Episode 49: Jeffrey Bacha - Chairman, Rakovina Therapeutics

Join Jeffrey Bacha, a pioneer in the fight against cancer and the creative force behind Rakovina Therapeutics. For 25 years, Jeffrey has been reshaping the industry landscape, and today, he gives us a peek into his world of innovation. We venture into Rakovina's research and development of oncology drugs. exploring their groundbreaking technique combining PARP and HDAC inhibitors into a single molecule, a game-changer in enhancing synergy and reducing toxicity.

First In Human is a biotech-focused podcast that interviews industry leaders and investors to learn about their journey to in-human clinical trials. Presented by Vial, a tech-enabled CRO, hosted by Simon Burns, CEO & Co-Founder. Episodes launch weekly on Tuesdays. To view the full transcript of this episode, click here.

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Chapters

• 0:07 Redefining Cancer Treatment
• 12:09 Advancements in Oncology Drug Development

Transcript

Speaker 1: 0:07

You are listening to First In Human, where we interview industry leaders and investors to learn about their journey to in-human clinical trials presented by Vile, a tech-enabled CRO hosted by Simon Burns, ceo and co-founder. Featuring special guest host Rich McCormick, evp of Clinical Strategy and Head of Oncology. In this episode, we are joined by Jeffrey Bacha, founder and chairman of Rackovina Therapeutics. Learn more about Jeffrey's 25 years of experience in the industry, the groundbreaking work of Rackovina and redefining cancer treatment, and the exciting future of the company's impact on fighting treatment-resistant cancers. Hi, I'm Rich McCormick, executive director of Rackovina Therapeutics. I'm a professor at Rackovina Therapeutics. I'm a professor at Rackovina Therapeutics.

Speaker 2: 0:56

Hi, I'm Rich McCormick, executive vice president of Clinical Strategy, here at Vile. Today I have the pleasure of welcoming the founder and chairman of Rackovina Therapeutics, Jeffrey Bacha, in Human Podcast. Good to see you, Jeffrey. Would you mind telling us a little bit about yourself?

Speaker 3: 1:12

Thanks, rich, it's great to be here. Yeah, as you mentioned, I've been involved in the industry for over 25 years in terms of drug discovery and development. My original background is actually biophysics, with the intention, once upon a time, of taking that and going off to medical school. I think that there were a number of things that shaped my career. One was actually the first job I had on the bench top at a commercial stage diagnostic company and watching how the leadership there evolved and some of the decisions that were made. In one case we had a decision around a new packaging for a commercial product In order to get this out the door and leverage the investment that had been made. The critical testing that should have been done wasn't that eventually led to the failure of an entire lot of product? That finally didn't happen for six months. It was a global recall six months in the making, which was a disaster.

Speaker 3: 2:11

We learned very early on through that experience and watching that happen around me that there are really no shortcuts to good research asking the right questions, designing the right experiments to answer those questions and then making decisions around them. That experience drove me towards saying, well, there are better ways to do this, rather than moving on toward medical school. It was business school for me. From there I was involved in Lark's accounting firm in their capital markets group, which was something everybody had at that time, and was doing a lot of consulting with emerging companies, some of which went on to become quite successful. When I was eventually recruited, actually out of that group into a turnaround company here in Vancouver, british Columbia, which is, of course, where Rack of Vena Therapeutics is located today. That was a wonderful experience of being able to take everything I had learned through the consulting world and put it to task in real life and helping to take a company that was in an interesting position from having good science with some other challenges around it and addressing those challenges along with the leadership team there, and having some great success. I left after a couple of years and I was sort of the venture backed company whose technology is now in a public company in the US.

Speaker 3: 3:28

Eventually, the key person I think that has really driven my career for the last dozen years or so was the introduction to a fellow called Dennis Brown. Dennis has been in the industry for well over 40 years, has a number of successes in terms of drug development and FDA approvals. One of his mantras was there are drugs out there that are very promising, that may have been overlooked. There are targets that are out there that are very important, where we could do better, and really you're driving research around that.

Speaker 3: 3:58

We started a company together called Edison Oncology, which is a private company in the US, which eventually led to the formation of racovina therapeutics as essentially a spin out of one of the assets that was at Edison Racovina. The name actually means cancer in Czech and a number of other Eastern European dialects, cancer Therapeutics. We had the opportunity to take that asset and combine it with a couple of others in the DNA damage response field, with a wonderful group of initial investors and a great team at the University of British Columbia, to form racovina therapeutics. Here we are today. I'm really excited in this position.

Speaker 2: 4:36

Great. So thanks for the intro, Jeffrey. And so over those 25 years, maybe could you think of an experience that you could share that has maybe significantly influenced your leadership style in terms of how you approach day to day at your company.

Speaker 3: 4:50

There have been a number of people along the way who have had a very important impact on how I view things and build companies around myself and a good team, and I think the key thing is that this is a very difficult business in terms of drug discovery and development. It requires a tremendous range of very diverse and very deep skill sets, and not one person has all of them, and, while there is a natural tendency to want to sort of take the reins of things around you the ability to identify and trust the right people who are experts in that particular thing that you're trying to do, and then let them do it, give them the tools, the support, the things that they need in order to move the ball forward in that particular aspect, and then make sure the entire team around that individual and together is cohesive in order to accomplish some very significant goals that are going to benefit patients.

Speaker 2: 5:44

Yeah, it's a great approach. So you mentioned raccovina stands for cancer. So how does raccovina aim to redefine cancer treatment and what is the inspiration behind the approach? The?

Speaker 3: 5:55

inspiration behind raccovina therapeutics is really driven by the success of a first generation class of therapies in the DNA damage response field called PARP inhibitors. Parp inhibitors have now become very important and mainstay treatments in certain types of breast, ovarian and prostate cancer. That's recent development and these things were very long in history. So the PARP enzyme was actually first discovered in Paul Mindell's laboratory back in 1963. And so 50 years later more than 50 years later we had the approval of the first PARP inhibitor in BRCA mutated cancers, and a number of things have to happen along the way for that to occur. But now we have these four PARP inhibitors on the market and they've been game changing for patients with BRCA mutated cancers. Our vision of this field is the first generation is disruptive, as I said, game changing. But then you start to learn about what could be done better. The iPhone 6 and the iPhone 14 look very similar in your hands, but we all know they're very different devices. The evolution of engineering that allowed that to happen is sort of a natural progress of science, biology, chemistry, cancer therapeutics. You'll follow a similar trajectory where we can now do things in the laboratory, in the cell, looking at DNA, with tools that we didn't have before. This happens with every new class of therapeutics. If you look at the EGFR tyrosine kinase inhibitors the first generation that started to enter the market in the early 2000s with ephidinib and inolatinib, those were great drugs but we learned we could do better. And the second generation, with ephidinib and its cousins, came along. Those were more important products and more impactful to patients. But now we even have a third generation in that field with azimertinib, and it's been a game changing drug at a different level. Yet again, the size of the opportunities in terms of the revenue generation from first to second to third generation is also very significantly different. We view the DNA damage response field in a very similar way. It's a young field. It's become a very important area of research and those PARP inhibitors on the market have been game changing for the patients who have benefited from them.

Speaker 3: 8:21

But we also over time start to understand some of the limitations. Tumors will respond initially very well to treatment but then eventually, almost in every case, cylindrical resistance will develop. The drug stops working as well. The tumor comes back and sometimes it comes back very aggressively.

Speaker 3: 8:39

Another limitation is the first generation drugs are not particularly good at chasing a cancer into the brain or the central nervous system. They're not very good at crossing what's called the blood brain barrier, which is there to keep things out of the brain. But when you have a cancer setting, like in breast cancer, for example, where roughly half of the patients will experience spread of the cancer or metastases into the central nervous system or into the brain within their course of treatment, we need to do something about that. Designing compounds, new assets, new drugs, new treatments in the PARP space that have the ability to treat those cancers that have metastasized into the brain is very important. We've also learned some of the side effects of the first generation PARP inhibitors. There are those some things that we might be able to improve there as well. So when we were thinking about assembling racovina therapeutics, it's let's pay homage to the success of that first generation and then build upon that by making very pragmatic, incremental improvements toward addressing those limitations.

Speaker 2: 9:40

Jeffrey, would you mind giving us a preview into the pipeline at racovina? How does your team at racovina envision synergizing different treatments within its pipeline?

Speaker 3: 9:52

Well, as you mentioned, we have assembled multiple assets, multiple shots on goal, if you will, all sort of based on PARP inhibition but then asking different questions about how we can do that better. The most advanced program is our KT 3000 series, which has been designed from a medicinal chemistry point of view to overcome treatment resistance. As we discussed, the initial treatment of the cancer with a PARP inhibitor, there's usually some great benefits for patients with BRCA mutations, but that mutation, the BRCA mutation, is very critical for the impact or the activity of that drug. If you don't have a BRCA mutation or other defect in homologous repair, parp inhibitors don't, frankly, do much. What happens in the cancer, which is always continually trying to evolve and overcome? Whatever you're trying to throw at it, the cancer will actually mutate and turn that gene back on. When that happens, the PARP inhibitors become less effective. The cancer can return. We know there are ways you can prevent that from happening potentially. But there are also ways to, even though it has happened, hide it from the cells that the PARP inhibitor could continue to be effective, and one of the ways to do that is inhibiting another enzyme called HDAQ. That's been something on paper, has made sense for a long time. When you inhibit HDAQ, you actually cause a degradation of the protein product of the BRCA gene, even though the gene is active, creating that resistance. If you degrade that protein then the PARP inhibitor would still work. On paper.

Speaker 3: 11:27

Combining PARP inhibitor and an HDAQ inhibitor makes a lot of sense. Unfortunately, combining those two with two different molecules has some challenges. One of the challenges is overlapping toxicity, so treating the patients with a PARP inhibitor and an HDAQ inhibitor has been daunting from a toxicity and safety profile. And the other is the fact that you need to have a correct ratio of the PARP inhibition and HDAQ inhibition in order to achieve the optimal synergy there. And if you have two different drugs with two different metabolisms then you really don't have an opportunity to have that fixed synergy for a longer period of time.

Speaker 3: 12:09

A very smart chemist called Wang Shen, who's almost legendary out there he's got a number of products in the oncology field in Elsewhere that have been approved by the FDA that he's designed. He had an idea of I could combine a PARP inhibitor and an H-DAC inhibitor those two functionalities in a single molecule. If I do that then I might be able to achieve the synergy, maintaining that correct ratio, but also avoid doubling down on the toxicity because I'm only delivering one treatment instead of two. So that was the theory that he started with and built some initial prototype molecules. We've known Dr Shen for a long time and when we were looking at putting racovina therapeutics together we had the opportunity to bring in that what is now the KT3000 series, that idea into the company of a dual function PARP H-DAC inhibitor. That's really emerged as our most advanced program, that racovina therapeutics. Here we now have molecules that have drug candidates that have been vetted in multiple preclinical models and we recently published a paper in the Journal of Clinical Cancer Research telling the story of discovery through the lead optimization process to now having viable candidates that are being targeted to move into human clinical trials next year.

Speaker 3: 13:29

Beyond the KT3000 series we have our 2000 series and 4000 series, which are a little bit earlier stage. The 2000 series is a little more of the traditional PARP inhibitor, let's call it, where we're selecting for profiles that would reduce side effects and also allow for optimizing brain penetration to be able to treat those cancers that are spreading to the brain. In the 4000 series combines PARP inhibition with an alkylating functionality. Again, the idea of combination therapy is very important in cancer. Parp inhibitors plus chemotherapy have been something that has been a vision, but again the overlapping toxicity has been a challenge.

Speaker 3: 14:14

By adding an alkylating functionality to a very potent PARP inhibitor, the KT3000 series of data we've shown says that we've been able to overcome treatment resistance and be active where the first generation drugs are not. The 3000 series, being the most advanced, is where a lot of our work is being focused today to advance something there into human clinical trials in the 2024 timeframe. The synergy in our research is really not necessarily looking at how we would combine one of the drugs from the 3000 series with a 2000 series molecule. It's more the synergy in the lead optimization platform that we've established because the earlier experiments that we are doing in evaluating different drug candidates are very congruent across all three series, so we can really leverage that infrastructure in a very synergistic way. Then, as we go forward, looking at opportunities for combination therapies with each of our classes of candidates, either with immunotherapy or chemotherapy for example. That's something that's always in the forefront of our thinking.

Speaker 2: 15:18

Very good. You mentioned during your intro of your collaboration with the University of British Columbia. How does this partnership bolster rapid research capabilities and expedite that drug development process?

Speaker 3: 15:30

The collaboration with the University of British Columbia is a wonderful collaboration that has really positioned us for success. It comes out of some history. There's a professor at the University of British Columbia called Madge de Gard who's also now the president and chief scientific officer of Rackabita Therapeutics. We've had a relationship with Professor de Gard in his laboratory that goes back a number of years. His team had been sort of go-to academic collaborators for us in a number of different projects and he has a deep expertise in DNA damage response and so when we were looking at these various assets and doing some due diligence on them as we were putting Rackabita Therapeutics together, I actually asked Madge to look at some of the early data that Wang Shen had developed, and he got quite excited and said, hey, how can I be involved? Is it possible we might be able to do this in my laboratory? And so, having a good relationship over the years with the university, we approached them and said how do we put something together that will allow us to operate within the de Gard laboratory with a dedicated team for Rackabita Therapeutics? So we have that set up and it's wonderful in terms of the lead optimization infrastructure, the dedicated team and all the expertise around that in that particular laboratory, but beyond that, the infrastructure that's available at the University of British Columbia and the BC Cancer Agency and the Vancouver Prostate Center.

Speaker 3: 16:54

It's really a big pharma infrastructure that we have access to that most young companies wouldn't and so there is. If we had to send out our drug candidates to a CRO and spend lots of time and high expense waiting and waiting for data, that really is limiting in terms of how quickly you can move. Having everything under one roof down the hall at our fingertips really has changed our turnaround and our biological information to inform the next round of chemistry. We can do this in a matter of weeks rather than months in other scenarios. So it's really led us moved very, very quickly to the point where we now have viable preclinical candidates from the 3000 series that are realistically positioned to potentially enter human clinical trials next year. So it's been a wonderful relationship and we look forward to continuing that as we go forward.

Speaker 2: 17:50

Yeah, very fortunate to have that relationship. So, in terms of like market opportunities, prominent pharmaceutical companies are investing heavily in DNA damage response research. So what opportunities does Raccabina foresee in these markets, particularly for treating resistant cancers?

Speaker 3: 18:06

Well, as you know, cancer is a continuously evolving disease and where the first generation prep inhibitors have become critically important for a subset of cancers, we believe that the next generation will do even better.

Speaker 3: 18:20

Our data with the KT 3000 series, we've shown quite robustly that we can overcome treatment resistance.

Speaker 3: 18:27

So when that broccogene is reinstated by the cancer cell, that combination in one molecule of PARP plus H-deccan ambition allows us to maintain activity against that cancer.

Speaker 3: 18:39

But interestingly, in the vast majority of cancers where you don't have that underlying broccomutation, where the PARP inhibitors would not generally be anticipated to have any impact, we've shown that we can treat those cancers too. So being able to go into a cancer where that underlying broccomutation doesn't exist, being able to achieve this synergy with the combination of PARP plus H-decc, has opened doors, for example, into childhood tumors like Ewing sarcoma where the PARP inhibitors have not had an impact. And part of that publication in the Journal of Clinical Cancer Research is really towing the story of the potential impact in those childhood tumors such as Ewing sarcoma and we've been very lucky to have some great support of the St Baldrick's Foundation toward that program into a rare childhood tumor. In the big picture, the ability to treat resistant cancers that have become resistant to that first generation of PARP inhibitors in major areas such as ovarian cancer and breast cancer and prostate cancer. Those are front and center in our vision because we believe that we can have a great benefit to those patients and really have a profound next generation type of impact.

Speaker 2: 19:53

So Rackabina has achieved some significant milestones, such as recent program selection obtaining patents. So, jeffrey, what do you see for short-term future for Rackabina and how you're going to have an impact on treating cancer?

Speaker 3: 20:07

Well, as we know, drug development and drug discovery is a long and difficult process, and I've been very impressed with the speed that the RACAVINA team has gone from early proof of concept chemistry to viable preclinical candidates that are really positioned to start human clinical trials in the next year. Being able to build a strong patent portfolio around the candidates is also something that we're very proud of, and we've been able to showcase some of our research at peer-reviewed scientific meetings, which leads us into conversations with potential partners, because everybody's in the same room as we go forward in moving a KT3000 candidate into human clinical trials and having a pipeline behind that that are all designed to build upon the success of the first generation PARP inhibitors into new areas where we can do even better for patients. That's something that we find very exciting and are looking forward to seeing the initial first human clinical trial results with the KT3000 series lead and then following that with our other programs into the clinic thereafter.

Speaker 2: 21:18

That's really exciting, Jeffrey. It's been great catching up with you today. Thank you for being a guest on the first in human podcast. The team here at Vile wishes you and your team at RACAVINA Therapeutics nothing but success in the future.

Speaker 3: 21:31

Thanks, Rich. It's been a pleasure to be here and we look forward to providing some updates down the line.

Speaker 1: 21:44

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