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Pieris Pharmaceuticals Presents Positive Data for Its Lead Bispecific Drug Candidate, PRS-343, at the 2016 CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference

On September 26, 2016 Pieris Pharmaceuticals, Inc. (NASDAQ: PIRS), a biotechnology company advancing novel biotherapeutics through its proprietary Anticalin technology platform, reported that it has today presented new preclinical data demonstrating in vivo efficacy of its lead 4-1BB (CD137)-based bispecific cancer immunotherapeutic drug candidate, PRS-343, at the 2016 CRI-CIMT-AACR International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper) – Translating Science into Survival, taking place in New York City (Press release, Pieris, SEP 26, 2016, View Source [SID:SID1234515414]).

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The in vivo data show that treatment of HER2-positive tumor-bearing animals with PRS-343 provided dose-dependent, dual anti-tumor activity by increasing the frequency of tumor-infiltrating lymphocytes via bispecific targeting of 4-1BB and HER2, as well as mediating tumor growth inhibition by direct antagonism of HER2 on tumor cells. In contrast, an agonistic anti-4-1BB benchmark monoclonal antibody (mAb) displayed neither tumor growth inhibition nor enhanced lymphocyte infiltration into tumors compared to an isotype control mAb, but preferentially activated T cells systemically, resulting in significant toxicity. A copy of the poster can be viewed and downloaded by clicking View Source

Louis Matis, M.D., Pieris SVP and Chief Development Officer, commented, "These new data support a differentiated mode of action for PRS-343 and demonstrate the potential benefits of tumor microenvironment-localized costimulatory T cell activation for both reduced systemic toxicity and higher efficacy in comparison to conventional agonistic anti-4-1BB mAbs. We look forward to the initiation of our phase 1 clinical trial of PRS-343 for the treatment of cancer patients planned for the first half of 2017."

About PRS-343
PRS-343 is a bispecific monoclonal antibody/Anticalin fusion protein comprised of a HER2 tumor-targeting mAb genetically linked to a potent anticalin specific for the immune costimulatory TNF family receptor 4-1BB (CD137). PRS-343 is being developed as the first 4-1BB based therapeutic to mediate the activation of tumor-specific T lymphocytes selectively within the tumor microenvironment (TME). 4-1BB is a potent costimulatory immunoreceptor and an established marker for tumor-specific infiltrating T lymphocytes (TILs), and is therefore, an attractive target for cancer immunotherapy. In in vivo preclinical tumor models, PRS-343 has demonstrated potent T lymphocyte activation localized to the TME of established HER2-positive tumors, indicating the potential for both enhanced safety and efficacy.

Kite Pharma Announces Positive Topline KTE-C19 Data from ZUMA-1 Pivotal Trial in Patients with Aggressive Non-Hodgkin Lymphoma (NHL)

On September 26, 2016 Kite Pharma, Inc., (Nasdaq:KITE) reported positive topline results from a pre-planned interim analysis of ZUMA-1 for its lead product candidate, KTE-C19, in patients with chemorefractory diffuse large B-cell lymphoma (DLBCL) (Press release, Kite Pharma, SEP 26, 2016, View Source [SID:SID1234515409]). KTE-C19 met the primary endpoint of objective response rate (ORR), p < 0.0001, with ORR of 76 percent, including 47 percent complete remissions (CR).

ZUMA-1 enrolled patients with chemorefractory aggressive NHL into two cohorts. Cohort 1 included patients with DLBCL, and Cohort 2 enrolled patients with transformed follicular lymphoma (TFL) and primary mediastinal B-cell lymphoma (PMBCL). Kite’s intent is to seek regulatory approval of KTE-C19 in DLBCL, TFL and PMBCL based upon the combined data of both cohorts.

The interim analysis of ZUMA-1 evaluated the ORR in the first 51 patients in Cohort 1 with at least three months of follow-up. This analysis also included an additional 11 patients in Cohort 2. The table below summarizes the response rates from this interim analysis together with the previously reported results from the Phase 1 portion of ZUMA-1 (Neelapu ASCO (Free ASCO Whitepaper) 2016).

ZUMA-1 Phase 1 ZUMA-1 Phase 2
DLBCL (n=7)
DLBCL (n=51) TFL/PMBCL (n=11) Combined (n=62)

ORR
(%)
CR
(%)

ORR
(%)
CR
(%)
ORR
(%)
CR
(%)

ORR
(%)
CR
(%)
ORR 71 57 76 47 91 73 79 52
Month 3 43 43 39 33 64 64 44 39
Months 6 and 9 43 43 Data Pending

Across the combined 62 patients, the most common grade 3 or higher adverse events included neutropenia (66 percent), anemia (40 percent), febrile neutropenia (29 percent), thrombocytopenia (29 percent), and encephalopathy (26 percent). Grade 3 or higher cytokine release syndrome (CRS) and neurological toxicity was observed in 18 percent and 34 percent of patients, respectively. Two patients died from KTE-C19 related adverse events (hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of CRS).

The Phase 2 interim outcomes in ZUMA-1 are largely consistent with results from the Phase 1 portion of the study and the National Cancer Institute (NCI) study based on the same CAR construct, a low-dose cyclophosphamide-fludaribine conditioning regimen, and Kite’s proprietary manufacturing process (Kochenderfer ASCO (Free ASCO Whitepaper) 2016).

"ZUMA-1 enrolled patients with chemorefractory aggressive NHL, a disease that is very difficult to treat. The combined CR rate of 39 percent at three months is very exciting as it represents nearly a five-fold increase from the CR rate of 8 percent seen in the SCHOLAR-1 study in a similar patient population," said Jeff Wiezorek, M.D., Senior Vice President of Clinical Development. "ZUMA-1 is the largest CAR-T study reported in NHL. We were able to manufacture KTE-C19 for 99 percent of patients enrolled in the study, and successfully handle the study logistics and adverse event management at over 20 sites, most of which had no prior experience in CAR-T therapy."

Additional data from this interim analysis will be submitted for presentation at an upcoming scientific meeting. The primary analysis of 101 patients with chemorefractory aggressive NHL (DLBCL, TFL and PMBCL) will include approximately six months of follow-up and is expected in the first quarter of 2017.

"We are grateful to the study participants and investigators who have made this important research possible. What started at the NCI over a decade ago with the pioneering work of Steven A. Rosenberg, M.D., Ph.D., has evolved into a technology that has the potential to fundamentally change the outlook of patients with cancer. For patients with aggressive NHL, every day matters and a new treatment option like KTE-C19 is desperately needed," said Arie Belldegrun, M.D., FACS, Chairman, President and Chief Executive Officer of Kite. "I am proud of what we have achieved to date and excited to apply our advanced learnings from ZUMA-1 to our ongoing clinical development programs to bring continued innovation to patients and the scientific community at large."

ZUMA-1 is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program.

About KTE-C19

Kite Pharma’s lead product candidate, KTE-C19, 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. KTE-C19 has been granted Breakthrough Therapy Designation status for DLBCL, TFL, and PMBCL by the U.S. Food and Drug Administration and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

Mateon Announces Collaboration with US Oncology Research to Participate in Phase 2/3 FOCUS Study

On September 26, 2016 Mateon Therapeutics, Inc. (Nasdaq:MATN), a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, reported a collaboration under which sites affiliated with US Oncology Research will participate in the FOCUS Study, Mateon’s recently initiated phase 2/3 clinical trial in platinum-resistant ovarian cancer (Press release, Mateon Therapeutics, SEP 26, 2016, View Source [SID:SID1234515403]).

"We are pleased to work with US Oncology Research, an outstanding organization that has had tremendous success in oncology-related clinical trials," stated William D. Schwieterman, M.D., President and Chief Executive Officer of Mateon. "US Oncology Research is selective regarding the studies in which it participates. So we are pleased they recognize the importance of developing CA4P for women with platinum-resistant ovarian cancer."

US Oncology Research is a premier organization in the United States dedicated to bringing physicians, clinics and patients together for innovative cancer research in the community setting. One of the largest community-based oncology research programs in the U.S., US Oncology Research has nearly 150 affiliated locations as well as more than 900 affiliated investigators. The organization has played a role in the development of more than 60 FDA-approved cancer therapies, which represents about one-third of all cancer therapies approved by the FDA to date, and manages about 300 active clinical trials at any given time.

"Inhibition of tumor-related angiogenesis provides an important therapeutic option for women with recurrent ovarian cancer," stated Michael A. Bookman, M.D., Director, Gynecologic Oncology Research, US Oncology Research. "Strategies to combine Mateon’s CA4P, a novel vascular disrupting agent, with other agents, including bevacizumab, appear promising, and we are excited to offer our patients the opportunity to participate in this high-priority randomized trial."

About FOCUS
The FOCUS Study is a randomized, double-blind, 2-arm, parallel-group, phase 2/3 study to evaluate the efficacy and safety of physician’s choice chemotherapy (PCC) plus bevacizumab and CA4P versus PCC plus bevacizumab in patients with platinum-resistant ovarian cancer. The primary endpoint of the FOCUS Study is progression free survival (PFS). The Study will also evaluate CA4P’s effect on objective response rate (ORR), overall survival (OS) and other parameters. For additional information on the FOCUS Study, please visit www.clinicaltrials.gov, study identifier NCT02641639.

Array BioPharma and Pierre Fabre Announce COLUMBUS Phase 3 Study of Encorafenib plus Binimetinib For BRAF-Mutant Melanoma Met Primary Endpoint

On September 26, 2016 Array BioPharma (Nasdaq: ARRY) and Pierre Fabre jointly reported top-line results from Part 1 of the Phase 3 COLUMBUS (Combined LGX818 Used with MEK162 in BRAF Mutant Unresectable Skin Cancer) study evaluating LGX818 (encorafenib), a BRAF inhibitor, and MEK162 (binimetinib), a MEK inhibitor, in patients with BRAF-mutant advanced, unresectable or metastatic melanoma (Filing, 8-K, Array BioPharma, SEP 26, 2016, View Source [SID:SID1234515368]). The study met its primary endpoint, significantly improving progression free survival (PFS) compared with vemurafenib, a BRAF inhibitor, alone.

Array BioPharma.
"The COLUMBUS Part 1 trial results demonstrate a robust PFS benefit associated with the combination of binimetinib plus encorafenib versus vemurafenib in patients with BRAF-mutant melanoma," said Ron Squarer, Chief Executive Officer, Array BioPharma. "We look forward to working with global regulatory authorities as they evaluate our planned submission."

In the analysis of the primary endpoint, the median PFS for patients treated with the combination of encorafenib plus binimetinib ("combination") was 14.9 months versus 7.3 months for patients treated with vemurafenib; HR (0.54), [95% CI 0.41-0.71], p<0.001. The combination was generally well-tolerated and reported adverse events were overall consistent with previous combination encorafenib plus binimetinib clinical trial results in BRAF-mutant melanoma patients.

"The preliminary results from Part 1 of COLUMBUS suggest that the combination of encorafenib plus binimetinib represents a potentially unique therapy for the BRAF-mutant melanoma population," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital and Professor of Medicine, Harvard Medical School. "In addition to the robust activity observed in Part 1, the combination appeared to be generally well-tolerated."

Analysis of a secondary endpoint comparing the PFS of patients treated with combination to patients treated with encorafenib showed a median of 14.9 months versus 9.6 months with HR (0.75), [95% CI 0.56-1.00], p=0.051, which did not reach statistical significance. A complete analysis of these results will be provided to global regulatory authorities as part of planned submissions. In addition, data from Part 2 of the COLUMBUS trial are anticipated in mid 2017 and will also be provided to global health authorities as part of planned regulatory submissions for approval of these product candidates.

Further results from Part 1 of the COLUMBUS trial, including objective response rates, disease control rates, safety endpoints, exploratory analyses such as a Part 1 PFS comparison of encorafenib to vemurafenib and pre-specified subgroup analyses including outcomes in patients who received prior treatment with immunotherapy will be presented at an upcoming medical meeting. Analysis of the secondary endpoint of overall survival (OS) was not planned as part of these initial results.

Frédéric Duchesne, Chief Executive Officer Pharmaceutical Division, Pierre Fabre remarked, "We are very pleased with the COLUMBUS Part 1 results and look forward to the possibility that, if approved, the combination of encorafenib plus binimetinib could offer a new treatment option for patients suffering from this devastating disease."

About the Phase 3 COLUMBUS Study
The COLUMBUS trial, (NCT01909453), is a two-part, international, randomized, open label Phase 3 study evaluating the efficacy and safety of the combination of encorafenib plus binimetinib to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAF V600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the study. Patients were randomized into two parts:

In Part 1, 577 patients were randomized 1:1:1 to receive the combination of 450mg encorafenib plus 45mg binimetinib, 300mg encorafenib alone, or 960mg vemurafenib alone. The primary endpoint for the COLUMBUS trial was a PFS comparison of the combination versus vemurafenib. PFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Review Committee. Secondary endpoints include a comparison of the PFS of encorafenib monotherapy to that of the combination and a comparison of OS for the combination to that of vemurafenib alone.
In Part 2, 344 patients were randomized 3:1 to receive 300mg encorafenib plus 45mg binimetinib or 300mg encorafenib alone. Part 2 is designed to provide additional data to help evaluate the contribution of binimetinib to the combination. While formal statistical analysis of Part 2 is only planned if both the comparison of PFS between combination versus vemurafenib and the combination versus encorafenib achieve statistical significance in Part 1, data from Part 2 are anticipated in mid 2017 and will be provided to global health authorities as part of planned regulatory submissions in 2017.
Binimetinib and encorafenib are investigational medicines and are not currently approved in any country.

About BRAF-Mutant Melanoma
Melanoma is the fifth most common cancer among men and the seventh most common cancer among women in the United States, with more than 76,000 new cases and over 10,000 deaths from the disease expected in 2016. Novel therapies that target the RAS/RAF/MEK/ERK pathway have a strong scientific rationale for activity in this disease, as up to 50 percent of patients with metastatic melanoma have activating BRAF mutations, the most common gene mutation in this patient population. Current marketed MEK/BRAF combination agents have a run rate forecasted to approach $1 billion in annual worldwide sales.

About Binimetinib & Encorafenib
MEK and BRAF are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as melanoma, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor and encorafenib is a late-stage small molecule BRAF inhibitor, both of which target key enzymes in this pathway.

Binimetinib and encorafenib are being studied in clinical trials in advanced cancer patients, including the recently initiated Phase 3 BEACON CRC trial that will study encorafenib in combination with cetuximab with or without binimetinib in patients with BRAF V600E-mutant colorectal cancer. Array submitted a New Drug Application (NDA) for binimetinib in NRAS-mutant melanoma to the FDA at the end of June 2016. The FDA accepted the NDA with a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2017.

Array BioPharma retains exclusive rights to binimetinib and encorafenib in key markets including the U.S. and Japan.

Onconova Announces Successful End-of-Phase 2 Meeting with FDA for Oral Rigosertib and Azacitidine Combination

On September 26, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported receipt of the End-of-Phase 2 meeting minutes from the U.S. Food and Drug Administration (FDA) for the combination of oral rigosertib with azacitidine for the treatment of patients with higher-risk myelodysplastic syndromes (HR-MDS) (Press release, Onconova, SEP 26, 2016, View Source [SID:SID1234515367]).

Based on these discussions, Onconova will design a randomized, controlled Phase 3 clinical trial comparing the combination of oral rigosertib plus azacitidine to azacitidine plus placebo in 1st-line HR-MDS patients. The primary endpoint of this pivotal trial will be overall response rate (ORR); ORR will be a composite of complete remission (CR) and partial remission (PR). Onconova could potentially pursue additional available paths from FDA for accelerated or enhanced review and further input on the development of a final trial protocol. Full details of the protocol will be available following completion of all regulatory discussions.

As part of the End-of-Phase 2 meeting with FDA, Onconova presented updated results from its Phase 2 trial of oral rigosertib and azacitidine. These results are expected to be presented by study investigators at a scientific conference later this year.

"We are encouraged that our interactions with FDA resulted in agreement on the patient population to be evaluated and the selection of overall response as the primary endpoint in this pivotal trial," stated Steven Fruchtman, M.D., Chief Medical Officer of Onconova. "We will provide additional details on the design of this trial and the full Phase 2 data set supporting our pivotal study plans at upcoming meetings and scientific conferences later in 2016."

Onconova is developing rigosertib for patients with MDS where there is a paucity of therapeutic options. Two hypomethylating agents (HMAs), azacitidine and decitabine, the mainstays for eligible 1st-line patients, were approved by the FDA more than a decade ago. In addition to the oral rigosertib and azacitidine combination program, Onconova is currently enrolling patients in the global, pivotal Phase 3 INSPIRE trial of IV rigosertib for 2nd-line MDS patients, who have failed HMA therapy. This trial of 225 patients is now enrolling in the U.S., Europe, Japan and Australia.

About Oral Rigosertib

The oral form of rigosertib provides a more convenient dosing for use where the duration of treatment may extend to multiple years. To date, more than 350 patients have been treated with the oral formulation of rigosertib, either as a single agent or in combination with other drugs. Phase 1 studies with oral rigosertib were conducted in hematological malignancies, lower-risk MDS and solid tumors. Combination therapy of oral rigosertib with azacitidine and chemoradiotherapy has also been explored.

About Trial 09-08 (NCT01926587): Combination therapy with oral rigosertib and azacitidine

The current standard of care for higher-risk MDS patients is one of two approved hypomethylating agents (Azacitidine and Decitabine, approved by the FDA in 2004 and 2006). Although these drugs are currently the mainstays in HR-MDS therapy, their overall response rate and duration of benefit is limited to a subset of eligible patients and all responding patients ultimately progress. Therefore, there is an urgent need for developing therapeutic options for newly diagnosed MDS patients. The 09-08 Phase 1/2 trial tested oral rigosertib in combination with injectable azacitidine in a dose ranging study (Phase 1), followed by an expansion cohort (Phase 2) to evaluate the efficacy and safety of the combination. Interim results from this trial were presented at the 2015 ASH (Free ASH Whitepaper) conference indicating that the combination was generally well tolerated and that clinical responses were observed in 23 of 30 MDS patients evaluable for efficacy assessment.1 Both 1st-line and 2nd-line patients were included in this study.