We’re thrilled to share our enlightening exchange with Spiro Rombotis, the seasoned CEO of Cyclacel. He peels back the curtain on the breakthrough discovery of B53, a commonly mutated gene in cancer patients, and the inspiring success of FADRA, their lead drug in clinical trials. Furthermore, Spiro delves into the highs and lows faced by Cyclacel, including the triumphant moment a patient was declared cancer-free thanks to their groundbreaking drug.
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.
Interested in being featured as a guest on First In Human? Please reach out to catie@vial.com.
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We’re thrilled to share our enlightening exchange with Spiro Rombotis, the seasoned CEO of Cyclacel. He peels back the curtain on the breakthrough discovery of B53, a commonly mutated gene in cancer patients, and the inspiring success of FADRA, their lead drug in clinical trials. Furthermore, Spiro delves into the highs and lows faced by Cyclacel, including the triumphant moment a patient was declared cancer-free thanks to their groundbreaking drug.
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.
Interested in being featured as a guest on First In Human? Please reach out to catie@vial.com.
🎧 Stay in the Loop!
For the latest news and updates, visit our website: https://vial.com
Follow us on social media for real-time insights:
Twitter: https://twitter.com/VialTrials
LinkedIn: https://www.linkedin.com/company/vialtrials
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 connect with Spiro Rombottis, ceo of Psych-The-Cell, to discuss the groundbreaking developments in cancer research, emphasizing the importance of patient empowerment and adapting to the ever-evolving landscape of drug development and clinical research.
Speaker 2:Hi, I'm Rich McCormick, Executive Vice President of Clinical Strategy, here at Vile. Today I have the pleasure of welcoming Spiro Rombottis, CEO of Psych-The-Cell Pharmaceuticals, to our First In Human podcast. Spiro, thanks for joining. Would you mind telling us a little bit about yourself?
Speaker 3:Thank you for having me. I'm trained in public health and clinical trials. I've been in the industry for 38 years. Most of that has been spent in oncology, and Psych-The-Cell is my fifth employer. I work for two pharma and two biotechs, both of which are successful exits after bringing drugs to markets in the respective era of center core and deposal.
Speaker 2:Great Thanks for being here with us today. You joined Psych-The-Cell Pharmaceuticals as their first CEO in 1997. Could you share some specific milestones from your tenure that you're particularly proud of?
Speaker 3:Yes, it goes that far back because the Nobel Prize in 2001, four years later, was about the discovery of the enzymes that we are targeting with our molecules and therefore it was a seminal moment in the history of cancer biology. Psych-the-cell founder Professor David Lane is credited with discovering P-23, one of the most commonly mutated genes in people with cancer. There are many downstream of P-23 switches that we can exploit to arrest cancer cells who stop them from dividing and activate the body's suicide program called apoptosis, by which the cancer cells get disposed of, then the kidney clears them. So David Lane's ideas were reduced to practice In the pivotal moment in those early years. Of course, when we get into our lab, we start doing experiments to take David's discoveries in the academic laboratory into the company laboratory and found that we have anti-cancer activity in animal mode. So both of our lead drugs around that time maybe a few years after the Nobel Prize award were shown to be active. However, it took 15 years before the first enzymatic inhibitor from this class, dr Conan Ibrans from Pfizer, reached the market and is to this day a blockbuster drug in the area of breast cancer. So it took a long time for the science to mature. So the stops along the way were very informative, particularly the first in the human results. We entered the clinics before the pandemic with an oral form of the drug and we saw activity in patients were huge moments of encouragement for us. I should also mention quite a few years back that the Veeamon collapse around the turn of the decade almost killed the company. It took the stock market down to absurd valuations not much like we are today after serial Black Swan events in 2023. And of course, that created the shortage of capital that threatened survival of may-bought companies. But the mantra of some of my mentors did come true that the good drugs don't die. We did succeed in securing capital, move the programs forward and have high confidence. Given our current results will be the same now.
Speaker 3:The last moment that I would highlight is a pretty unique memory. If you want, that was a moment of celebration in the company was when our chief medical officer reported that a patient in one of the earliest trials with endometrial cancer, who had an early response to our drug as a single agent, had actually a PET scan in which he was found that a few foci in her lung were not lesions from the endometrium. They were not cancer, they were just scar tissue. So she was deemed to be cured and declared a CR. Now a complete remission.
Speaker 3:A cure in a highly refractor endometrial patient is not something you hear about every day, but we hear that our drug is the only agent that they received, that Veeamon caused it and the patient is still on study three years later. There's obviously a huge moment of excitement in the company where actually helping people not only not harming them, but actually helping them and in the very rare cases could even cure them with our drug and of course that's a major motivating factor to go forward. So it's been a very long journey with lots of ups and downs, but certainly the ups have kept us going all this time and we're now just about to turn the cards on very exciting new data. That's a great story.
Speaker 2:What inspired the development of FADRA.
Speaker 3:It's an exciting topic because, of course, we've been doing this for a long time, but it also remains a topic of controversy to this day. Conventional wisdom in drug pharmacology is that we pursue a single target, because mono-selectivity pursuing a single enzyme, for example, gives us answers to some very simple questions. If you get into the complexity of hitting two targets with the same drug, people say, oh, that was not designed. This is not the case with Cyclosylphadra CDK inhibitor. When I joined the company, as you asked earlier, david Lane had a clear clinical data in his own models that two N9s, cdks, two N9s, had to be hit in order for the apoptotic program to be triggered. We did experiments against CDK and N1 and CDK2 alone, and they were not effective. Two years later, a former clinical government from Brisfamara, scwit, was known as the leading scientist in the Spanish equivalent of the NCI, the National Cancer Institute of that country, published a paper together with the group from the University of California, san Francisco, showing exactly the same thing that hitting CDK2 alone is not an effective target. The animals recover if you knock out CDK2. It's not a valid target on its own In the body. Of course, that means that if we hit CDK2 alone, the tumor is going to continue to divide after a certain amount of pause.
Speaker 3:Hitting CDK9, the other target, was also very controversial and to this statement. It's controversial because most of the compounds who were chasing FADRA our molecular and the clinic have now been either discontinued or for an encountered significant severe hematologic toxicity, which means that they were either withdrawn or deprioritized by their sponsors, leaving FADRA in an enviable position is the only molecule that hits both two N9, but again is the target hypothesis that David Lane started the company on and the fact that when we're seeing single agent activity in multiple cancer types without the hematologic toxicity, the other agents haven't counted. So I hope that David Lane has the last laugh. He's now a fetid scientist across the globe and received many distinctions, but it's certainly very exciting for me in this very long journey, to see that perhaps he was right that hitting 2N9 is critically important by achieving apoptosis and cancer cells without harming a lot of normal cells and causing toxicities.
Speaker 2:So staying with FADRA, would you mind elaborating a little bit on your phase one two dose escalation and maybe talk through some of the encouraging outcomes and treating those solid tumor and lymphoma?
Speaker 3:patients. First of all, the phase one, two dose escalation studies. The brainchild of our clinical team led by a brilliant chief medical officer, dr Mark Kirschbaum, who has a long record not only as an industrial scientist and several farmers and biotechs, but also in academia. He was the head and founder of the phase one unit in the city of Hope in LA. So Mark's design is what we call a seamless concept, although we escalate in the phase one part of the design each dose level until we hit dose limit in toxicity and then go to one level below that to declare this is the recommended dose for phase two or RP2D.
Speaker 3:In phase two we test several tumor types and we are approaching that river from two sides of the riverbank, building a bridge to cross. Namely we look at the tumor type by anatomy, astrology. There could be, for example, cohorts in that phase two portion of the study which are endometrial ovarian lymphoma and so on. And then, on the other hand, we also look at a single cohort where the patients can enroll because they have biomarkers which are relevant to the drug's mechanism, even though they don't have one of the tumor types that was described in the previous cohorts. So they're all together eight cohorts in the phase two, seven by a tumor type and one is the basket, which means that we have eight distinct chances to win here. If any one of these cohorts meets the fertility criteria or the phase two component of our study would hopefully enroll an expanded data set and then go to the FDA in what is typically called end of phase two meeting and ask for their advice and support If the data is strong enough to support early approval through the accelerated pathway or we need to go and do other, more randomized studies perhaps, or even combinatorial studies to find more consistent activity.
Speaker 3:So the beauty of this design is that it compresses the time frame that we normally use for phase one and phase two from two to three years to one and a half.
Speaker 3:Subject to a sufficient capital, of course, we can enroll one, two or more cohorts, or all eight if there's sufficient money in the bank. But the beauty is that each of these outcomes is discrete and independent of each other, which means that as physicians get informed about the study and their ethics committee and IRBs and institutional review boards are informed, they will enroll patients. So the patients have the highest demand, get to see the protocol first. So in a way the system is regulating demand and enrollment based on what the need is highest and, of course, what the drug is shown activity, which means that the cohorts that have the tumor type. We've seen certain dipithosacitivity in phase one, where we enroll the fastest. So the beauty of this design is that we get seven, plus the basket, eight shots on goal, each independently of each other, without the enrollment of one affecting the other, and then we have a very effective and efficient design to ask multiple questions where is the drug most promising and where should we help focus for achieving a registration direct outcome?
Speaker 2:Thanks for that. So your cyclocell pipeline also has a PDK1 inhibitor called PLOVIL. Would you mind telling us a little bit about that compound as well?
Speaker 3:Yes, this is a controversial area of oncology. Plk stands for Poluli kinase one and there are historically other compounds that have targeted PLK1, but they've encountered substantial toxicity. Perhaps that was an attribute of the chemical structure. Another compound recently came into the clinic which is not very toxic, so obviously that can be addressed. Perhaps the issue with the early generation drugs was that they were at very long life. They lasted in the blood for days as opposed to hours, and it's important to have quick off mechanisms for cancer agents Once they trigger the relevant switches, the relevant trigger apoptosis would don't want them to stick around because they only cause toxicity. So it's possible that there was a second problem why this class of compounds, that PLK inhibitors, do not meet success and that is the fact that it's a paradox that at high doses in the traditional chemotherapy like dosing regimen they're very toxic to normal cells and they don't have as much of an effect on castle cells. Spectacularly and there's a lot of published literature on that when given at low doses we see more cancer cell kill. That's not what you'd expect in cancer pharmacology. You expect as you increase the dose you get more efficacy. But that's an encephalopyridine from the 70s.
Speaker 3:We're now in the era of precision medicine where we need to understand why do we see activity in patients with this drug, plogo, in phase one? And the answer is a complicated technical term epigenetics. And a drug that's active at doses that are almost homeopathic levels, not supposed to have any activity in proclinical models. That's because they don't necessarily kill cancer cells for the reprogram what the cancer cells do. They have some approved drugs that do that. Perhaps the best known is a hypo-methylating agent called azocytidine or vidyza. It's a blockbuster drug in leukemia, over a billion dollars in sales, but in its early development years it had a bad name because at high doses it was just toxic, not very effective. It had some activity but it was not persuasive as a single agent. When given a low dose is, though, together with another agent which is now approved in the United States, they became the US standard of care in the toughest of leukemias. They become now the frontline therapy of choice in acute marbol leukemia, and the community understand this is because of this epigenetic consequences.
Speaker 3:So we're now very confident that Plogo has an epigenetic mechanism. That scientific documentation for that is available in our website and our presentations. We haven't told the community yet is what is the group of patients that we can target to achieve a robust clinical benefit. It's just like with FALDA that we're not reaching the point that we are understanding how to select patients. We have crossed this very difficult question with Plogo. I'm not disclosed it yet, so this remains to be described in public, but we're very excited about what we're seeing. We have five independent laboratories from top institutions around the world that have confirmed our data. We'll disclose those results as well, with a consent of the investigators. So we think we have a totally new pathway and a totally new way of giving this class of compounds that has not been discovered up to now. So a very exciting moment for us and for those that have been in the PLK field for decades have not seen reduction of benefit to man.
Speaker 2:That's really exciting. So maybe more generally speaking, what challenges and opportunities do you see in the current drug development and just oncology research?
Speaker 3:I think the biggest challenge that we face with the time being is to find a way to fund innovation. This is from both ends, both with the early development and discovery, given that recent congressional legislation has perverse incentives, for example for intravenous drug versus oral drugs. It gives longer exclusivity to a type of agent that requires extensive medical involvement and therefore has a higher cost administration than a pill or a capsule by a patient that they can hold. This is not a good thing for patients. In fact, we found that after the pandemic, people refused to get IV therapy in early stage clinical trials because unless we can persuade them that there was a chance of benefit, we simply don't vote with their feet to come. But they will take oral drugs, particularly if they don't make them feel sick. The other point is that some IV drugs, like immunocombolegy drugs, have made epochal progress in cancer development. So we can certainly expect that antibody drug conjugates and IO compound will continue to be important in the frontline therapy of many tumor types. But once patients progress and not all patients respond to these therapies the typical hit ratios become 20% and 30%. But about all the rest, they have to serve them not only when they don't respond in the first place, but also if they respond to it and they relapse, and that's where sacroasal molecules come in. So our opportunity is to work in refractory disease, because we're dealing with the problem of resistance, epigenetics and how both of these drugs fibroids. All the work is about reversing resistance and making cells sensitive again, or resensitizing them cancer-thera.
Speaker 3:Now, a moment of extreme cardiac activity is when you see that your drug is doing that as a single agent and the label, because you see this in combination. We see it happening in a single agent. It means that you're fundamentally hitting a mechanism which cancels cells depending. If you deny them this mechanism, they're instructed to commit suicide through the apoptosis program. So we now have evidence that both of these drugs do that. So I would say that the IRA, the Inflation Reduction Act, and its incentives will probably have a chilling effect on innovation unless Congress steps up and correct some of the issues in the IRA, which has good intentions of how to fund medical innovation once drugs are approved. That certainly a global society desires. That we should address both as a drug industry and as administration, as well as regulators. On the other hand, we need to make sure that innovation is funded and when investors start to calculate my time for return is worse for an oral drug than an IB drug. We have distortion of what should happen, which is the best drug for us to patients as fast as possible, but these unintended consequences need to be addressed.
Speaker 3:The other area that I think is both a challenge and an opportunity is artificial intelligence. There is a lot of hype about AI and how it could possibly speed up drug development. In my humble opinion, like many breakthrough innovations, from the internet to Twitter and everything else in between take time. Take time not only for society to understand how to use them and the experts to figure out applications, but also because we have to dispose of older approaches and, as we need to understand on the basis of objective evidence that the new technology is useful, we're going to be slow in adopting Because, like medical doctors are conservative in adopting new drugs and do their proven to work long after the FDA lets them get on the market. So AI may have a period of gestation. I would expect that in early drug discovery, as we look in the computer for molecular structure, for example, ai could enrich dramatically our hit ratio, but I don't think it's going to increase our chance to get drugs in the clinic that are favorable to patients. I either don't have more toxicity in their work as designed, that would take a lot longer, certainly because teaching a computer to think in fuzzy terms is very challenging, and drug development is about fuzzy logic Seeing an observation that was not in the playbook and then making associations how this could allow you someday to select patients that could benefit most from the drug. To do that, we need to, of course, use human logic, which is much more tolerant of such ambiguity, and that means that AI may take a while to finally reach there.
Speaker 3:The last point I'd like to address is patient empowerment. I've been obviously raised in the environment of public health and I've been acutely aware of the importance of patient choices as we go forward. That was 35 years ago. The day patients come into the hospital, they go to informed consent discussion with a doctor who's offering them a clinical trial. They say doctor, my son printed these documents. I read all about this new approach and it's killing people. I don't want it. I'm with the hospice at 85 years old. I want it forever.
Speaker 3:That is the challenge that we face. Patients have choices and, of course, younger patients have more diet choices. They have family issues they can run off for it to be in a chair four days a week for an hour because they have children to pick up from school or work careers to pursue and so on. So we have the industry to align quickly with patient demands. That means that the majority of drugs in my hermaphroditeal opium will have to be oral toxicity and work in via precision medicine rather than old-fashioned chemotherapy approaches.
Speaker 3:Gimo isn't dead but is dying slowly because patients refuse to get it. So in the front line of course he has a space. But once you go in second and third line therapy there's even modern drugs that are toxic and not going to succeed even if the FDA approves them. So clinical relevance, a topic that we often use in our industry, is very important. Patient choices are even more important than the fact that we're now at least in the United States. We have to ask ourselves when we develop countries, patients who are empowered to refuse. We have to ask ourselves whether we can deliver on the lofty goals we set for ourselves if we persist on approaches that do not address these issues early on in the drug design stage. But I'm confident that we have the tools to do that. In industries like ours, survive and flourish because people are willing to adapt and of course we will to these new challenges.
Speaker 2:Great insight. Lastly, what message or advice would you like to share with the broader community of professionals and entrepreneurs involved in clinical research and biotech?
Speaker 3:I think the most important question is not to be caught by stereotypes, particularly true for investors who may have been trained in an area of science and they worked into clinical development with the view that everything happens as in a petri dish or an animal model.
Speaker 3:It doesn't happen that way, and often we have seen drugs that reach the market and even become bloodbusters, who were deemed to be targeting target A but was found several years after they reached the market with a different target.
Speaker 3:This is therefore the value of serendipity.
Speaker 3:Every drug development executive has been taught that from their mentors, and the mentees know that true observation, when we're surrounded by talent that can spot the observation in associations with biochemical phenomena and genetic attributes of a tumor type, can be extremely enriching.
Speaker 3:So my takeaway is that people should not rush to judgment because a drug hits a target at a certain potency level or low IC50 and therefore will work as design, but rather, once it goes into the clinic, if the sponsor is astute and supplies information to investors and other constituents like investigators or how the drug works, what genes does it actually turn on and off? That's what epigenetics is about Conscription factors that turn genes on and off. Thousands of genes and finally, a few that are relevant to the drug, is how we can thread the needle and demonstrate both to clinicians. We have to convince patients as well as investors who want to fund our companies that we have molecules of interest. Ultimately, it's not what we desire the drug to do, but what it actually does in patients that matter, and how we prosecute that, in my opinion, is where we have a big disconnect between understanding and knowledge, which can hopefully lead to more effective therapy. On the second, health patients.
Speaker 2:That's great advice. So, spiro, it's been a pleasure meeting with you today and thank you for being a guest on the First In Human podcast. The team here at Bio wishes you and your team at Cyclocel Pharmaceuticals nothing but future success.
Speaker 3:Thank you for having me. It was a pleasure.
Speaker 1:Thanks for listening. Be sure to follow us on Spotify, apple, youtube and Google.