Moving on from our Precision Medicine in Neurosciences, Kineticos’ Founder and CEO, Shailesh Maingi, talks with a diagnostics expert on how companion diagnostics is impacting various therapeutic areas. Roche Dx CMO, Alan Wright, provides his insights on when is too early to start a companion diagnostics strategy as a therapeutic company as well as the nuances of companion diagnostics in Oncology, Rare Diseases, and Cell and Gene Therapy.

Moderator:

  • Shailesh Maingi, Founder and CEO, Kineticos

Panelist:

  • Alan Wright, CMO, Roche Dx

Kineticos: One thing that we talk about a lot is a therapeutic company working with a precision medicine company or diagnostic company and how early should a therapeutic company start to think about a companion diagnostics strategy. Is there a time that is just right, or do you try and get to it as early as possible?

AW: People always say early and that is a little too vague for most. As soon as a product has a product manager, it is apparent that they need a product management strategy. Often, one of our earliest projects is re-working a target that they have chosen because the actual biochemistry is not durable enough to be sustainable in community deployment. For example, we look at their target and say the pre-analytic handling is not sustainable in the community, and we have to come up with something different. This is that phase 2 in pharma where we would start thinking about commercial or community deployment of a companion diagnostic.

Kineticos: There is also the idea of going after and targeting more rare diseases. There’re about 9,000 rare diseases worldwide that impact 30% of the population. In the US, about 100 million people are affected by some rare disease; that’s pretty significant. Can you talk about how that rare disease model is changing development?

AW: It’s going to change the way we think about disease. One of the things that got me thinking was carrier screening for rare genetic diseases. One of them is DiGeorge’s syndrome, which is a relocation of genetic material which causes a clinical syndrome. A pregnant mother was screened for this and she tested positive. Something wasn’t right and they continued the evaluation. It was not the child but the phenotypically normal mom that had this mutation. A lot of our traditional observations of disease has been on phenotypes. These 9,000 diseases are on a large genetic database of a represented population that has been extrapolated where they have identified the genetic abnormalities in 30% of the population. I don’t know how many of them are actually phenotypically expressing the disease. It really gets to the point of When do we treat? What do we treat? How do we screen? Who is eligible for screening? Do we sequence entire populations and then monitor them? It really changes the way we approach medicine.

Kineticos: The article had the idea that if 30% of the population is impacted by one of these rare diseases, how can we afford to treat these patients given that the pathways of these rare diseases are so different. Companies can charge however much they want, there’s no competition, they have IP protection for a long time. It’s all done with the right intent but I’m not sure we know what the alternative is.

AW: The financing becomes very interesting. In some of these situations, companies are going to start bumping up against insurance. Insurance is all about risk and unknown, but what about when it’s known? The companies will have a very different approach.

Kineticos: We’ve had good success in Oncology with companion diagnostics and precision medicine and we know why to a point. We know the molecular pathways in oncology better, we were able to get targets, and understand genetics. What is it going to take when we think about precision medicine and companion diagnostics in the context of other therapeutic areas? Do we have to go back and do more basic research or is the biology different for oncology vs. other areas?

AW: We’ve had some early success. Companion diagnostics and precision medicine have a long way to go in oncology. Oncology is, essentially, a disease of DNA and you can make a great deal of progress just by examining the DNA either through sequencing or specific proteins that sequencing expresses. In most other diseases, they don’t have the somatic mutations, so we’re dealing with the same set of germlines and all the action is in the proteins. In the case of inflammatory diseases, it will be more proteomics or immune-assays and developing panels and looking at ratios.

But we’re getting there, now with precision medicine projects looking at proteins. In the case of infectious diseases, it’s actually organisms other than the human body. We’re making progress there, both in proteins and DNA. We’ve had projects in ophthalmology with macular degeneration, for instance. There will be a wide-spread emphasis on companion diagnostics and precision medicine. We are also using non-biochemical measures for precision medicine, such as physical measures assessing heart rate and tremor.

Kineticos: In specifically oncology, one of the things, from a therapeutic perspective, is all of the rave these days in immuno-oncology and we’ve had successes. There’re nearly 3,000 trials in combination with PD-1 and PD-L1. There’s a lot of activity that we have in that one area. Combination therapies are going to rule the day. How does precision medicine or companion diagnostics evolve in the area of all of these combination therapies?

AW: It’s going to invoke a fundamental change in the practice of pathology, in particular anatomical pathology. We’re starting to encounter that now. Early on, when PD-L1 was first launched, we had a single clone, but it was read in different ways. Now, there are many immunologic markers, tumor types, and ways to read them. In addition, you are not only doing tissue stains but that is combined with sequencing. Pathologists will need “just-in-time” decision support to guide which test to use and in what situations to use them. Within the next decade, artificial intelligence for image analysis is going to come into play as well.

Kineticos: There’s quite a bit of work being done in gene and cell therapy and gene editing. It is early days in those areas. How is that therapeutic work going to affect what we have to consider on the diagnostics side? How are we going to be able to support that? What other things are we going to have to consider?

AW: It will be driven by germline sequencing. People will jump to the conclusion that we will just sequence everybody in the world. I don’t know if that’s the strategy or if you come up with cheaper screening strategies to see if people are phenotypically expressing the condition to identify someone who is presented with a particular syndrome and may have one of these abnormalities.

We are only seeing the most extreme examples of this, and a lot of these are spontaneous mutations. We will discover people who present with much milder forms of the disease. The discussion will center around when and if those people need to be treated. Gene therapy has great potential. It’s going to change the way we think about diagnosing disease and what disease is.

There will be cohorts of people who express the gene but are phenotypically normal. The questions to be answered will be: How often are they treated? What does it do to change your all-cause mortality?  And ultimately, what is disease?

Kineticos: What is disease? It sounds like a philosophical question but it’s extremely practical. What is normal and what is abnormal? I don’t think we have to answer to that.


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