BTI 51 | Cell Cycle

 

Cell cycle biology is key to understanding cancer. You have to hit the cancer cells early before they become smart and adapt. There is a stage in the cell cycle called mitosis. This is where, if done right, can cause cancer cells to suicide. This is where the biotech company, Cyclacel comes in with all their research into the cell cycle of cancer. Join Ammon Rivera as he talks to Spiro Rombotis about some of Cyclacel’s cell cycle therapies. Spiro is the CEO of Cyclacel. His mission is to use cell cycle biology to treat cancer and other serious diseases. Ammon and Spiro go over the use of Cyclin-dependent Kinase and its role in the cell cycle. Spiro also talks about Cyclacel’s pipeline and drug candidates. They also go through discussion strategy, the drug approval process, and what it means to fail fast.

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Cell Cycle Therapy: Understanding The Cell Cycle Biology To Treat Cancer With Spiro Rombotis

Thank you so much for being here with us. If you are new to the show, thanks for stopping by. I hope you find some value in this episode. You can go back and read the previous episodes as well. If you’ve been a regular audience of the show, thank you for sticking with us. I really appreciate it. As I’ve said before, and I’ll say it again, the guests and the audience are the ones that make the show. I really appreciate that.

Our guest is Spiro Rombotis, the CEO of Cyclacel Pharmaceuticals. Cyclacel Pharmaceuticals is a company that is focused on what they call the cell cycle in cancer. One of the ways they explain that is if checkpoint control events are not completed correctly, then cancer cells may actually commit suicide by a process of program cell death called apoptosis.

What they’re doing is they’re seeking to enhance and facilitate apoptotic outcomes to treat patients with cancer. Spiro gives us a beautiful explanation, a much more in-depth explanation of what that is, what the company is doing, where they’re at, what strategies they’re approaching. We also have a conversation a little bit about current market pressures and things that are happening generally. I love getting into those types of conversations about strategy and how companies are built and all of that with these leaders that I do interview. Spiro graciously has that conversation with me.

A little bit of background on Spiro himself, Spiro holds an MBA from Northwestern University, the Kellogg School of Management, and has previously held positions with Centocor as Head of Corporate Development, Head of European Marketing. He was also with Bristol Myers Squibb as a VP of Pharmaceuticals in Central and Eastern Europe. Before joining Cyclacel as a CEO, he was with one other company before that, and it’s The Liposome Company, as the VP of International Operations and Business Development.

It’s a great background. He gives us a great explanation of what the company is doing and some great insight into the market and in how things are going. Don’t forget to like, subscribe and share this episode with those around you. I appreciate all the support from everybody. To let you know, I’ve actually been down in Southern California. I had the opportunity to do some onset recording and interviews with both Aristea Therapeutics, as well as with Lineage Cell Therapeutics, who are both companies that I’ve had on the show.

It was awesome to get to go and be with them in their offices, and get some more update and insight into what’s going on with them, and give you the audience an in-depth look at what the culture looks like and what they’re doing. Those are going to be coming out on some YouTube videos here. Check us out on YouTube. It’s just BioTech IQ Podcast on YouTube. We’re working on some things for you there. Without further ado, I will go ahead and roll the intro and get you to the episode.

Welcome to the show, Spiro Rombotis.

Thank you. It’s nice to see you.

I’m glad to have you on here. I’m excited to get into this discussion on your background and how you got started in the industry. Also, to talk a little bit about Cyclacel Pharmaceuticals, the company that you founded. Is that correct?

No. I was the first CEO. The founder is a world-class academic, which we can speak about. I was the first business executive that the company hired.

I was looking over your background on LinkedIn, and I can see that you have been with Cyclacel for quite some time. That’s pretty impressive. I didn’t know exactly how the company started, so that will be an interesting story, I’m sure. Tell me a little bit about your background, and what were some of the driving factors that led you to where you are at?

I have been in the industry for many years. I started my career in clinical trials as part of my graduate study in Chicago. I had a degree in Public Health along with an MBA. I decided to go into the industry I love for a number of reasons. Primarily because I wanted to help people. I wanted to do something with my life that would be helping people that have some very difficult to treat diseases. Cancer is at the very top of that.

I worked for two biotech companies and two pharmas on this journey. Cyclacel is my fifth employer. As you said, I have been there for a while now, and it has been more than one could have possibly imagined. It has been a journey full of ups and downs but also a tremendous success and great disappointments, nevertheless full of learning and excitement.

What was it that inspired you to study what you did and to go the route of the life science industry?

I was involved in medical things in childhood. My father had a small business serving these industries with primarily supplies. I was always in contact with physicians, and this is a field I wanted to dedicate my life to. As we all do in our journey through early education, it wasn’t until grad school that I became enamored with the field of cancer research. This is to understand to be a very difficult area to explain to a young person. Once I got into it and realized what huge odds were stacked against success in cancer research, the sheer challenge of that and its implication for humanity is what drove me to do what I do.

I have been listening to an audiobook, and it’s called The Emperor of All Maladies: A Biography of Cancer.

BTI 51 | Cell Cycle

Cell Cycle: Cyclin-dependent kinase 2 and 9 were best suited to address the problem of resistance. This happens when the cancer drugs stop working and the patients go back and relapse.

 

It’s by Siddhartha Mukherjee.

I’m about halfway through but listening and understanding a little bit about where things have come in terms of the types of treatments and the progress that has been made is pretty amazing. You could see how difficult of a challenge it has been to find treatments that, for lack of a better term, get the job done and have a lasting effect on the patient. It’s definitely a tough space. We are seeing a lot of pretty innovative treatments coming. Before we jump into what Cyclacel is doing, what were some pivotal experiences that shaped you throughout your early stages in your career?

My early service in the industry was with a biotech startup called Centocor, which was eventually absorbed by Johnson & Johnson in an acquisition in the late ‘80s. Centocor was the pioneer in a whole new class of therapeutics in the area of cancer, inflammation, and other indications called monoclonal antibodies. Now, it’s a multi-hundred-billion-dollar industry, and we were the first company to try those new approaches in humans in clinical trials.

We flirted with bankruptcy several times in my early days in the company. I was employee number nine. You can imagine how high-risk that project was and probably out of the scale but in the end, we persisted and were successful, which is what culminated in the acquisition of the company by Johnson & Johnson at the end of that decade. It was a very important lesson early on that we learned from failure in this industry.

The reason this is the case, Ammon, is because the odds are overwhelmingly against us about success early in clinical development. Typically, even to this day, three-day or so decades later, the odds of success of a drug in Phase 1 in cancer research are less than 10%. 9 out of 10 molecules will fail, and we, society, need hundreds if not thousands of companies to try so that the few that go through can give us the medicines we want at a clip of about 45 to 50 or so per year, approved by the FDA and put on the bedside to help patients.

The pandemic has also taught us some very important lessons that are that it has enabled the patient’s voice, which has not been absent but perhaps wasn’t as loud as it has become during the pandemic. That has to do with the choices that patients make about cancer drugs and, by extension, all of the medicines. For example, it has become very clear to many of us that patients who are afraid of exposure, particularly immunocompromised cancer patients that have a higher chance of morbidity and possibly death because of COVID-19 will demand oral drugs they can take at home.

IV drugs are great as a short-term measure but to contain the disease for a long time, other than vaccination, to treat something that potentially could expose you to double jeopardy of acquiring an infection requires oral dose medicines. We also have learned that patients do not accept anymore the toxic rigors of chemotherapy that our grandparents accepted a few decades ago because there was no other choice.

These patients push back on toxicity, even if the drug is active. We regularly see the rather disappointing situation where the FDA would withdraw a drug that was approved on an accelerated basis because subsequent data did not produce a survival advantage as toxicity sometimes can overcome the benefit of survival shown in early studies and result in more deaths.

The test arm that we are looking for is the new drug to do better than the control arm. For all these reasons, we’ve learned early on failure is the master teacher that allows one to reach success after persistence is applied and, very importantly, to ensure that the patient’s voice is heard. None of us will imagine drugs or visualize what drugs could look like but need to consider very early on how patients will receive, not just, “Do they work and are they safe,” but how will patients accept to use them so that we can achieve a therapeutic goal we are set out to do.

You’ve said multiple things there that we could probably take each of those and go into a little bit of a discussion on those. I find it very interesting the amount of treatments that actually make it through the clinical trial process and the early stage. It seems like every month or couple of months, we are hearing about a certain company having a Phase 3 and not getting the results on that. You mentioned the FDA, and I don’t know if I misunderstood you, so I want to clarify this. They are approving somewhere between 40 and 50 new drugs a year in total or in the space of oncology.

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That is total. Most of those or over half of those, tend to be in oncology was, a direct reflection of the fact that nearly half of development projects aren’t going to oncology cancer, both solid cancers are oncology as well as liquid cancers, which we will call hematological malignancies. Not surprisingly, the approvals track those statistics.

One of the topics that for maybe a future discussion is I’ve always wondered a little bit about how companies come in and pick up a molecule that maybe has fallen by the wayside. Figure out a way to maybe address a different type of disease space or change things, combinations or whatever and figure out how to make something as long as the toxicity is not to the point that it’s not safe for patients. Those are interesting topics. Tell me about Cyclacel. What’s the genesis of Cyclacel, and what is that you are uniquely addressing?

The genesis of the company started with two of the world’s most distinguished chemists and geneticists. There are two individuals, Professor David Lane and Professor David Glover, the proponents of certain biological hypotheses that became the template on which we designed two lead compounds and medicines. The ideas behind David Lane, who is in the area of cell cycle biology, which was the company’s name derived. David Lane was the Founder of Cyclace. He was particularly interested in certain enzymes called CDKs or Cyclin-Dependent Kinases, which actually received the Nobel Prize in 2001 for their discovery and the elucidation of their role as potential targets for medicines for new drugs.

He particularly proposed that CDKs, maybe there are fifteen or so enzymes known to science at that time. Now, they are over 20 but CDKs 2 and 9, in particular, were best suited to address the problem of resistance, which is a technical term for what happens when the cancer drugs we have now stop working. In other words, we have treatment failure, and the patients go on to relapse. Although they may have had a good response, even a period of stability in the disease and death is not something that is an immediate concern. At some point, the drugs stopped working.

The reason for that is that these cancer cells are smart, and they develop ways to evade to avoid the mechanisms that we apply to them and therefore become resistant. Everybody around the globe now is aware that we have variance-induced mutations and even viruses that are relatively simple biological systems. The virus is not an entity in itself. Cancer cells are much more complex than viruses. They are normal cells that degenerate over time. They lose part of the control mechanisms that, in a healthy human being, we apply to avoid multiplication or proliferation out of control.

In patients with cancer, these mechanisms don’t exist, and cancer multiplies out of control which eventually overwhelms the patient. David Glover is also very famous for his work in the last stage of the cell cycle, an area called mitosis. Mitosis Biology is about the field in which the two cells actually divide, whether normal or cancerous. They separate the material from the parent cell into 2 nuclei and 2 components of the cellular architecture. At the divide, this process of mitosis in cancer can be disrupted.

There are particular targets called Polokinesis, which David Glover discovered as Chairman of Genetics at the University of Cambridge in England many years ago, which are valid targets for the drug industry to pursue. The goal there is that if you can somehow block PLK1 by using PLK1-inhibitors as one of the leading enzymes in this family, we can actually induce cancer cells to commit suicide.

They cannot withstand incomplete separation or mitosis and commit suicide in the natural way by which the body degrades or destroys dangerous cells. In cancer, this mechanism doesn’t work. It has become either mutated or is absent. Both of these approaches, those for CDKs or PLKs, share some of the same mechanistic end game to induce cancer cells to commit suicide the natural way. We don’t want to kill those cells as we do with chemotherapy because that will be escorted by toxicity.

We would like to have them undergo cell suicide or apoptosis. That’s essentially what the company’s thesis has been for a long time in designing molecules that are very selective for the targets proposed by the two founders. Hopefully, after animal tests and submitting for approval from regulatory authorities around the world to do trials in humans, to then demonstrate in early trials that drugs do work as designed. Hopefully, at some point, conduct regulatory studies, which are necessary for approval before we can see them reach the bedside.

Cancer is basically adapting to the treatments that we currently have on the market now. How big of a percentage of patients are you dealing with now? Are you talking about relapse like patients that have gone into remission and now they are relapsing? Are you talking about patients that are in the middle of treatment, and then all of a sudden, cancer becomes completely resistant to the treatment? How are you segmenting that?

BTI 51 | Cell Cycle

Cell Cycle: If you can somehow block PLK1 by using PLK1 inhibitors, you can actually induce cancer cells to commit suicide. They cannot withstand incomplete separation or mitosis so they commit suicide.

 

Both of those. This is a universal biological phenomenon, which is why we have a Nobel Prize for this. There is so fundamentally critical in the history of human evolution. It happens in both of the groups of patients you described. Those who responded to disease and had a good course or history but then lost it and progressed or relapsed. For those that did not achieve a good outcome but are in the middle of treatment, the drug stops working. Even those that have not been treated yet, although this is certainly a higher hurdle with whom we know based on a certain genomic analysis or profile of those patients, that they already show signs of resistance before we even give them anything.

In which case, we need to think ahead, “How do we stay ahead of this very smart population of cancer cells to make sure that we suppress the mechanisms that they use to overcome treatments that are available sometimes with more than one drug, if necessary but certainly, with one drug in certain cancer types to achieve this suicide outcome or apoptotic death for cancer cells.” What we really like to achieve in the end is to have the body’s mechanism that stopped working to control out of control division to now work again. We call the molecular breaks or something along that kind of an analogy that can be applied to stop cancer from progressing.

How do you isolate that in a patient? Let’s say you have ten patients, and each of those patients has some type of leukemia or cancer in the blood. Each patient is different. Leukemia, in a sense, being a blood cancer of some type but each patient could technically be different. Each patient’s cancer could be different based on their body, cells, and all those things. How are you isolating that to attack it?

The vast majority of cancers, and there are hundreds of anatomically defined cancers, are not just those in the bloodstream but also in solid tumor tissues as well. Also, now the thousands of subtypes that have genetic changes and possibly tens of thousands that have protein changes are a vast landscape. It’s very hard to identify patients likely to benefit early or unless we have already had the benefit of decades of research, sometimes by academic scientists, sometimes by company scientists, to identify specific profiles of these patients. We will do a human genome scan to see what exact genes or proteins are elevated in these patients that fail to respond to available therapies or did respond but then lost it by undergoing relapse.

We have now learned, for example, that there is one drug on the market that does exactly that. It’s a compound called venetoclax. The brand name is Venclexta. It’s approved for both chronic and acute leukemia and addresses one such protein called BCL-2. BCL-2 is a protein that is elevated in patients that become resistant to frontline therapies in those two indications. Now, we know that we do not need a companion diagnostic, which is sometimes needed in drugs that hit specific mutations a bit like the virus when I want to have a new vaccine-specific, for example, for the Omicron variant of the virus.

In the cancer is not terribly different. We would like to have drugs that hit specific mutations. This is not about mutations. Mutations happen late in the development of a certain organism or cell system, whether it is cancer, parasite or, in this case, a virus. Here, we are talking about proteins, which normal cells need to progress, do their job, and provide the function. In cancer, these proteins, when they are expressed at abnormal levels, are associated with resistance.

In other words, one of the ways by which the cancer cell signals or notifies us that it won’t respond to the available therapies is by elevating these proteins. You can call them a flare or some kind of signaling mechanism that tells us that this patient would benefit from a different approach. For example, patients who fail venetoclax who have had some response to the venetoclax early on for their leukemia or even if they haven’t had a response, we’ve seen a stabilization of the disease for some longer period that they will be expected to survive, eventually, lose the benefit of venetoclax.

They see another protein compensating for the inhibition of the BCL-2 protein that venetoclax blocks called MCL-1. BCL-2, on one hand, addressed by this approved drug, and MCL-1, which we don’t have an approved drug are parts of the same cellular system machinery that cancer uses to progress in a leukemic setting. Our goal, for example, with our lead drug, the CDK drug fadraciclib or fadra for short, is to suppress MCL-1. We have announced at the beginning of 2022 that 1 of our 3 clinical programs is addressing exactly this population in various cohorts of patients.

Some of which the drug is given on its own. In some ways, the drug is given in combination with venetoclax. If I make sense, the underlying theory is not to wait for the patient to fail venetoclax because BCL-2 inhibition is no longer important for the cancer cells that survived, the ones that drive relapse but rather it hits simultaneously both BCL-2 with the approved drug and MCL-1 with our drug.

This idea of a dual approach or I will call it a dual hit strategy, is critically important to avoid the cancer cell to evolve and become resistant. Hit them early before they get smart. The same concept applies to solid tumors, with one important exception. BCL-2 is not very widespread in solid tumors. MCL-1 is abundant, which means they will find patients that have MCL-1 amplification, which is a fancy scientific term for high levels of the MCL-1 protein. We can possibly benefit those patients more with our drug than a patient with normal levels or MCL-1.

Cancer cells are much more complex than viruses. They are actually normal cells that degenerate over time. Share on X

Critically, to come back to your earlier question, although we cannot use a companion diagnostic to choose patients with, sometimes, we do for mutations. The goal is to see if the patient has a resistance mechanism already, as evidenced in a human genome sequencing scan, and then to prescribe a medicine, either approved or in a clinical trial, that would address this, suppress the protein, and then restore the body’s own way of weeding out dangerous cells.

I really appreciate you explaining that, and that will be good, especially for me to go back and read some of those things. With that question, we started bringing up perhaps some of the things that you already are working on in terms of your pipeline. I would like to try and pivot the conversation to talk a little bit more about your pipeline and what you are specifically addressing in terms of indications and where you are at in the process. I went ahead, went to your website, and pulled up the pipeline here to talk a little bit about what they’ve got going on.

First of all, Cyclacel obviously has been around, and it seems like you have been working on some things, and you are on a pretty interesting track. As you are talking about, you got solid tumors going on. You’ve got leukemias. Tell us a little bit about what I’m looking at here in terms of pipeline. I probably should have gone through and read this before and made sure I understood how to pronounce this. I can never pronounce the drug names.

You can say fadra for short. It’s easier on the tongue than fadraciclib, which is the World Health Organization name that we are required to use. Fadra works just as well. The next drug is 140.

That one’s pretty easy. Fadraciclib or fadra and then 140. Is it sapacitabine?

Yes. That’s right.

Tell me a little bit about what’s happening here with the pipeline. On fadra, this is all the way into Phase 1, 2. Are you transitioning to Phase 2 or have you already started? What’s the process here?

Yes, we are already actually in what we call the mid-stage trial because of the same trial design or protocol for fadra, we are doing Phase 1, and Phase 2 compressed into 1. Although we started our work just before the pandemic, it was underway with the drug given intravenously, we realized quickly in the pandemic that if we were to continue to enroll, although we were getting adequate enrollment and very promising data, the big number of cases would not be easy to procure.

As we said, people pushed back, especially now with a pandemic to sit in a doctor’s office or an infusion center for an hour with a tube in their vein and then also be exposed to the risk of viral infections. It is a non-starter, particularly if you are talking about older patients, which tend to be the people that have leukemia or other advanced cancers.

The idea behind our medical team a conception of what we call in the industry a Phase 1/2 two trial is to compress the 2 trials into 1. There are two components to this Phase 1/2 study, which we are running now for fadra in both patients with solid tumors and one protocol and a separate protocol in leukemia. The idea behind this study design concept is to do an initial dose escalation to elevate the dose based on animal data. I would call from a surgical modeling advanced computer software.

BTI 51 | Cell Cycle

Cell Cycle: In phase two, you have to look at different cancer types all at once. This is called a multi cohort study. There are endometrial and ovarian cancer, cholangiocarcinoma, hepatocellular carcinoma, and more.

 

We look at the dose-response to benefits, “Can we suppress those proteins based on what we expect to see the blood reach the bloodstream? Therefore, can I give the drug once a day, twice a day for 4 days or 5 days, and so on?” Also, I would like to give the drug orally. Finally, once we get to the optimal dose level, which is usually one step in the dose-escalation below where we see toxicity, we can then can move into Phase 2.

Historically, that would take six months. Six months when patients are dying without any chance of being helped to have this problem. With this trial design, we don’t have to go to the hospital ethics committees or Institutional Review Boards. We have to make a safety report to the FDA from the Phase 1 part and move in the same protocol and trial without spending six months of downtime and saving also an enormous amount of patient opportunity to go into trials and go straight into Phase 2.

Phase 2 in this idea is to look at different cancer types all at once. We call this a multi-cohort study. In this protocol, we have eight cohorts. We have patients with endometrial and ovarian cancer. These are women’s cancers, patients with a rare cancer of the bile tract or cholangiocarcinoma. Patients with liver cancer are sometimes called hepatocellular cancer. Two types of lymphoma, every subtype of breast cancer and also cancer of the intestine or colorectal cancer.

We look at these different types of tumors and can enroll them. We also have an eighth cohort in which the criteria are not based on the tumor type or what organ of the body the tumor began but rather do they have the proteins elevated that we talked about. We call this a basket cohort. Basket is a technical term to say that we select patients only because they have elevated MCL-1 or some of the other 2 or 3 proteins that we will look for in this particular mechanism.

This patient population can have lung cancer, which is not included in the previous group or they can have a sarcoma or neuroblastoma. It’s almost universally fatal with the after cancer but they can enroll in this study based on having the proteins elevated. This criterion allows us to build a bridge from two sides of the river and meet in the middle. We can look at patients who have specific cancers by anatomy and then have patients that have cancers defined by molecular profile, the protein level that I discussed, and then see if we can identify at the end of Phase 2 a population where the drug is most active.

If we are successful and a little bit fortunate because luck plays a role here, we would like to go to the FDA at the end of Phase 2, after this journey Phase 1/2, at the end of this program, have a discussion with the FDA on each of these cohorts. Also, to see if they would agree that we could pursue this as a registration program. This typically means that if they are interested, they would say, “In the absence of available options for these patients, if you can enroll a larger patient data set from the X number you have now and Y number later, we might consider this for approval.”

There is a legislative provision by Congress to allow companies to get to the market early, which is technically called accelerated approval. As a condition of accelerated approval, the company is required by law to have begun a confirmatory study, which is a larger trial, randomized, usually between the drug we are giving either on itself or with something else against the placebo or an active control but we need to beat the other arm based on improving survival and also capturing safety data for these patients.

The whole regulatory system of the United States is skewed to help patients. We can give patients earlier access to medicines but there’s a certain amount of risk. If the drug was found after the early approval to be toxic, it can be withdrawn from the market. The sponsor, the company, has a disincentive to develop a toxic drug, which by the way, is what patients will not accept.

On the other hand, if we have a drug that we have the fortune of having good tolerability with and we can get to that early finish line, that would simply be an enormous saving. Both in terms of patients willing to altruistically offer the last few months of the life so we can learn something but also capital, which is critical. It’s the lifeblood of our industry to ensure that capital resources are allocated efficiently.

All this works to the benefit of society. If we don’t succeed in achieving the early approval, there’s always another chance to get into the market by doing a larger program that will cost more money but certainly, it would have an equal if the not better chance of success because we all know from our everyday family experiences that sometimes cocktails work better on a single drug. That’s more expensive. It takes longer to get there but it’s also a well-established and validated way to reach the market.

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This whole idea that Phase 1/2 collapsed into one allows us to do a maximum number of cancers with probably a third of the cost is probably half of the time we would otherwise do with the conventional program of Phase 1. Wait for six months, start Phase 2 in 1 or 2 more times, then we do 10 or 12 Phase 2s to find the same result. This way, although we sacrifice some statistical value to can get to the finish line much faster and then have the chance to possibly serve patients sooner, which is what they demand of us.

I love this approach that you are taking here, and this is one of the reasons that BioTech IQ exists. The readers know, and many of the people I talk to know. I started in this industry as a professional recruiter. I still am. I started back in 2018, and when I started recruiting, I got on this journey of trying to understand the biotech world and how drug approval works, what’s discovery, preclinical, what’s clinical, what’s Phase 1, Phase 2, Phase 3, Phase 4 or approval, post-market and all of these things.

I realized there’s so much more to continue learning. I love having these conversations. From the strategic side of things, another thing that makes the biotech industry so interesting is, number one, you are developing treatments that make the lives of people better and save lives, and there’s a scientific and a medical aspect to all of that.

You have the business and the strategic side of things that is also very interesting. You are explaining this combination, this Phase 1, Phase 2, the multi-cohort, and all of these things. I hope the readers are capturing some of this because they can look at this and go, “I learned from Spiro a little bit. Maybe a strategy and approaching how we develop our pipeline, develop our clinical trials that maybe we didn’t think about before.” I wanted to ask how common is this approach that you are taking? Maybe I’m the one late to the party. Is this a pretty common approach in how you are doing this?

It is not common but it’s not unique to Cyclacel by any means. It has been used by other companies in the very near past. The realization of this possibly dawned first because of the emergence of the data from the Human Genome Project which are the turn of the Millennium. For the last many years or so, we have become enormously more knowledgeable about how genetics play a vastly important role in cancer, and we are trying to harness that.

The FDA, on the other hand, is very fortunate to be operating in the United States, so we have a regulator who is very forthright. They have, in my opinion, probably the best attitude that a government agency sworn to serve the people would have, which is to find ways to encourage the industry to develop new drugs or vaccines for COVID, for that matter. Get them to the bedside as fast as we can but with a certain amount of checks and balances, which means they want to protect patients’ safety and know maybe face the predicament of having nothing for an indication.

We may have a bit more elastic approach to what we might consider for approval. In the big indications, the hurdle is higher. If we take children with neuroblastoma, which is a terrible diagnosis to encounter, especially for the families, there may be some room for maneuver but if it comes to the frontline treatments for breast cancer, with millions of women countering that everywhere in the Western world. Many of them now are living for 20 or 25 years. They couldn’t have gotten there without having this type of approach.

It’s not just Cyclacel. What is new about this is the insight of our Chief Medical Officer, Dr. Mark Kirschbaum, who, in addition to his years in the industry where he joined Cyclacel, was also an academic clinical trialist. He actually founded and was the Director of the Phase 1 Clinical Trials Unit at City of Hope Medical Center outside of LA. Mark’s background and being on the other side of our conversation with clinicians was very important because he was in the business of motivating companies to give to his institution trials to run for new drugs.

He was soliciting new medicines based on their perception of what were important new mechanisms that would work in specific cancer types for different patients. When he came to the industry, he realized that this was wonderful. “I now know what needs to be done from the provider of healthcare side.” Now, that can help the industry speed up things rather than follow the antiquated ways of doing it in a very stilted way in the past years and possibly do it much less expensively, which, of course, is a topic for everyday debate.

From the average American who faces a hard time at the pharmacy counter paying their copay or extensive insurance deductibles for the treatments all the way to Congress, which of course, has been trying and struggling for years to find a way to make healthcare more accessible. All these are critical issues for the industry. We cannot ignore them, stick our hands in the sand like ostriches, and pretend they are not there.

BTI 51 | Cell Cycle

Cell Cycle: This whole idea of collapsing phases one and two into one, allows you to do more cancers with a third of the cost. Also, it would take half of the time that would otherwise do with the conventional program of phase one.

 

They’re going to be detrimental, possibly fatal, if we ignore them. We have to respond, and one way to respond is to shorten development times without sacrificing quality. Will the regulator be willing to innovate or the industry is compressed because of pricing pressures from Congress and other regulatory authorities around the world who also have to face similar budget restrictions, especially now after a post-pandemic spending spree.

It’s critically important to provide value, and value means that we don’t do incremental innovation. There is room to take medicine already there and make something a bit better. That’s fine. That’s important but do we need fifteen drugs getting the same mechanism for hypertension? It’s not so clear. Maybe we need five. Certainly, the mindset has evolved in the psyche of many executives in our industry that we should be looking for value but not to be 1st or 2nd in class.

Truly innovative medicines will always find resources in our capitalist Western system whether we like it or not, it is the most efficient allocation resource that man can ask devise to get resources allocated to make medicines. Guns versus butter and this gives me to have resources allocated to medicines. Therefore, we have to find ways to not only convince physicians and regulators but also investors early on who provide the capital that what we are doing is sensible. We will be reimbursed by payers but also patients will vote with their feet, considering the rather unattractive outcome where we work for a decade or two to get medicine to market. Patients vote with their feet, and nobody wants it to be prescribed.

That is not a good outcome. We wasted a lot of resources to get there, and in the end, the result was voted down by public acclaim. It’s important to think of these approaches, whether it’s Phase 1/2 designs or something called adaptive designs. It’s the technical term for saying that we can change direction midstream in the trial if we see data that requires us to reconsider the trial design and make the appropriate statistical adjustments. Also, to do things that are more innovative, even with cell therapies and immuno-oncology therapies, which are the rage in the last few years before the pandemic started. It opened a whole new way of harnessing the immune system to also support what we do with small molecule drugs like the drugs that Cyclacel has.

Putting all this together, you can see a very clear picture emerging that the industry is in a critical moment, a Eureka moment. It’s adapt, survive, and flourish and we have to do that. What you saw here is a very small example of a vast array of discussions going on across the industry but how we make things faster and cheaper and get to serve patients sooner with better medicines.

A lot of times, when we hear the word innovation, people always think of the next technology or chemical development or drug coming to the market. Innovation, obviously, applies to the approach in how you run the process. It would stand to make sense that if you shorten the cycle, doing so safely, developing the very best treatments, the safest treatments for the patient but doing so with a shorter time at a lower cost, translates down the line to the patient in terms of costs.

If it costs $100 a million, that’s probably just Phase 3 but if it costs a few hundred million to develop something, then those investors that have input capital into the system to be able to help develop that are going to want a return on that investment. If we can obviously shorten the cycle and lower the costs, it translates down the line. I wanted to ask a question about the potential challenges that exist when developing therapies like this that address cancer resistance. Maybe we’ve touched on some of those but are there any specific challenges that you see or that you are working to overcome in this area?

There are always challenges. There are plenty in our industry. It is never boring, and after three and a half decades on the cold face, I never stopped getting excited. I’m very fortunate to work in this industry. Remember that success doesn’t matter so long as we are publishing our data, good or bad, society learns, and humanity can move forward. Somebody else can use that data.

I have to think is the movie Interstellar the very elegant statement in the end when the astronauts know they don’t have enough fuel and oxygen to return to Earth but the chief scientist tells the captain, who’s distraught, “If you think like a cell, like an individual, a human being, maybe your death is pointless. If you think as part of a system that mankind will learn, maybe we can go somewhere. Let’s make sure that this spaceship, even without us, goes back to Earth, and data banks can teach them what we have discovered in our interstellar journey.”

Discovering cancers is a bit like that. We have learned over the last few years that we have these wonderful new tools with genomic sequencing. They have at least a huge goldmine of information that we are only now starting to harness with various approaches. The more traditional approach of making small-molecule pills or tablets we can take by mouth has a long way to go.

Success doesn't matter, as long as you're publishing data, good or bad, society learns. Share on X

We are like children and a huge play store. We have this enormous playground to work with and find new ways to address different types of cancers that evolve. You mentioned resistance. The bigger issue with resistance that we face now is that multiple things are happening at the same time. We have a bit of a joke in the industry called Pac-Man. You remember that game, perhaps revealing my true age but in the ‘70s and ‘80s, we had a whack of the Pac-Man games on primitive computers.

This is like whacking the Pac-Man several times because other circuits and proteins will be elevated in response to the one that we are trying to inhibit with our drug. A good example of this was why David Lane, our Founder proposed CDK-2 as well as CDK-9. The CDK-9 is the main mechanism to go after. That’s the one associated with MCL-1. It turns out that the escape hatch for drugs that inhibit CDK-9, where they stop working after a while in preclinical tests, is the elevation of CDK-2.

Professor Lane reasonably hypothesized that if we hit CDK-2 and 9 with the same drug at the same time, we are going to shut down this escape hatch, and the cancer cells won’t have a way to evade the activity of medicine, and they will undergo apoptosis. It is exactly what’s happening. I’ve seen other independent authors through Cyclacel publishing studies, even one in neuroblastoma that appeared a couple of years ago, showing that we apply a CDK-9 drug, this very difficult to kill neuroblastoma cancer cells don’t die but they get killed or induced to commit suicide by a CDK-2 to 9 drugs. That’s incredible.

We see cocktails of drugs but these are harder to give. Sometimes you have to mix an oral drug with an intravenous drug. There are other kinds of issues or have overlapping toxicity but to give them at the same time with the same medicine to shut down, both mechanisms that affect the cancer cells become resistant, that’s very normal. This is a huge challenge because you always ask the question, “What is that I don’t know that will kill the program.” The unknown unknowns.

“Do we have something else that also could compensate?” Luckily, after some very gifted mathematicians applied themselves to the problem in the last decade, the answer appears to be no. It’s a finite number of circuits we have to regulate to convince the cancer cell to undergo apoptosis or more appropriately, to teach the body to instruct ourselves to commit suicide. We can say now, with some degree of confidence, that 2, maybe 3 but not 10 of the circuits are more than enough. Although this is a huge challenge we face every day in our work, will this be adequate? It’s time to be addressed.

A good example is a patient that was treated in our trials during the pandemic, which made things very difficult for her. She had the rare kind of endometrial cancer and failed seven lines of therapy before being offered on trial in one of the premier cancer centers in the world, which is Dana-Farber Cancer Center in Boston. She lived about 45 minutes Southwest of Boston, which meant a good commute to go there, receive the drug and also give blood and undergo examinations as part of the trial.

After failing 7 therapies, all within 3 to 5 months, she receives our drug fadra as a single agent. In a month and a half, the tumor lesions all over her body had gone down by half, and on her one-year anniversary of getting the drug, 100% of the tumor lesions were gone. She is now past the second anniversary of getting the drug all through the pandemic with all the assorted issues that we discussed at the beginning of our conversation. She’s functionally cured because she had a negative PET scan showing that there is no active disease that the PET scan can find anywhere in the body.

It is spectacular. That thing was not predicted to happen in a patient who is so highly resistant to other tumor types and existing medicines because all of them have been tried. Endometrial cancer is one of those rare women’s cancers that can be universally fatal. It also has some very complex molecular machinery but MCL-1 appears to play a very important role, at least for this patient.

Although it’s challenging, success stories like that encouraged us to go forward and find better ways to achieve the therapeutic outcome we are pursuing, whether it is in this cancer or its sister tumors like uterine cancer, ovarian cancer or breast cancer. We are hitting both CDK-9 and CDK-2, which can affect other proteins, and we give these patients a chance. Obviously, if we see it in 2 or 3 Phases, it’s very exciting. Was it more than enough? We then have a chance to go and talk to the regulators about that early approval that we talked about.

These weren’t your exact words but you mentioned embracing a failure or learning from it. You said this earlier on, and you mentioned it again. Being able to take challenges and then basically turn them into positives. I mean that not just in a way of words but obviously, in a physical aspect. Challenges are always going to exist, as you were saying. It’s never boring but it’s pretty interesting what people are able to do with taking that and obviously, the good that comes from that.

BTI 51 | Cell Cycle

Cell Cycle: You don’t have to do incremental innovation. There is room to take medicine already there and make it a bit better. That’s fine and important. But people don’t really need 15 other drugs for hypertension.

 

Moving forward, what is your strategy, and how do you see the application of this? Just to preface, I know we scheduled time. The readers know I schedule a certain amount of time with the guests, and we have had a good conversation with a lot of great detail here. I know we are running up on the end of that, so I want to make sure I gave you some time to answer the final three I ask. Briefly, what’s your strategy moving forward, and how do you see this in the marketplace?

Very simply, and thank you for your kindness. Our goal is to demonstrate the value at the bedside. We have to show to either the regulators if we are fortunate to have a shot at early approval or to a larger company who may wish to own the assets and go forward in a much larger randomized Phase 3 program in multiple indications that the drugs that we call de-risk. What does de-risk mean? That it is efficacious, that we know how to dose it and whom to dose it to. You think of this three-legged stool as the cornerstone of demonstrating value in our industry.

For a small company, very much like you eloquently said before, Ammon, it’s possible to do that with a relatively modest amount of money. If we get to the end of Phase 2 and have de-risk the molecule, demonstrated with clinical data that the drug is well-tolerated, is dosed to the right patients, and you know how to dose it. There is a path forward that regulators can agree on, it’s very likely that somebody would want to own that drug before we need to go and raise much more money to conduct a Phase 3 trial to get to the big indications.

That typically is the purview of larger companies. It will have multiple programs and can absorb the risk of individual programs rather than a smaller company running its own Phase 3 experiment, which is a binary event. It also means that we are better suited. If you think of society allocating resources, small biotech becomes better-suited than early development. Identifying multiple programs that may have overlapping mechanisms. Instead of putting all of our eggs in one basket and living or dying by one program, it’s better to have 2 or 3 programs in early development. We are going to this point of handover of clear values and then having them licensed to bigger companies or the bigger company wishing to own the whole thing and acquire our company.

The strategy here is to demonstrate value. It is not to sell the company but if the companies don’t get sold, they get bought, and they get bought only if they demonstrate value. De-risk the program and found a way to demonstrate long implications, particularly when it comes to large populations of patients in the marketplace where there’s not a lot of competition or ideally, we are number one, as is the case with fadra. We have about six companies chasing us. In that mechanism, we are by far ahead of everybody else. At least two years from the nearest competitor.

We are the only ones who have shown, as I mentioned, with endometrial patients and other patients very soon that we have single-agent activity without toxicity, which is critical. Strategy is a consequence of understanding what the customer wants. The customer is the patient, first of all, the physician but also the larger companies or industries that need to refill their pipelines as they meet patent expiration challenges over the years to come.

You have multiple directions you can go, whether it’s developing all the way on your own or, as you mentioned, looking at larger companies needing what’s being developed in the smaller biotech company. Again, I want to be respectful of your time. You are a busy person. I know most people in the industry are very busy doing a lot of things.

I appreciate you coming on the show and dedicating some time to explain things in-depth to us. I like to end the interviews with three questions to get a little bit more insight from you and your experience. The first question is if you could go back to the start of your career and give yourself advice, what advice would you give yourself?

Probably the most important lesson I’ve learned is to find the best people that the company can afford to hire and hire and retain. You cannot beat cancer with a B-class team. I’m very privileged at Cyclacel to have an A-class team working alongside me. It probably more means that I’m perhaps sitting on the sidelines, watching them perform and ensuring that we don’t run out of capital rather than do the work myself. It’s an industry of teams.

You are going to live five lives to do what we do in a small pharma company. You need a team of competent people that are willing to risk their livelihoods for this very low chance of success but when they come together, they produce something very powerful with creative thinking. It’s possible that when we are starting back in my early days at Centocor, the fact that we had a thriving new technology, many people were risk-averse. Maybe they will never get there. Maybe technology never pans out.

You cannot beat cancer with a B-class team. Hire and retain the best people for the job. Share on X

With Cyclacel, it is a lot simpler. We are doing something which everybody knows works. Small molecule drugs are available on the pharmacy shelf all the time. It’s not terribly exotic but it is very effective and innovative. People are the key to our success. If I had perhaps some second thoughts about the early stages of my career, where affordability or other issues got in the way of hiring the best people, I would probably have waited a little longer for the best candidate to come around and ensure that I’m not going to hire them but retain.

I love the people’s side of things. I mentioned that I’m a recruiter. I’ve heard multiple executives and people say something very similar, which is, “Your people are your absolute best asset. You can have the best science in the world but if you don’t have the right team assembled to move that forward, you are not going to have the same success.” As a recruiter, obviously, there are different approaches, and there are companies that focus on volume. It’s like, “Let me get whoever’s got the checkbox qualifications, and I will give you those people.”

It’s usually done on a smaller boutique scale, which is how I tend to function, “How do I help the companies that I work with find not just somebody that checks the boxes of I’ve got the qualifications but how do I help understand this company?” When I go to find people, I’m finding people that match the company culture and other things that they’ve got going on. That’s a topic I probably should do an episode on talking about the people aspect. The second question I have here is, are there any books that you’ve read that you want to share with us that maybe had an impact on your life or a career?

Certainly, and the one that I would urge your readership to consider, which is available on online service, is The Billion Dollar Molecule by Barry Werth. It’s a story of Vertex, one of the pioneers in the industry. Now, it’s a major company in the area of cystic fibrosis and early in virology. It’s a great success story, but it started as a Cyclacel, a cancer company.

In fact, it’s quite remarkable that a couple of years after the book was published, I was handing out copies to all employees at Cyclacel. I said, “Read about this. If you understand what’s going on there, you have a chance to succeed in our little business.” Years after that, I was in Davos in 2003 and met with the CEO of the company, Richard Aldrich, and we had a very nice dinner on the fringe of this very important meeting.

We talked about how you manage a small company. Vertex is a huge success story but the important point of the earliest steps is that they learned from failure. It’s a story of a drug that didn’t happen, not the somewhat self-gratuitous story of what did succeed, which you see sometimes in our industry and the literature but more like a drug that didn’t make it.

What was the company like in the early days with the scientists arguing with each other about what is their approach and the executives worrying about running out of money? All the issues that we face every day in our industry are played out in great relief by a very gifted writer, which gives people a very good firsthand account of what’s still going on in this vast majority of the companies pursuing a very similar agenda, even though it’s on different drugs and therapeutic technologies.

I’m going to have to pick that book up. That’s probably the third time that book was mentioned. The second time on the show but I’ve talked to other people. It’s come up before. I appreciate that. I wrote it down again. I’m like, “I need to pick it up and read it.” The last question I have for you is where do you think the industry is headed?

As I mentioned in the beginning, we are in a bit of a toy shop situation. Not only has the human genome uncovered a vast goldmine of targets that we are not mining. For example, CDK, PLK, and a Cyclacel are an example of that. We are number 1 or 2 in these critical areas even though they were discovered years ago, and the reason that we only now started to understand what the battle is about. This is a very important new driver of a huge number of new medicines that can be conceived and executed in the next two decades.

The second bit that is perhaps not visible to most people who are watching our industry from the sidelines is artificial intelligence. I know it sounds a little bit exotic but there is a huge number of new medicines being discovered as we speak using massive amounts of data. The idea is to use computing power to dissect vast troves of data, for example, of failed trials or even simulated clinical trials that can be done in a computer rather than human beings to ask critical questions that could guide drug development.

BTI 51 | Cell Cycle

Cell Cycle: Larger companies with multiple programs that can absorb risks are better than small companies running their own phase three experiment. Don’t put all your eggs in one basket, it’s better to have multiple.

 

Also, CROs and the other service providers in our industry who do clinical trials have embraced this approach as a way to reduce their costs, whether it’s what I described before. For example, there’s a new technique or risk-based monitoring. Instead of looking at headaches, for example, in leukemia patients who won’t be alive for more than six months after they get diagnosed with acute leukemia, we could look at things that matter.

There are statistical models that we can use to identify risks and safety observations, which could be critical for these patients and, by extension regulators, rather than worry about all side effects and collect them indiscriminately, which wastes a lot of resources and possibly irritates physicians. It is a burden to patients.

Lastly, we have a whole new philosophy of designing molecules. Up to now, we could imagine a protein target, and maybe in a three-dimensional model, after we solve the crystal structure of how light diffracts across the crystal of our new molecule drug, we could find the ways like a lock and key could fit into the pocket of the target. That is a rather crude way, much like using a chisel to make a beautiful sculpture. Now, with the 3D printing area, we can make a beautiful sculpture by Rodin using a 3D printer. That wasn’t possible years ago.

Our development has gone through the same exact evolution in earlier discovery stages where we can actually envision new molecules that were not possible before by trolling chemical space or we can imagine them on the computer and actually make them and then put them into animal systems to see if they work. Whenever we look in our industry, AI and the nexus of large data sets and the computing power to understand and analyze those data sets or evolutions that we do both in the clinical development side and the early stage of discovering new medicines.

With all of that, I appreciate it. I know there’s a lot of great information in this episode that I hope the readers go back and read to again. One of the things that I enjoy doing is being able to read to my conversations with individuals like yourself. Again, thank you so much for your time, Spiro. I appreciate it. We will look to see how things continue to progress with Cyclacel.

Ammon, thank you very much for having me. I enjoyed our conversation.

 

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