By Hank Safferstein, Ph.D., J.D.
PLSG Executive In Residence

Cognitive disorders, such as Alzheimer’s dementia, are devastating and will put an increasing strain on our healthcare system as the population ages. As of February 2016, there were approximately 174 drugs in clinical development, with only 5 marketed therapeutics. This disparity, in large part, is due to difficulties demonstrating efficacy in clinical trials.

Efficacy can be difficult to demonstrate for two primary reasons. First, Alzheimer’s patients likely comprise a heterogeneous population where the disease can stem from disparate pathologies. Patients are segmented primarily on the presentation of symptoms. This is important because two patients with similar symptoms may have dysfunction in different pathways, meaning a therapeutic may work for one patient but not the other. When an investigational new drug is given to a specific patient population, it provides more power to a clinical trial. Second, traditional outcome measures are centered around cognition, a relatively “soft” and imprecise clinical endpoint. Cognition is considered “soft” because it naturally changes from morning to evening, from day to day, and between individuals. Additionally, patients in both the placebo and drug groups learn these cognitive tasks over the course of a clinical trial. Identification of factors that consistently report the severity of the disease across time and individuals will also provide more power to a clinical trial.

Identification of Alzheimer’s specific biomarkers can bridge these challenges. Biomarkers can provide important information on the presence and progression of the disease. An ideal biomarker can effectively link a drug’s mechanism of action to its intended effects on disease pathways. Therefore, instead of relying solely on cognitive function, drug efficacy can be based on changes in expression of molecular biomarkers. Likewise, these biomarkers can be used to segment the population based on the presence or expression of specific biomarkers instead of subjective measures of symptoms. Failure rates in Alzheimer’s clinical trials could be reduced significantly if patients were segmented based on molecular profiling.

Our challenge, to both clearly measure outcomes and segment patient populations, boils down to a core need to identify specific biomarkers of these diseases. Plasma, cerebrospinal fluid (CSF), and imaging (MRI, PET) biomarkers have the potential to improve diagnosis, stratify or otherwise segment patients, and provide measures on which to track disease progression and the effects of therapeutic and lifestyle interventions. There is a real need for the successful translation of biomarker data generated through the use of mass spectrometry, immunoassays, and imaging into patient endophenotypes. Researchers believe this will happen, but the question remains: Will regulatory agencies accept biomarkers as clinical endpoints?

The PLSG continues to conduct outreach and engage in direct involvement with life sciences innovators working to better understand and treat these cognitive disorders.

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In J.K. Rowling’s collection of “Harry Potter” novels, the titular character becomes increasingly immersed in an epic showdown between the forces of good and evil in the fictional world of magic.  At the same time, he increasingly feels the need to go it alone – wanting to protect his friends and mentors from further danger.

This goes on until, at a critical moment, his friends Ron and Hermione remind Harry that he doesn’t have to do all of this himself.  They will always be there to help, the same as all of the teachers and others who have provided guidance, direction, and support all along.

Anyone who has aims for success in the business world knows the value of seeking, cultivating, respecting, and listening to respected mentors.  No single person knows every aspect of an industry, a career choice, the best way to balance personal and professional desires and obligations, and a thousand other issues.  Mentors help fill in those blanks because they’ve been through the fire.  They’ve handled the negotiations.  They’ve seen and worked through stretches when plans go awry and you have to fight to get back on track.

Mostly, mentors know you and believe in you.  They want to help you succeed, and will do all they can to bring about that result.

I faced a challenging decision some months ago regarding whether to invite an individual to a PLSG event, based on a past experience that didn’t work out so well.  My gut told me this was an important decision, and to reach out to my network.  After considering their input and perspective, the decision was made to be completely inclusive, and to keep the open nature of PLSG strong.  While I would have felt good about making that decision on my own, the validation from others I respect so highly added a level of confidence that otherwise might have been missing or diluted.

It is worth the effort to identify and court people who have blazed the trail ahead of you.  Let them know what you stand for, where you would like to go with your career and life, and ask for their help as you make your way.  It has been my experience – especially in this friendly city of Pittsburgh, where relationships and associations between people can be so easily connected – that most people would be very happy to serve as mentors and supporters.  At PLSG, we consider mentoring a key part of our mission, in fact.

After all, as that noted business coach Harry Potter learned while on his famous quest, no one has to go it alone.

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