“Don't change horses in midstream” is a quote attributed to Abraham Lincoln from a speech in reply to an attempt to persuade “Honest Abe” to change political parties. The advice he attempted to convey was to not change your leader or your basic position when part-way through a campaign or project. While refraining from a change in leadership may have been good advice for politics during Lincoln’s time, changing your horse, even in midstream, may be the most prudent advice relevant to some drug development programs. Or better yet, having options relative to disease indications can substantially increase the probability of a drug making it through the development process. The best laid plans don’t always come to fruition. A change or addition, based upon the most relevant data from preclinical or early human studies, may be warranted to ensure that you and your company achieve success.
From a preclinical perspective, the standard route in research to development comprises the identification of compounds via assays from a validated disease target. Once a compound class is qualified, the best compounds are tested in various assays involving the target resulting in the determination of the lead drug with appropriate backup compounds. This compound then enters a battery of animal studies to qualify the efficacy and safety. If the data justify the initial hypothesis for efficacy and the compound exhibits an acceptable safety profile, a positive decision for human clinical studies is the likely next step. While the safety data is fundamental, for some drug developers, the efficacy results should be considered within a broader context than the initial hypothesis. Does the drug have activity at other targets or is the main target relevant to other disease indications? Answers to these questions are of considerable value to a company with limited resources. It is worth their while to use those resources wisely. Spending a little extra money during the preclinical stage may not only aid in better stewardship of resources during the clinical stage, a broader preclinical profile may offer an additional or alternative development plan for the drug. Having alternatives or additions to your development plan is like having several horses when you are ready to cross the stream or find yourself mid-stream and face key decisions regarding if or how to continue expensive and uncertain human clinical programs.
In my view, the ultimate example of having a team of horses when crossing that stream in the development program is duloxetine (Cymbalta) from Lilly. Duloxetine is often referred to as the “Swiss Army Knife" of drugs considering the multiple indication approvals. The drug is approved by the FDA for the treatment of depression, general anxiety disorder, fibromyalgia and diabetic nerve pain. Lilly is pursuing additional indications including chronic knee and low back pain as well as chronic fatigue. Although Lilly states that the exact mechanism of action of duloxetine is not known, their scientists have generated data that demonstrates the drug causes an increase in activity of serotonin and norepinephrine in the central nervous system along with other data that links these effects with the approved and pending indications. This knowledge of the effects of duloxetine and its translation into clinical evidence and approved indications resulted in annual sales in excess of $2B over the last several years. The anti-TNF (tumor necrosis factor) biological drugs represent another example of a drug class where a good understanding of the target and its implication in other diseases was exploited early in development resulting in additional indications that have contributed substantial value to drugs such as etanercept (Enbrel) and adalimumab (Humira). Both drugs are approved for the treatment of rheumatoid and juvenile idiopathic arthritis as well as the related psoriatic arthritis. The drugs are also approved as treatments for psoriasis and ankylosing spondylitis.. Adalimumab has an added approved indication for Chron’s disease. The fundamental role of TNF in the initiation and progression of these inflammation-based diseases no doubt led to the obvious preclinical studies that ultimately supported the human clinical work and resulting indication approvals. These drugs had combined annual sales of over $8B.
I know what you are thinking – “What do these blockbusters from large pharmaceutical companies have to do with my program?” While these companies may have vast resources compared to your company, the analogy of a robust preclinical program is still relevant. After all, the preclinical program is the most affordable part of your entire development program. Why not pretend you are a large pharmaceutical company and at least consider additional or alternative indications? You may be surprised about what such an exercise presents to you and your colleagues. Need a relevant example? Consider the Janus kinase (JAK) inhibitor program from Incyte. Perhaps by considering the success of the related anti-TNF drug development programs, Incyte scientists explored similar preclinical studies of the JAK inhibitor INC 18424 which ultimately set the stage for justification of several clinical programs for inflammation-based diseases including myelofibrosis, polycythemia vera and essential thrombocythemia. A topical formulation of the drug is in clinical trials for the treatment of psoriasis. In late 2009, Incyte announced that it entered into an agreement with Novartis for INCB18424 for myelofibrosis and the other indications. The company stated that it received upfront and immediate milestone fees totaling $210M (which included rights to an earlier-stage drug), a handsome reward for extending the preclinical effort to justify programs in more than one hematology indication. The company announced that it will engage dermatology companies in discussions concerning the development of the topical psoriasis treatment which may be viewed as “icing on the cake”. Had Incyte not succeeded in advancing the hematology indications, the dermatology treatment may be viewed as an extra horse to carry the company across the stream to the side of a drug approval.
In my experience, more and more companies have extended their preclinical programs to ensure that they achieve an approval of their drug and thus increase prospects of the company. In addition, companies have been responsive to consider additional or alternative development programs when presented with potential value of their drug in an indication that was not contemplated prior to the clinical development decision. While there are concerns such as an adverse events or safety issues arising from trials for an alternative indication affecting the lead treatment under investigation, such issues can be managed by effective preclinical programs and advice from potential partners that have the experience from pursuing multiple indications for a single drug. Development-stage companies should also consider potential partners as a good source of advice on commercial issues (e.g. price differential between indications) that can be invaluable to a small company considering whether to increase investment in an alternative indication. Think about the analogy of crossing the stream. How many horses would you like to have at mid-stream?
Robert Morrison, Ph.D. is Director, The Invotex Group, a specialty consulting firm that provides a range of financial and technical services to companies and academic institutions. Dr. Morrison’s practice focuses on issues associated with clinical development and intellectual property of pharmaceuticals and medical diagnostic applications.