Hitting the Target, Missing the Mark: How Targeted Therapies Have Left Patients Wanting


It is not unusual to read about another drug failure in a challenging neurological disease such as multiple sclerosis, Alzheimer’s disease, or Parkinson’s disease. Designing therapeutics with exquisite specificity has been the goal of modern drug development, and significant resources continue to be allocated towards this approach, only to see treatments fail due to inadequate efficacy or intolerable side effects. How we approach the development of new therapeutics for treating complex diseases will be key for achieving better patient outcomes.

A recent example of a once promising drug candidate using a targeted approach is semagacestat, a treatment developed by Eli Lilly and Elan. Proposed to lower the build-up of harmful plaques in the brain of Alzheimer’s disease patients, its Phase III trial was halted last August because semagacestat worsened clinical symptoms compared to placebo. Semagacestat targets a single enzyme called gamma secretase, which turns a protein found in normal brain into amyloid, the building block of the plaques found in Alzheimer’s disease. Semagacestat’s failure represents the difficulties in developing treatments that target specific molecules, whether these targets are surface proteins or signaling pathway intermediates inside of cells.

Several stumbling blocks can be identified in the development of targeted therapies, using semagacestat as an example:

1. The role of the target is not well established.

Many drugs target proteins whose function within a specific disease is difficult to ascertain. Alzheimer’s disease is characterized by the presence of plaques that prevent nerve cells from communicating. The therapeutic value of targeting plaque build-up is unclear, and a lack of definition for the exact role of amyloid in disease progression adds uncertainty for the therapeutic effectiveness of drugs like semagacestat.

2. Redundancy in cellular communication prevents efficacy of the drug in the absence of toxicity

Obstructing the generation of amyloid alone has limited effect on the complex nature of Alzheimer’s disease. The dysregulation of a group of proteins called Tau has recently taken the forefront as another important contributor. Genetic factors, such as variations in the lipoprotein APOE, play a significant role in disease progression and may greatly impact the ability of proposed therapeutics to affect the entire patient population. In addition, inflammation has been recognized as a key component of the disease. The complex interplay of these factors makes it difficult to use a therapy that targets one specific intermediate in one specific pathway and expect it to have disease-modifying effects at acceptable dosing levels.

3. Hitting multifunctional targets can cause unwanted effects.

Many proteins consist of different subunits or exist in multiple isoforms. Different subunit and isoform combinations can be involved in a variety of tissue- and cell type-specific processes. Inhibition of the semagacestat target outside of the brain, for example, has been associated with an increased frequency of cancer and alterations of the gastrointestinal lining. Using a single-target approach to affect multi-functional proteins can result in outcomes that differ significantly from the anticipated effect.

These difficulties are not unique to Alzheimer’s disease. New therapies for multiple sclerosis using similar targeted approaches have received “black box” warnings while still in clinical development. The complexity of disease mechanisms creates many challenges in choosing a specific “drugable” target and, once a target is chosen, often requires large doses to demonstrate efficacy.

New approaches for treating chronic disease should be explored. The current view of a cell as a collection of distinct and separate targets responsible for individual biochemical reactions presents substantial challenges for drug development. Approaching the cell as a whole may better reflect the way the human body functions and may have a higher likelihood of yielding new therapeutics.

Developing therapeutics that do not compromise “normal” cellular functions could also minimize side effects. Targeting the activation of specific immune cell populations could allow broad therapeutic action by dampening an exaggerated inflammatory reaction without crippling the entire immune response. In chronic inflammatory diseases, T and B cells, along with antigen-presenting cells, present an opportunity to block the amplification of the immune response that ultimately is responsible for the damage caused by the disease. Recent work examining a protective effect of regulatory T cells in Parkinson’s disease has given credence to this approach.

The challenges of developing novel therapeutics remain daunting. New approaches to chronic disease processes are needed to provide a more comprehensive solution to complex disease mechanisms while maintaining low side effect profiles. The current paradigm for the isolation of specific targets may not be sufficient to accomplish this goal. New classes of therapeutics will be required to address these issues. Success in this challenging endeavor will ultimately benefit patients.

Richard Watson is the director of clinical research at Tacoma, WA-based Revalesio. Follow @

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  • Ted

    “Why do you want to stop neutrophils, anyway? They do good things. The body didn’t make them to cause problems, they’re in there to solve problems, and now you want to stop them from moving around?”

    Our presentation to the pulmonary physician didn’t go so well. We figured, hey, these cells are found in elevated levels in diseased tissue, they’re activated, they’re causing problems, right? If we can stop them from getting there – bingo, problem solved.

    He was right, of course. Inflammation is much more complicated than that.

    It turned out, the bigger problem was the myriad avenues neutrophils had to get them around. Shut down one pathway, and six others take over without missing a beat. Shut down the wrong one, and the cells die – stimulating the production of replacements… We never even got to the point where we could fail from “inappropriate efficacy!”

    This was over a decade ago, but the lesson is still fresh, to me.

    I don’t know if Dr. Watson has the answers, but I agree wholeheartedly with his view of the problem. I think our ability to identify potential intervention targets has clearly outstripped our ability to discern the variety of roles they serve in an intact organism. This is why I believe ongoing investment in “academic” medical research is so critical.


  • Richard Watson

    Great comments. I agree, neutrophils are our friends! As we look at inflammation in a new light, it will force us to look at treatments and research in a new way. Academic research is critical to this and the collaborations between academic centers and bio-techs need to advance to meet the challenges.

  • http://austinpreclinical.com Eric Austin

    One thing to remember as well is that specific targeting might not be the best goal and multi-targeting might yield a better result. Sometimes a “soft touch” at multiple targets might yield a much better result than a “hammer” at one specific target. Considering the exquisitely complex biochemical pathways that our bodies use to manage themselves, saturating a single receptor can have many unforeseen downstream consequences. Hopefully we can solve some of these issues using smart system biology approaches, but it will be a complex juggling act.

  • Richard Watson

    I think you are exactly right. When treating hypertension, for example, it is known that using small amounts of multiple drugs would often have higher efficacy and fewer side effects. I think this could be an effective strategy at a cellular level as well. I think that is also one of the reasons Copaxone, the Teva Multiple Sclerosis drug, has been so successful. While its mechanism isn’t entirely known, it seems to keep the immune system “busy” during critical phases of the development of the disease. Probably this is occurring by this “soft targeting” you are speaking of.
    Great comment.