On August 7, 2017 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) (Cyclacel or the Company), a clinical-stage biopharmaceutical company using cell cycle, transcriptional regulation and DNA damage response biology to develop innovative, targeted medicines for cancer and other proliferative diseases, reported the selection of a recommended Phase 2 dose (RP2D) from part 1 of a dose-escalating, Phase 1, first-in-human, clinical study of CYC065, a Cyclin Dependent Kinase (CDK) 2/9 inhibitor (Press release, Cyclacel, AUG 7, 2017, View Source [SID1234520060]). RP2D was determined to be dosing level 6 which enrolled 9 evaluable patients with advanced cancers. Prolonged reduction of the Mcl-1 biomarker was observed in 7 out of the 9 patients for at least 24 hours following a single dose of CYC065, which was generally well tolerated. Preliminary anticancer activity was observed in three patients with Mcl-1, MYC and Mcl-1/cyclin E amplified cancers.

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"Our early clinical results and selection of RP2D support progressing clinical evaluation of CYC065 in selected, molecularly-defined, patient populations," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "Durable reduction of Mcl-1 expression in the majority of patients at RP2D is an important differentiator, as other CDK inhibitors only do so transiently. Like other CDK inhibitors, we expect CYC065 to work best in combination with existing anticancer drugs. Indications of anticancer activity after a single dose of CYC065 alone in patients with molecular features related to the drug’s mechanism are unexpected and potentially exciting. We plan to apply part of the net proceeds from our July financing to progress CYC065 studies, alone and in combinations, in both liquid and solid cancers with such molecular features. There are currently no drugs available for patients with such features. Our highest priority is to finalize designs for a Phase 1/2 study testing CYC065 in combination with venetoclax, a Bcl-2 inhibitor approved for chronic lymphocytic leukemia, where we believe Mcl-1 suppression will be beneficial, while in parallel enrolling a new part 2 of the Phase 1 study in patients with advanced solid tumors."

Phase 1 first-in-human trial

The objective of part 1 of the Phase 1 dose escalating, monotherapy study was to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD) and identify RP2D. Certain key features of the trial are as follows:

24 heavily treated patients with various advanced solid tumors were enrolled;
The trial advanced through seven DL cohorts with a range of 8 to 288 mg/m2/day, administered as a 4-hour intravenous infusion once every 3 weeks;
Dose limiting toxicity at DL7 was reversible neutropenia, febrile neutropenia and diarrhea;
Ten patients were treated at DL6, of which 9 are evaluable at present;
PK parameters have demonstrated dose proportional increases in CYC065 exposure with increasing dosing levels;
A biologically effective dose was established from analysis of surrogate tissue, supporting a RP2D of 192 mg/m2/day;
Consistent Mcl-1 suppression over 24 hours after a single dose was observed in 7 out of 9 evaluable patients at DL6; and
Anticancer activity was reported by the investigators in patients with Mcl-1 (ovarian cancer: reduction of CA-125 tumor marker levels), MYC (larynx: radiographic tumor shrinkage) and Mcl-1/cyclin E (ovarian: radiographic tumor shrinkage) amplified tumors
Having successfully achieved the objectives of part 1 of the study, part 2 of the study has been initiated aiming to enroll patients with advanced solid tumors, and in particular cyclin E amplified tumors. Such tumors include subsets of high grade serous ovarian and uterine cancers. Part 2 will evaluate CYC065 in a more intensive schedule for 2 days per week for 2 weeks of a three week cycle. Biospecimens will be collected for assessment of biomarkers related to CYC065’s mechanism of action.

About CYC065
Cyclacel’s second generation CDK2/9 inhibitor, CYC065, is being evaluated in an ongoing, first-in-human, Phase 1 trial in patients with advanced solid tumors. In part 1, CYC065 was well tolerated, there were robust and durable effects on the Mcl-1 biomarker and the recommended Phase 2 dose has been selected. Evidence of target engagement was observed by decreases in target cyclin-dependent kinase substrate phosphorylation accompanied by robust and prolonged Mcl-1 suppression in peripheral blood cells in patient samples from the study, consistent with the Company’s preclinical data. CYC065 is mechanistically similar but has much higher dose potency, in vitro and in vivo, and improved metabolic stability than seliciclib, Cyclacel’s first generation CDK inhibitor. As with palbociclib, the first CDK inhibitor approved by FDA in 2015, and ribociclib approved in 2017, CYC065 may be most useful in combination with other anticancer agents, including Bcl-2 antagonists, such as venetoclax, or HER2 inhibitors, such as trastuzumab.

CYC065 is a highly-selective, orally- and intravenously-available, second generation inhibitor of CDK2 and CDK9. It causes apoptotic death of cancer cells at sub-micromolar concentrations. Antitumor efficacy has been achieved in vivo with once a day oral dosing at well tolerated doses in preclinical models. Evidence from published nonclinical studies show that CYC065 may benefit patients with adult and pediatric hematological malignancies, including certain Acute Myeloid Leukemias (AML), Acute Lymphocytic Leukemias (ALL), Chronic Lymphocytic Leukemias (CLL), B-cell lymphomas, multiple myelomas, and certain solid tumors, including breast and uterine cancers and neuroblastomas. Independent investigators published nonclinical evidence that CYC065 induced regression or tumor growth inhibition in a model of HER2-positive breast cancer addicted to cyclin E that is resistant to trastuzumab, reduced tumor growth in models of CCNE1-amplified uterine serous carcinoma and reduced tumor burden and prolonged survival in several neuroblastoma models in vivo.

On August 7, 2017 Kura Oncology, Inc., (Nasdaq:KURA) a clinical stage biopharmaceutical company focused on the development of precision medicines for oncology, reported second quarter 2017 financial results and provided a corporate update. In the company’s ongoing Phase 2 trial of tipifarnib in patients with HRAS mutant squamous cell carcinomas of the head and neck (SCCHN), partial responses have been observed in three of five evaluable patients and two of the responses have demonstrated durability beyond one year (Press release, Kura Oncology, AUG 7, 2017, View Source [SID1234520073]).

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"Although our data is preliminary, three responses out of the first five evaluable patients is very uncommon in the relapsed/refractory setting of SCCHN, and it underscores the potential of using small molecule drug candidates such as tipifarnib to target driver mutations such as HRAS in difficult-to-treat solid tumors," said Troy Wilson, Ph.D., J.D., President and CEO of Kura Oncology. "Furthermore, the durability of response – beyond one year in two patients – has been impressive, particularly when considering these patients received limited clinical benefit from prior therapy before enrolling in the study. Given response rates of 13-16% and median overall survival of up to 7.5 months with the currently approved treatments in the second line, including anti-PD1 antibodies, we are very encouraged both by the response rate and the durability of response we’ve observed thus far with tipifarnib."

"In addition to the clinical progress, we recently established a collaboration with Foundation Medicine to expand patient outreach," continued Dr. Wilson. "We also secured a U.S. patent directed to the use of tipifarnib in patients with HRAS mutant SCCHN that has an expiration date in August 2036. Together, these achievements are key elements of our strategy to advance tipifarnib to a first pivotal registrational trial in 2018, and we look forward to providing additional updates later this year."

Update on Phase 2 Clinical Trial in HRAS Mutant Solid Tumors

An update on the progress of the HRAS mutant SCCHN clinical trial as of July 27, 2017 is as follows:

As previously reported, among the eleven evaluable patients in the first stage, two confirmed partial responses were observed out of three patients with HRAS mutant SCCHN and, as a result, the protocol was amended to enroll an additional seven patients in the second stage.

Among the three head and neck patients enrolled in the first stage of the trial, one patient with a PR remained on study through cycle 20 and then came off study in cycle 21 due to progressive disease. The second patient with a PR is ongoing in cycle 18 of treatment. The third patient experienced tumor shrinkage and prolonged disease stabilization and withdrew from the trial at cycle 8. Each cycle is 28 days.

In the second stage of the trial, three additional HRAS mutant SCCHN patients have been enrolled. Of those three patients, the first patient experienced a confirmed partial response according to the RECIST 1.1 criteria and is in cycle 4. The second patient is in cycle 2 and was reported as having stable disease, and the third patient is not yet evaluable for response assessment.

Patients on the study who had failed cetuximab, alone or with chemotherapy, or immune therapy, have achieved objective partial responses upon treatment with tipifarnib. Notably, none of the five evaluable patients were reported to have experienced a PR on their prior line of therapy, and at least three of the five patients experienced only progressive disease on their prior line of therapy, including one patient receiving pembrolizumab.

Response rates for the three agents approved for treatment of SCCHN in the second line are in the range of 13-16%, and median overall survival is up to 7.5 months.

The Phase 2 study is ongoing, and the company is continuing to recruit patients in both the U.S. and Europe. As the trial was initially designed, one additional, confirmed objective response is required for the trial to be positive per the study protocol. Kura anticipates providing additional data later this year and presenting the results at an upcoming scientific or medical conference.
Recent Operational Highlights

U.S. patent issued for tipifarnib – In July, the U.S. Patent and Trademark Office issued U.S. patent 9,707,221, which is directed to the use of tipifarnib for treating patients with relapsed and/or refractory HRAS mutant SCCHN and has an expiration date of August 2036.

Collaboration with Foundation Medicine – In July, Kura entered into a collaboration agreement with Foundation Medicine to support patient enrollment for Kura’s clinical program for tipifarnib in patients with relapsed and/or refractory HRAS mutant SCCHN. Through this collaboration, Foundation Medicine’s SmartTrials Precision Enrollment program will contact physicians treating individuals across the U.S. diagnosed with SCCHN whose tumors harbor HRAS mutations.

ICML and EHA (Free EHA Whitepaper) presentations of clinical and preclinical data from PTCL program – In June, Kura presented clinical and preclinical data for tipifarnib in the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) at the International Conference on Malignant Lymphoma (ICML) held in Lugano, Switzerland and the Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) held in Madrid, Spain.

Identification of the CXCL12 chemokine as a potential biomarker of tipifarnib activity in PTCL – CXCL12 is secreted in large amounts by lymph nodes, bone marrow stroma, and liver and lung tissue, and plays key roles in tumor invasion, bone marrow homing and site of metastasis. Based on the company’s preliminary data, the identification of the CXCL12 biomarker may have the potential to unlock the therapeutic value of farnesyl transferase inhibition in PTCL and other tumor indications.

Presented HRAS clinical data at ASCO (Free ASCO Whitepaper) – In June, Kura presented a trial-in-progress poster presentation for the Phase 2 trial of tipifarnib in HRAS mutant SCCHN, including supporting rationale from patient-derived xenograft models at the ASCO (Free ASCO Whitepaper) Annual Meeting.
Upcoming Potential Milestones and Expectations for Clinical and Preclinical Programs

Additional data from the Phase 2 trial of tipifarnib in HRAS mutant SCCHN in the second half of 2017.

Additional data from the Phase 2 trial of tipifarnib in PTCL in the second half of 2017.

Data from the Phase 2 tipifarnib trials in myelodysplastic syndromes (MDS) and in chronic myelomonocytic leukemia (CMML) in the first half of 2018.

Data from the KO-947 Phase 1 trial in 2018.
Financial Results for the Second Quarter 2017

Cash, cash equivalents and short-term investments totaled $53.2 million as of June 30, 2017, compared with $59.2 million as of March 31, 2017. Management expects that current cash, cash equivalents and short-term investments will be sufficient to fund current operations into the second half of 2018.

Research and development expenses for the second quarter of 2017 were $5.7 million, compared to $4.9 million for the second quarter of 2016.

General and administrative expenses for the second quarter of 2017 were $2.3 million, compared to $1.9 million for the second quarter of 2016.

Net loss for the second quarter of 2017 was $7.8 million, or $0.40 per share, compared to a net loss of $6.7 million, or $0.36 per share, for the second quarter of 2016.

On August 7, 2017 FibroGen, Inc. (NASDAQ:FGEN), a science-based biopharmaceutical company, reported financial results for the second quarter of 2017 and announced positive topline results of the company’s Phase 2 randomized, double-blind, placebo-controlled study and two combination sub-studies of pamrevlumab in idiopathic pulmonary fibrosis (IPF) (Press release, FibroGen, AUG 7, 2017, View Source [SID1234520068]). Pamrevlumab is a proprietary anti-connective tissue growth factor (CTGF) antibody being evaluated in fibrotic disease and cancer.

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"We are very encouraged by the topline IPF Phase 2 clinical study results that we announced today, in which pamrevlumab-treated patients had a significantly lower rate of decline in lung function, as compared to the placebo-treated patients. In addition, pamrevlumab continued to be well tolerated as a monotherapy in this IPF study, and was well tolerated in combination with pirfenidone and nintedanib," said Thomas B. Neff, FibroGen’s Chief Executive Officer. "We believe that the promising outcomes of these studies enable us to advance pamrevlumab into Phase 3 clinical development."

Recent Developments
Pamrevlumab for Idiopathic Pulmonary Fibrosis (IPF)

Reported positive topline Phase 2 clinical results from a double-blind, placebo-controlled study, and two double-blind, active-controlled combination sub-studies
Pamrevlumab for Pancreatic Cancer

Orphan Drug Designation status was granted by the U.S. Food and Drug Administration (FDA)
Phase 2 clinical results are expected year-end 2017/first quarter 2018
Roxadustat for Anemia in Chronic Kidney Disease (CKD)

On track to submit the new drug application (NDA) to the FDA in 2018
The independent data safety monitoring board, which reviews the U.S. and European Phase 3 programs quarterly, recommended in August 2017 that all trials continue without modification to current protocols
U.S. Roxadustat for Anemia in Myelodysplastic Syndromes (MDS)

Phase 3 clinical trial is anticipated to start in the third quarter of 2017
China Roxadustat for Anemia in CKD

On track to submit the NDA for anemia associated with CKD in dialysis-dependent and non-dialysis patients to the China Food and Drug Administration in the third quarter of 2017
China Roxadustat for Anemia in MDS

Phase 2/3 clinical study is on schedule to initiate in the fourth quarter of 2017
Corporate and Financial Highlights

Net loss per basic and diluted share for the quarter ended June 30, 2017 was $0.48, as compared to a net income per diluted share of $0.35 a year ago
At June 30, 2017, FibroGen had $414.7 million of cash, restricted time deposits, cash equivalents, investments, and receivables
Closed an equity financing in April 2017 that generated $115.1 million in net proceeds

About Pamrevlumab
Pamrevlumab is a proprietary therapeutic antibody developed by FibroGen to inhibit the activity of connective tissue growth factor (CTGF), a common factor in chronic fibrotic and proliferative disorders characterized by persistent and excessive scarring that can lead to organ dysfunction and failure. FibroGen is currently conducting clinical studies of pamrevlumab in idiopathic pulmonary fibrosis (IPF), pancreatic cancer, and Duchenne muscular dystrophy (DMD). In desmoplastic or fibrotic cancers, such as pancreatic cancer, CTGF promotes abnormal proliferation of stromal cells and tumor cells. For information about pamrevlumab studies currently recruiting patients, please visit www.clinicaltrials.gov.

About Roxadustat
Roxadustat is a first-in-class, orally administered small molecule currently in global Phase 3 clinical development as a therapy for anemia associated with chronic kidney disease (CKD). Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. Administration of roxadustat has been shown to induce coordinated erythropoiesis – increasing red blood cell count while maintaining plasma erythropoietin levels within or near normal physiologic range in multiple subpopulations of CKD patients – including in the presence of inflammation and without a need for supplemental intravenous iron.

Roxadustat is currently advancing through Phase 3 clinical trials worldwide, supported by extensive Phase 2 clinical data demonstrating correction and maintenance of hemoglobin levels in multiple subpopulations of CKD anemia patients. To date, roxadustat has been evaluated in Phase 1 and Phase 2 studies involving more than 1,400 subjects. Globally, a total of 15 studies are currently underway involving a total of more than 11,000 patients. Of these, 15 are Phase 3 pivotal studies comprising 10,400 patients, and are currently being conducted to support independent regulatory approvals of roxadustat in both non-dialysis and dialysis CKD patients in the U.S., Europe, Japan, and China. Later this year, roxadustat will also enter a Phase 3 clinical trial in the U.S., and a Phase 2/3 trial in China, for the treatment of anemia in myelodysplastic syndromes (MDS). For information about roxadustat studies currently recruiting patients, please visit www.clinicaltrials.gov.

On August 7, 2017 Celyad (Euronext Brussels and Paris, and NASDAQ:CYAD), a pioneer in the discovery and development of CAR-T cell therapies, and its fully-owned subsidiary OnCyte LLC, reported revised terms to their agreements with Celdara Medical LLC and Dartmouth College (Filing, 6-K, Celyad, AUG 7, 2017, View Source [SID1234520066]).

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Following encouraging initial results of the THINK trial, which have led to increased confidence in the long-term potential of Celyad’s CAR-T assets, Celyad has amended its existing agreements with Celdara Medical, LLC and Dartmouth College. Under the amended agreements Celyad will receive an increased share of future revenues generated by these assets, including revenues from its sublicensees. In return, Celyad will pay Celdara Medical LLC and Dartmouth College an upfront payment of $12.5 million (€10.6 million) and $12.5 million worth of Celyad shares at a share price of €32.35 corresponding to a 14% premium versus last trading day.

Christian Homsy, CEO of Celyad, commented: "With our increased confidence in the clinical opportunity of our lead product candidate CYAD-01 and the significant potential value creation opportunities of our allogeneic IP patents, we have decided to shift some of the value of the original deal upfront, in order to increase our share of potential future revenues from sublicenses. We believe these revised agreements provide incremental value to Celyad’s shareholders while the increased ownership of Celdara Medical in Celyad signals a clear and long-term commitment to our development of promising CAR-T cell therapies."

Celyad obtained access to its CAR-T NKR cell drug product candidates and related technology, including technology licensed from Dartmouth College, in January 2015, through its acquisition of OnCyte, LLC from Celdara Medical, LLC, a privately-held U.S. biotechnology company. This portfolio included three autologous CAR-T cell therapy products and an allogeneic T cell platform. Since the acquisition, Celyad has focused on further developing the portfolio and is currently in pre-clinical or clinical phase for a number of product candidates.

Christian Homsy, CEO of Celyad, further commented: "The upfront payment related to our deal with Novartis covers partially the cash portion of our renewed agreements with Celdara Medical LLC and Dartmouth College. Therefore, our ability to finance all of our operations remain unaltered. With our current cash position, we continue to have the means to fund our operating expenses and capital expenditure requirements through H1 2019."

Through its activities and expertise, Celyad is gaining international recognition for the discovery and development of CAR-T cell therapies and has established partnerships with industrial and academic world-class players such as Novartis (Switzerland), ONO Pharmaceutical (Japan), Moffitt Cancer Center (United States) and Institut Curie (France).

On August 7, 2017 Kite Pharma, Inc., (Nasdaq:KITE), a leading cell therapy company, reported that patients in the European Union (EU) are now being treated with its lead investigational candidate, axicabtagene ciloleucel, in the safety expansion cohort of ZUMA-1 (ClinicalTrials.gov, NCT: 02348216) (Press release, Kite Pharma, AUG 7, 2017, View Source [SID1234520063]). Kite is currently enrolling adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL) at multiple EU medical centers. Kite filed a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for axicabtagene ciloleucel in July 2017, the first CAR-T application in Europe.

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"This important milestone underscores our commitment to providing a potentially curative therapy to patients with serious blood cancers worldwide," said David Chang, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Kite. "Our CAR-T expertise established in the United States will be key as we expand our global footprint this year."

The first patient treated in the safety expansion cohort was at the Academic Medical Center (AMC) in Amsterdam by Professor Dr. Marie José Kersten. Additional patients are expected to be treated in multiple clinical sites across Europe in 2017.

"We are encouraged by the promising results observed in ZUMA-1 in the United States and are excited to be one of the first medical centers to bring this novel treatment modality to the EU," said Professor Dr. Marie José Kersten, Principal Investigator and Head of the Department of Hematology of the AMC in Amsterdam. "As a lymphoma specialist, I am gratified that we can now offer this potentially transformative therapy to patients with refractory, aggressive NHL who previously had no other therapeutic options."

Kite has been granted access to Priority Medicines (PRIME) regulatory support in the EU for treatment of refractory DLBCL. Access to the PRIME initiative is granted by the EMA to support the development and accelerate the review of new therapies to treat patients with a high unmet need.

About axicabtagene ciloleucel

Kite’s lead product candidate, axicabtagene ciloleucel, is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. Axicabtagene ciloleucel is currently under review by the U.S. Food and Drug Administration (FDA) for aggressive non-Hodgkin lymphoma and was granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL).