By Lisa Natanson, Senior Analyst, Deloitte Recap LLC
A new report  analyzing FDA-approved monoclonal antibodies (mAbs) produced by a select group of leading biotechnology companies shows that clinical development times – specifically the duration of Phase II and Phase III trials – are lengthening, while FDA review times have remained constant. The average time from investigational new drug (IND) filing to market was 6.7 years for 11 mABs approved between 1994 and 2003 but shot up to 8.3 years for 12 mAbs approved between 2004 and March 9, 2011, according to Deloitte Recap LLC’s analysis, Therapeutic Monoclonal Antibodies – Insights, Strategies and Data .
Deloitte Recap data show that mAbs developed in the 2004-2011 time period spent an average of 2.4 years in Phase I trials, 2.2 years in Phase II trials and 2.7 years in Phase III trials, followed by about a year of FDA review, on average. Longer trials may be the result of mAb developers’ continued focus on unmet medical needs, including intractable diseases. The recently approved mAbs, Benlysta for auto-antibody positive systemic lupus erythematosus (9.4 years from IND to US approval) and Yervoy for inoperable or metastatic melanoma (10.6 years from IND to US approval), are prime examples of this trend. Both mAbs were generated by companies in the Deloitte Recap data set, Human Genome Sciences Inc. discovered Benlysta and Medarex (subsequently acquired by Bristol-Myers Squibb) discovered Yervoy.
The report also reveals that mAb developers’ extensive use of special FDA mechanisms to speed development – specifically, Fast Track designation , Accelerated Approval  and Orphan Drug status  – has not decreased the number of years it takes to get from Phase I trials to market in the US. The only FDA mechanism that had a measurable impact on mAb development time was Priority Review , which cut the mean time spent at FDA from 18.7 months to 10.1 months. Surprisingly, Fast Track-designated mAbs (about a third of all FDA-approved mAbs to date) had development times that were an average of 12 months longer than non-Fast Track mAbs.
Importantly, biotechnology companies tracked in Deloitte Recap's Development Optimizer database  have achieved a relatively high compound approval success rate (ASR) of 23% for mAb development, with notable success in immunological and inflammatory indication pursuits (24%) and cancer indications (14%). ASRs in this range, combined with the fact that about one-third of approved mAbs have surpassed $1 billion in sales annually to achieve blockbuster status, are undoubtedly a driving force behind the biopharmaceutical industry’s current heavy investment in mAb technologies and products.
The new report also analyzes 130 novel mAb compounds currently in the pipelines of 27 biotechnology companies in the group and shows that the vast majority (88%, or 114 out of 130)of these product candidates remain in early-stage (Phase I and II) development. More than half of the data set’s 130 mAbs in development - 55% - are focused on cancer while 32% target immunological and inflammatory disorders and 13% are in development for infectious diseases, cardiovascular indications and other miscellaneous illnesses.
Attrition rates for Deloitte Recap’s entire data set of mAbs that have reached a definitive clinical outcome (80 failed compounds and 24 approved drugs) have historically been 26% in Phase I development and 52% in Phase II, suggesting that most of the early-stage compounds in the pipeline today remain at high risk of termination. The top indication targets for the group of biotech companies studied are lymphomas, leukemias, multiple myeloma, lung cancer, colorectal cancer, prostate cancer, rheumatoid arthritis, systemic lupus erythematosus and asthma.
Importantly, approved mAbs have proven their value to patients, physicians and third party payors despite the fact that a majority of these drugs (69% of currently marketed compounds) carry the FDA’s most stringent safety caution, a so-called “black box” warning, on their label. In fact, two FDA-approved mAbs were withdrawn from market post-licensure due to safety concerns.
The report also presents an in-depth examination of post-approval strategies that have broadened the patient populations and laid the foundation for blockbuster products, such as Centocor Ortho Biotech’s Remicade, which generated $7.1 billion in 2009 sales.Methodical label expansion, including judicious selection of an initial “landing indication” for the first approval sought, has been a hallmark of the most versatile and highest selling mAbs. For example, Remicade, Abbott’s Humira (originating from a collaboration between biotech company Cambridge Antibody Technology and Knoll), Genentech’s Avastin and Biogen Idec’s Rituxan represent four mAbs that are now approved in a total of 19 distinct indications and, collectively, these molecules generated more than $24 billion in 2009 sales.