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Intrexon and Oragenics Expand Collaboration to Pursue Development of Biotherapeutics for the Oral Cavity

On June 10, 2015 Intrexon Corporation (NYSE: XON), a leader in synthetic biology, and Oragenics (NYSE:MKT – OGEN) reported a new Exclusive Channel Collaboration (ECC) to pursue development of biotherapeutics for oral mucositis (OM) and other diseases and conditions of the oral cavity, throat, and esophagus, including clinical advancement of the ActoBiotic AG013 for the treatment of OM (Press release, Intrexon, JUN 10, 2015, View Source [SID:1234514823]). OM results in the painful inflammation and ulceration of the membranes lining the oral cavity, throat, and esophagus and is among the most frequently reported adverse events associated with cancer therapy affecting up to 500,000 patients annually. At present there is no drug approved to prevent the condition broadly and therapies are primarily palliative, alleviating symptoms without addressing the underlying pathology, resulting in a significant unmet medical need.

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"We are eager to advance therapeutic programs through the established clinical foundations of the ActoBiotics platform, and moving forward in the clinic with AG013 is a natural fit for our focus on the treatment of oral cavity diseases with innovative biopharmaceuticals," said Frederick Telling, Ph.D., Chairman of the Board of Oragenics. "Work continues under our current collaboration with Intrexon centered on the development of a novel class of antibiotics known as lantibiotics, and we are excited to build on this relationship in the field of oral health to realize the promise of microbial approaches in the generation of efficacious new medicines."

"I am pleased that this new collaboration provides an opportunity for continued development of AG013 as an intervention for oral mucositis," said Stephen T. Sonis, DMD, DMSc, Senior Surgeon, Divisions of Oral Medicine, Brigham and Women’s Hospital and the Dana-Farber Cancer Institute. "AG013’s successful attenuation of chemotherapy-induced oral mucositis in the Phase 1B trial suggests that this innovative delivery platform may offer a new approach to the treatment of this important unmet clinical need."

Through the molecular engineering of food-grade microbes (Lactococcus lactis), biologically-contained ActoBiotics allow for in situ expression and secretion of novel biotherapeutic proteins and peptides. AG013 is formulated as a convenient oral rinsing solution and designed to deliver the therapeutic molecule Trefoil Factor 1 (TFF1) to the mucosal tissues in the oral cavity. TFFs are a class of peptides that are involved in protection of the gastrointestinal tissues against mucosal damage and have an important role in subsequent repair.

A phase 1B clinical trial with AG013 in 25 cancer patients with OM across 5 cancer referral centers showed that AG013 was safe and well tolerated. Data published in the journal Cancer showed a 35% reduction of the duration of ulcerative OM in the AG013-treated patients versus the placebo-treated patients. Furthermore, close to 30% of the patients treated with AG013 were full responders while all placebo-treated patients developed ulcerative OM. Additionally, a phase 1 pharmacokinetic (PK) study in 10 healthy volunteers showed that live AG013 bacteria adhere to the buccal mucosa and actively secrete protein locally, resulting in homogeneous exposure to the entire mucosal surface up to 24 hours after administration of a rinse. AG013 has already been granted Orphan Drug status in the European Union and has potential eligibility for Biologic License Application exclusivity as well as Fast Track designation with the United States Food and Drug Administration.

Under the terms of the agreement, Oragenics will have access to Intrexon’s technologies and expertise to develop products for the treatment of oral mucositis or products containing genetically modified Lactococcus lactis expressing trefoil factors in the oral cavity, throat, and esophagus for a technology access fee and will reimburse Intrexon for the research and development costs. The agreement also provides for commercial and regulatory milestone payments to Intrexon, as well as a low double-digit percentage royalty based on the net sales from collaboration products.

"AG013 represents a promising product from a truly innovative platform for the prevention of oral mucositis in cancer patients," commented Gregory Frost, Ph.D., Senior Vice President and Head of Intrexon’s Health Sector. "We are very pleased with the expanded collaboration with Oragenics, especially given their unique experience in the field of oral health using novel approaches. This ECC will further the clinical development of AG013 in the hope of providing cancer patients with a much needed adjunctive therapy for oral mucositis, a challenging side effect that can become a treatment-limiting toxicity for effective cancer therapy."

CTI BioPharma And Baxter Announce Patient-Reported Outcomes (PROs) From Pacritinib Phase 3 In Patients With Myelofibrosis To Be Presented In Late-Breaking Session At EHA

On June 10, 2015 CTI BioPharma and Baxter International reported that Patient Reported Outcomes (PROs) data from the Phase 3 PERSIST-1 trial, evaluating pacritinib in patients with myelofibrosis, will be highlighted in a late-breaking oral presentation at the upcoming 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper), June 11-14, Vienna (Press release, CTI BioPharma, JUN 10, 2015, View Source;p=RssLanding&cat=news&id=2057957 [SID:1234505406]). Pacritinib is an investigational oral multikinase inhibitor with specificity for JAK2 and FLT3. These data were also selected for inclusion in the official EHA (Free EHA Whitepaper) Press Briefing on Friday, June 12, 2015 at 08:30 CEST.

Myelofibrosis is associated with significantly reduced quality of life and shortened survival. As the disease progresses, the body slows production of important blood cells and within one year of diagnosis the incidence of disease-related thrombocytopenia (very low blood platelet counts), severe anemia, and red blood cell transfusion requirements increase significantly. Among other complications, most patients with myelofibrosis present with enlarged spleens (splenomegaly) as well as many other potentially devastating physical symptoms such as: abdominal discomfort, bone pain, feeling full after eating little, severe itching, night sweats, and tiredness.

Full details for the abstracts involving pacritinib in this year’s EHA (Free EHA Whitepaper) program are below:

Title: Patient-Reported Outcomes (PROS) in PERSIST-1: A Randomized, Multi-Country Phase III Trial of the JAK2 Inhibitor Pacritinib (PAC) VS. Best Available Therapy (BAT) in Myelofibrosis (MF)
First Author: Ruben Mesa, M.D., Deputy Director, Mayo Clinic Cancer Center, Chair of the Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ and one of the principal investigators for PERSIST-1
Date/Time: Sunday, June 14 at 12:15 CEST
Location: Room A7
Presentation Type: Oral Presentation
Abstract #: LB2072
This abstract is under a press embargo until Friday, June 12 at 09:30 CEST.

Title: PERSIST-1: A Phase III Study of Pacritinib (PAC) vs Best Available Therapy (BAT) in Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (PPV-MF) or Post-Essential Thrombocythemia MF (PET-MF)
First Author: Claire Harrison, M.D., Consultant Hematologist, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, United Kingdom and one of the principal investigators for PERSIST-1
Date/Time: Friday, June 12 at 17:15 to 18:45 CEST
Location: Poster area (Hall C)
Presentation Type: Poster
Abstract #: LB314
The full abstract can be viewed here.

About Pacritinib

Pacritinib is an oral multikinase inhibitor with specificity for JAK2 and FLT3. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia, and lymphoma. The kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and chronic lymphocytic leukemia (CLL) due to its potent inhibition of c-fms, IRAK1, JAK2, and FLT3.1

Cellectis Announces Promising Study on Next Generation Engineered Allogeneic CAR T-cells

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]).

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

Agios Pharmaceuticals Announces FDA Orphan Drug Designation Granted to AG-120 for Treatment of IDH1-Mutant Positive Acute Myelogenous Leukemia

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.

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.

FDA Agrees with OncoGenex’ Phase 3 AFFINITY Protocol Amendment

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).

"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.