Cancer Therapeutics – Advice for the Future

Mana Chandhok:
Hi everyone. Welcome to this podcast from Cambridge HealthTech Institute for the World Preclinical Congress, which runs from June 12th to the 16th an Boston, Massachusetts. I'm Mana Chandhok, an associate producer. We have with us today Aidan Synnott, and executive director at Charles River Laboratories. Charles River Laboratories will be giving a bridging presentation between the preclinical models and tools and oncology track, and the tumor models for cancer immunotherapy track at the World Preclinical Congress. Dr. Synnott, thank you for joining us.

Aidan Synnott:
Thank you for having me.

Mana Chandhok:
What are some of the challenges in identifying new oncology therapies and bringing them to market?

Aidan Synnott:
There's a number of different challenges in this realm, They've broken out in several different buckets. Obviously, you have the scientific challenges, which are involved around finding novel targets, new spaces to work in. That has been somewhat modified over the past two years due to the success of immuno oncology, which has kind of broadened people's horizons a lot in terms of what they are able to aim for from an economic and/or general investment standpoint. In the last five years now we've seen a huge increase in the range of targets and modalities that people are looking to test.

Another scientific challenge has been, as well, people have become more aware of the immune system, whether or not they're looking to target it, they've become aware that the immune system can sometimes have unexpected effects on the therapies and the treatments, and retrospectively people are looking back at results they've had in the past and realizing that the immune system may have influenced that somewhat as well.

Another set of challenges is all along the whole process. I mentioned earlier on, the idea of return on investment and inevitably whether it's a large drug maker that's producing a therapy or whether it's a small startup, or a virtual company, it's a 15 year lifespan to get a drug from concept into the clinic. It's a lot of money invested, and the inevitable valley of death where a lot of therapies will end up dying is not always related to the fact that a therapy would not ultimately be useful. It's just to do with the fact that every company has to have a set of criteria which helps them rationalize the decision making in the next process, and sometimes an asset which is promising can fail for other reasons.

Obviously, another part of the process is ensuring that you have the resources to see that through. Again, we've seen some promising early stage therapies that have been developed by smaller companies, and due to the fact that those companies were not able to get adequate funding, they weren't able to progress along the development pipeline. Usually what happens with companies is they either get bought up or at least their assets do. Sometimes they can unfortunately be shelved.

The final big hurdle, I would say is regulatory. Sadly, in oncology the rate of development in the biology, the science of the biology, has been so rapid in the last few years that the regulatory authorities like the FDA and other organizations are struggling to keep up. They're not sure how to interpret some of the new data. One good example is checkpoint inhibitors. Initially when the DMS developed their CTLA-4 checkpoint inhibitor with Ono Pharma, they didn't need to test it in animal models. That's not something that necessarily applies to every immunotherapy. There's a lot of question marks around what the right model to assess a therapy, and we would like to see that be down to more than just dumb luck as to which therapies make it through and where the regulators are pushing back. There's a real need for a conversation between the drug makers and academia and the regulatory authorities in order to make sure that decision making around regulatory approval of these drugs is rational and leads to the best results.

There's also question mark around the models and in particular, I would use as an example humanized mice, which are a relatively new type of model that's been developed where you ingraft an aspect of the human immune system onto an immunodeficient mouse and then you test the therapy in that mouse. Some people are looking to use this in efficacy. Some people are looking to use it in safety studies. This, again, is just a question of people don't know how to deal with, partly on the regulatory side, but also on the scientific side in terms of interpreting the data and figuring out what are the right questions to be asking that the model will actually be able to answer.

Mana Chandhok:
What are some of the newest technologies and therapies in cancer immunotherapy that you are most excited about and why?

Aidan Synnott:
The thing that jumps out to me right now, it's still relatively a niche, because there's a limited number of companies that are investing in this, but cellular therapies such as chimeric antigen T-cells, or CAR T-cells, are starting to look promising. There's been a lot in the headlines recently about companies like Juno or Kite who have had some very good successes in terms of efficacy and then you have an unexpected death in the clinic or some kind of immunological side effect, off target effect and some people have kind of said, "Well that's the end of that," so the therapies won't go much further for two reasons. One is because the unexpected impact it can have on the immune system can lead to some very deadly side effects. The other reason being that the most common type of CAR Ts at the moment are personalized, so it does involve taking cells out of a patient, modifying them, and putting them back in, which is logistically quite challenging to do and doesn't necessarily seem like it could be an option for every single patient. I do believe that we'll overcome those technical challenges in the future.

A much larger type of therapy that we're seeing now in terms of the size of the market and the number of therapies that people are setting the pipeline are various combination agents that will seek to leverage the success of checkpoint inhibitors. These are either drugs that will enhance the narrow range of checkpoint inhibitors in order to make sure that they apply to more than just a subset of patients, or that will somehow enhance the immunogenicity of a tumor in order to allow the immunomodulators to do their work, or else drugs that look to mitigate the toxic side effects of those drugs. We've seen a lot of very promising therapies come through, so that's very exciting.

Finally, I'd like to mention, it's not quite mature yet, but the epigenetic approaches that were quite hot, and people made lots of noise about them a few years ago, have definitely not gone away. There's a number of companies working on epigenetics and it's my view that the science is still not mature enough. Epigenetics is so huge, and we don't yet know enough about it, but I do believe that's going to be very impactful over the next five to 10 years as we learn more about it.

Mana Chandhok:
Do you have any advice for drug companies looking to work with CROs?

Aidan Synnott:
I would encourage people to look beyond pricing and think about the value that's generated. I think that the prime characteristics that a drug maker should be looking for when they're vetting a CRO are based around the experience of their scientists. That's in terms of how many times has that particular scientific group run, given essays, they're expertise, which comes down to the knowledge of the scientific personnel and how much they can contribute to the project beyond just the immediate study that's there.

Thinking about the context and the background of the therapy, the capability, so you may go and talk to the CRO about one given study, but you never know what other studies you may need to run. It makes sense to talk to the CRO about what else they can do. The more that they can do for you, the more likely it is that they'll be able to help you unless it becomes more of a long term relationship. Capacity in terms of how quickly they can get studies run and how much they can handle at a given time, and of course quality in terms of the error rate and the operation and execution.

Ultimately, if you have a partner who really understands what you're trying to do with your drug, who knows from experience what to look out for as kind of warning signs or other irregularities in the data that you may want to investigate more closely. It will save you money and more importantly time, in the long run because you just need to make the right choices at the right point.

Then, the other thing is if you work with a CRO where people have a good amount of expertise, it brings a different perspective to a project. It becomes a collaboration and that will benefit you. Even if you work for a large company, there's always a certain amount of culture that influences the way that people think and I believe that having the widest range of perspectives will help you, guide you to make the right choices, challenge you and enable that the drug or the therapy that you're exploring will be guided as best as possible. If you're going to fail, it's better to fail early, and if you're going to succeed, it's better that's it's rigorously tested by somebody who doesn't necessarily share the mindset as you.

Mana Chandhok:
Dr. Synnott, thank you for your time and insights today.

Aidan Synnott:
Thank you very much.

Mana Chandhok:
That was Aidan Synnott, an executive director at Charles Rivers Laboratories. Charles River Laboratories will be giving a bridging presentation between the preclinical models and tools in oncology track and the tumor models for cancer immunotherapy track at the upcoming World Preclinical Congress. That will be held June 12th to 16th in Boston, Massachusetts. If you'd like to hear from him in person, go to www.worldpreclinicalcongress.com for registration information and enter the key code 'podcast'. I'm Mana Chandhok. Thank you for listening.