Good morning, everyone, and thank you for joining the H.C. Wainwright's twenty-sixth Annual Global Investment Conference. My name is Max Marr. I'm an analyst in the corporate access team. H.C. Wainwright is a full-service investment bank dedicated to providing corporate finance, strategic advisory, and related services to both public and private companies across multiple sectors and regions. We have a total of twenty-four publishing research analysts and over six hundred and forty companies co-covered across all sectors. Please visit hcw.com for more information. Now, I'd like to welcome Spiro Rombotis, who is CEO of Cyclacel Pharmaceuticals.
Thank you, Max, and thank you to H.C. Wainwright for inviting us to share our progress with Cyclacel Pharmaceuticals at the annual conference. I would like to, first of all, turn your attention to the usual disclaimer regarding forward-looking statements and refer you to our filings with the SEC. As many of you know, who have been following the story, we're active with two discovered the compounds that the company has discovered internally two kinase inhibitors, FADRA and PLOGO, who are developing for cancer indications. FADRA is a next generation CDK2/9 inhibitor with unique phase two precision medicine approaches being used in the current development stage of the program. The drug has shown single-agent activity, including complete response, partial response, and stable disease, with good safety in several solid tumor indications.
We are currently enrolling the phase two proof of concept part of our study, particularly two cohorts that are potentially supporting of registration pathways. One, enriched for patients with CDKN2A or CDKN2B abnormalities, and another one with T-cell lymphoma. So what is the problem we're trying to solve with this kinase inhibitor approach using Fadraciclib or FADRA? First of all, the body has its own innate genetic tumor suppression mechanism, which protect against cancer progression. When these mechanisms fail or are deleted or lose their function, then cancer wins and advances. So the possibility of using pharmacologic inhibitors like FADRA, that act on the p16 and p53 pathways, is a very valid approach in terms of restoring some of the innate tumor suppressor function that has been lost.
We have found, in particular, that a subgroup of patients who have the CDKN2A or B abnormalities are presumably more sensitive to the activity of the drug, and part of our objective in the phase two study to demonstrate this in prospectively defined patient cohorts. There are opportunities and challenges in this space. In particular, are we going to target CDK2 and CDK9, as in the case of our drug, FADRA, or as other companies have, either CDK2 or CDK9, but not both? A further question is, are these drugs active as single agents in certain specific patient subgroups, or should we go on with combinations, and the last question is some historical challenges with toxicities, particularly around the blood, the hematological area, which have been found to be limiting for dose for this type of drugs that we have not seen with FADRA to date.
CDKN2A alterations are very common across a range of solid tumors. This is data from cBioPortal, downloaded last year, which shows that the majority of these alterations are deep deletions or loss of function in the dark blue of the bar chart. About 10% of tumors or higher incidence of CDKN2A alterations occur in head and neck tumors, pancreatic, esophageal, lung, including squamous, hepatobiliary, breast, melanoma, and sarcoma. Interestingly, in lymphoma, we see these deletions in about half of patients with peripheral T-cell lymphoma, not otherwise specified.
The data I will share with you come from two patient groups, one from the original intravenous studies of Fadraciclib before the pandemic, and the more recent oral study, with about six of the 20 patients that had sequencing data in the IV study, and five of the 21 patients that had sequencing data in the oral study, having CDKN2A or CDKN2B alterations, so of these six plus five, 11 patients, eight had indications of activity, including one, a ninth one, which occurred after the study was closed for enrollment. As you can see, in the first three rows of this chart, we have patients that had response and various level of clinical benefit after being treated intravenously, only two days or one day a week. These patients, ranging from endometrial to ovarian to salivary gland cancer, were receiving the drug, however, suboptimally.
We have since discovered that giving the drug daily is a superior strategy, as continuous pressure on these targets confer higher clinical benefit, so patients with a squamous lung subtype, another patient with the angioimmunoblastic subtype of PTCL, a cholangiocarcinoma patient, a pancreatic patient, and more recently, a testicular patient, had shown benefit in the presence of these mutations. This hypothesis-generating data gave rise to the hypothesis that can be tested in phase two. This is to test for T-cell lymphoma patients in cohort five of phase two design, as well as the cohort eight, which is the basket part of the design, in which patients have to be selected by a biomarker, in this case, CDKN2A/B, or related, mechanistic phenomena apparent in the genomic sequence.
The dose we've picked for phase 2 is dose level 5 or 100 milligrams twice a day, given as a capsule, Monday to Friday, four weeks out of four. Again, giving us a very satisfactory, continuous exposure to the drug in sufficient levels, as you will see from PK, and ultimately, PD data will show you secondarily. Safety for FADRA in this oral phase 1 study has been good, mostly grades 1 and 2 and reversible. GI effects, including nausea, vomiting, diarrhea, and constipation, and some general effects, including fatigue and hyperglycemia, but very little, if any, hematological activity. Certainly, the DLTs are observed at the higher dose, so this is RP2D plus one, 125 milligrams BID, were grade 3 nausea and hyperglycemia, which both were manageable and reversible to baseline upon titration or discontinuation.
Dose levels one through five, five being recommended phase two dose, were tolerated without any DLTs reported. In this waterfall plot, we can see a sense of the clinical benefit, but I would caution you that this is difficult to interpret, as the current dataset is not selected. This is all-comer, meaning that we did not necessarily bring patients in because they have the abnormality I mentioned. You can see that retrospectively, some of these patients were found to have the abnormalities shown in the red, but again, this is very hard to deduce quantitatively what the benefit is until we go into the phase two part, and every patient in the respective cohort eight has the abnormality. It is nevertheless encouraging to see a long period of treatment, stable remission for patients.
People are staying on study for quite a long time, with the pancreatic patient on the very top of the row, staying on for about five and a half months, which tells us that even in the phase one setting, which uses, of course, dose escalation, when 80% of patients don't get the drug at the recommended phase two dose, we can achieve some respectable levels of durability of effect, and clearly, one of the important goals in phase two is to show that we have durable effect, especially if we see partial response, as in this patient with T-cell lymphoma, where the blue suggests that the patient is continuing on study. The activity summary can best be summarized in terms of non-quantitative analysis, because, again, the numbers are irrelevant, as we are treating patients who are all comers, not selected.
Of the 35 evaluable for efficacy, 34 had measurable lesions at baseline and could be therefore quantitated using the RECIST 1.1 algorithm. Two patients with T-cell lymphoma out of three enrolled achieved PR in the first cycle, and notably, two patients with solid tumors, one with lung cancer, heavily pretreated and squamous subtype, showed 22% reduction in the sum of all target lesion at about a month in the first scan, and this patient was found retrospectively to have CDKN2B loss, and also the recent testicular cancer patient, which I mentioned, who achieved 20% reduction in the sum of all lesions at one month, was found to have CDKN2A and CDKN2B loss.
In broad terms, the clinical benefit of best response, meaning PR or stable disease over four cycles or tumor decrease above 10%, was found in eight patients, two each with T-cell lymphoma and endometrial cancer, and one each with non-small cell lung, ovarian, pancreatic, and testicular cancer. This data was shown also at ASCO 2024, and I will show you a couple of images to understand what these patients are going through and what the potential benefit would be with this drug, coming quite early in the treatment window, almost, within the first month. So this is the PTCL patient suffering from this rare and difficult-to-treat angioimmunoblastic variety, not known to respond very well to available therapy.
This patient had received frontline therapy with ADC, was treated for refractory disease, and you can see in this PET scan, which means that we're not only measuring the anatomy and want to see these lesions reducing in opacity, in color, but also reduced tumor energetics as we are measuring glucose uptake, a measure of metabolism. But this occurs literally within the first twenty-eight days of the treatment cycle. And we see reduced uptake and therefore reduced activity, with exception of the lung, bladder, and kidney, of course, and the urethra, where the tracer is going to accumulate. But all of the lesions pre-specified at baseline appear to have reduced opacity. This patient achieved PR within the first cycle by the Lugano criteria and was found to have CDKN2A loss.
The squamous lung patient also had a very impressive reduction of the dominant lesion, which is just above the spine in this cut of their CT in September of 2023. This patient failed, immunotherapy as well as chemotherapy, was treated with Fadraciclib single agent about a month after the second-line treatment failed and was found to have 22% reduction of the sum of all lesions to an 8% of this dominant lesion within one month after treatment started and had CDKN2B loss. Finally, that patient, which we mentioned in the beginning, the very first row, with endometrial cancer, who were treated with two days a week with our IV part of the study, had, within four cycles, a reduction of about 50% in their pre-specified baseline lesions, and by a year, almost 20 cycles, all the lesions were gone.
After a negative PET scan, the patient was reclassified as a complete remission. This is striking because we now know, having enrolled a number of patients and have very compelling PK evidence, that pharmacokinetically, exposure levels with these drugs are quite sufficient to beat the required predicted threshold for CDK2 in blue, and we definitely get there on day seventeen or eighteen, which is the third week of the treatment window, with the IV and oral drugs in the case of CDK9 in the orange line. Clearly, we can exceed target engagement levels if with those patients at dose level five, at day seventeen and eighteen, as well as have comprehensive coverage for CDK2 throughout the treatment window. Last, let me point out that these patients have single dose of drug because we cannot ask patients to give blood twice in the same day.
These are very brave, altruistic patients. They only come in once a day. But we'll give them the drug twice a day, BID dosing, meaning we have another peak like this at the 12-hour time point. So we have two overlapping curves in most patients for the majority of the treatment window, except for phase one patients during day one and day 17, where they give blood only once a day. So it's really important to understand that exposure for this drug is comprehensive, and this is further demonstrated by pharmacodynamic data showing suppression of transcription of the relevant tumor suppressor gene, CDKN2A and CDKN2B, in patients. In this chart, blue is reduction in log size, and red is increase in protein level or transcription level.
And as you can see, from dose level two up to dose level five, we achieve comprehensive reduction in protein levels or suppression of transcription, meaning that we're actually changing the biology of these cancer cells and inducing them hopefully to apoptosis, which might translate to tumor shrinkage. So to summarize, FADRA has great potential as a precision medicine drug. It has shown single-agent responses and broad activity in both liquid and solid cancers, a rarity in cancer drug development. And importantly, it gives rise to the hypothesis that perhaps CDK2 and CDK9 inhibition in the same molecule may be superior to either alone...
This is possibly true because cancer cells have learned to adapt to CDK2 inhibition alone, and therefore, we presume that CDK2 inhibitors work better if CDK9 inhibition is present at the same time to silence MYC, one of the most important oncogenes, which oftentimes muck the works and reverse the effects of cancer therapy. Exploiting the CDKN2A or B abnormality vulnerability is also important because if it's proven to be correct, it would allow us to pursue a precision medicine strategy, not only in current development, but also for registration. FADRA has been that unusual next-generation CDK inhibitor, which has threaded the needle of avoiding broad hematologic toxicity, what's been a major impediment for other compounds to pursue further development.
I will leave you with a few words with our second drug, PLOGO, which is the next generation PLK-1 inhibitor, which is a bit further behind FADRA's development stage. Now, PLOGO is a single-agent, nanomolar inhibitor, highly specific for PLK-1. We have found preclinically, through the collaboration of major laboratories across the world, in the U.S. and abroad, that it's susceptible to specific biomarkers that could potentially be used for patient selection, and have shown that the drug can be given with best-in-class half-life of around twelve hours. Therefore, once-a-day dosing is entirely possible. We have escalated to five dose levels with PLOGO in phase I studies, have found no dose-limiting toxicities.
But before moving further, we have decided that, we need to identify a patient subtype where patient benefit might be better. So although we're seeing satisfactory durability of effect, even in phase I, early low-dose patients, which is very encouraging, we don't want to go forever into phase I and keep escalating, hoping to find dose-limiting toxicities.
It might be better to improve the formulation and achieve higher exposures. This is because data which came from one of the top laboratories in Europe in this field have shown that in models of colon cancer, sensitivity of the xenograft to PLOGO is higher in the presence of mutation of either ARID1A or TP53. Both of these genes are highly, highly frequent. They are observed regularly in patients' pathology analysis and genomic sequencing, and as you can see, become now a potential hypothesis to test this compound across a spectrum of very important tumors, where incidence is above 15%, including endometrial, bladder, esophageal, cholangiocarcinoma, colon cancer, melanoma, hepatobiliary, and others. So to summarize, PLOGO is a very interesting drug. It has potential activity across mechanistically relevant tumors.
It potentially could address patients that have specific mutations in epigenetic complex, called the SWI/SNF complex, subunit proteins of which include ARID1A, and it potentially could generate activity in areas of molecular pathways where there's unmet medical need and no other available therapy, either in approval or registration or preclinical status. So we have patient selection, biomarker-driven phase I expansion groups, but we're gonna pause the program in order to obtain a new formulation, which not only would increase substantially exposure levels, thereby shortening our time to DLT, but also would achieve significant enhancement of our patent life out to twenty forty. To summarize our milestones, we expect over the next few months to report the initial data from about a dozen patients we have now enrolled in the phase II part of the FADRA study.
This is the proof-of-concept study in patients with CDKN2A/B abnormalities, and also at about the same timeframe, it has a few weeks behind, as lymphoma has started later, also, patients with T-cell lymphoma. We also wish to complete our tablet manufacture and validation and have a commercially available put-up form of the drug in clinical trials, and also available for future use, which also may help strategic discussions, and also to bring the PLOGO alternative salt formulation into clinical supply and continue our trials. I want to thank you for your attention. I'll be happy to take any questions submitted to us via the webcast. Thank you.
Thank you to you and the Cyclacel team for putting together this very productive presentation. We appreciate the time and effort that went into preparing for this. We're grateful for your flexibility and your presence at the conference this year. Truly, just thank you to the entire team here at H.C. Wainwright.