Therapeutic antibodies have changed the cancer treatmentlandscape over the past decade. Both in liquid and solid tumors, antibodieshave become an integral component of treatment regimens that have improved andextended the lives of cancer patients. In addition, antibodies have been ableto improve efficacy while not significantly adding more toxicity. Inhematologic cancers, Rituxan, in combination with chemotherapy, has become thestandard of care in many non-Hodgkin's lymphoma (NHL) subtypes due to theimproved efficacy that it adds to chemotherapy regimens. In solid tumors,Avastin, in combination with chemotherapy, is becoming a standard of care incolorectal, non-small cell, breast and renal cancers.
The traditional challenge in oncology drug development hasbeen that incremental increases in efficacy have been accompanied bysignificant increases in toxicities as the number of chemotherapy drugs beingcombined became unwieldy. Antibodies have overcome this challenge by providingsignificant increases in efficacy with minimal toxicity. This is possiblebecause of the targeted nature by which antibodies work.
The clinical success of antibodies to treat cancer hastranslated into significant commercial success. Antibody oncology sales are forecastedto be more than $27 billion by 2018 in the seven major markets. Despite theseadvances, however, there remains significant unmet need in cancer treatment.
Antibody therapies have historically been used incombination with standard therapies because their activity as monotherapy islimited. Today, antibodies work with a larger proportion of patients and make asignificant contribution to overall or disease-free survival as part of acombination regimen with established cytotoxic chemotherapies. Also, eachantibody is marketed for only a small segment of patients, while many of themost frequent human cancers cannot be treated with these antibodies. Forexample, there are no antibody therapies currently available for the treatmentof many cancers, including ovarian, gastric, pancreas, liver, bladder, brain orprostate cancers.
This unmet need, coupled with the commercial attractivenessof the oncology market, has led to a significant number of drugs indevelopment (1). Oncology is one of the most attractive therapeutic markets; it isprofitable due to low sales and marketing expenses and relatively high drugprices. There are 861 drugs in development to treat cancer (2), many of which areantibodies.
The cancer antibody space is also attractive from a commercialand licensing perspective because several of the leading antibodies will likelyface biosimilar competition in the near future. Rituxan, Herceptin and Erbituxwill lose their exclusivity between 2011 and 2020. As companies seek to developnext-generation antibodies, they will be faced with significant development andcommercialization challenges. Success in the future will be defined much morestringently than in the past. For antibodies, product profiles will need to bemore differentiated than before due to biosimilars and the changing pricing andreimbursement landscape. Small, incremental improvements in efficacy and safetywill not be rewarded in the marketplace as they were in the past. New antibodyapproaches will need to show significant improvements in efficacy to commandsignificant utilization and premium pricing.
One of the key limitations of current antibodies is thatthey have limited single agent efficacy. The vast majority of antibodies aregiven as part of a combination chemotherapy regimen to realize their fullpotential. Enhancement approaches are designed to create more potent antibodiesthat work better in combination or possibly as single agent therapy. Companiesare pursuing three types of enhancements to antibodies in search of improvedproduct profiles. These enhancements include tuned, conjugated andbi-specifics. The enhancements all have a common goal of improving upon theefficacy seen with current antibody approaches.
Tuned antibodies are engineered to better engage the immunesystem's natural killer cells to target and attack cancer cells. A recentexample of a tuned antibody in development is GA101 from Glycart and Roche.GA101 is a humanized anti-CD20 monoclonal antibody engineered to increasetarget cell death. This compound is in phase I/II trials for NHL and CLL. PhaseI data presented at the American Society of Hematology meeting in 2008 showedthat GA101 produced a 58 percent overall response rate in relapsed/refractoryNHL patients (3).
Conjugated antibodies are a second method of antibodyenhancement currently being explored by pharma. Conjugated antibodies containcancer-killing agents such as chemotherapy, toxins or radioisotopes. Therationale for this approach is that the antibody can bring the cancer-killingagent directly to the cancer cell with minimal damage to nearby healthy cells.Conjugated antibodies have experienced limited success as a result of toxicityissues and complicated methods of administration. The toxicity has arisen fromthe fact that the toxic payload is often delivered to both cancerous andhealthy tissues. Examples of conjugated antibodies include theradioimmunotherapies Bexar and Zevalin and the drug-conjugated antibodyMylotarg. More recent approaches in development appear to largely avoid theseunwanted side effects.
The third antibody enhancement approach is bi-specifics. Onesuch approach, developed by Micromet Inc., is called bi-specific T-cellengagers, or BiTE antibodies. BiTE antibodies utilize the body's own immunesystem, specifically T-cells, to kill cancer cells. T-cells are the immunesystem's most potent killing cells due to the fact that they can proliferateand can kill targeted cells serially. BiTE antibodies have two arms, one thatconnects to a cancer cell, and the other that connects to a T-cell. Once bothconnections have been made, the T-cell releases its deadly toxins into thecancer cell.
Development approaches for antibodies are evolving toreflect the targeted nature of cancer treatment. Companies are pursuing nicheindications that previously would have been avoided due to lack of commercialpotential. The advantages of pursuing niche indications, especially for acompound's first indication, are numerous. Some of these advantages includeunencumbered regulatory pathway, few competitors, ability to conduct single-armtrials with response rate as an endpoint and premium pricing. Companies canthen expand development beyond these niche indications to maximize thepotential of their products. Several antibodies and targeted small moleculeshave been clinically and commercially successful with this approach, includingHerceptin, Gleevec and Rituxan.
In addition to the high level of activity in antibodydevelopment, novel antibodies are an area of intense licensing activity andinterest. There are several reasons for this interest. First, these therapieshave the potential to extend the lifecycle of successful antibody products. Aprime example is trastuzumab DM-1 from Immunogen. This compound is a conjugatedversion of Herceptin. Trastuzumab DM-1 was licensed to Genentech as a lifecyclemanagement approach to the impending patent expiration of Herceptin. Inaddition, these approaches provide risk mitigation by diversifying a company'sproduct pipelines. By utilizing different approaches and mechanisms againstsimilar targets, the high risk of failure can be mitigated.
In summary, antibody enhancement represents an approach toimproving the clinical performance of these agents in an environment that willdemand significant advances in efficacy to be commercially successful. Thepromise of these agents is evidenced by the early clinical data and the intensedevelopment and licensing activity seen in this space.
Mark Reisenauer is senior vice president and chief commercialofficer of Micromet Inc. in Bethesda, Md. Reisenauer joined Micromet fromAbbott, where he served as the general manager of the Oncology franchise from2002 to 2006 and divisional vice president and general manager of theNeuroscience franchise from 2006 to September 2007. Before joining Abbott,Reisenauer was the director of marketing for breast cancer and the director ofbreast cancer products at Pharmacia from 1999 to 2002. From 1997 to 1999, hewas the associate director of oncology global marketing at Bristol-Myers SquibbCo., and from 1988 to 1997, he held various positions in sales and oncologymarketing at Zeneca. Reisenauer holds a B.A. degree in Political Science fromthe University of Wisconsin.
1. DataMonitor, Commercial Insight: Molecular TargetedCancer Therapies, August 2009
2. PhRMA 2009 Report, Medicines in Development for Cancer
3. Dr. Gilles Andre Salles, et al., A Phase I/II Study ofRO5072759 (GA101) in Patients with Relapsed/Refractory CD20+ Malignant Disease, Abstract 234, ASH 2008