Dr. Kalpana Merchant has deep expertise in the neurobiology of chronic neurodegenerative and psychiatric disorders. She has nearly 25 years of experience in drug discovery and development with a special emphasis on translational strategies that improve the success rate of drug development.
In March 2014, Kalpana established a life sciences business that provides consultancy services to non-profit foundations and start-up pharmaceutical and biotechnology companies. She has recently joined a start-up company, Vincere Biosciences, as the Chief Scientific Officer to help develop small molecule drugs aimed at slowing the progression of Parkinson’s disease. She continues to remain engaged in training and mentoring of graduate students, postdoctoral scientists and junior faculty through her adjunct academic position at Northwestern University.
Prior to establishing TransThera Consulting Co, Kalpana worked in the US pharmaceutical industry as a scientific contributor and in strategic leadership/management roles. She retired in March 2014 from Eli Lilly and Company where she was the Chief Scientific Officer for Tailored Therapeutics-Neuroscience, accountable for scientific and business strategies to deliver personalized therapies and associated biomarkers for the neuroscience portfolio – from discovery through Phase III.
The following has been paraphrased from an interview with Dr. Kalpana Merchant on October 17th, 2018.
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In 2014 you decided to step away from a very successful career in pharma, could you talk about why you made that decision?
I learned a lot in my 20+ year career in pharma about how to develop a drug but at some point the bureaucracy of decision-making gets to you. I also wanted to work in an environment that allowed for more risk-taking and where things could move faster. Additionally I was seeing a lot of exciting scientific and technological discoveries emerging and believed that the time was right for me to help translate these into therapies.
You recently joined a biotech company called Vincere Biosciences working on mitochondrial dysfunction in Parkinson’s. It seems that in the affected cells of people with Parkinson’s there is a cascade of cellular dysfunction, do you see mitochondrial deficits as the starting point of all that dysfunction or just the most critical lynchpin?
The short answer is we don’t know it definitively. The arguments for mitochondrial deficits being a critical lynchpin are: first, we know that aging is the biggest risk factor of non-genetic PD and aging is associated with the accumulation of damaged and dysfunctional mitochondria. Secondly, postmortem studies of PD brains show mitochondrial damage and deficits. Finally, we know that several genetic or familial forms of PD are caused by mutations in proteins that regulate mitochondrial functions. Thus it appears that mitochondrial deficits may be a common pathogenic mechanism of PD or a lynchpin, as you suggest.
What we are targeting at Vincere is a pathway called mitophagy, which is how cells remove damaged/dysfunctional mitochondria. Impaired mitochondria lead to a reduction in cellular energy and production of reactive oxygen species that starts a cascade of further damage. If we can remove damaged mitochondria we could restore cellular health and prevent a damaging cascade that could lead to neuronal death.
What is your opinion of the divide between academia and industry? How much does it slow development of new therapies and what needs to be done to bring them closer together?
The basic fundamental discoveries that provide insights into disease biology and thereby therapeutic targets have to come out of academia, pharma on its own is not set up for that. What is impeding the progress on drug discovery is a lack of optimal collaboration among basic scientists in academia followed by collaborations on “applied or translational science” in pharma. Having said that, the situation today is significantly better than where it was a decade ago, but it is still not optimal.
In my opinion, one big issue is the reward systems in academia. Individual scientists are rewarded, recognized and promoted based on research initiated and executed in their own laboratory, the number of papers they publish and where they publish the papers. To improve the system and advance therapies people need to work together in teams, freely share ideas, results, and reagents, etc. rather than competing for discoveries. Everything from Nobel prizes to career progress is based largely on individual contributions rather than collaborations. On the industry side, there generally is reluctance to share tools, molecules, reagents, expertise and technologies with academia, which hampers translational studies. However, on the optimistic side, the growing recognition of this wasteful divide has led groups such as government institutes, private foundations and angel investors to disrupt the system by bringing people together to work on complex problems that can’t be solved by individuals. We need more of these kinds of programs.
It currently takes over a decade to go from discovering a target to getting a drug to market, why does it take so long and do you see anything that can be done to speed this up?
Therapeutic development for neurodegeneration is on the extreme side of this because these diseases progress slowly and there is a high variability in the rate of progression among patients measured by traditional clinical end-points. As a result, even initial efficacy trials have to be conducted in a relatively large number of patients and for 12-18 months to demonstrate the effect on disease progression. One way to get around this would be discovery of biomarkers of disease progression. The longer it takes to complete each phase of the clinical trial, the longer it will take for drugs to get to market. Biomarkers that accurately reflect progression of the disease in shorter duration could really speed this up. To get there we will need more patients and healthy volunteers to enroll in observational studies of biomarkers.
The second area contributing to the delay in getting a therapy to the market is not specific to neurodegenerative disorders, it is in the earliest phase of going from discovery of a target to getting optimized molecules that can reach the brain adequately to target the desired pathway and are safe for humans. This is where interrogating a broader chemical space to find the right molecules can accelerate development. Several new technologies such as computational tools that allow virtual screening of compounds, protein crystallization to inform therapeutic molecule design, and facile but accurate robotics-aided screening methods have improved the optimization process but there is still room for improvement in these methods and techniques.
Big pharma seems to be withdrawing support for neurodegenerative disorders. Why do you think this is and what needs to be done to change this?
There has been some withdrawal of support for neuroscience in general, psychiatry has fared even worse than neurodegeneration. Some of the big pharma companies have withdrawn support primarily based on the failures of the very large Alzheimer’s trials. These trials required upwards of five hundred million dollars per program. Pharma executives also look at other therapeutic areas such as oncology, which are deemed to be less risky, at least for now, and have shifted resources away from neurodegenerative diseases.
The other side of the equation is the so-called divide between big pharma and small pharma or biotechs, which is somewhat artificial. Mid- and small-sized companies have come up and filled some of the gap to the point that today we have the largest number of clinical and discovery-stage programs for Parkinson’s disease that I have ever seen. More importantly, some of these small companies have the freedom to pursue innovative approaches that target specific, and thereby smaller patient populations, without being encumbered by comparison to other therapeutic areas or larger market size considerations. Although such approaches are not at all beyond the risk of failures, a number of them will likely deliver sufficient clinical stage data to de-risk the approach and make it attractive for big pharma’s engagement into the program to conduct larger trials and take it to the market. Since leaving big pharma I have seen many of these smaller companies filling gaps in both earlier discovery and clinical development phase that some large pharma may be walking away from. This new ecosystem is working and as a result PD is one of the areas where venture capital support is actually on the rise. So I am not as pessimistic about the apparent withdrawal of support from big pharma.
What role do you see patients being able to play in all of this?
This is an extremely important question. I think that when academic and industry scientists get to interact with patients and see how their work could ultimately be applied, the therapeutic goal becomes a beacon for them. We are all human beings at the end of the day, we want to do the right thing. At the start of any therapeutic program it is important to interact with patients to understand the disease better and to set the right goals in mind. As programs progress towards the clinic, getting patient input on the design of the trials is also critical. Over the last decade, there has been a clear recognition that patient engagement and input in all aspects of a therapeutic program – from formulation development to the design of clinical trials to patient recruitment strategies – are critical for the ultimate success of a therapy. But patient engagement remains sub-optimal; we need more interactions at scientific and strategic conferences, as well as all the way through the drug development process.