On June 10, 2015 OncoGenex Pharmaceuticals reported that the U.S. Food and Drug Administration (FDA) has agreed to the Company’s proposed amendment to the Phase 3 AFFINITY protocol and statistical analysis plan (Press release, OncoGenex Pharmaceuticals, JUN 10, 2015, View Source [SID:1234505390]). The amendment includes the addition of a co-primary endpoint designed to prospectively evaluate the survival benefit of custirsen in men who are at increased risk for poor outcomes when treated with cabazitaxel for metastatic castrate-resistant prostate cancer (CRPC).

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"There are limited effective treatment options for men with metastatic CRPC who have risk factors for poor outcomes and who fall into a poor prognosis category. Recent findings from the SYNERGY trial showed a significant survival benefit in this group of patients," said Cindy Jacobs, PhD, MD, Chief Medical Officer and Executive Vice President of OncoGenex. "We have applied this key insight from the SYNERGY trial to the AFFINITY protocol to better evaluate this vulnerable subpopulation of men who have poor prognosis and shorter survival time."

The FDA is in agreement with plans for prospectively defining a poor prognostic subpopulation in the Phase 3 AFFINITY trial. OncoGenex, in collaboration with study investigators, has defined a simple 5-criteria characterization for poor prognosis in prostate cancer based on the Phase 3 SYNERGY trial, which includes: poor performance status, elevated prostate specific antigen (PSA), elevated lactate dehyrdogenase (LDH), decreased hemoglobin, and the presence of liver metastasis. Patients with poor prognosis will be identified as having 2 or more of these 5 well-recognized high-risk criteria. The proposed change for AFFINITY is also consistent with custirsen’s mechanism of action, since custirsen was designed to address treatment resistance which may be more prevalent in this subpopulation.

In the revised statistical analysis plan for the AFFINITY trial, the hypothesized hazard ratio (HR) for the poor prognosis subpopulation is specified to be 0.69 with the critical HR ≤ 0.778. The hypothesized HR for the intent-to-treat patients (ITT population) remains unchanged as 0.75 with the critical HR ≤ 0.820.

Timing for the final analysis of the poor prognosis subpopulation is projected to occur by the end of 2015, while the final analysis for the ITT population is projected to occur in the second half of 2016. FDA and OncoGenex have further agreed that an interim analysis will occur for the ITT population when the final analysis for the poor prognosis subpopulation occurs. This interim analysis will have both futility and early efficacy criteria defined for the ITT population. If the earlier final analysis on the poor prognostic subpopulation shows a survival benefit for custirsen, OncoGenex could initiate a regulatory submission. The entire trial could also be stopped early due to efficacy based on the interim assessment for the ITT population by the Independent Data Monitoring Committee (IDMC).

"Findings from the SYNERGY trial recently presented at ASCO (Free ASCO Whitepaper) have provided important insight into the patient population in whom custirsen treatment is most relevant," said Scott Cormack, President and CEO of OncoGenex. "We are pleased that the FDA has agreed with our amendment and look forward to announcing top-line results at the end of this year and in 2016."

OncoGenex has also initiated a review with the European Medicines Agency (EMA) for the proposed amendment to the Phase 3 AFFINITY protocol and statistical analysis plan, and expects to have this completed in the second half of 2015.

A retrospective analysis of data from the Phase 3 SYNERGY trial recently presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) showed a benefit with custirsen therapy when added to first-line docetaxel chemotherapy in men with metastatic CRPC who had a poor prognosis. The analysis showed that over 40 percent of men in the trial had at least 2 of the 5 common risk factors for poor prognosis as stated above. In these men, the analysis found a 27 percent lower risk of death when custirsen was used in combination with first-line docetaxel compared to docetaxel alone.

AFFINITY is being conducted at 95 global clinical trial sites and earlier this year, the IDMC recommended the trial continue following the completion of an interim futility analysis. The trial is fully accrued, and the protocol amendment does not affect the conduct of the study.

On June 10, 2015 Agios Pharmaceuticals reported that the U.S. Food and Drug Administration (FDA) has granted the company orphan drug designation for AG-120 for treatment of patients with acute myelogenous leukemia (AML) (Press release, Agios Pharmaceuticals, JUN 10, 2015, View Source;p=RssLanding&cat=news&id=2058334 [SID:1234505391]). AG-120 is an oral, first-in-class IDH1 mutant inhibitor being evaluated in a Phase 1 clinical trial in patients with advanced hematologic malignancies that carry an IDH1 mutation.

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The FDA’s Office of Orphan Drug Products grants orphan status to support development of medicines for underserved patient populations, or rare disorders, that affect fewer than 200,000 people in the U.S. Orphan drug designation provides to Agios certain benefits, including market exclusivity upon regulatory approval if received, exemption of FDA application fees and tax credits for qualified clinical trials.

"Receiving orphan drug designation for AG-120 is an important milestone as we continue to move this program to late-stage development," said Chris Bowden, M.D. chief medical officer of Agios. "We are pleased with the progress we are making in the clinic and look forward to presenting new data from our ongoing Phase 1 study of AG-120 at the Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) later this week. We believe that AG-120, which is on track to initiate multiple expansion cohorts in the next month, has the potential to play a significant role in shifting the treatment paradigm for IDH1-mutant positive hematologic cancers from the conventional chemotherapy approach."

AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia in adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society the median age is 66. Less than 10 percent of U.S. patients are eligible for bone marrow transplant, and the vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH1 mutations are present in about 6 to 10 percent of AML cases.

On June 10, 2015 Cellectis reported the publication of a study in Molecular Therapy, a Nature Publishing Group Journal, describing the development of the next generation of engineered CAR T-cells compatible with allogeneic adoptive transfer immunotherapy (Press release, Cellectis, JUN 10, 2015, View Source [SID:1234505394]).

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Study Highlights

• The adoptive transfer of allogeneic CAR T-cells represents a promising strategy to fight multiple cancers worldwide.

• Cellectis has streamlined an engineering process to generate CAR T-cells that could be compatible with allogeneic adoptive transfer in combination with nucleoside analogues lymphodepleting drugs.

When allogeneic CAR T-cell infusion is considered, host versus graft and graft versus host reactions must be avoided to prevent rejection of adoptively transferred cells, host tissue damages and to elicit significant antitumoral outcome. In this report, Julien Valton Ph.D. and his collaborators addressed these requirements by developing a multidrug resistant TCRαβ-deficient CAR T-cell. This engineered T-cell displayed efficient antitumor activity and significant resistance to purine and pyrimidine nucleoside analogues, which are currently used clinically in preconditioning lymphodepleting regimens. Their properties could prevent their alloreactivity and enable control over engraftment in patients. In addition, they are compatible in combination therapy, an approach likely to improve clinical outcomes. By providing a basic framework to develop a universal T-cell compatible with allogeneic adoptive transfer, Cellectis is laying the foundation for the large-scale utilization of CAR T-cell immunotherapies.

Julien Valton, Ph.D. Innovation Senior Scientist

Dr. Julien Valton obtained his Ph.D. degree at Université Joseph Fourier in Grenoble (France) where he was trained as enzymologist. He then joined the Yale School of Medicine to apply his knowledge to therapeutic research, by investigating the mechanism of inhibition of receptor tyrosine kinases involved in the development of gastrointestinal cancer. In 2009, he moved a step further into the field of applied science by joining the R&D Department of Cellectis, where he actively participated to set, improve and use meganucleases and TALEN for targeted gene therapy and genome engineering purposes. He is now part of the NYC based Cellectis, Inc.

A Multidrug Resistant Engineered CAR T-Cell for Allogeneic Combination Immunotherapy

Julien Valton, Valérie Guyot, Alan Marechal, Jean Marie Filhol, Alexandre Juillerat, Aymeric Duclert, Philippe Duchateau and Laurent Poiro

On June 9, 2015 Varian Medical Systems reported RapidArc Radiosurgery, a term for volumetric modulated arc radiosurgery delivered using a medical linear accelerator (linac) from Varian Medical Systems (NYSE: VAR), enables the precise and simultaneous treatment of multiple metastases in the brain, spine, head & neck, or lung, according to four notable clinical experts who spoke yesterday at a Varian-sponsored symposium at the 12th International Stereotactic Radiosurgery Society (ISRS) Congress taking place here this week (Press release, InfiMed, JUN 9, 2015, View Source [SID:1234505381]).

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Clark C. Chen, MD, PhD, co-director of neurological oncology and chief of stereotactic radiosurgery at the University of California, San Diego, offered a neurosurgeon’s perspective on the clinical use of surface imaging to guide RapidArc Radiosurgery for the treatment of brain metastases. He favors this more targeted approach over whole-brain radiotherapy for patients with a limited number of brain metastases to avoid the neurocognitive decline that is associated with the latter.

"The Varian TrueBeam is a powerful linear accelerator that allows precise and efficient delivery of high dose radiation to multiple brain metastases in a remarkably efficient manner," Chen said. His team also uses an optical surface image tracking device during treatment to help ensure accurate radiation delivery. "The combination of surface image tracking and RapidArc Radiosurgery allows us to treat patients with a level of efficiency that we could not achieve previously," he said.

Evan Thomas, MD, PhD, postdoctoral research fellow in the Department of Radiation Oncology at the University of Alabama at Birmingham (UAB), talked about the UAB approach to RapidArc Radiosurgery planning, which makes use of key features of Varian’s Edge and TrueBeam STx platforms for image-guided stereotactic radiosurgery (SRS), including Varian’s HD120 high-definition multileaf collimator for fine beam shaping and the High Intensity Mode for delivering high doses quickly.1 "Multiple refinements and iterations in the UAB technique have enabled us to reliably duplicate Gamma Knife plan quality on TrueBeam STx," Thomas said.2

At the Henry Ford Health System (HFHS) in Detroit, SRS treatments are delivered using Varian’s Edge radiosurgery system. Ian Lee, MD, neurosurgeon with the Hermelin Brain Tumor Center at HFHS, raised the question of how to determine whether surgery, radiosurgery, or both are indicated in cases of metastatic brain cancer. The HFHS uses a multidisciplinary tumor board to make those determinations as a team. He presented a broad range of metastatic brain cancer cases that were treated with stereotactic radiosurgery. "SRS is usually the treatment of choice for oligometastatic disease," he said, referring to patients with multiple brain metastases.

Farzan Siddiqui MD, PhD, director of head and neck radiation oncology at HFHS, described soon-to-be-published data on the precision and accuracy of the Edge system for radiosurgery, showing his institution’s findings of sub-millimeter accuracy for each of the system’s component parts.3 In addition to several metastatic brain tumor cases, Siddiqui presented about cases where the Edge system was used to deliver RapidArc stereotactic body radiotherapy (SBRT) –a medical term for radiosurgery of non-cranial targets—to simultaneously treat multiple metastatic lesions in the spine, lung or head & neck. "The Edge radiosurgery system has been shown to possess high accuracy localization and meets requirements for precisely treating patients with tumors in the various sites using SRS/SBRT-based techniques," he reported.

On JUNE 9, 2015 Cellectis reported in order to comply with NASDAQ financial practices, is publishing for the first time its 1st quarter results (Filing, 6-K, Cellectis, JUN 9, 2015, View Source [SID:1234505385]).

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Cellectis previously published consolidated financial statements for the first six months of 2014 and for the full year 2014. The Company did not publish financial statements for first half-year and full year 2014. Cellectis did not have consolidated financial statements for the 1st and 3rd quarters 2014. Therefore, no comparative 2014 figures will be presented for 1st and 3rd quarters in 2015. Cellectis will publish full quarterly comparative figures starting 2016.

Consolidated financial statements have been prepared in accordance with International Financial Reporting Standards, or IFRS, as issued by the International Accounting Standards Board ("GAAP").

First Quarter 2015 Financial Results

Revenues and Other Income: Total revenues and other income were of €9.2 million for the first quarter 2015 (€26.5 million for FY2014) and mainly comprised €7.9 million of collaboration revenues (€11.9 million for FY2014) and €0.4 million of license revenues (€7.3 million for FY2014).

Total Operating Expenses and Other Operating Income: Total operating expenses and other operating income for the first quarter of 2015 were of €12.8 million (€31.7 million for FY2014).
R&D Expenses: Research and development expenses for the first quarter of 2015 were of €5.6 million (€14.4 million for FY2014). These expenses mainly consisted of personnel expenses (€3.5 million), external purchases and other expenses (€2.1 million).

Research and development expenses for the first quarter also reflect the impact of social charges related to stock-options and free shares granted during the first quarter (€1.9 million).

SG&A Expenses: Selling, general and administrative expenses were of €7.2 million for the first quarter 2015 (€13.1 million for FY2014). These expenses mainly related to personnel expenses (€4.9 million), and to external purchases and other expenses (€2.3 million). Selling, general and administrative expenses for the first quarter also reflect the impact of social charges related to stock-options and free shares granted during the first quarter (€3.3 million). For the first three months 2015, the non–recurring IPO expenses amounted to €0.5 million.

Financial Gain: Financial gain was of €9.9 million for the first quarter 2015 (€7.1 million for FY2014), which is mainly attributable to a favorable Euro-Dollar exchange rate applied to U.S. dollar-denominated cash and cash equivalents during the first quarter of 2015.

Net Income (Loss): Net income was of €6.3 million, or €0.23 per share, for the first quarter of 2015 (net loss of €1.0 million, or €0.00 per share, for FY2014). Adjusted net income for the first quarter of 2015 was €7.1 million, or €0.23 per share. Adjusted net income for the first quarter of 2015 excludes a non-cash stock-based compensation expense of €0.8 million. Please see "Note Regarding Use of Non-GAAP Financial Measures" for a reconciliation of GAAP net income to adjusted net income.

Cash Position: Cash and cash equivalents include cash, bank accounts, money market funds and fixed bank deposits that meet the definition of a cash equivalent. As of March 31, 2015, Cellectis had €118.4 million in cash and cash equivalents compared to €112.3 million as of December 31, 2014. Our initial public offering closed on March 30, 2015 and as of March 31, 2015, the €196.8 million of net proceeds from the initial public offering are classified under Other Current Assets. We believe that our cash and cash equivalents, together with the net proceeds from our initial public offering and our cash flow from operations (including payments we expect to receive pursuant to our collaboration agreements) and government funding of research programs will be sufficient to fund our operations through at least 2017. However, we may require additional capital for the further development of our existing product candidates and may also need to raise additional funds sooner to pursue other development activities related to additional product candidates.