Follow The Patients: The Case For Neuroscience And Other “Challenging” Fields

Posted September 11th, 2014 by Ankit Mahadevia, in Biotech investment themes, From The Trenches, Personalized Medicine, Translational research

This blog was written by Ankit Mahadevia, CBO of Rodin Therapeutics and Spero Therapeutics, as part of the “From the Trenches” feature of LifeSciVC.

There’s an ebb and flow in our business around interest in specific therapeutic areas; hot TAs such as immunooncology raise all boats and make capital and other fuel for the biotech fire (just a little) easier to find.   In other fields, one needs to “push religion” about the disease while doing the hard work of building a company.

Howard CosellHoward Cosell (and posters in elementary schools nationwide) makes my point – by shying away from fields not in vogue we sometimes miss the boat by overemphasizing market sentiment vs. unmet medical needs. My fellow blogger Jeff Hatfield has written eloquently about this  – we are in the business of making patients better, and given our limited time and capital, we might as well go after the biggest needs.

Cognition is a great case example. Progressive disorders such as Alzheimer’s (AD) rob patients of their sense of self and ability to live independently. Limited therapeutic options exist – the moderately effective symptomatic therapies we currently have still top the billion-dollar mark in sales.  The prevalence and impact of these diseases also bears repeating as the impact is just staggering. The Alzheimer’s Association  estimates AD and related dementias affect 5 million patients in the US alone today and that this figure will triple by 2050.

The gap between need and sentiment is not an awareness problem, or a problem in grasping the vast size of market for a successful therapy.  There have been challenges in the field (just like in others!) that have moved some to the sidelines. However, Pharma and biotechs are finding creative solutions (and many thanks to Marty Jefson at Rodin and @jeffreysnye at Johnson and Johnson for their opinions on the topic). A not so comprehensive list of some of the possible solutions:

  • Smarter clinical trials:    The failure rate of AD trials at the latest, most expensive stages has thrown cold water on the investment case over the past several years (sort of the anti-ice bucket challenge). However, developers in AD have gotten off the mat and are finding ways to reduce the cost of trials and increase likelihood of seeing treatment effect when one exists

Smaller, genetically defined subpopulations and defined syndromes such as the population with a preseninlin-1 mutation defined by NIH-Genentech’s crenezumab trial –  more pathophysiologically homogeneous populations with better defined natural histories may simplify the complex question of when to intervene in a clinical trial of  a disease modifying therapy.  Other solutions to creating a more homogeneous study population under exploration include the study of specific syndromes, such as frontotemporal dementia and patients with Down Syndrome with early onset of cognitive decline.

  • Advancement of validated diagnostics:  The approval of Lilly’s Amyvid and GE’s Vizamyl  are a step up in stratifying patients for clinical trials and tracking their progress relative to observer-dependent diagnostic criteria.  Siemens in conjunction with Lilly has developed similar tools for stratification and tracking of Tau-focused interventions.   The next step in these agents is achieving CMS reimbursement, which has been a challenge in part given conflicting views about the evidence linking plaque burden to definitive diagnosis of disease. This is a nice segue to my next point about choice of mechanism.
  • Complementary therapies with clear mechanism:  There’s a central theme to perceived challenges in CNS– we still have much to understand about what biology causes disease in which patients over what time course. It is no wonder that finding the right population, the right models, and the right biomarker has required some thought.  New biological approaches with clear links between target biology, effect, and disease natural history may be another solution to moving forward:

The example of behavioral epigenetics: Companies such as Forum Pharmaceuticals and Rod
in Therapeutics
are stepping outside of the plaque/tangle arena by addressing HDACs and other epigenetic targets. Their role on learning and memory is increasingly well understood, including the gene expression profile linked to HDAC inhibition that impacts synaptogenesis and formation of new associations.  Given understanding of the target biology, such therapies have amenability to target engagement markers such as HDAC selective neuronal imaging agents that can better correlate effect to target engagement in a trial setting.  In addition, mechanisms can simplify patient stratification; since they have the potential for benefit more independently of natural history and etiology of cognitive decline.

These are a few of the many developments in the AD field – and are a long way of saying that the current challenges and others that may arise are surmountable and that they are worth surmounting.   I would also be remiss if I didn’t mention that there is a cadre of biotechs (e.g., Alector, iPieran (now part of BMS)) and Pharma (Roche, JNJ, BMS, Takeda to name a few) who have remained committed to the huge opportunity that exists for effective, safe AD drugs regardless of the near term challenges.

It takes some optimism to plunge into biotech, and even more when one’s disease of focus is not grabbing positive headlines. For those of us spending our time and capital in cognition, obesity, heart failure and other less sexy but high unmet needs, the near-term challenges are all worth it.

Ankit Mahadevia

Serial biotech entrepreneur and executive
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