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Cancer Targeted Technology Files Investigational New Drug Application for CTT1403, a Novel Radiotherapeutic Drug for Prostate Cancer

On November 6, 2018 Cancer Targeted Technology (CTT), a privately-held Seattle-based biotechnology company, reported that it filed an Investigational New Drug Application (IND) with the FDA to move forward a radiotherapeutic drug, CTT1403, into human clinical trials for prostate cancer (Press release, Cancer Targeted Technology, NOV 6, 2018, View Source [SID1234530938]). CTT1403 is a peptidomimetic drug that targets Prostate Specific Membrane Antigen (PSMA). PSMA is over-expressed on prostate cancer and this expression increases as the cancer metastasizes and becomes hormone-resistant. Unlike other drugs, CTT’s molecules bind irreversibly to PSMA. This distinctive mode of binding enhances uptake and results in rapid and extensive internalization of these drugs by tumor cells, leading to increased uptake within the tumor. CTT1403 is labeled with the radionuclide 177-Lutetium and, unlike other PSMA-targeted drugs in clinical development, contains a unique albumin binding component. The albumin binding moiety on CTT1403 acts to increase the circulation of the drug in the body and further substantially increases the dose of drug that accumulates at the tumor sites. Once targeted to the tumor, the radionuclide on CTT1403 leads to tumor cell destruction. CTT1403 has shown excellent safety results to date in animal studies and CTT1403 treatment results in prolonged survival of animals with prostate cancer tumors

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"We are very excited with the potential for CTT1403 to make a difference in men with advanced stage prostate cancer. This is a highly innovative molecule that combines excellent PSMA-targeting characteristics, already proven effective in prostate cancer, with the ability to enhance circulation time allowing for greater anti-tumor effects," stated Dr. Beatrice Langton-Webster, CTT’s CEO and Principal Investigator for the clinical program. The unique chemical structure for CTT1403 was designed by Dr. Cliff Berkman, Professor of Chemistry at Washington State University (WSU) and consultant to CTT as its Chief Scientific Officer. The work to discover and progress CTT1403 through preclinical development to IND was funded by a $2.3M Small Business Innovation Research contract from the NIH.

CTT recently completed clinical trials of CTT1057, the companion PET diagnostic to CTT1403, with excellent safety and imaging results. CTT1057 is undergoing further development and commercialization by CTT’s licensing partner AAA/Novartis. CTT1057 and CTT1403 can act as a theranostic pair to both diagnose and treat prostate cancer. Phase I clinical trials for CTT1403 are expected to start January, 2019.

Fortis Therapeutics Receives FDA Clearance of Two IND Applications for Novel Anti-CD46 Therapeutic for Treatment of Late-Stage Prostate Cancer and Multiple Myeloma

On November 6, 2018 Fortis Therapeutics, Inc., an immuno-oncology biotech developing a novel antibody-drug conjugate (ADC) against CD46, reported the U.S. Food and Drug Administration (FDA) has cleared two investigational new drug (IND) applications for the company’s lead candidate, FOR46, for the treatment of metastatic castration-resistant prostate cancer and late-stage multiple myeloma (Press release, Fortis Therapeutics, NOV 6, 2018, View Source [SID1234530937]). The Phase 1 trial of FOR46 in metastatic castration-resistant prostate cancer is planned to launch by the end of the year. The second program, in late-stage multiple myeloma, is expected to move into clinical trials in early 2019.

FOR46 targets a novel immune modulatory receptor, CD46, which is highly expressed in multiple tumor types and is part of the tumor’s immune defense shield. While CD46 is expressed throughout the body, preclinical studies show that FOR46 activity is primarily restricted to prostate and other tumor tissue types, as opposed to normal tissue.

"CD46 is an attractive target for a number of cancers but has yet to be exploited due to its role in healthy tissues," said Jay Lichter, Ph.D., President and CEO of Fortis Therapeutics. "FOR46 cracks the code, in a sense, by binding a specific conformational epitope of CD46, that appears to be specific to tumor cells. This results in targeted tumor killing, while not impacting the natural role of CD46 in the complement system."

Discovery of FOR46

The FOR46 program originated at the University of California, San Francisco, in the laboratory of Bin Liu, Ph.D. It was identified through an antibody selection process that uses living tumor cells residing in their tissue microenvironment, thereby preserving the natural range of surface antigens present on the cells.

"It’s really a testament to the work of our scientists and the scientists at UCSF. By generating antibodies against tumor cells in situ, we developed a drug that readily translates to animal studies and, soon, human trials," said Marc Nasoff, Ph.D., Chief Scientific Officer of Fortis Therapeutics. "We’re confident in the science and in our therapeutic, which builds upon decades of innovation and refinement of antibody-drug conjugates."

To create FOR46, the fully human antibody was conjugated to a potent payload using a proven chemistry platform with well-characterized in vivo properties. Early in vitro studies of FOR46 have demonstrated its potential to kill tumor cells with no effect on normal cells. In rodents with human prostate cancer, it eliminated the tumor and led to long-term survival.

Fortis Therapeutics exclusively licensed rights to the antibody in 2016, and the company maintains a strong intellectual property position.

First Patient Enrolled in Investigator-Initiated Study of Tinostamustine in Glioblastoma

On November 6, 2018 Purdue Pharma L.P. reported that the first patient has been enrolled in a Phase 1 investigator-initiated clinical trial of tinostamustine, an investigational treatment, in patients with newly-diagnosed unmethylated O6-Methylguanine-DNA-methyltransferase (MGMT) glioblastoma multiforme (unmethylated nGBM),1 the most common and aggressive type of primary malignant brain tumor.2 Now open at The University of Texas MD Anderson Cancer Center, the open-label, non-randomized trial will investigate the safety profile, maximum tolerated dose (MTD), and efficacy of tinostamustine (Press release, Purdue Pharma, NOV 6, 2018, View Source [SID1234530936]).

Glioblastoma is an incurable cancer with a very poor prognosis.2 Median overall survival is only 15 months and survival rates have shown no notable improvement in the past 30 years.3,4 The current standard of care for the disease includes surgery and postoperative radiation therapy with concurrent and adjuvant chemotherapy using temozolomide.5-7 Prognosis is significantly worse for patients with the unmethylated MGMT form of glioblastoma because that tumor type is less likely to respond to currently available treaments.8 Under current standard of care, the two-year overall survival rate was 46 percent in patients with MGMT-methylated nGBM versus 14 percent in patients with unmethylated nGBM.8

"We are excited to see tinostamustine advance into a Phase 1 study in patients with unmethylated glioblastoma multiforme, an extremely aggressive and fatal form of brain tumor," said John Renger, PhD, vice president, Head of Research & Development and Regulatory Affairs, Purdue Pharma. "The limited brain penetration of some medications across the blood-brain barrier contributes to the poor prognosis of this disease, however, preclinical data suggest tinostamustine may have the potential to cross the blood-brain barrier to deliver therapeutic central nervous system concentrations."

The dual-acting therapy candidate tinostamustine, previously known as EDO-S101, is a novel and potentially first-in-class alkylating deacetylase inhibitor (AK-DACi) therapy. Clinical research is underway to evaluate its ability to improve access to and break the DNA strands within cancer cells, and counteract the cancer cells’ attempts to repair the DNA damage.9-12

The potential utility of tinostamustine in the treatment of glioblastoma is supported by various pre-clinical data, and the molecule has shown anti-tumor activity in multiple in-vitro models of glioblastoma. In a pharmacokinetic analysis of tinostamustine administered to murine models by IV bolus and continuous IV infusion (CIVI), tinostamustine crossed the blood-brain barrier with central nervous system (CNS) penetration of 16.5 percent and 13.8 percent for IV bolus and CIVI administrations, respectively.13 CNS penetration with adequate therapeutic CNS concentration is essential for the treatment of brain tumors.

Tinostamustine is an investigational treatment and it is not approved for use in glioblastoma patients. Tinostamustine is also in development for a range of rare or difficult-to-treat blood cancers and advanced solid tumors. The completion of the first-in-human Phase 1 dose escalation study of tinostamustine in patients with relapsed or refractory (difficult-to-treat) hematological malignancies for which there are no available therapies was announced recently, and a Phase 1/2 study in advanced solid tumors was initiated in 2017. Tinostamustine is being developed in the US by Mundipharma EDO on behalf of Purdue Pharma.

To find out more about the study, visit clinicaltrials.gov.

This release discusses an investigational new drug under development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such investigational drug will successfully complete clinical development or receive regulatory approval.

Sensei Biotherapeutics Presents Clinical Trial Data Demonstrating SNS-301 Induces Rapid and Robust Antigen-specific Immune Responses at the Society for Immunotherapy of Cancer’s 33rd Annual Meeting

On November 6, 2018 Sensei Biotherapeutics, Inc., a clinical-stage biopharmaceutical company developing precision immuno-oncology therapies, reported that clinical and immunological data from the Phase 1 clinical trial of SNS-301 will be highlighted in a poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 33rd Annual Meeting, to be held November 9-11, 2018 in Washington, D.C (Press release, Sensei Biotherapeutics, NOV 6, 2018, View Source [SID1234530933]). Data showed rapid and significant antigen-specific B-cell and T-cell responses induced by SNS-301, a first-in-class cancer immunotherapy targeting human aspartate β-hydroxylase (ASPH), a novel tumor-specific embryonic antigen.

"These data clinically confirm the immunogenicity and mechanism of action of SNS-301, as we see strong, ASPH-targeted activation of the immune system in patients who received the immunotherapy. Taken together, the data indicate that SNS-301 is capable of overcoming central immune tolerance. We plan to target ASPH with both cancer vaccines and cell therapies to benefit different patient populations," said John Celebi, President and Chief Executive Officer of Sensei Biotherapeutics. "Based on these encouraging results, we look forward to initiating a Phase 2 trial for SNS-301 in various hematological malignancies and solid tumors in early 2019."

Twelve patients with biochemically recurrent prostate cancer who were screened for ASPH using Sensei’s proprietary companion diagnostic were treated with SNS-301 in the Phase 1, multi-center, proof-of-concept study. SNS-301 was administered every 21 days via intradermal injection using a fixed dose-escalation schema through which patients received between 8 and 23 doses at three different dose ranges, and the recommended Phase 2 dose was determined based on the immunogenicity data and changes seen in prostate specific antigen (PSA) doubling times at the three evaluated doses. Highlights of the immunogenicity data from the SNS-301 Phase 1 study presented at SITC (Free SITC Whitepaper) include:

Natural Killer (NK) cell levels in patients treated with SNS-301 were higher than NK cell levels in healthy donors, indicating activation of the innate immune system.
All patients evaluable for immune profiling experienced dose-dependent, ASPH-specific immune responses including B-cell, T-cell and antibody responses.
Increases in activated interferon gamma (IFN-γ) releasing T cells were demonstrated, and both ASPH-specific CD4+ helper T cells and CD8+ cytotoxic T cells showed dose-dependent activation over the first six cycles of SNS-301 dosing with peak responses often occurring after only three or four doses.
An average of eight to ten-fold increase in the percentage of ASPH-specific CD8+ T cells was observed post-treatment, compared to baseline measurements.
Anti-ASPH antibody titers increased in a dose-dependent manner over the first four to six cycles (80-120 days) after administration of SNS-301. This increase in antibody response correlated with concomitant increases in the percentages of ASPH-specific B cells, as measured by flow cytometry.
An average five to seven-fold increase in the percentage of ASPH-specific B-cell responses was observed post-treatment, compared to baseline measurements.
Eight out of the twelve patients (67%) achieved improvements in PSA doubling time and/or absolute PSA level, leading to decreased PSA velocity and suggesting a disease stabilizing effect of SNS301.
Based on evaluation of the three different dose ranges (2 x 1010, 1 x 1011, 3 x 1011 particles), immune responses occurred more rapidly at the two higher doses, as compared to the lower dose. Immunologic efficacy generally correlated with biochemical responses in these patients.
In the Phase 1 study, SNS301 was well tolerated with a favorable safety profile at all three dose levels with no dose-limiting toxicities or grade 4 or 5 adverse events.

About SNS-301
SNS-301 is a first-in-class cancer immunotherapy targeting human aspartate β-hydroxylase (ASPH), a cell surface enzyme that is normally expressed during embryonic development. Following embryonic development, the protein is no longer expressed in healthy adults. Expression of ASPH is uniquely upregulated in more than 20 different types of cancer and is related to cancer cell growth, cell motility and invasiveness. ASPH alters signaling that occurs through the Notch pathway and its expression levels in various tumors are inversely correlated with disease prognosis. SNS-301 is a bio-engineered, inactivated bacteriophage virus expressing a fusion protein of native bacteriophage gpD (gene product D) and a selected domain of ASPH. SNS-301 is designed to overcome immune tolerance and induce robust and durable ASPH-specific humoral and cellular responses. SNS-301 is paired with a companion diagnostic to ensure appropriate patient selection and is delivered easily through an intradermal injection to aid in generating robust immune response.

Atreca to Present Data Further Demonstrating Ability of the Company’s Discovery Engine to Identify Patient-Derived Antibodies that Target Non-Autologous Tumor Tissue

On November 6, 2018 Atreca, Inc., a biotechnology company focused on developing novel therapeutics based on a deep understanding of the human immune response, reported that it will present results from a study that further demonstrates the ability of the Company’s proprietary Discovery Engine, featuring the Company’s Immune Repertoire Capture (IRC) technology, to identify antibodies from treatment-responsive cancer patients that bind to non-autologous tumor tissue (Press release, Atreca, NOV 6, 2018, View Source [SID1234530932]). The study will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 33rd Annual Meeting being held November 7-11, 2018, at the Walter E. Washington Convention Center in Washington, D.C.

"Atreca has built a proprietary and unique discovery platform that enables us to discover, in a very efficient and industrialized manner from active immune responses, antibodies that can serve as the foundation of therapeutics," said Tito A. Serafini, Ph.D., Chief Strategy Officer and an Atreca founder. "The results to be presented at this conference provide another example of what this Discovery Engine enables in oncology; namely, our ability to identify tumor-targeting antibodies in treatment-responsive patients with the potential to be developed into therapeutics designed to treat large patient groups. Our most advanced program, ATRC-101, which we anticipate entering clinical trials in 2019, is a product of this approach."

In the study, (Abstract #O3; Title: Anti-tumor immune responses in metastatic breast cancer exceptional responder patients) to be presented both as an oral presentation and a poster by William Robinson, M.D., Ph.D., Professor of Medicine at Stanford University and an Atreca Founder, Atreca researchers collaborated with researchers led by Joyce O’Shaughnessy, M.D., at Baylor University Medical Center and Texas Oncology. Atreca researchers investigated the properties of antibodies identified in the active immune response of eleven metastatic breast cancer patients who had exceptional and durable responses to systemic therapy. Of the patient-derived antibodies assessed, over 40% displayed specific immunoreactivity to breast carcinoma tissue from unrelated patients, but not to adjacent tissue, indicating that they bind to public tumor antigens. Multiple antibody lineages, predominantly of the IgG2 subclass, showed evidence of convergent antibody evolution across patients, and a subset of responder antibodies drove killing of tumor cells in in vitro functional assays.

Abstract Title: Anti-tumor immune responses in metastatic breast cancer exceptional responder patients (Abstract #O3)

Oral Presentation

Concurrent Session 216: Role of B cells in Immunotherapy & Toxicity
Date & Time: Saturday, Nov. 10, 6:10 – 6:25 p.m. EST
Location: East Salon ABC
Atreca also has a second presentation. Details are below:

Abstract Title: The identification of potent anti-tumor antibodies applicable for ADC therapeutics from patients undergoing immunotherapy (Abstract #P1)

Poster Display (for both posters)

Date & Time: Friday, Nov. 9, from 8 a.m. – 8 p.m. EST and Saturday, Nov. 10, from 8 a.m. – 12 p.m. EST
Presentation Hours: Friday, Nov. 9, 12:45 – 2:15 p.m. EST and 6:30 – 8 p.m. EST
Location: Hall E