In September, we turn our focus onto Precision Medicine and its impact on the life sciences. Kineticos held 3 conversations with different industry experts to gain insights into how Precision Medicine impacts Neurosciences, Oncology, and Diagnostics.

Our first discussion dives into Precision Medicine in Neurosciences. Kineticos’ Neurosciences expert, Jason Kralic, discusses various Precision Medicine topics with Neurotez CEO, Nik Tezapsidis. Below is part 1 of 3 of their discussion.

Moderator:

  • Jason Kralic, Operating Executive, Kineticos

Panlist:

  • Nik Tezapsidis, President and CEO, Neurotez

Kineticos: Precision Medicine and Companion Diagnostics have seen success in oncology. Why is it that neurosciences is so far behind oncology when it comes to application of companion diagnostics and precision medicine?

NT: It is simply because we have spent less time and money in unraveling some of the pathways that are relevant to the neurosciences. Whether any of the CNS disorders or any of those neurological disorders are more complicated than any of the oncology indications, that’s debatable. Each indication is going to be governed by specific pathways and if we identify the target that is upstream of the ongoing process, in any of these diseases, we are halfway through the discovery and development of new drugs. It’s a matter of time and effort that needs to be devoted to define targets allowing the neurosciences field to catch up with oncology.

Kineticos: I’m interested in your view towards how neurosciences may experience what has occurred in oncology. Advances in our understanding of cancer and the increasing number of variants has allowed for subtype-specific targeting of treatment and improved outcomes. Do you see the same thing happening in the neurosciences with psychiatric or neurologic diseases?

NT: We are struggling with a very heterogeneous disorder. Unfortunately, the amyloid hypothesis has dominated the field. However, the recent failures in addressing this (Abeta) as a culprit has sparked interest in alternative approaches. We believe that there is a metabolic dysfunction that triggers the disease. The concept of type three diabetes is highly relevant to our approach. We also believe that, as with type two diabetes, you could treat the underlying disease process with different agents targeting different components of affected metabolic pathways. Similarly, you should be able to target type three diabetes, or diabetes of the brain or Alzheimer’s disease with different components. In our case, we have the means by which we can identify a subgroup (leptin levels) and treat it with what we believe is the most appropriate agent.

Similarly, there could be a number of different pathways that are affecting neurodegeneration, neuroplasticity, and neurotransmitter levels, that could also be the target for drug development.

Symptomatic relief medicines could provide a substantial benefit in alleviating symptoms. They themselves could be delivered, modified on their own, and prescribed in combination with other medicines. The more we learn about Alzheimer’s disease, the more we unravel important pathways that can be modulated with therapeutic agents, and the more we’re going to be following up on the principles and strategies employed in oncology.

Kineticos: When looking at industry strategy on biomarkers of Alzheimer’s disease, the investment remains primarily in detection of beta-amyloids. What explains that? Why has the focus not changed?

NT: It was the logical target. Definite confirmation of Alzheimer’s involves the detection of plaques and tangles in the brain, which in the past could only be achieved in postmortem samples. That is no longer the case with the advancement of innovative brain imaging techniques. The first thing that we should have tried to see whether it would be impactful is to eliminate or remove a bed of plaques and tangles. Unfortunately, so far, all the efforts to identify an agent that would also be a pro cognitive therapy have failed. Significantly, Abeta remains a very useful biomarker, for diagnosis and perhaps monitoring of potential therapies. However perhaps not the right target for a cure.

The metabolic angle as a drug cadre has been explored for Alzheimer’s disease by a number of companies, including GSK and Takeda that used PPRgamma agonists as insulin sensitizers. None of them provided a solution, because of issues including toxicity, and perhaps BBB impermeability. Takeda’s long-term studies have not resolved any significant cognitive benefits. The nasal insulin spray studies are still under investigation.

The driving force that led us to metabolic pathways comes from genetic studies that have identified ApoE4 as the strongest genetic risk factor that is out there. This underlines the significance of lipid metabolism in the brain and metabolic pathways in general. The lipids, other than being components of membranes (Abeta is partially imbedded in membranes prior to secretion), are also components of lipid signaling pathways. These have been hugely ignored as a field for investigation. Within the lipid signaling molecules category, are a variety of compounds like steroid hormones, prostaglandins, endocannabinoids, etc.  none of these are contained within vessels like neurotransmitters. They are produced on site and are bound usually to proteins. I fundamentally believe that lipid biology is very important and relevant for Alzheimer’s disease. There are numerous pathways, involving lipids that could potentially regulate metabolic pathways.

Kineticos: You raise a good point there. Drug targets in Alzheimer’s disease and other neuroscience indications are increasingly identified through a precision medicine approach. There may be markers of disease that we can use in stratifying patients for precision medicine, that then become targets for treatment. Vice versa, several of the areas that have been mentioned in Alzheimer’s pathology are targets for disease that could also be useful for developing precision medicine tools to help both with the clinical development and in following those patients as they are treated with experimental or approved treatments.

NT: I agree 100%. Systems biology is a major theme in neuroscience. I think that it is very important that we can get biomarker profiles using blood samples. It won’t necessarily have to be CSF samples. Changes in metabolites or proteins are going to be associated with disease diagnosis, disease staging and also used for monitoring treatments. This is an ongoing long-term process; it’s just a matter of collecting and analyzing the data from large number of samples. It’s the new era – Big Data, Cloud, computing, allowing complicated analyses. Restoring altered levels of metabolites or proteins, caused or causing disease progression, can be a fruitful strategy in the neurosciences and in oncology. Of course, genetic variants of proteins associated with altered function causing disease are also part of the overall picture

Theoretically, with precision medicine, you won’t have to work with thousands of patients to determine the safety and efficacy of new treatments. Analysis of the data from a single patient biomarker profile should provide all the data you need. One day we will reach that point. In conjunction with a genetic readout, we will have a complete picture of the holistic makeup for every person. Each disease can be mapped as a continuum of changes on biomarkers. Our knowledge will enable us to ideally enhance wellness or prevent the transition from wellness to sickness. This is conceptually where we’re heading in the future, but we have a lot of catch up to do.

Kineticos: It may be more my hope than expectation, but we are going to see application of big data science approaches to those data sets to understand the differences in pathology and disease among patients that we are categorizing into large buckets like Alzheimer’s disease, depression, psychosis, etc. We are going to be able to better identify, develop, and then treat. I am increasingly hearing talk of the use of precision medicine in the understanding of brain health prior to disease onset. This is a value proposition for the development of diagnostic tools as we begin to follow our brain health and wellness prior to development any neurologic or psychiatric complications.

NT: Being able to predict based on availability of data and prevent progression to disease from wellness is something that we should be focusing more as a proactive approach rather being reactive with drug treatments. We are far from it as a field. However, some of these concepts are imbedded in our approach – the preventative and predictive aspects.

The therapy that we are pursuing is involving Leptin, a metabolic hormone. We know that 70% of MCIs (early Alzheimer’s) patients had leptin levels that were lower than the median found in a normal age matched elderly person. Approximately 30-35% of all patients had leptin levels that fell within the first quartile of the normal population.

Our strategy will involve screening these patients for low leptin levels. So, here’s the diagnostic companion for our treatment permitting the selection of a subgroup within the early phase of the disease. So, people that have an MMSE score of above 24, who are not severely cognitively affected. To ensure we are dealing with Alzheimer’s-to be-patients they will be enriched based on their genetic risk profile.

It’s a fairly safe approach, you are increasing your low leptin levels with an agent that has been proven to reduce Abeta and reduce phospho-tau in preclinical models. We do have some interventional human studies with some supporting data for pro cognitive properties. In a small number of clinical studies involving congenital leptin deficient patients, intervention with leptin increased gray matter concentration and improved their behavioral profile. Finally, there are numerous epidemiological studies, involving thousands of patients, both longitudinal and cross sectional that support the association of low leptin to high risk for Alzheimer’s. So, our approach is very relevant to the concept of predictive, preventive, and personalized precision medicine.


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