Good afternoon, and welcome to the Cyclacel Pharmaceuticals First Quarter 2022 Results Conference Call and Webcast. . Please note, today's call is being recorded. I would now like to turn the conference call over to the company..

Good afternoon, everyone, and thank you for joining today's conference call to discuss Cyclacel's Financial Results and Business Highlights for the first quarter of 2022.

Before turning the call over to management, I would like to remind everyone that during this conference call, forward-looking statements made by Management are intended to fall within the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and Section 21E of the Securities Exchange Act of 1934 as amended.

As set forth in our press release, forward-looking statements involve risks and uncertainties that may affect the company's business and prospects, including those discussed in our filings with the SEC, which include, among other things, our Form 10-Q. This filing is available from the SEC or our website.

All of our projections and other forward-looking statements represent our judgment as of today, and Cyclacel does not take any responsibility to update such information. With us today are Spiro Rombotis, President and Chief Executive Officer; Paul McBarron, Executive Vice President, Finance and Chief Operating Officer; and Dr.

Mark Kirschbaum, Senior Vice President and Chief Medical Officer. Spiro will begin with an overview of our business strategy and progress on Cyclacel's clinical programs, and Paul will provide financial highlights for the first quarter of 2022, which will be followed by a Q&A session. At this time, I would like to turn the call over to Spiro..

Thank you, Irina, and thank you, everyone, for joining us today for our quarterly business update. I am happy to report that the significant progress we made in expanding our clinical development programs in 2021 has continued into the first quarter of 2022.

At present, enrolling patients in new clinical trials remains a headwind from many biotechnology companies. Despite these ongoing challenges, the Cyclacel team has executed well on this clinical development plan.

We are now dosing patients across 3 separate registration-directed Phase I/II clinical trials with our 2 drug candidates fadraciclib and CYC140. Such productivity speaks volumes to the skill and dedication of our team and the strong relationships we continue to build with several leading cancer centers in the U.S. and abroad.

Importantly, for our stockholders, we are on track to meet our key milestones for our 2 drug candidates during 2022, including initial data for oral fadraciclib. Despite the broad selling pressure waiting for several weeks on biopharma equities, Life Science innovators with competitive assets will be rewarded when markets recover.

To this end, we estimate that we have sufficient resources to fund planned operations through mid-2023 and are well placed to deliver initial clinical data highlighting our competitive leadership position. Let us update you on our progress in our CDK 2/9 inhibitor program with fadraciclib or fadra for short.

We continue to enroll patients in 2 Phase I/II studies with oral fadra. The most advanced of these studies, 065-101 is evaluating fadra in patients with advanced solid tumors and lymphomas. Since our last update, the study has reached dose level 5 or DL5, with 13 patients treated in the dose escalation stage.

Pharmacokinetic analysis from the first 3 DLs have shown dose proportional exposure with more data coming through in real time. We are pleased to report that fadra has been well tolerated and no dose-limiting toxicities or DLTs have been observed thus far.

As provided in the protocol, the study has escalated to dose level 5 with patients dosed continuously that is daily dosing from Monday through Friday each week in the entire 4-week treatment cycle.

Following completion of enrollment of DL5, the last 1 specified in the protocol, we will review safety, activity, pharmacokinetic and pharmacodynamic data from all Phase I patients and determine whether appropriate exposure of a threshold has been observed.

In addition, we will determine pharmacogenomic profiles of enrolled patients and analyze correlative data regarding protein levels. The totality of data will help us determine that Recommended Phase II dose, or RP2D, for fadra in patients with solid tumors and lymphomas.

We anticipate completing these analyses in the coming weeks and remain on track to initiate the Phase II part of the 065-101 study in the second half of 2022. In our second Phase I/II study, 065-102, fadra is being evaluated in patients with advanced leukemias.

Both City of Hope and MD Anderson Cancer Center are open and enrolling patients with DL1 now fully recruited. We are evaluating safety and PK in this study in parallel with findings in the solid tumor program. As patients with blood cancers can often tolerate higher treatment levels this study may determine a different RP2D than 065-101.

As a reminder, 065-102 will explore single-agent activity and also combinations of oral fadra with approved therapies for various hematological malignancies including oral venetoclax. This strategy is supported by recently published preclinical data by researchers from MD Anderson Cancer Center.

They confirmed that fadraciclib inhibited CDK9 mediated transcription and reduced levels of MCL1 in primary cell lines of chronic lymphocytic leukemia or CLL both as a single agent and in combination with venetoclax. Single agent fadra showed activity across all primary CLL cell lines.

The combination of fadraciclib and venetoclax was highly effective against CLL lines with the difficult-to-treat 17p chromosomal deletion, whereas each drug alone was not effective. As a highly selective inhibitor of both CDK2 and CDK9, fadra can help restore apoptosis in a cancer cell in 2 important ways.

By targeting CDK9, fadra suppresses the expression levels of anti-apoptotic proteins such as MCL1 and MYC by targeting CDK2 fadra jams a cancer escape mechanism when CDK9 is inhibited. Targeting CDK2 also suppresses cyclin E, a cancer protein to which tumor cells become addicted.

Dosing drugs with an apoptosis enabling mechanism is thought to require continuous daily dosing. Applying constant pressure to anti-apoptotic proteins like MCL1, MYC or BCL2 is required to prevent their recovery and regrowth of tumors.

Continuous daily treatment is how we dose oral venetoclax, the only FDA-approved medicine in this class of anticancer therapeutics. We believe that oral fadra safety profile with a continuous daily schedule is an important competitive advantage, which has not been matched by other competitors in the transcriptional CDK inhibitor field.

Let us now turn to our oral PLK1 inhibitor, CYC140 or 140 for short. We designed 140 to have distinct biological and structural properties that can leverage its apoptosis enabling mechanism.

We believe that these characteristics in addition to high potency and promising anticancer activity in multiple preclinical models of tumors and leukemia suggest a differentiated biological mechanism to other PLK inhibitors currently in development.

Consequently, our clinical development plan for 140 will initially explore its potential for single-agent activity across a range of solid tumor types and hematological malignancies. In April, we announced that the first patient was dosed in 140-101 and our Phase I/II trial of 140 as a single agent for the treatment of solid tumors and lymphomas.

We're also pleased to have opened City of Hope and MD Anderson Cancer Center as the initial sites for the 140-101 study, and both have enrolled patients in DL1. Similarly, with our fadra strategy, 140-101 is a registration-directed trial with a streamlined design beginning with 3+3 dose escalation to determine safety and RP2D.

Once RP2D has been established, the trial will immediately enter into proof-of-concept or cohort stage using a Simon 2-stage design.

In this Phase II stage, 140 will be administered to patients in up to 7 mechanistically relevant cohorts, including patients with bladder, breast, liver and biliary tract, lung, colorectal, including KRAS mutant cancer and lymphomas. In addition, an 8 basket cohort will enroll patients with biomarkers relevant to the drug's mechanism.

We will provide updates as the Phase I dose escalation progresses with initial data expected in the first half of 2023. Having reviewed our clinical progress and the status of our programs, I will turn the call over to Paul to review our financials.

Paul?.

Thank you, Spiro. As of March 31, 2022, cash and cash equivalents totaled $29.6 million compared to $36.6 million as of December 31, 2021.

Following receipt after the quarter end of $3.6 million of United Kingdom research and development tax credits and $1.3 million in royalty receipts pro forma March 31, 2022, cash and cash equivalents are $34.5 million. The company estimates that its available cash will fund currently planned programs through June 2023.

Research and development or R&D expenses were $5 million for the 3 months ended March 31, 2022 as compared to $2.6 million for the same period in 2021.

R&D expenses relating to fadraciclib were $3.6 million for the 3 months ended March 31, 2022, as compared to $1.7 million for the same period in 2021 due to increase in clinical trial costs associated with the ongoing clinical trials evaluating fadra in Phase I/II studies along with an increase in non-clinical expenditure.

Additionally, R&D expenses related to CYC140 were $1.1 million for the quarter ended March 31, 2022, as compared to $0.7 million for the same period in 2021 due to costs associated with the opening of clinical trial sites and the start of the Phase I/II study, evaluating CYC140 in solid tumors and lymphomas.

General and administrative expenses for the 3 months ended March 31, 2022 was $1.6 million compared to $1.7 million in the same period of the previous year due to a decrease in professional and recruitment costs.

Total other income net for the quarter ended March 31, 2022, was $1.3 million compared to $0.1 million for the same period of the previous year. The increase of $1.2 million for the 3 months ended March 31, 2022, is primarily related to royalty income received from Thermo Fisher Scientific.

United Kingdom research and development tax credits were $1.1 million for the 3 months ending March 31, 2022, as compared to $0.7 million for the same period in 2021 as a direct consequence of increased qualifying R&D expenditure. Tax credit receipts of $3.6 million in respect to the financial year ended December 31, 2021, were received in May 2022.

Net loss for the 3 months ended March 31, 2022, was $4.1 million compared to $3.5 million for the same period in 2021. Operator, we are now ready to take questions..

. We will take our first question from Kevin DeGeeter of Oppenheimer & Company..

Congrats on a lot of solid progress in terms of enrollment. Spiro, with regard to oral fadra, I guess really two questions.

First, have any patients been dosed in cohort 5, your comment with regard to no DLTs to date? I just want to appreciate if that includes any exposures at cohort 5?.

Sure, Kevin. Thank you for your question.

Mark, would you please answer that?.

The answer to the question is positive. Yes, we have a patient who's almost done with the first cycle and is doing very well..

Great. And then in terms of time frame or venue to update the investment community on the dose escalation for oral fadra in solid tumors. Still reasonable to expect an update in the summer time frame or just any perspective there...

Yes. So we expect to do company R&D events, this R&D Day is probably going to happen in the summer, more like the early summer than late summer. But that, of course, depends on the totality of data becoming available as we mentioned in the prepared remarks. So this is imminent..

Terrific. And then with regard to 065-102, the hematologic malignancy study.

Can you just remind us of kind of where the starting dose is there relative to the exposures we've seen in solid tumors and kind of thought process on, how one might think about the pace of dose escalation, particularly in light of their being experienced with IV fadra in this population?.

Yes. This is also a question for Mark, if you could please answer the question on the strategy behind the heme dosing..

Sure. So essentially it's identical to the solid tumor dosing. It was just a question of which 1 would start first. And of course, the solid tumor trial has pulled way ahead. And we're taking steps now to bring the leukemia trial in line with the doses that we have in the solid tumor trial. So there's a gap, but it will be closed very shortly..

Our next question comes from Ahu Demir of Landenburg Thalmann..

Congratulations on Group progress. This is impressive. So I will ask about the 140 program.

My first question will be how many active sites do you have? And how many additional sites do you plan to open? And following up on that question would be if you could elaborate on the dosing schedule, I know it's a little bit different than other PLK inhibitors, just curious on the dosing schedule as well?.

I'll take the first part of your question, Ahu. And Mark will answer the second question about the dosing strategy. To open the same 2 sites for this drug as well for 140-101 based on strong interest in the mechanism, but there's a large number of centers behind, which we might not open right away. The reason is that this is a new program.

We have about less information about the drug IV than we do with fadra and we'll need to move carefully, but also and very strategically, we have strong reasons to believe that 140 may have single-agent activity.

This was the case with the earliest member of this family of anticancer drugs Volasertib but that has not been thoroughly explored by other sponsors pursuing the same mechanism.

So this is something that we'd like to do very carefully and very thoughtfully before we're going to open to a wide number of sites to identify both PK and PD profile as well as look for correlates. So that's 1 of the reasons why going with 2 initial centers is probably the best strategy. And I would like Mark to discuss the dosing..

As Spiro said correctly, we're very interested in exploring the single-agent possibilities of this drug. So we have an oral drug, which we believe from our studies is well tolerated. So we're attempting to maximize the potential of the oral drug and to give as frequently as is tolerated following the PK and the mechanism of action.

And -- so I guess the goal is try to get this continuously as possible as tolerated, but as I was just getting starting, it's hard to predict, but that's our plan..

Just to give some more color to Ahu's question on starting dose. We are in the single-digit milligram range. This is a very potent drug, possibly the most potent drug we ever made at Cyclacel in our history, which means that we will escalate in slow steps.

If you compare our agents with Onvansertib, the other clinical candidate in this space, you would note that we have almost identical IC50s or potency against PLK1 and very similar salability, which means that we're not going to be very far away from the flat dosing that they have seen in their studies.

Of course, we need to escalate in our program and identify, as Mark said, all of the other information we need but we feel very comfortable this is the right dosing strategy..

One of the remarks you had made a differentiating profile of 140 compared to other PLK1 inhibitor.

Could you elaborate on that? What are the differentiating factors?.

Sure. Thank you for that. I would say that in the context of Volasertib, the earliest drug in this class, 140 has more in common, including the potential to show a single agent activity, which was reported with Volasertib some years ago.

The main issue with Volasertib, which is differentiated in the 140 profile is IV dosing and long half life, almost 3 days or 100 hours plus. In the case of 140, the drug is given orally, as Mark explained, and we have a very short half-life, possibly best-in-class around 11 hours.

The second drug in the class, Onvansertib has 24 hours of half-life that is given orally. It seems to be well tolerated. However, it has not been tested as a single agent. The sponsor when straight into combinations also in the beginning of the clinical development plan.

That may be appropriate for that drug and we feel that based on its differentiated biological mechanism, 140 deserves an evaluation as a single agent.

We will be able to show at our R&D event some additional preclinical data, some of which is produced by investigators who we hope will join our study, which will document that on top of company-owned data. So we have strong clinical fact base to believe that single-agent activity is feasible and with them to pursue this in the clinic..

I have 1 last question, again on the 140 program.

Looking at the indication selection, what is the rationale behind choosing such different indications, letter, TNBC? What was the rationale behind it?.

Sure.

Mark, would you like to answer Ahu's question, please?.

Well, since every 1 of the targets that we've identified as the cohorts that you see has a PLK1-related mechanism. So there's either data that we have from investigators, preclinical work, work that was done with previous agents in this class or published data on PLK1 mechanism independents.

So they're all -- these are all -- all these targets were verified with group with investigators, and we believe they are all potential single-agent registration strategies if we should see efficiency adequate response..

. We'll move next to Kumar Raja of Brookline Capital..

I'm Shivam for Kumar. I just have 1 question with regards to the CYC140 program. So different cancer tissue types, so different levels of over expression, which we call full change in PLK1 expression.

So do you have a threshold for that for the different cancers that you have included in the trial? And would you then match the specific biomarkers with levels of PLK1 over expression?.

Mark, would you like to answer this question, please?.

I think the best answer would be that the trial is designed to answer that question. So we have a lot of science built in to the study, specifically to answer that question. But I don't think at this point in time, there's a known threshold through expression and sensitivity.

But as I said, we have a large amount of correlative studies built into the study. This before and after treatment that should help clarify this issue..

Okay. Just 1 more follow-up question. So you have different tissue types in your trial.

Do you expect more success on 1 tissue trial versus the other? Or do you have -- what is the expectation going into the trial?.

Mark?.

Sure. So 1 of the major pluses of the trial design that we have with the biostatistical design and the cohorts that we have is the flexibility and to specifically target the last question. So we think there are another -- a number of -- a number of possible tumor tests that may respond and we'd like to not miss them.

So we have the cohorts that we define it as well as a basket. If data comes forward that suggests that this -- another tumor that we haven't recognized may have over expansion of PLK1 in this rapidly moving scientific field. So the trial has the flexibility to take those into the basket and then treat them and then open them as independent cohorts.

And each of these cohorts have a utility designed to it so that if we treat X number of patients, and we don't see a response, that cohort will close.

So it's a nice way to be able to treat a large number of different tumor types and identify, which are the best ones that will be most likely to respond with the normal cost because it's all grouped into 1 big study. Does that answer -- I hope that answers your question..

. We'll move next to Jonathan Aschoff of ROTH Capital..

I joined a bit late. I was wondering, so if this was already covered. Is there any point at which you rethink the liquid tumor trial, it's been enrolling since November and it's still in that first dose cohort.

I was just curious if you kind of had a by which you might we think doing that at all?.

That's an excellent question, of course, given the stock market pressures that we discussed earlier, this could be an important time to give it some attention. However, we do believe that fadraciclib is particularly well suited to this mechanism.

Consider, for example, that the standard of care in the United States, which is the venetoclax with hypomethylating agents is associated with treatment failure when MC1 levels go up. This is almost too good to be missed an opportunity to test the CDK inhibitor. The delay you mentioned was primarily due to logistics.

It took us longer to open 1 of the 2 sites we have in the study, primarily because of process and year-end issues. Now that both sides are open, they expect the state to move rapidly. I also made the remark earlier regarding the fact that we can analyze safety data from the solid tumor study and hopefully interpolate that into the leukemia program.

As we all know, patients with leukemic and sometimes tolerate higher doses of anticancer therapy. So this is a program that we're at some point by 4K possibly diverge from the solid tumor recommended Phase II determination. So that's 1 of the reasons why this could being in this program now would not be appropriate.

But certainly, it's something we will consider a totality of data once we get across 1 or 2 more dose levels. So we're not far away, we will soon have an answer whether this drug is suited for patients with hematologic and malignancy Jonathan. Are there any other questions, Jonathan? I guess no. So operator we can take the next question please..

. And it appears that we have no further questions via the phone lines. I'd be happy to return the call to Mr. Rombotis for any closing remarks..

Thank you, Leo. And thank you, everyone, for joining Cyclacel's first quarter earnings call. As mentioned earlier, Cyclacel is poised to enter an important period as we expect key pipeline readouts, which may be transformative for the company.

We believe that oral fadraciclib and CYC140, our 2 differentiated clinical assets with strong potential for activity across multiple types of cancers, and first or second in their respective classes. We look forward to providing additional updates and initial clinical data in the next quarters. Thank you..

This does conclude the Cyclacel Pharmaceuticals first quarter 2022 results conference call and webcast. You may now disconnect. And everyone have a great day..