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Next-gen antibody approaches to cancer treatment offer improved product profiles, greater commercial success
October 2009
by Mark Reisenauer  |  Email the author

Therapeutic antibodies have changed the cancer treatment landscape over the past decade. Both in liquid and solid tumors, antibodies have become an integral component of treatment regimens that have improved and extended the lives of cancer patients. In addition, antibodies have been able to improve efficacy while not significantly adding more toxicity. In hematologic cancers, Rituxan, in combination with chemotherapy, has become the standard of care in many non-Hodgkin's lymphoma (NHL) subtypes due to the improved efficacy that it adds to chemotherapy regimens. In solid tumors, Avastin, in combination with chemotherapy, is becoming a standard of care in colorectal, non-small cell, breast and renal cancers.  
The traditional challenge in oncology drug development has been that incremental increases in efficacy have been accompanied by significant increases in toxicities as the number of chemotherapy drugs being combined became unwieldy. Antibodies have overcome this challenge by providing significant increases in efficacy with minimal toxicity. This is possible because of the targeted nature by which antibodies work.  
The clinical success of antibodies to treat cancer has translated into significant commercial success. Antibody oncology sales are forecasted to be more than $27 billion by 2018 in the seven major markets. Despite these advances, however, there remains significant unmet need in cancer treatment.  
Antibody therapies have historically been used in combination with standard therapies because their activity as monotherapy is limited. Today, antibodies work with a larger proportion of patients and make a significant contribution to overall or disease-free survival as part of a combination regimen with established cytotoxic chemotherapies. Also, each antibody is marketed for only a small segment of patients, while many of the most frequent human cancers cannot be treated with these antibodies. For example, there are no antibody therapies currently available for the treatment of many cancers, including ovarian, gastric, pancreas, liver, bladder, brain or prostate cancers.  
This unmet need, coupled with the commercial attractiveness of the oncology market, has led to a significant number of drugs in development (1). Oncology is one of the most attractive therapeutic markets; it is profitable due to low sales and marketing expenses and relatively high drug prices. There are 861 drugs in development to treat cancer (2), many of which are antibodies.  
The cancer antibody space is also attractive from a commercial and licensing perspective because several of the leading antibodies will likely face biosimilar competition in the near future. Rituxan, Herceptin and Erbitux will lose their exclusivity between 2011 and 2020. As companies seek to develop next-generation antibodies, they will be faced with significant development and commercialization challenges. Success in the future will be defined much more stringently than in the past. For antibodies, product profiles will need to be more differentiated than before due to biosimilars and the changing pricing and reimbursement landscape. Small, incremental improvements in efficacy and safety will not be rewarded in the marketplace as they were in the past. New antibody approaches will need to show significant improvements in efficacy to command significant utilization and premium pricing.  
One of the key limitations of current antibodies is that they have limited single agent efficacy. The vast majority of antibodies are given as part of a combination chemotherapy regimen to realize their full potential. Enhancement approaches are designed to create more potent antibodies that work better in combination or possibly as single agent therapy. Companies are pursuing three types of enhancements to antibodies in search of improved product profiles. These enhancements include tuned, conjugated and bi-specifics. The enhancements all have a common goal of improving upon the efficacy seen with current antibody approaches.
Tuned antibodies are engineered to better engage the immune system's natural killer cells to target and attack cancer cells. A recent example of a tuned antibody in development is GA101 from Glycart and Roche. GA101 is a humanized anti-CD20 monoclonal antibody engineered to increase target cell death. This compound is in phase I/II trials for NHL and CLL. Phase I data presented at the American Society of Hematology meeting in 2008 showed that GA101 produced a 58 percent overall response rate in relapsed/refractory NHL patients (3).
Conjugated antibodies are a second method of antibody enhancement currently being explored by pharma. Conjugated antibodies contain cancer-killing agents such as chemotherapy, toxins or radioisotopes. The rationale for this approach is that the antibody can bring the cancer-killing agent directly to the cancer cell with minimal damage to nearby healthy cells. Conjugated antibodies have experienced limited success as a result of toxicity issues and complicated methods of administration. The toxicity has arisen from the fact that the toxic payload is often delivered to both cancerous and healthy tissues. Examples of conjugated antibodies include the radioimmunotherapies Bexar and Zevalin and the drug-conjugated antibody Mylotarg. More recent approaches in development appear to largely avoid these unwanted side effects.  
The third antibody enhancement approach is bi-specifics. One such approach, developed by Micromet Inc., is called bi-specific T-cell engagers, or BiTE antibodies. BiTE antibodies utilize the body's own immune system, specifically T-cells, to kill cancer cells. T-cells are the immune system's most potent killing cells due to the fact that they can proliferate and can kill targeted cells serially. BiTE antibodies have two arms, one that connects to a cancer cell, and the other that connects to a T-cell. Once both connections have been made, the T-cell releases its deadly toxins into the cancer cell.  
Development approaches for antibodies are evolving to reflect the targeted nature of cancer treatment. Companies are pursuing niche indications that previously would have been avoided due to lack of commercial potential. The advantages of pursuing niche indications, especially for a compound's first indication, are numerous. Some of these advantages include unencumbered regulatory pathway, few competitors, ability to conduct single-arm trials with response rate as an endpoint and premium pricing. Companies can then expand development beyond these niche indications to maximize the potential of their products. Several antibodies and targeted small molecules have been clinically and commercially successful with this approach, including Herceptin, Gleevec and Rituxan.
In addition to the high level of activity in antibody development, novel antibodies are an area of intense licensing activity and interest. There are several reasons for this interest. First, these therapies have the potential to extend the lifecycle of successful antibody products. A prime example is trastuzumab DM-1 from Immunogen. This compound is a conjugated version of Herceptin. Trastuzumab DM-1 was licensed to Genentech as a lifecycle management approach to the impending patent expiration of Herceptin. In addition, these approaches provide risk mitigation by diversifying a company's product pipelines. By utilizing different approaches and mechanisms against similar targets, the high risk of failure can be mitigated.   
In summary, antibody enhancement represents an approach to improving the clinical performance of these agents in an environment that will demand significant advances in efficacy to be commercially successful. The promise of these agents is evidenced by the early clinical data and the intense development and licensing activity seen in this space.

Mark Reisenauer is senior vice president and chief commercial officer of Micromet Inc. in Bethesda, Md. Reisenauer joined Micromet from Abbott, where he served as the general manager of the Oncology franchise from 2002 to 2006 and divisional vice president and general manager of the Neuroscience franchise from 2006 to September 2007. Before joining Abbott, Reisenauer was the director of marketing for breast cancer and the director of breast cancer products at Pharmacia from 1999 to 2002. From 1997 to 1999, he was the associate director of oncology global marketing at Bristol-Myers Squibb Co., and from 1988 to 1997, he held various positions in sales and oncology marketing at Zeneca. Reisenauer holds a B.A. degree in Political Science from the University of Wisconsin.  
1. DataMonitor, Commercial Insight: Molecular Targeted Cancer Therapies, August 2009  
2. PhRMA 2009 Report, Medicines in Development for Cancer
3. Dr. Gilles Andre Salles, et al., A Phase I/II Study of RO5072759 (GA101) in Patients with Relapsed/Refractory CD20+ Malignant Disease, Abstract 234, ASH 2008



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