictable chemical process. Biologics are complex—or heterogeneous—and small molecule drugs are simpler and well defined. A small molecule such as aspirin, for example, contains just 21 atoms; a typical biologic has more than 25,000 atoms.
This is an important distinction. Small molecules by virtue of their size, structure and chemical composition can infiltrate most anywhere in the body, easily penetrating cell membranes. Large molecules such as mAbs, on the other hand, recognize explicit structures on cell surfaces or soluble proteins and are able to bind to specific receptors associated with a disease process or soluble proteins. It’s their specificity -- this finely targeted approach to therapeutics – that also gives large molecules a better safety profile and where biologics are making their impact. Most noteworthy, is that we’re seeing this effect in complex diseases such as cancer and diabetes and others in which the immune system is involved—respiratory and inflammatory conditions like lupus, for example. Collectively, these illnesses affect millions of people worldwide. Biologics now offer a tangible hope for treatment, particularly for the most severe and relentless forms of these diseases.
Challenges in developing biologics
But, there are challenges. Because of their comparative complexity, biologics require a significant investment—of time, money, and a multitude of resources—perhaps more so than anywhere else in the pharmaceutical industry. Where small molecules have a fixed, defined and, relatively speaking, inexpensive process -- one that has been cultivated and refined over decades -- the making of a biologic is far more intricate and costlier. In addition to the numerous clinical trials needed to establish safety and efficacy (as with small molecules), development includes a more complex manufacturing process that begins with genetically engineering a cell to produce a protein, testing to ensure quality, and harvesting, purifying, and stabilizing the protein.
As our technologies for developing biologics continue to advance and improve, we will almost certainly see the cost of manufacturing decrease. In our own labs, our preeminent concern is creating safe and effective medicines for patients. But, we also are focused on developing new technologies that can help us to streamline the design, development and manufacture of biologics—from protein engineering and advanced manufacturing technologies to innovative collaborations that enhance flexibility and scalability, while simultaneously improving quality and throughput, and controlling costs.
Now and toward the future
Despite these challenges, there are vast opportunities for biologics now and even more promising ones for the future. The industry is in the midst of numerous innovations that include immunotherapies, antibody drug conjugates, bispecific antibodies, combination therapeutics, companion diagnostics, and gene and cell therapies—all of which are setting the stage for significant disruption, creating more therapeutic targets and, ultimately, taking personalized healthcare to new and astounding heights.
In our own labs, there are more than 120 biologics in research and development, with more than 40 of those in the clinic. Among those trials are biologics for cancer and autoimmune diseases, and we’re currently completing phase 3 trials for a best-in-class biologic for severe asthma—benralizumab. This is the largest phase-3 development program for a biologic in respiratory disease and it could potentially have a profound impact on the quality of life for those with severe asthma.
We, and our industry peers, are not stopping here. There are a number of technology platforms that will fuel the next generation of biologics, and we are all attuned to their potential for helping to create even more powerful medicines.
The rise of biosimilars
Making a quick ascent on this front are biosimilars -- approved biologic versions of original “innovator” products that can be manufactured when a patent has expired. The US Food and Drug Association (FDA) has approved four biosimilars in the US—Zarxio, Inflectra, Erelzi and Amjevita.
In contrast to a generic, which is a relatively straightforward replication of a chemical formulation, a biosimilar is not an exact copy of the original biologic. While the process of translating DNA to a protein is a fixed process, slight modifications – what is known as post-translational modifications -- can impact immunogenicity, safety or effectiveness of the product. Further, minor changes in the manufacturing process could cause significant changes in the quality and safety of the molecule. As with all biologics, we must make sure that there is a regulatory framework that protects patient safety, ensures product effectiveness, and incentivizes continued innovation.
Biosimilars are an increasingly important part of the core business of several pharmaceutical companies, representing an alternative for patients and their healthcare providers even though the cost to manufacture a biosimilar is not significantly lower. To ensure these products meet the expectations of both regulators and patients, we all need to increase our understanding and expertise in this area.
But this, of course, is science. And as scientists, our innate desire is to seek and find answers; to follow the science; to not let failure discourage us, but rather to use it as a stepping stone for more determined inquires. After all, our patients are waiting.
1Marks, L. The birth pangs of monoclonal antibody therapeutics: The failure and legacy of Centoxin. MAbs [Internet]. 2012 May; 4 (3); 403-412.