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Curis Announces Initiation of Phase 1 Trial of CA-4948, a Small Molecule Inhibitor of IRAK4 Kinase in Patients with Lymphoma

On January 17, 2018 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development and commercialization of innovative and effective therapeutics for the treatment of cancer, reported initiation of patient dosing in a Phase 1 trial of CA-4948, an orally available small molecule inhibitor of the IRAK4 kinase, for treatment of patients with lymphoma (Press release, Curis, JAN 17, 2018, View Source [SID1234523297]). CA-4948 was discovered at Aurigene and is the second licensed program from the Curis-Aurigene collaboration to enter the clinic.

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The Phase 1 study is designed to evaluate the safety, tolerability, and pharmacokinetic profile of CA-4948; identify any dose-limiting toxicities; and establish the recommended Phase 2 dose for the treatment of patients with lymphomas. The dose escalation stage of the trial will enroll patients with relapsed/refractory non-Hodgkin’s lymphoma, and the expansion stage will focus on specific populations of patients with lymphomas harboring alterations in the MYD88 gene or Toll-like receptor (TLR) signaling pathway.

"We are pleased to announce the advancement of our clinical pipeline with the initiation of the Phase 1 trial for this selective IRAK kinase inhibitor in patients with lymphomas," commented Ali Fattaey, Ph.D., Curis’s president and CEO. "Given the prevalence of activating mutations in the MYD88 gene and the TLR pathway, IRAK4 represents a significant target for the precision treatment of patients with different hematologic malignancies. In addition to its preclinical anti-tumor activity in MYD88-mutated lymphomas, we have observed encouraging effects of CA-4948 in animal models of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) as well as non-oncology inflammatory disease models. We look forward to working with our partner Aurigene to develop CA-4948 and explore clinical opportunities for these conditions in the near future."

"We are excited to have enrolled the first patient in this lymphoma clinical trial and look forward to further investigating CA-4948 as a potential new treatment option for patients with hematologic malignancies," said Mathew Lunning, DO, University of Nebraska Medical Center, an investigator for the study.

"We are delighted with our collaboration that has led to the advancement of the second program into the clinic, an IRAK4 targeting molecule that came out of Aurigene’s discovery efforts over many years," said CSN Murthy, Aurigene’s CEO. "Our investment into Curis exhibits our belief and commitment for this program and beyond as we work with Curis to focus our collective resources to advance exciting drug candidates."

About CA-4948, a Small-Molecule Inhibitor of IRAK4 Kinase

Innate immune responses orchestrated through Toll-like receptors are important mediators of the body’s initial defense against infections, while their dysregulation is associated with certain inflammatory conditions. Toll-like receptor signaling through the adaptor protein MYD88 results in the activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression. MYD88 gene mutations occur in approximately 30 percent of activated B-cell subtype of diffuse large B-cell lymphomas (DLBCL)1,2 and in over 90 percent of cases of the B-cell malignancy Waldenstrom’s macroglobulinemia (WM).3 IRAK4 has been validated as a target in DLBCL and WM disease setting, and its inhibition by CA-4948 has been shown to provide potent in vivo anti-tumor activity in animal models.4,5 IRAK4 inhibitors are also in clinical testing for treatment of patients with rheumatoid arthritis.

1Nature. 2011; 470(7332):115–119
2Immunology and Cell Biology. 2011; 89(6):659–660
3N Engl J Med. 2012; 367(9):826–833
4Cancer Res. 2017; 77(13 Suppl): Abstract 1168
5Blood. 2015;126(23):4004–4004

CTI BioPharma to Receive $10 Million Milestone Payment for TRISENOX®

On January 17, 2018 CTI BioPharma Corp. (NASDAQ and MTA:CTIC) reported that it expects to receive a $10 million milestone payment in February, 2018 from Teva Pharmaceutical Industries Ltd. related to the achievement of a milestone for U.S. Food and Drug Administration approval of TRISENOX (arsenic trioxide) for first line treatment of acute promyelocytic leukemia (Press release, CTI BioPharma, JAN 17, 2018, View Source;p=RssLanding&cat=news&id=2327170 [SID1234523276]). The milestone will be paid pursuant to an acquisition agreement for TRISENOX previously entered into with Teva under which CTI BioPharma is eligible to receive up to an additional $50 million in payments upon achievement by Teva of specified sales and development milestones related to TRISENOX.

VBI Vaccines Announces Dosing of First GBM Patient in Phase 1/2a Clinical Study of VBI-1901

On January 17, 2018 VBI Vaccines Inc. (Nasdaq:VBIV) (TSX: VBV) (VBI), a commercial-stage biopharmaceutical company developing next-generation infectious disease and immuno-oncology vaccines, reported that the first patient has been dosed in a Phase 1/2a clinical study of VBI-1901 for the treatment of recurrent glioblastoma multiforme (rGBM) (Press release, VBI Vaccines, JAN 17, 2018, View Source [SID1234523238]). The multi-center, open-label, two-part study will enroll up to 28 patients and is designed to evaluate safety, tolerability, and the optimal therapeutic dose level of VBI-1901.

"We are excited to announce that the first patient has been dosed in this initial clinical study of VBI-1901, our first clinical study in immuno-oncology," said Jeff Baxter, President and CEO of VBI. "Recurrent GBM is a devastating CMV-associated tumor with few effective treatment options. We developed VBI-1901 to target two highly immunogenic CMV antigens, and, based on preclinical studies, we believe it has the potential to induce a strong anti-tumor immune response in these patients."

About the Phase I/IIa Study Design

This two-part Phase 1/2a study is a multi-center, open-label, dose-escalation study of VBI-1901 in approximately 28 patients with rGBM:

● Part A: Dose-escalation phase to define the safety, tolerability, and optimal dose level of VBI-1901 in rGBM patients. This phase is expected to enroll up to 18 patients.

● Part B: A subsequent extension of the optimal dose level, as defined in the dose escalation phase. This phase is expected to enroll an expanded cohort of approximately 10 additional patients.

VBI-1901 will be administered intradermally and will be adjuvanted with granulocyte-macrophage colony-stimulating factor (GM-CSF), a potent adjuvant that mobilizes dendritic cell function. Patients in both phases of the study will continue to receive vaccine every four weeks until tumor progression.

The study will take place at two leading sites in the U.S. – NewYork Presbyterian-Columbia University Medical Center in New York City, New York, and Inova Health System in Falls Church, Virginia. Andrew Lassman, MD, the John Harris Associate Professor of Neurology and Chief of Neuro-oncology at Columbia University, has been named as the lead investigator.

Additional information, including a detailed description of the study design, eligibility criteria, and investigator sites, is available at ClinicalTrials.gov using identifier NCT03382977.

About VBI-1901 and GBM

VBI-1901 is a novel immunotherapy developed using VBI’s eVLP technology to target two highly immunogenic cytomegalovirus (CMV) antigens, gB and pp65. Scientific literature suggests CMV infection is prevalent in multiple solid tumors, and recent research has demonstrated that an anti-CMV dendritic cell vaccination regimen may extend overall survival in patients with GBM. Additionally, recent preclinical studies confirmed that VBI-1901 may be a potent, "off-the-shelf" therapeutic vaccine.

Glioblastoma is among the most common and aggressive malignant primary brain tumors in humans. In the U.S. alone, 12,000 new cases are diagnosed each year. The current standard of care for treating GBM is surgical resection, followed by radiation and chemotherapy. Even with aggressive treatment, GBM progresses rapidly and is exceptionally lethal, with median patient survival of less than 16 months.

To learn more about VBI-1901, visit: View Source

Onconova Moving Forward with Phase 3 INSPIRE Pivotal Trial with Increased Sample Size Following Promising Interim Analysis

On January 17, 2018 Onconova Therapeutics, Inc. (Nasdaq:ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing small molecule drug candidates to treat cancer, reported that it is moving forward with its Phase 3 INSPIRE pivotal trial following the interim analysis, consistent with the DMC’s recommendation (Press release, Onconova, JAN 17, 2018, View Source [SID1234523237]). The DMC recommended continuation of the trial with a one-time expansion in enrollment, using a pre-planned sample size re-estimation, consistent with the Statistical Analysis Plan (SAP). The INSPIRE pivotal trial is studying intravenously-administered (IV) rigosertib in patients with higher-risk myelodysplastic syndromes (MDS) who have progressed on, failed to respond to, or relapsed after prior hypomethylating agent (HMA) therapy. The Company remains blinded to the interim analysis results.

Guillermo Garcia-Manero, M.D, Professor and Chief of the MDS Section at the MD Anderson Cancer Center, a lead investigator on the INSPIRE study, commented, "Choices are very limited for higher risk MDS patients after failure of HMA therapy and no second-line therapy has ever been approved by the Health Authorities for these patients. These patients have a very short life-span and there is a tremendous unmet medical need. We remain highly supportive of Onconova’s efforts. After the interim analysis, continuation of the INSPIRE study is encouraging for patients."

The SAP for the INSPIRE trial featured an adaptive trial design, permitting several options following the interim analysis, which included continuation of the trial as planned, discontinuation of the trial for futility, trial expansion using pre-planned sample size re-estimation, and trial continuation for only the pre-defined treatment subgroup of patients classified as VHR based on the Revised International Prognostic Scoring System (IPSS-R).

The expanded INSPIRE study will continue to enroll eligible patients based on the current trial design of the overall ITT population and will increase enrollment by adding 135 patients to the original target to reach a total enrollment of 360 patients, with the aim of increasing the power of the trial. Due to the adaptive trial design and the DMC’s assessment, the INSPIRE trial will continue to analyze both the ITT and the VHR population for the primary endpoint of overall survival. The design of the trial with the expanded study enrollment will be identical to the current study design and will include the analysis of the overall survival endpoint in the ITT and the pre-specified VHR subgroup.

Steve Fruchtman, M.D., Chief Medical Officer of Onconova, added, "With no FDA approved therapies for many patients with higher-risk MDS who are refractory to HMAs, we are encouraged by these results and pleased to be at the forefront of advances in this treatment landscape. The DMC’s recommendation based on the pre-planned interim analysis includes the expansion of the INSPIRE trial and retains the analysis of survival in both the ITT and the VHR pre-defined subgroups. Patients with MDS who are refractory to HMAs have the highest unmet medical need due to an extremely poor prognosis following failure of HMA therapy. We look forward to completing enrollment and for the opportunity to analyze overall survival in the higher-risk MDS patients who have failed prior HMA therapy."

Currently, the INSPIRE study is active at approximately 175 trial sites in 22 countries across four continents, and has enrolled more than 170 patients. In Japan, patients have been enrolled to this study by SymBio Pharmaceuticals, our collaboration partner for Japan and Korea. Onconova believes that this trial is the most advanced study for a new therapeutic agent in this indication, and there are no FDA approved therapies specifically for MDS patients after failure of front-line HMAs.

The Company will host a conference call today, January 17th at 8:30 a.m. Eastern Time to discuss the interim results and answer any questions. Interested parties may access the call by dialing toll-free (855) 428-5741 from the US, or (210) 229-8823 internationally and using conference ID: 8899928.

The call will also be webcast live. Please click here to access the webcast.

A replay will be available at this link until April 30, 2018.

BioLineRx Announces Partial Monotherapy Results from Phase 2a COMBAT Study in Pancreatic Cancer

On January 17, 2018 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a clinical-stage biopharmaceutical company focused on oncology and immunology, reported partial results from the monotherapy portion of BL-8040’s Phase 2a COMBAT study showing that BL-8040 increases infiltration of T cells into the tumor in patients with metastatic pancreatic cancer (Press release, BioLineRx, JAN 17, 2018, View Source;p=RssLanding&cat=news&id=2326963 [SID1234523236]). The data will be presented as a poster titled "Evaluation of Pharmacodynamic Biomarkers in Patients with Metastatic Pancreatic Cancer Treated with BL-8040, a Novel CXCR4 Antagonist (Abstract 276)" at the ASCO (Free ASCO Whitepaper) 2018 Gastrointestinal Cancers Symposium, on January 19, 2018 in San Francisco, CA.

The partial results from the BL-8040 monotherapy portion of the COMBAT trial show that BL-8040 was safe and well-tolerated. BL-8040 also induced an increase in the number of total immune cells in the peripheral blood, while the frequency of peripheral blood regulatory T cells (Tregs), known to impede the anti-tumor immune response, was decreased. In addition, analysis of available biopsies (N = 7) showed infiltration of various types of effector T cells, known to attack cancer cells, into the tumor periphery and tumor micro-environment (TME). In this regard, the results show up to a 15-fold increase in CD3+ T cells, and up to a 2-fold increase in CD8+ T cells, in the TME of 43% (3/7) of the patients, after five days of BL-8040 monotherapy.

Dr. Manuel Hidalgo, Chief of Hematology Oncology and Co-Director of the Pancreatic Cancer Research Program at Beth Israel Deaconess Medical Center in Boston, commented, "This is the first time we see results of BL-8040 in pancreatic cancer patients. The results of the monotherapy part of the COMBAT trial are extremely encouraging as they confirm the mechanism of action of BL-8040 in this difficult-to-treat patient population, resulting in T-cell infiltration into the tumor after only 5 days of monotherapy with BL-8040. These results support the rationale for combining BL-8040 with checkpoint inhibitors, and I am looking forward to the topline results of the COMBAT study expected later this year."

"The results show that BL-8040 induces robust infiltration of anti-tumor T cells into liver metastases in almost half of the pancreatic cancer patients who underwent a biopsy, effectively transforming these tumors from immunologically ‘cold’ to ‘hot’, which is seen as key in the objective of improving the responsiveness of patients with pancreatic cancer to front-line immunotherapy" stated Philip Serlin, Chief Executive Officer of BioLineRx. "These results support the mechanism of action proposed by pre-clinical studies, namely that BL-8040 mobilizes immune cells into the peripheral blood and promotes T cell infiltration into tumors. As previously reported, enrollment of the study has been completed and we expect to meet our timelines for conclusion of the study and topline results by the second half of 2018."

The Phase 2a study, named the COMBAT study, is an open-label, multicenter, single-arm trial designed to evaluate the safety and efficacy of the combination of BL-8040 and KEYTRUDA (pembrolizumab), an anti-PD-1 therapy marketed by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside the United States and Canada), in over 30 subjects with metastatic pancreatic adenocarcinoma. The study is primarily designed to evaluate the clinical response, safety and tolerability of the combination of these therapies. In addition, the study evaluates multiple pharmacodynamic parameters, including the ability to increase infiltration of T cells into the tumor, for both BL-8040 as a monotherapy, as well as for the combination of BL-8040 and KEYTRUDA. The study is being conducted in the US, Israel and additional territories.

The COMBAT study is being conducted by BioLineRx under a collaboration agreement signed in 2016 between BioLineRx and MSD, through a subsidiary, to support a Phase 2a study investigating BioLineRx’s BL-8040 in combination with KEYTRUDA in patients with metastatic pancreatic cancer.

BL-8040, BioLineRx’s lead oncology platform, is a CXCR4 antagonist that has been shown in several clinical trials to be a robust mobilizer of immune cells to peripheral blood and to be effective at inducing direct tumor cell death. Additional findings have suggested that CXCR4 antagonists may be effective at increasing the infiltration of anti-tumor T cells into tumors that were previously immunologically "cold" and devoid of immune cell infiltrate. Checkpoint inhibitors (such as KEYTRUDA) produce anti-cancer effects by increasing the activity of T cells through blockade of the interaction between the immunosuppressive elements PD-1, on T cells, and PD-L1, on tumor cells. Pancreatic cancers have very little T-cell infiltrate, making them less susceptive to checkpoint blockade than other tumors that are infiltrated by T cells. Therefore, combining BL-8040 with checkpoint blockade is predicted to increase the responsiveness of pancreatic cancer patients to immunotherapy.

About BL-8040

BL-8040 is a short peptide for the treatment of acute myeloid leukemia, solid tumors, and stem cell mobilization. It functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells and immune-cells from the bone marrow, thereby sensitizing cancer cells to chemo- and bio-based anti-cancer therapy, as well as a direct anti-cancer effect by inducing cell death (apoptosis) and mobilizing immune-cells. In addition, BL-8040 has also demonstrated robust stem-cell mobilization, including the mobilization of colony-forming cells, T, B and NK cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.