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Innovation Pharmaceuticals Obtains Direct Evidence of Molecular Pathways Modulation in Tumors from First Patients in Kevetrin Ph2a Ovarian Cancer Trial

On December 27, 2017 Innovation Pharmaceuticals Inc., (OTCQB:IPIX) ("the Company"), a clinical stage biopharmaceutical company, reported highly encouraging preliminary data from the first patients treated in the Company’s Phase 2a clinical trial (see NCT03042702) of Kevetrin for ovarian cancer (Press release, Innovation Pharmaceuticals, DEC 27, 2017, View Source [SID1234522779]).

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Modulation of the p53 protein was observed in response to administration of Kevetrin. Pathways analyses also point to concomitant cell cycle modulation at the level of gene expression. Importantly, these data are the first to directly support, in ovarian cancer patient tumors, Kevetrin’s ability to affect p53 and associated molecular pathways—a central gene signaling network involved in regulating cell growth and the cell cycle, helping to prevent cancer.

In more detail, preliminary analyses used Western Blots to assess relative levels of key proteins extracted from tumor biopsies before and after a series of nine Kevetrin infusions administered over three weeks. The level of phospho-p53, the activated form of the protein, in addition to the noted p53 modulation, was also seen to change in response to Kevetrin administration. These findings confirm in patient tumors Kevetrin-induced anti-cancer effects similar to those demonstrated (pdf) preclinically in ovarian cancer cell-lines. These new data reinforce prior clinical data, from the earlier concluded Phase 1 study of Kevetrin in advanced solid tumors (see NCT01664000), in which observations of p21 expression in peripheral blood monocytes supported p53 involvement in Kevetrin’s mechanism of action.

Data from RNAseq analyses of expressed mRNAs and sRNAs in tumors, before and after treatment with Kevetrin, are being further analyzed to assess the nature and scope of molecular pathways modulations. The strongest signal so far detected concerns the cell cycle and a variety of transcription factors.

Running in parallel, the Company is making plans to develop Kevetrin as an oral agent (tablet or capsule) that could be dosed multiple times per day, leveraging its short half-life and pharmacokinetic profile. Bioavailability and other lab studies have been encouraging. Last, linked below is a blog post, published on the Company’s website, further elaborating on Kevetrin’s treatment potential as a novel, p53-modulating anti-cancer drug candidate.

"Kevetrin’s Effect on the p53 Signaling Pathway in a Broader Scientific Context"

Management Comments

"In a majority of cancers, p53 is mutated, preventing the body from performing its anti-tumor functions," said Leo Ehrlich, Chief Executive Officer at Innovation Pharmaceuticals. "As a result, therapies targeting p53 have long been pursued, highly sought-after by Big Pharma, but have largely been met with limited success due to the inherent complexity of p53. So, to see Kevetrin modulate p53 in a clinical setting in tumor biopsies from patients is an exciting moment for the Company, positioning us at the forefront of developing a potentially transformative anti-cancer therapy."

"Our science team has been working on Kevetrin for over a decade now, studying its unique anti-cancer profile across multiple cancer types, from solid tumors to leukemias—a function of Kevetrin’s ability to induce apoptosis in both wild type p53 and mutant p53 tumors," said Arthur P. Bertolino, MD, PhD, MBA, President and Chief Medical Officer at Innovation Pharmaceuticals. "It’s rewarding to think—after so many years of research in the lab and in the clinical setting—that we now have more direct evidence of how Kevetrin’s multiple mechanisms of action modulate p53, helping to restore the body’s natural ability to fight cancer. Such mechanistic insights of the kind we’re observing will prove invaluable as we continue to advance Kevetrin into later-stage clinical development."

About Ovarian Cancer

Ovarian Cancer is a common type of cancer that commonly begins in women’s ovaries and associated tissues. Malignant ovarian tumor cells metastasize either directly through the organs of the pelvis region, or through the bloodstream, or the lymphatic system. The causes of ovarian cancer are still not known, though women over the age of 63 represent more than 50 percent of newly diagnosed cases, with the cancer more frequently found in white women than other ethnicities. Ovarian cancer ranks fifth in cancer deaths among women worldwide. It is estimated that in 2016, in the United States, over 22,000 women will be diagnosed with ovarian cancer, with approximately 14,000 women dying from the disease. A $1.6 billion market, current treatment is often limited to surgery and chemotherapy and there is no cure.

About Kevetrin and p53

Kevetrin is a small molecule that has demonstrated the potential of becoming a breakthrough cancer treatment by modulating p53, a protein frequently referred to as the "Guardian of the Genome" due to its critical role in controlling cell mutations. In the majority of cancers, and regardless of origin, type, and location, the p53 pathway is mutated, preventing the body from performing its natural anti-tumor functions. Conducted at Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center, a Phase 1 clinical trial (see NCT01664000) of Kevetrin in treating advanced solid tumors has been successfully completed, with patients showing good toleration and encouraging signs of potential therapeutic response (see ASCO (Free ASCO Whitepaper) 2015, ASCO (Free ASCO Whitepaper) 2013). Additional pre-clinical work supporting Kevetrin’s anti-cancer activity has recently been presented at scientific conferences (see EHA (Free EHA Whitepaper) 2017, AACR (Free AACR Whitepaper) 2017). The Company has initiated a Phase 2a trial of Kevetrin (see NCT03042702) in late stage, platinum-resistant/refractory ovarian cancer. Patients will receive more frequent dosing (3 times per week) at higher levels and then receive standard of care treatment after trial conclusion. Efforts also are underway to develop Kevetrin as an oral anti-cancer agent that can be administered daily, potentially multiple times per day. The FDA has awarded Kevetrin Orphan Drug status for ovarian cancer, pancreatic cancer, and retinoblastoma, qualifying it for developmental incentives and a potential extra 7 years of market exclusivity upon drug approval. The FDA also has granted Kevetrin Rare Pediatric Disease designation for childhood retinoblastoma.

Diffusion Pharmaceuticals Begins Phase 3 Clinical Trial with TSC in Glioblastoma Multiforme Trial in newly diagnosed inoperable patients now open for enrollment

On December 27, 2017 Diffusion Pharmaceuticals Inc. (NASDAQ:DFFN) ("Diffusion" or "the Company"), a clinical-stage biotechnology company focused on extending the life expectancy of cancer patients, reported that a Phase 3 clinical trial using its lead small molecule trans sodium crocetinate ("TSC") in patients with newly-diagnosed inoperable glioblastoma multiforme ("GBM") brain cancer, is now open for enrollment (Press release, Oncolytics Biotech, DEC 27, 2017, View Source [SID1234522778]). The trial, which has been named INTACT (INvestigating Tsc Against Cancerous Tumors), follows a previous Phase 2 GBM study in which the inoperable patient subgroup showed a nearly four-fold increase in survival compared with historical controls when TSC was added to their treatment regimen (40% alive at two years vs. 10.4%). TSC’s innovative mechanism of action affects the tumor micro-environment, making treatment-resistant cancer cells more susceptible to the tumor-killing power of conventional radiation therapy ("RT") and chemotherapy (temozolomide) by re-oxygenation of the hypoxic portion of the tumor. The Company believes that a largely intact GBM tumor vasculature with limited surgical resection is conducive to TSC’s tumor re-oxygenation properties, and that this contributed to the survival increase in the Phase 2 GBM inoperable patient subgroup.

The trial will screen 300 patients and enroll 264 in an effort to ensure that results from 236 patients will be available for analysis. Enrolled patients will be randomized in a 1:1 ratio into treatment and control groups. Patients in the treatment group will receive standard of care ("SOC") temozolomide and RT plus an intravenous bolus of TSC administered shortly before their SOC treatments. Patients in the control group will receive SOC alone. The study will compare overall survival at two years between patients in the two groups. Up to 100 clinical sites in the U.S. and Europe are expected to participate. The Company projects that enrollment will be completed by early 2019, with interim safety and efficacy data possible in 2020 and trial completion in 2021. Further site initiation is on-going, with first patient enrollment targeted for January 2018.

"Given the dire prognosis of inoperable GBM brain cancer, we are especially gratified to have the INTACT clinical trial open for enrollment. We believe that TSC can provide new hope for these patients, whose treatment options are so limited," said David Kalergis, Chief Executive Officer of Diffusion Pharmaceuticals. "The four-fold increase in inoperable GBM patients alive at two years in our Phase 2 trial is a particularly strong efficacy signal, and informs the design of our Phase 3 trial."

About the GBM Phase 3 INTACT Trial

The INTACT clinical trial is an open-label, randomized, controlled, Phase 3 safety and efficacy registration trial. Subjects will be randomized at baseline to SOC for first-line treatment of GBM plus TSC, or to SOC alone. The SOC for GBM is temozolomide plus RT for 6 weeks followed by 28 days of rest, followed by 6 cycles of post-radiation temozolomide treatment.

TSC will be administered during both the RT and post-radiation temozolomide treatment periods to those subjects so randomized.

During the RT treatment period subjects will receive:

Focal RT delivered as 60Gy/30 fractions scheduled at 2Gy/day for 5 days each week (Monday through Friday) for 6 weeks.
Temozolomide 75 mg/m2 orally once daily (usually administered the night preceding each RT session) starting the evening before the first RT session over a period of 42 calendar days with a maximum of 49 days.
TSC 0.25 mg/kg IV for 3 days each week (e.g., Monday, Wednesday, Friday, or other schedule that supplies a minimum 3 TSC doses per week) administered between 45 to 60 minutes prior to each RT session.
During the 28-day rest period all subjects will receive no treatment.

During the post-radiation 6-cycle temozolomide treatment period:

All subjects will receive 28-day oral temozolomide (150 mg/m2 first cycle and 200 mg/m2 all subsequent cycles as tolerated) administered on Day 1-5 (Monday through Friday) of each 28-day cycle.
Controls will receive oral temozolomide at night at home per the SOC and are not required to attend clinic visits during this period.
Subjects randomized to TSC will receive TSC 1.5 mg/kg (or another dose if recommended by the DSMB) 1.5 to 2 hours before their temozolomide dose during the daytime for 3 days during the first week of each 28-day cycle (Days 1, 3, and 5; e.g., Monday, Wednesday, Friday or other schedule that supplies at minimum 3 TSC doses per week). The Tuesday, Thursday doses will be given at night at home. Long-acting antiemetics may be administered prior to daytime temozolomide dosing on Days 1, 3, 5.
The safety, tolerability and pharmacokinetics ("PK") of TSC at higher doses than 0.25 mg/kg with temozolomide will be assessed during adjuvant therapy. TSC at doses between 0.25 mg/kg and up to 1.5 mg/kg in combination with concomitant temozolomide will be assigned (not randomized) in the first 8 subjects enrolled in the INTACT trial. These patients will undergo RT plus temozolomide plus TSC treatment (0.25 mg/kg) for 6 weekly cycles followed by 4 weeks of rest in standard fashion. At the Week 10 clinic visit the same 8 subjects will be assigned to treatment, with 2 subjects each assigned to TSC at doses of 0.25, 0.50, 1.0, and 1.5 mg/kg. These subjects will be studied in parallel for 2 28-day cycles with inclusion of appropriate blood sampling collection for TSC and temozolomide PK. The Data Safety Monitoring Board ("DSMB") will examine the resultant safety data after 2 cycles (Weeks 11 through 18 of post-radiation temozolomide treatment period; Days 1 to 56). The DSMB may recommend continued use of the 1.5 mg/kg TSC dose for the post-radiation temozolomide treatment period, or may prescribe another dose based on their observations. Subjects then entering into the INTACT trial will be randomized at baseline between TSC plus SOC, or SOC alone.

Further details about the trial protocol will be available shortly at www.clinicaltrials.gov.

The baseline assessment for determining progression-free survival ("PFS"), overall response rate ("ORR") and to rule out pseudo-progression, will be at 10 weeks via MRI using the "modified Response Assessment in Neuro-Oncology" ("mRANO") scale. The hazard ratio for the trial will be 0.67, which corresponds to 22% two-year survival in the TSC arm, the lower limit of the 95% confidence interval for the biopsy-only subjects in Diffusion’s Phase 2 trial, and 10% survival in the SOC arm. The estimated median survival is therefore 10 months for the SOC arm vs. 14.9 months for the TSC plus SOC arm. In order to achieve 80% power, the trial requires 118 subjects in each arm.

The study will achieve the designed 80% statistical power at 198 events, where an event is defined as death. The first analysis will occur at the earlier of two years follow-up for all subjects or 198 events. If the first analysis is at 198 events, the analysis will be a standard 2-sided stratified log-rank test at the α=0.05 significance level. If the first analysis is at two years, the Company will perform the analysis using the O’Brien-Fleming Method.

About Treatment-Resistant Cancers and TSC

Oxygen deprivation at the cellular level (hypoxia) is the result of rapid tumor growth, causing the tumor to outgrow its blood supply. Cancerous tumor cells thrive with hypoxia and the resultant changes in the tumor microenvironment cause the tumor to become resistant to RT and chemotherapy. Using a novel, proprietary mechanism of action, Diffusion’s lead drug TSC appears to counteract tumor hypoxia – and therefore treatment resistance – by safely re-oxygenating tumor tissue, thus enhancing tumor kill and potentially prolonging patient life expectancy. Oxygen levels of normal tissue appear to remain unaffected upon administration of TSC.

Regeneron Announces Presentation at the 36th Annual J.P. Morgan Healthcare Conference

On December 27, 2017 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported that it will webcast its presentation at the 36th Annual J.P. Morgan Healthcare Conference on Monday, January 8, 2018 (Press release, Regeneron, DEC 27, 2017, View Source [SID1234522780]). The presentation is scheduled for 11:30 a.m. Pacific Time (2:30 p.m. Eastern Time) and may be accessed through the Company’s web site, www.regeneron.com, on the ‘Events and Presentations’ page. A breakout session will immediately follow the formal presentation and can also be accessed at www.regeneron.com. An archived version of the presentation and the breakout session will be available for 30 days.

Halozyme Therapeutics To Present At The 36th Annual J.P. Morgan Healthcare Conference

On December 27, 2017 Halozyme Therapeutics, Inc. (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies reported that it will be presenting at the 36th Annual J.P. Morgan Healthcare Conference in San Francisco on Tuesday, January 9 at 3:00 p.m. PT / 6:00 p.m. ET (Press release, Halozyme, DEC 27, 2017, View Source [SID1234522777]). Dr. Helen Torley, president and chief executive officer, will provide a corporate overview.

The presentation will be webcast through the "Investors" section of Halozyme’s corporate website at www.halozyme.com, and a recording will be made available for 90 days following the event. To access a live webcast, please visit Halozyme’s website approximately 15 minutes prior to the presentation to register and download any necessary audio software.

FDA Approves Nanobiotix’s First Immuno-Oncology Trial: a Phase I/II Study of NBTXR3 Activated by Radiation Therapy (SABR) for Patients with Non-Small Cell Lung Cancer or Head and Neck Squamous Cell Carcinoma Cancer Treated with an Anti-PD1 Antibody

On December 26, 2017 NANOBIOTIX (Paris:NANO) (Euronext: NANO – ISIN: FR0011341205), a late clinical-stage nanomedicine company pioneering new approaches to the treatment of cancer, reported the U.S. Food and Drug Administration (FDA) has approved its Investigational New Drug (IND) Application for NBTXR3, a first-in-class nanoparticle designed for direct injection into cancerous tumors, activated by stereotactic ablative radiotherapy (SABR) and administered in combination with an anti-PD1 antibody (nivolumab or pembrolizumab) (Press release, Nanobiotix, DEC 26, 2017, View Source [SID1234526519]).

Laurent Levy, CEO of Nanobiotix, stated: "The FDA’s approval of Nanobiotix’s IND application for this trial is a major milestone for our Company. We’re ready and excited to launch our first immuno-oncology clinical trial in the U.S. combining NBTXR3 with a checkpoint inhibitor. Advancing our demonstration of NBTXR3’s potential to turn checkpoint inhibitor non-responders into responders could be game-changing, and the approach could address the unmet medical needs of a significant number of patients. Based on existing pre-clinical and clinical data, NBTXR3 could become a backbone in immuno-oncology."

The IND approval enables Nanobiotix to initiate NBTXR3-1100, a Phase I/II prospective, multi-center, open-label, and non-randomized clinical trial evaluating the efficacy and safety of NBTXR3 activated by SABR combined with checkpoint inhibitors (nivolumab or pembrolizumab). NBTXR3-1100 includes three cohorts of patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC), or with metastatic non-small cell lung cancer (NSCLC). The study will be conducted in two consecutive phases. The first of these will be dose escalation, followed by a dose expansion phase. The study will seek to enroll between 36 to 72 patients in Phase I and 40 patients in Phase II.

NBTXR3-1100’s dose escalation phase is based on a classical 3+3 Phase I study and planned as a 3-level program to identify the appropriate dose of NBTXR3 injected into the tumor as well as the activation dose of SABR. While NBTXR3 and Radiotherapy doses will be escalated, the anti-PD1 antibody dose will remain constant. One approved anti-PD1 antibody for the dose expansion phase will be selected based on the preliminary risk-benefit ratio assessment observed in Phase I portion of the trial.

Primary and secondary endpoints will evaluate efficacy and safety, while exploratory endpoints further characterize the treatment-induced genomic alterations previously reported, including enriched cytokine activity and markers of adaptive immune response and T-cell receptor signaling pathways.

The NBTXR3-1100 trial will be led by coordinating investigator Tanguy Seiwert, M.D., of The University of Chicago Medical Center, and principal investigator Jared Weiss, M.D., of The University of North Carolina – Chapel Hill.

The potential for immuno-oncology agents to boost immune system response by priming it for active attack against tumor cells has long been a source of excitement.

While the response to checkpoint inhibitors in so-called "hot" tumors, infiltrated by T-cells and characterized by an inflammatory profile, has been striking with long-lasting clinical benefits in some cancer patients, most patients exhibit little or no response to existing treatments.

According to published data, only 15% to 20% of non-small-cell lung cancer patients (NSCLC), and 13% to 22% of head and neck squamous cell carcinoma patients (NHSCC) respond to current immunotherapy treatments.

The physical mode of action by which NBTXR3 works induces a different immunogenicity and could be the key to significantly increasing the number of cancer patients who can benefit from immuno-oncology therapies.

As presented earlier this year at ASCO (Free ASCO Whitepaper) & SITC (Free SITC Whitepaper) 2017, NBTXR3 activated by radiotherapy was shown to induce a specific adaptive immune pattern that could potentially convert a non-responder into an immune-responsive patient receptive to treatment with available checkpoint inhibitors.

On top of NBTXR3’s core developments as a single agent across seven oncology indications, Nanobiotix’s immuno-oncology combination program opens the door to new developments, potential new indications, and important value creation opportunities.

The first patient first visit in the potentially paradigm changing trial is expected in Q2 2018 with with first expected results in the summer of 2019.

***

About Nanobiotix’s immuno-oncology research program

Many IO combination strategies focus on ‘priming’ the tumor, which is now becoming a prerequisite of turning a "cold" tumor into a "hot" tumor.

Compared to other modalities that could be used for priming the tumor, NBTXR3 could have a number of advantages: the physical and universal mode of action that could be used widely across oncology, the one-time local injection and good fit within existing medical practice already used as a basis for cancer treatment, as well as a promising chronic safety profile and well-established manufacturing process.

After 18 months of development, the Company presented preclinical proof of concept demonstrating that NBTXR3 actively stimulates the host immune system to attack tumor cells.

Recently, Nanobiotix presented new translational data. Taken together, these non-clinical and preliminary clinical results confirm that NBTXR3 activated by radiotherapy could efficiently prime an adaptive antitumor immune response, turning "cold" tumors in "hot" tumors. Additionally, these results suggest that the physically-induced response and subsequent immune activation triggered by the NBTXR3 treatment could be generic. Results suggest that NBTXR3 activated by radiotherapy could transform tumors into an effective in situ vaccine, opening up very promising perspectives in the treatment of local cancer and metastases.

On top of the Company’s core development activities, these findings could open new collaborations for NBTXR3 through combinations with other immuno-oncology drugs.

About NBTXR3

NBTXR3 is an injectable aqueous suspension of hafnium oxide nanoparticles designed as an innovative therapeutic agent for the treatment of solid tumors, currently in clinical development by Nanobiotix.

Once injected intratumorally, NBTXR3 can deposit high energy within tumors only when activated by an ionizing radiation source, notably radiotherapy. Upon activation, the high energy radiation is physically designed to kill the tumor cells by triggering DNA damage and cell destruction and improve clinical outcomes.

Promising results indicate that NBTXR3 activity could be applicable across solid tumors triggering immunogenic cell death, leading to an immune response, reinforcing a local and potentially systemic effect, and contributing to transform "cold" tumors into "hot" tumors. NBTXR3’s major characteristics are represented by a high degree of biocompatibility, one single administration before and during the whole therapy and the ability to fit into current standards of radiotherapy care.

NBTXR3 entered clinical development in 2011 in a Phase I/II with patients suffering from advanced soft tissue sarcoma of the extremities and is currently in the final stages of its subsequent phase II/III. In parallel, it is currently being tested in numerous Phase I/II clinical trials with patients suffering from locally advanced squamous cell carcinoma of the oral cavity or oropharynx (head and neck), liver cancer (hepatocellular carcinoma and liver metastasis), locally advanced or unresectable rectal cancer in combination with chemotherapy, head and neck cancer in combination with concurrent chemotherapy, and prostate adenocarcinoma.