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Edited Transcript of CYCC earnings conference call or presentation 12-May-20 8:30pm GMT

Q1 2020 Cyclacel Pharmaceuticals Inc Earnings Call

Berkeley Heights Jun 9, 2020 (Thomson StreetEvents) -- Edited Transcript of Cyclacel Pharmaceuticals Inc earnings conference call or presentation Tuesday, May 12, 2020 at 8:30:00pm GMT

TEXT version of Transcript

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Corporate Participants

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* Judy Chiao

* Paul McBarron

Cyclacel Pharmaceuticals, Inc. - Executive VP of Finance, CFO, COO, Secretary & Executive Director

* Spiro George Rombotis

Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director

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Conference Call Participants

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* Jonathan Matthew Aschoff

Roth Capital Partners, LLC, Research Division - MD & Senior Research Analyst

* Kumaraguru Raja

Brookline Capital Markets, LLC, Research Division - Director & Senior Biotechnology Analyst

* Wangzhi Li

Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology

* Jan Medina

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Presentation

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Operator [1]

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Good afternoon, and welcome to the Cyclacel Pharmaceuticals First Quarter 2020 Results Conference Call and Webcast. (Operator Instructions) The company will also be accepting a limited number of questions submitted via e-mail to the address ir@cyclacel.com. (Operator Instructions) Please note, today's call is being recorded. I would now like to turn the conference over to Jan Medina, Investor Relations for Cyclacel Pharmaceuticals. Sir?

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Jan Medina, [2]

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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 ending March 31, 2020.

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 forms 10-Q and 10-K. These filings are 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. Judy Chiao, Vice President of Clinical Development and Regulatory Affairs. Spiro will begin with an overview of our business strategy and accomplishments on Cyclacel's multiple clinical programs, and Paul will provide financial highlights for the first quarter of 2020, which will be followed by a Q&A session.

At this time, I would like to turn the call over to Spiro.

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [3]

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Thank you, Jan, and thank you, everyone, for joining us today for our first quarter 2020 business update call. First and foremost, we hope that all of you listening to our webcast are safe and well. The global pandemic caused by COVID-19 disease continues to affect nearly all human activity and creates uncertainty in every business sector. The events over the last few months have made it clear that we need novel science-based solutions to emerge from the crisis.

At Cyclacel, we take our social responsibility very seriously, in particular, protecting the health and safety of our employees, the patients we serve and the communities in which we live and work. As indicated in today's press release, we have taken relevant protective measures and are following government orders, with our employees mostly working from home. We're working closely with clinical trial sites to ensure adequacy of clinical supplies and that our trials are following specific FDA guidance during the pandemic.

We have been advised by clinical investigators that they continue to screen and register patients in our studies and remain on track with enrollment. At the same time, we cannot assume that circumstances, such as a second surge, will not make it more difficult for patients to remain on or join our studies.

Cancer patients faced increased risks in this environment. As we design new dosing schedules and subsequent protocols, we are, therefore, considering such matters as frequency of visits and translational research requirements. Despite these challenges, we are committed to our mission of serving cancer patients and maintaining the integrity of our clinical research.

Cyclacel's business strategy is to build an innovative pipeline, addressing the rising problem of cancer resistance. We are studying the ability of our agents, alone and in combination with other drugs, to improve anticancer effectiveness and treatment outcomes. We are pleased to report continued progress and will briefly describe on today's call our plan for advancing our lead drug, fadraciclib. Based on current spending plans, we estimate that our pro forma cash and equivalents of $27.3 million, including the spring equity raise, will provide a cash runway to the end of 2022.

We will first review fadraciclib, formerly known as CYC065. Fadraciclib is a novel CDK inhibitor, targeting the CDK2 and 9 isoforms, which act as key components of the p53 pathway. Activity against CDK2 results in reduction of cyclin E, and again, CDK9 in suppression of MCL1 levels. Cyclacel is evaluating fadraciclib as a single agent in patients with solid tumors, and in combination with other drugs in patients with hematological malignancies. Overexpression of cancer resistance proteins, or amplification of oncoproteins, such as MCL1 or cyclin E, respectively, are associated with cancer cell invasion. MCL1 is one of the 10 most frequently overexpressed cancer genes and is a member of the Bcl-2 protein family, including Bcl-2, BSL-1, BCL-XL and others, which act as prosurvival mechanisms for cancer. Cyclin E, a protein encoded by the CCNE gene, is overexpressed in several gynecological cancers, including breast, endometrial/uterine and ovarian.

Addiction to cyclin E enables cancer cells to escape test by anticancer treatment. Suppressing these proteins forces aberrant cells into apoptosis or programmed cell death. Cyclacel's therapeutic strategy is to suppress transcription of such proteins and reactivate the apoptotic machinery leading to cancer cell death.

Recent discoveries of the importance of MCL1 have resulted in a race to bring to market MCL1 suppressing medicines. We believe that fadraciclib is a leader in this race based on demonstration of durable suppression of the protein in peripheral blood mononuclear cells and anticancer activity as monotherapy in heavily pretreated patients with solid tumors. MCL1 suppression was observed in the majority of patients enrolled at the recommended Phase II dose, or RP2D, in Part 1 of our 065-01 dose escalation study using a sparsely administered schedule. We enrolled 26 patients who received fadraciclib as a single 4-hour infusion every 3 weeks. Nearly all patients who achieved stable disease with tumor shrinkage had molecular markers relevant to the drug's mechanism, including MCL1, cyclin E and/or MYC amplification.

We have enrolled a further 22 patients in the ongoing Part 2 of the study, with a more frequent dosing schedule of 1-hour infusion on days 1, 2, 8 and 9, every 3 weeks. Escalation in Part 2 has reached the fourth dose level and additional patients have been enrolled to establish RP2D.

As previously reported, a patient at the fourth dose level, with heavily pretreated MCL1 amplified endometrial cancer, achieved radiographically confirmed partial response, or PR, after 1.5 months on fadraciclib. This patient is continuing on study after approximately 9 months on the same dose. After the last restaging, shrinkage in her target tumor lesions has improved to 79%.

Another patient with cyclin E-amplified ovarian cancer achieved stable disease, with tumor shrinkage of 29% after 4 months of fadraciclib monotherapy.

Based on fadraciclib's clinical activity, durable suppression of MCL1 and extensive preclinical and clinical data on overexpression of cyclin E in various cancers, we plan to further explore fadraciclib in a tissue-agnostic, precision medicine-driven study, evaluating patients with gynecological cancers. The concept behind the study broadly follows the precedent-setting approval of pembrolizumab in Microsatellite instability high or mismatch repair cancers.

Briefly, we are planning a Phase I/II open-label, parallel cohort study design. The initial sample size is 60 patients, with each cohort enrolling 20 breast, endometrial/uterine or ovarian cancer patients, respectively. Patients will receive fadraciclib monotherapy and subsequently combination therapy depending on available options. Details of the trial will be forthcoming after consultation with experts. Primary endpoint will be objective response rate, or ORR, and duration of response will be an important secondary endpoint. Successful ORR performance will be measured against benchmark response rates. Once it has started in early 2021, we expect enrollment of this study to take approximately 1 year, notwithstanding pandemic delays.

In addition to intravenous administration of fadraciclib, we are evaluating an oral capsule formulation. We have dosed 3 patients and reached the second dose level. Initial pharmacokinetic, or PK data, demonstrated a predictable PK profile closely overlapping that of the IV administration with encouraging exposure levels.

In our hematological malignancies program, we have opened 2 dose-escalation studies to test the hypothesis that suppressing MCL1 and Bcl-2 can result in anticancer activity against relapsed or refractory leukemias. We are evaluating a fadraciclib and venetoclax combination in patients with relapsed or refractory AML or MDS in the 065-03 study and relapsed or refractory CLL in 065-02. Reflecting the unmet need for alternative AML treatments, we have rapidly enrolled 11 patients in 065-03, the primary endpoint of which is the termination of RP2D and safety. The rationale for our AML study is that MCL1 plays a dominant role and is supported by the clinical evidence of synergy of fadraciclib and venetoclax in inducing apoptosis. This suggests that double hit suppression may be more beneficial than suppressing either protein alone. Heavily pretreated patients received a combination of oral venetoclax and escalating doses of fadraciclib on a 4-hour infusion schedule once every 2 weeks. We have reached dose level 5 with 2 patients on 200 milligrams per meter squared, or approximately 300 to 400 milligrams total dose of fadraciclib and venetoclax in combination.

Tumor lysis syndrome, or TLS, was reported in both patients, consistent with antileukemic activity related to the drug's mechanism. This follows previously reported reductions of leukemic blasts in the peripheral blood of patients treated on lower doses with the combination. Based on these findings, we plan to evaluate additional, more frequent dosing schedules.

In CLL, Bcl-2 overexpression is the main feature and MCL1 is an escape mechanism. Leukemia cells, especially in the lymph nodes, may stop responding to venetoclax, followed by relapse, often associated with MCL1 overexpression. Eradicating CLL in the lymph nodes and achieving minimal residual disease, or MRD, negativity is an important treatment objective.

In the 065-02, enrollment thus far has been slow, reflecting the long relapse-free survival after frontline CLL therapies. Given that eventually a large number of patients will relapse, investigators have advised Cyclacel to persist, as an unmet medical need is emerging. In order to increase enrollment, we have implemented certain protocol amendments and opened 2 new sites in addition to MD Anderson. Five patients have been treated so far, up to dose level 4, or 150 milligrams per meter squared. The first 2 patients failed ibrutinib therapy and 1 of the 2 also failed CAR-T. They were dosed once every 2 weeks at 64 milligrams per meter square of fadraciclib and venetoclax as per label post ramp, for 5 and 6 cycles, respectively, which was well tolerated. Both patients had continuing shrinkage of their lymph nodes, and 1 was MRD-negative after 5 cycles on the combination.

Both of these studies are part of our risk-sharing alliance with the University of Texas MD Anderson Cancer Center, whereby MD Anderson assumes patient costs for all studies, and we provide investigational drugs and other limited support. The MD Anderson alliance also includes clinical trials with our other programs, sapacitabine and CYC140.

In our DNA damage response program, we are enrolling patients with relapsed or refractory AML or MDS, in Part 2 of our 682-11 study with sapacitabine, our nucleoside analog. This dose escalation study has enrolled 12 patients and is evaluating safety and effectiveness of an oral combination of sapacitabine with venetoclax.

In addition, an investigator-sponsored trial, or IST, is enrolling at the Dana-Farber Cancer Institute, evaluating a combination of sapacitabine with olaparib, AstraZeneca's Lynparza, in patients with BRCA-mutant breast cancer.

In our antimitotic program, we're evaluating CYC140, a Polo-Like Kinase, or PLK1 inhibitor, which, like fadraciclib, was discovered in-house. Five patients with advanced leukemias have been recruited to 140-01, our first in-human, single-agent dose-escalation study. No dose-limiting toxicities have been observed thus far. CYC140 is a small molecule, selective PLK1 inhibitor, that has demonstrated potent and selective target inhibition and high activity in xenograft models of human cancers.

Like many peer biopharma companies, we have responded to society's call by volunteering our medicines for testing in indications where they may be helpful to patients affected by the coronavirus. To this end, we have recently announced a collaboration with The University of Edinburgh to evaluate the potential of our CDK inhibitors, fadraciclib and seliciclib, for reducing runaway inflammation and acute lung injury in patients with COVID-19 disease.

In addition, 2 ISTs at Cedar-Sinai Medical Center and the University of Newcastle, are evaluating seliciclib, our first-generation CDK inhibitor, in patients with Cushing's disease and rheumatoid arthritis, respectively.

During the quarter, we laid the foundations for multiple data outcomes over the next 2 years. As we continue executing our strategy and advancing our clinical development programs, our upcoming key milestones include: report updated fadraciclib, Phase I safety and efficacy data with frequent IV dosing schedule in patients with advanced solid cancers; report initial safety and PK data from Phase I study of fadraciclib oral formulation; treat first patient in fadraciclib Phase I/II precision medicine-driven studies; report initial data from fadraciclib/venetoclax Phase I study in relapsed/refractory AML or MDS and CLL; report initial status from CYC140 Phase I first-in-human study in relapsed/refractory leukemias; report initial data from sapacitabine/venetoclax Phase I study in relapsed/refractory AML or MDS; and report data from Phase Ib/II sapacitabine/olaparib IST in BRCA-mutant metastatic breast cancer when reported by the investigators.

With capital on hand estimated through the end of 2022, we have the resources to deliver key milestones in our clinical studies.

I would now like to turn the call over to Paul to review our first quarter 2020 financials. Paul?

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Paul McBarron, Cyclacel Pharmaceuticals, Inc. - Executive VP of Finance, CFO, COO, Secretary & Executive Director [4]

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Thank you, Spiro. As outlined in today's press release for the quarter ended March 31, 2020, cash and cash equivalents totaled $8.9 million compared to $11.9 million as of December 31, 2019.

The decrease of $3 million was primarily due to net cash used in operating activities of $2.8 million and $0.1 million of net cash used in financing activities. The company raised net proceeds of approximately $18.4 million from an equity financing in April 2020. And we estimate that cash resources as of March 31, 2020, together with the $18.5 million net equity financing, will fund currently planned programs to the end of 2022.

Research and development expenses were $1.1 million for the 3 months ended March 31, 2020, as compared to $1 million for the same period in 2019.

Expenses relating to our transcriptional regulation program increased by approximately $0.3 million for the 3 months ended March 31, 2020, as we continue to progress the clinical development of fadraciclib.

General and administrative expenses for the 3 months ended March 31, 2020, were $1.3 million compared to $1.2 million for the same period of the previous year.

Total other income net for the 3 months ended March 31, 2020, was $0.9 million compared to $0.1 million for the same period of the previous year. The increase of $0.8 million for the 3 months ended March 31, '20, is primarily related to income received under an asset purchase agreement with Thermo Fisher Scientific. United Kingdom research and development tax credits were $0.3 million for each of the 3 months ended March 31, 2020, and 2019. And our net loss for the 3 months ended March 31, 2020, was $1.2 million compared to $1.8 million for the same period in 2019.

Following the April equity financing, our common stock outstanding is 4.9 million shares.

Operator, we are now ready to take questions.

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Questions and Answers

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Operator [1]

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(Operator Instructions) Our first question is from the line of Jonathan Aschoff with Roth Capital Partners.

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Jonathan Matthew Aschoff, Roth Capital Partners, LLC, Research Division - MD & Senior Research Analyst [2]

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I was wondering, given the increased effort for fadraciclib in solid tumors, could you describe the solid tumor landscape potentially addressable by the drug, such as breast cancer after, let's say, a CDK4/6 inhibitor failure or something like ovarian cancer after platinum failure or PARP inhibitor ineligibility? And then after that, what might you consider to combine fadraciclib with in cyclin E overexpressing solid tumors if monotherapy is not potent enough?

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [3]

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Jonathan, thank you very much for your question. The landscape for gynecological cancers is evolving, but the important clinical data has been reported in recent months. For example, with regard to the first part of your question, in breast cancer, this is, of course, hormonal receptor positive breast cancer, which is nearly 3/4 of the entire breast cancer population. The standard of care is CDK4/6 inhibitor together with hormonal therapy, with drugs like palbociclib, ribociclib and abemaciclib.

When CDK4/6 inhibitors fail, the primary correlate for resistance to this activity of this type of class of drugs is overexpression or amplification of cyclin E. This was shown in Pfizer's PALOMA-3 study with palbociclib 2 ASCOs ago. So we know that the vast majority of patients who receive standard of care, this is the combination of hormonal therapy and CDK4/6, will eventually fail this therapy combination and will overexpress cyclin E. So this is clearly a very important subset. We estimate from literature citations that approximately 1/3 of this hormonal receptor positive population will present with cyclin E amplification. It may take a few years, I remember that palbociclib was launched in the U.S. in 2015, before we see that, but we're now starting to see it.

So resistance to CDK4/6 plus hormone therapy inhibition is a very important marketplace and literally more than 50,000 patients available based on our modeling to address with a cyclin E amplification reducing therapy like fadraciclib. Now in terms of combinations, I will ask Judy to comment on this population before I go on to discuss ovarian cancer. Judy?

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Judy Chiao, [4]

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Okay. So I think our strategy is really try to combine it with one of the hormone therapies that commonly used in a population of patients who have failed the frontline. As you know that we basically have 3 types of hormonal therapies. The oldest one is tamoxifen, then we have aromatase inhibitors and also the estrogen receptor degraders, the SERD. I think that our plan is to combine with one of those in patients who have failed the 4/6 inhibitor frontline hormonal therapy.

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [5]

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Thank you, Judy. So the second part of your question was about ovarian cancer and what to combine with. That landscape is an even more flux. We just saw, literally a couple of days ago, a new approval for PARP inhibitors. This is addressing patients, not only who are potentially BRCA-mutant after testing, but possibly have HRD, homologous recombination deficient disease. And it has now been proven that in the subgroup of patients who are HRD positive and possibly also BRCA-positive, that PARP inhibitors, either alone or in some suitable combination, have high levels of activity, yet that tends to not have extremely long durability. Most patients tend to progress after about a year.

In the subgroup of patients who are HRD negative, a new standard of care appears to be emerging, which is that of Avastin or bevacizumab, based on recent data. And it's not entirely clear whether frontline ovarian cancer maintenance with PARP inhibitors in HRD-negative patients have the same benefit for patients as Avastin-based therapy may. And of course, one could combine PARP inhibitors and bevacizumab/Avastin to achieve some disease control. However, ovarian experts are telling us that the vast majority of patients who are never offered PARP inhibitor therapy, possibly because they have insensitivity to platinum, typically have cyclin E amplification. So we've estimated an addressable population of about 27,000 patients with the high-grade serous ovarian -- type ovarian cancer, which is the lion's share of this disease, who would present with not being suitable or not being candidates for either platinum and/or PARP inhibitor therapy. And 1/3 of that, as I mentioned, approximately 27,000 patients in total, are addressable market by a drug that can regulate cyclin E amplification. So Judy, could you answer what might be possible combinates in the ovarian cancer setting, particularly for patients who are not suitable for PARP inhibitor therapy?

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Judy Chiao, [6]

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Well, I think this is a question that certainly we need to have further discussion with ovarian experts in the field. As you know that, traditionally, we consider to retreat patients with platinum, if initially, they were platinum-sensitive. So I think that should we be combining and looking at the price sensitivity department and then retreat them and with the combination of 065 we're planning, that was one example, or some other agents that commonly use in very refractory settings.

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Jonathan Matthew Aschoff, Roth Capital Partners, LLC, Research Division - MD & Senior Research Analyst [7]

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Okay. I have one more question. I was just wondering what has been going on with the COVID-19 program since its April 20 announcement.

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [8]

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Thank you, Jonathan. We can certainly give to you and to our audience an update on that collaboration. As you all know from the press release, some days ago, the University of Edinburgh published a research starting in 2006, and with subsequent papers in 2012 and 2014, showing that in 3 different animal models of lung injury, ranging from acute lung injury to fibrotic disease, to pleurisy, there appears to be anti-inflammatory activity of seliciclib, first-generation CDK inhibitor. They further localized this anti-inflammatory activity on effects on activated neutrophils. Neutrophils are, of course, an important part of the immune system, but after inflammatory injury, such as the one caused by this bleomycin-induced models of lung damage, can produce overactive neutrophils that need to be directed to apoptosis or they're going to cause massive inflammatory cascade problems, oftentimes called cytokine storm.

In addition, a group from Dana-Farber Cancer Institute, in Boston, published data at about that same time many years ago, showing that seliciclib is also active in slowing down the rate of adhesion of myeloma cells when attaching to bone marrow stromal cells. Again, another inflammatory cascade hallmark in the context of myeloma, which is, of course, a cancer of the blood.

They have also demonstrated that set of experiments and xenograft models that seliciclib also regulates the transcription of Interleukin 6. Interleukin 6 is found in postmortem studies of COVID-19 patients to have been a major prognostic factor in the rapid decline. So for this reason, the University of Edinburgh is keen to, first of all, demonstrate whether the same observations applied to fadraciclib, our new SDK inhibitor, that has not been tested so far in models of inflammation, if they see a systemic effect, then perhaps this is a class property, and that would certainly encourage them. Assuming that they are confident that what we have is reproducible, they would like to go on to an exploratory medicine study, which would be done, probably at the University of Edinburgh, possibly other centers who collaborate with them under the auspices of the U.K. -wide effort to stop COVID, a program called STOPCOVID, which is funded by both charitable and government sources. So though we're not an inflammation company, we are and we will stay an oncology company, this is our area of expertise, we are very keen to help. And to the extent we can also, in addition to helping patients, potentially learn more about our drug, this is for us a win-win effort.

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Operator [9]

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And next, we have a question from the line of Wangzhi Li with Ladenburg.

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Wangzhi Li, Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology [10]

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Do you hear me?

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [11]

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We can hear you, Wangzhi.

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Wangzhi Li, Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology [12]

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Okay, good. The first question is regarding the fadraciclib single-agent IV dose escalation. Maybe I missed it, but I wonder what dose level you are now? It's still the 230? Or is it higher now?

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [13]

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So you're talking about the fadraciclib Phase I study in solid tumors. Is that correct?

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Wangzhi Li, Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology [14]

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Correct.

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [15]

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Okay. So this is the 065-01 Part 2 study. We're testing a frequent dosing schedule, and I will let Judy to maybe describe what we see at 230 and what happens next. Over to you, Judy.

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Judy Chiao, [16]

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Yes. We're still at the 230-milligram level. We're not going above it.

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Wangzhi Li, Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology [17]

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Okay. So -- and what -- so that will be the dose level for the precision tumor trial?

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Judy Chiao, [18]

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The precision tumor trials will be using the Part 2 dosing schedule.

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Wangzhi Li, Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology [19]

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Would it be the 230-milligram dose? Or is a different dose?

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Judy Chiao, [20]

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Well, I think that once we completely believe that it's going to be the recommended Phase II dose, it will be either 230 milligrams or it's a one dose level lowered, if we -- when we expand to 230, the candidate -- it's not tolerable. But so far that -- it is tolerable. We don't have excessive dose-limiting toxicities. We have some patients required dose reductions, but we're still in the phase of sorting that out. So we don't have excessive dose-limiting toxicities.

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Wangzhi Li, Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology [21]

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Got it. In terms of -- okay, in terms of the data reporting timing, the data report, should we expect still '20? Or maybe a little bit late because of the COVID-19?

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [22]

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Both the principal investigators in the Dana-Farber Cancer Institute program, with whom we've been doing our Phase I studies, both for the IV and the oral, are keen to publish the results. We have had those discussions with them. There are 2 conferences to the end of this year, major oncology meetings. We don't know if they will be held physically or virtually, but somehow, they will be held as we have seen with AACR and soon with ASCO. So we expect, by end of 2020, Wangzhi, we will have that data available in a peer-review setting.

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Wangzhi Li, Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology [23]

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Got it. And then shifting gears to the oral formulation. You have 3 patients so far, looks pretty consistent with the IV formulation. I'm just wondering how many dose levels of patients you need to see to really say, I think, that the oral formulation can replace the IV formulation?

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [24]

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Okay. So first of all, we have indeed, as you said, 3 patients, 1 at 75 milligrams flat dose and 2 at 150. So we are still a little bit below where we expect to be with the IV formulation, given that we're using exactly the same schedule, but this time with an oral capsule, days 1, 2, 8 and 9. Let me ask Judy about her expectations with a caveat that is still early in the oral development.

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Judy Chiao, [25]

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Well, it's always a bit challenging to predict between the 2 formulations. I think the good news is that the PKs of the oral looks favorite. And I think that we are close, we may be able to go up a 1 dose level, but I don't think we'll have to go up a lot because the bioavailability is pretty good.

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Wangzhi Li, Ladenburg Thalmann & Co. Inc., Research Division - MD of Equity Research of Biotechnology [26]

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Okay. Got it. My final question is on the CLL trial. You saw 2 MRD-negative response now. I'm just wondering, what do you think of the bar of ORR and/or DOR for this setting to give you confidence to advance this drug further in the CLL setting?

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [27]

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This is a great question, but I think we are still in a dose-escalation study, which was the first we ever did with this combination. The primary endpoint for this study is recommended Phase II dose and safety. So I don't think that this study was designed being that most patients will get the drug at lower doses to determine efficacy. We're still learning as to what the properties of the combination are. But as -- I think we mentioned in the CLL setting in our press release and previous communications, patients do very well on frontline regimens, whether they are BTK-inhibitor based, chemo-immunotherapy based or even combinations with venetoclax with antiCD20, they tend to last for at least 2 or 3 years before relapse.

More than 85% of patients will relapse because most of them will survive their initial period. So there was a large repository of relapsed patients to treat once they fail frontline therapy. Once we wait for the patients to fail all available therapies, then come to a Phase I study, things are sometimes very hard. So it's really hard to benchmark, at this point, Wangzhi, what the right level of response as well as duration of response would be. We are encouraged by the MRD-negativity observed, certainly concomitantly with reduction in lymph node size, which appears to be sustained on the combination, even if the patients were sensitive to venetoclax alone, they clearly do not achieve MRD-negativity on venetoclax alone, where the patient was persuaded to stay on treatment. But I would call those exploratory findings. I don't think we are yet at a level that we can give the drug consistently and start to make projections on what would be a suitable level of activity, let alone duration, and therefore, design, I suppose, ultimately, randomized study in CLL. First thing is to define RP2D. And we think we are close. We are now at 150 milligrams per meter square, which is, of course, much more than we're giving in solid tumors, but consistent with what we have in AML. So as an AML, we're topping around 200-milligram per meter square, we're not too far. So we should be able, by the end of this year, to get to the primary endpoint of this study and then start defining next steps.

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Operator [28]

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And our next question is from the line of Kumar Raja with Brookline Cap -- I'm sorry, Brookline Capital Markets.

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Kumaraguru Raja, Brookline Capital Markets, LLC, Research Division - Director & Senior Biotechnology Analyst [29]

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So with regard to the precision medicine approach, what would be the strategy in terms of company and diagnostic development of company in diagnostics there? And in terms of -- what are the expectation in terms of ORR and DOR? And obviously, based on the genetic background of this population, what are your expectations in terms of regulatory strategy there? Would it be like based on the genetic background that you can go ahead and get approval based on that? How big of trials do we expect going forward in that?

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [30]

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Kumar, thank you for your multiple questions. And of course, they're addressing a lot of important issues, which we are not yet ready to address because we don't have enough data. But let me pick on the first few and then Judy will discuss regulatory strategy and other options.

I think we are very seriously and diligently thinking of the companion diagnostic strategy. There are, however, some important differences. In solid tumors, at least, in the large U.S. tertiary referral centers, most patients get screened via NGS, next-generation sequencing. So it's possible to determine the status of cyclin E and/or MCL1 by doing NGS profiling in these patients, and therefore, we don't need classic, for example, BRCA assay to determine a patient suitable for PARP inhibition some 3 or 4 years ago. So that's an important distinction as the state of technological evolution in determining genomic status in patients has advanced by leaps and bounds in a short time.

We know that there are some needs to have standardized, centralized testing and would like to explore that further with potential investigators, and that will determine how we'll move forward. But we feel comfortable that at least we can determine the status of amplification of a protein at baseline by using NGS data.

Ultimately, in solid tumors, we want to have follow-on assessment of genomic status, but this would be quite challenging, particularly in the area of COVID-19, we cannot easily ask a relatively young patient with gynecological cancer to come in and give more biospecimens to determine that. That will have to be determined along the way. But certainly, to determine patients at baseline seems to be feasible as this is done routinely.

In terms of our overall response rate and duration of response benchmark, of course, this could be different by cohort. We have some pretty good ideas of what those are in breast cancer and ovarian cancer, based on the subgroups we discussed before. But as Judy mentioned, this need to be validated by KOL dialogue, which is ongoing. And we have to learn a little bit more about the rapidly evolving landscape in endometrial/uterine cancer, which has a lot of new options, but none that appears to be compelling as both its incidents and poor survival continue to be a feature of this disease. It's probably the only women's cancers that has increasing mortality over the last half a decade or so. So it remains a very big unmet medical need.

So these are important questions. We'll be better placed to answer them once we more precisely define eligibility criteria for our precision medicine-driven study, and that will happen in the second half of this year, and then we'll be able to give more color. Let me ask Judy to comment on your other question about regulatory strategy.

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Judy Chiao, [31]

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Well, Spiro, thank you. I think the regulatory strategy, I consider that's pretty straightforward. And -- by which I mean that, if we have sufficient single-agent activity, that -- in the refractory population that could be identified by either Mcl-1 amplification or cyclin E, then the response rate defined -- certain magnitude of response rate will suffice. And I think you probably already see the precedent in other FDA approval. We're talking about something probably around 15%, in that range and higher than that, that would be certainly very good, and we need durability. Well, that's just I think what the precedent is.

I think for regular approval after study's approval is probably required in randomized studies. And this is where the questions of combination chemotherapy comes in. And there are 2 ways to think about combination therapy. One is to have 2 drugs that actually both are active together, but they don't have overlapping toxicities, compared to one single agent alone. For example, if -- I'm just using example of ovarian cancer, if one were choose to combine with platinum, whether the cisplatin or carboplatin, and you know the predominant toxicity of platinum is 0 toxicities -- cisplatin, and myelosuppression, especially thrombocytopenia with carbo, then for CYC065 certainly, we have not yet seen any neurotoxicity at all. Your hypothesis will be both for active and you benchmarked it against cisplatin alone in patients who have the chance to respond to cisplatin because they previously have responded to cisplatin. So I -- and of course, the second hypothesis is based on mechanism of action, where there reducing MCL1 will actually chemosensitize the cells to certain chemotherapies. Now that, I think, is something that we don't have any approvals in the clinic until we do the randomized studies. So I hope this answers your question.

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Kumaraguru Raja, Brookline Capital Markets, LLC, Research Division - Director & Senior Biotechnology Analyst [32]

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Yes, it does. And maybe one more question with regard to the enrollment in the clinical trials. You guys mentioned that you are still continuing to screen and enroll patients. So from what time line are these, like is it more recent? And what differences are you seeing in terms of various sites, right, because like some states are opening up and some states are still closed. So what kind of differences are you seeing in the sites? And maybe you can talk a little bit with regard to the FDA guidance and what kind of changes are being made in terms of monitoring the patients who are already on the trials?

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [33]

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Thank you, Kumar. I'll take the first part of your question, and Judy will handle the FDA guidance that recently came out due to COVID-19.

So in terms of regional enrollment, our primary locus of enrollment is Boston, with Dana-Farber, of course, and Houston, where MD Anderson is. We have not seen dramatic decline. We know that Boston is an epicenter of the pandemic. And yet, there appears to be some downward slope in the curve based on reported new infections. It appears that Dana-Farber as one of the many hospitals in the Harbor Medical Complex is somewhat less affected and that Mass General is the primary referral center for COVID-19 patients. There was recently an article in the press about reduction in chemotherapies at Dana-Farber. It was in the LA Times and it pegged it at 15%. And obviously, our drug is not chemotherapy, so we are not, at this point, encountering issues, but it's hard to say how things will go if there was a second surge late in the year, for example, that is a risk factor.

Houston has been relatively spared in relative terms compared to our New York, New Jersey area, Boston and Seattle. But it remains, of course, of concern. MD Anderson has imposed restrictions on access. They have control entry, few entrances than before, and complete prohibition of unnecessary visits and no family and so on. But so far, we have been able to continue to enroll, patients are being screened and enter into our studies because they face very poor prognosis. I don't think anybody on this call is unaware of the very short survival that AML patients can expect. So that becomes a very serious problem for these patients if they are not receiving treatment or being considered for potential investigational trials.

In our CLL study, as we mentioned, we have 2 new sites. Both of those are in the mid-Atlantic region. They are not in a major metro area like Washington, D.C. or Philly. So they are so far not exposed to risks from the virus as of this moment. We don't know how this will move forward, but so far, they have been able to enroll their respective patients so the study continues.

So in relative terms, we have been spared, it's hard to predict how the future will go. But -- for instance, we have stopped pursuing a dialogue with European investigators. Europe is in the midst of the pandemic. They are going to have to, first of all, demonstrate that they can safely handle going back to work over the months to come before we can consider opening studies there. And we have also slowed down the possibility of adding new sites in the U.S. until we further understand the trajectory of the pandemic, pretty much along the lines of what you described.

So with that, let me turn to Judy to address the regulatory question.

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Judy Chiao, [34]

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Well, I think the FDA guidance that is really trying to provide some framework how to do the clinical study in this very unusual and challenging pandemic. So I think the first of all is that, if somebody who doesn't need to be in a hospital, then they don't need to be in the hospital. Well, to me, that criteria is not terribly relevant to the population of patients that we try to target. You know that when you fail the multiple lines of therapies, you have refractory disease and the tumor is growing. I mean that is a life and a death issue. So it's not something you can sit on and wait for months until the COVID-19 cases go down. What we have seen is that the sites are getting better because we work with major sites and to prescreen the patients and really try to be more specific in making sure if they do come in, they are eligible and instead of just taking a lot of patients, screen them and then 3 of them says what, I have something else, as they don't -- they are doing a much careful job. So I think that's good news. And the second, in terms of how we monitor, we work with the sites very closely. And we were -- we have been, anyway, with phone calls. And so that, to us, is -- remains the same.

In terms of the traditional monitoring, and to be honest, that we see -- most of the sites we work with are allowing us to access the medical charts remotely due to the pandemic. So that is helpful to us to directly get to the source to making sure that data captures are accurate.

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Operator [35]

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And at this time, I'm showing -- we have no other questions on the phone lines. I'd like to turn it back over to Spiro Rombotis for any closing remarks.

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Spiro George Rombotis, Cyclacel Pharmaceuticals, Inc. - President, CEO & Executive Director [36]

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Thank you, operator, and thank all of you for participating in Cyclacel's First quarter 2020 Earnings call, and your ongoing support of our efforts to deliver on our strategy to realize stockholder value by demonstrating safety, efficacy, and cost effectiveness of our pipeline assets. We look forward to updating you on our progress and meeting, although virtually, some of you, at upcoming conferences or the annual meeting. Please stay safe. Operator, at this time, you may end the call.

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Operator [37]

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Ladies and gentlemen, thank you for joining us for today's call. You may now disconnect.