On October 1, 2018 InteRNA Technologies reported its results from a set of confirmatory in vitro and in vivo studies further validating the unique mechanism of action (MoA) of InteRNA’s lead microRNA drug candidate, INT-1B3, for the treatment of cancer (Press release, InteRNA Technologies, OCT 1, 2018, View Source [SID1234529688]). Most strikingly, the company was able to demonstrate that INT-1B3’s earlier reported long-term memory immune protection activity against re-challenge with tumor cells is cytotoxic CD8+ T cell-mediated. INT-1B3 is a lipid nanoparticle (LNP) formulated, chemically modified microRNA 193a-3p mimic, a known tumor-suppressor microRNA, that has been shown to induce immune-modulation of the tumor microenvironment, reduction of metastases development leading to improved animal survival, and pronounced long-term immunity with a good safety and tolerability profile. The data were presented in two posters at the 14th Annual Oligonucleotide Therapeutics Society (OTS) Meeting, held in Seattle, WA from September 30 – October 3, 2018.

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"These confirmatory results are consistent with the original preclinical proof-of-concept data we presented at the AACR (Free AACR Whitepaper) Annual Meeting this year and thereby serve as a fundamental validation of INT-1B3’s differentiated mechanism of action," said Dr. Roel Schaapveld, CEO of InteRNA. "It is also very exciting that we were able to demonstrate that the pronounced long-term anti-tumor immunity we have seen is CD8+ T cell-dependent which further clarifies a key aspect of these promising effects. We are convinced that INT-1B3, next to its potential in combination regimens, represents a unique and novel monotherapeutic opportunity in immuno-oncology and we look forward to evaluating its efficacy in cancer patients."

The data presented at the 14th Annual OTS Meeting confirm and expand on the preclinical data presented at AACR (Free AACR Whitepaper) in April 2018 as summarized in the following announcement http://bit.ly/2NnruRI.

In a syngeneic orthotopic mouse model of triple negative breast cancer (TNBC 4T1), systemic administration of INT-1B3 was proven to efficiently modulate the immunosuppressive tumor microenvironment. Upon resection of the primary tumors, this resulted in: 1) the inhibition of tumor re-growth, 2) reduction of distant (lung and intraperitoneal) metastases development with significant impact on animal survival, and 3) long-term immunity to newly injected 4T1 tumor cells in the absence of further drug treatment. Most notably, CD8+ T cell depletion greatly impacted protection of surviving INT-1B3-treated animals against such re-challenge with 4T1 tumor cells, suggesting a CD8+ T cell-dependent long-term immune protection. Furthermore, the results presented in a second poster verify that upon transfection in a wide panel of human tumor cell lines, the microRNA 193a-3p mimic was able to inhibit tumor cell proliferation and survival, modulate the tumor cell cycle, induce apoptosis and/or senescence and decrease tumor cell migration and invasion. In addition, and consistent with results in cell-based assays, significant anti-tumor efficacy of INT-1B3 was demonstrated in several human xenografts and in an extended panel of syngeneic subcutaneous mouse tumor models. Based on these results, INT-1B3 provides a novel and promising therapeutic approach in the immuno-oncology armamentarium.

MicroRNAs are naturally occurring small RNA interfering molecules which represent a part of the body’s arsenal to regulate gene expression, each targeting a specific set of genes that have gained recent attention as a novel therapeutic approach in a variety of disease states. MicroRNA 193a-3p specifically is a known tumor suppressor microRNA that is downregulated in many cancers. InteRNA’s formulated and chemically modified synthetic mimic combines anti-tumor activity with modulation of the immunosuppressive tumor microenvironment, and long-term immunity upon systemic delivery to cancer cells upregulating microRNA 193a-3p’s original function across the pathways involved in the initiation and progression of cancer and the evasion of the immune system in parallel.

The posters entitled "A novel synthetic miR-193a-3p mimic (INT-1B3) targeting multiple hallmarks of cancer reveals potential for therapeutic intervention in oncology" (poster #114) and "INT-1B3, a novel synthetic microRNA mimic and its monotherapy potential in immune-oncology armamentarium" (poster #63) as well as the original proof-of-concept data were presented by InteRNA’s Chief Executive Officer, Dr. Roel Schaapveld and Chief Development Officer, Dr. Michel Janicot and are available on InteRNA’s website through the following link:
View Source

On October 1, 2018 Adaptive Biotechnologies reported that the U.S. Food and Drug Administration (FDA) has granted De Novo designation for the clonoSEQ Assay to detect and monitor minimal residual disease (MRD) in patients with multiple myeloma (MM) and B-cell acute lymphoblastic leukemia (ALL) using DNA from a patient’s bone marrow sample (Press release, Adaptive Biotechnologies, OCT 1, 2018, View Source [SID1234529689]). The clearance of clonoSEQ marks several "firsts" for patients and for the FDA. The clonoSEQ Assay represents a first-in-class MRD assay that uses next-generation sequencing (NGS) technology to assess disease burden, representing an important additional use of NGS in cancer. clonoSEQ is the first and only assay to be cleared by the FDA for MRD assessment in any lymphoid cancer and the first FDA-cleared diagnostic assay powered by immunosequencing. It is also a major milestone for Adaptive Biotechnologies as the first regulatory clearance for the company’s proprietary (NGS) platform for immune system profiling.

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MRD refers to the small number of cancer cells that can remain in a patient’s body after treatment, which often cause no signs or symptoms but eventually can lead to recurrence of the disease. These residual cells can be present at very low levels and require highly sensitive tests to identify them. Even very small amounts of MRD can have a profound effect on treatment success and patient outcomes. A test that can reliably determine the presence and amount of residual disease at very low levels can be used by physicians in conjunction with other clinical information to predict treatment outcomes, guide management decisions and improve patient care.

"MRD testing provides patients with real-time insights about their response to therapy or the depth of their remission, therefore the MMRF is deeply committed to this important advancement in patient care," said Paul Giusti, president and chief executive officer, Multiple Myeloma Research Foundation (MMRF). "The sensitivity of the test is extremely important, as the number of cells remaining after treatment has been linked to patient outcomes. This clearance provides patients and physicians with access to a highly sensitive, standardized MRD test that can be an important tool in guiding treatment decisions."

There are more than 200,000 MM and ALL patients living in the U.S., and more than 35,000 new cases are diagnosed each year. The clonoSEQ Assay uses NGS to precisely identify and monitor MRD in these patients throughout treatment and remission, with greater sensitivity than other technologies for any given amount of bone marrow sample.1 Detecting MRD with deep sensitivity can be clinically informative for the many patients being treated for these cancers.

"The FDA clearance of clonoSEQ is an important advance for patients with MM and ALL and for the oncologists who care for them. This milestone underscores the importance of MRD as a predictor of patient outcomes," said Aaron Logan, associate professor, Division of Hematology and Blood and Marrow Transplant, UCSF. "Quantification of MRD should be standard practice to assess response to treatment, monitor disease progression and direct patient care. It is thus essential to have an MRD assay that meets regulatory standards and can accurately and reliably measure and track disease burden over time."

For patients who achieve complete response to cancer treatment by traditional response criteria, the presence or absence of MRD has been demonstrated to have a significant relationship with patient outcomes.2 For this reason, many pharmaceutical companies have begun using MRD as a clinically meaningful endpoint to evaluate efficacy and to guide use of their therapies.

"This year has been historic for the field of hematology, with a paradigm-shifting FDA decision to approve the first therapy, BLINCYTO, based on the MRD status of a patient with ALL, validating the clinical relevance of MRD in ALL as a clinically meaningful endpoint," said Greg Friberg, M.D., vice president, Global Development, Oncology at Amgen. "Now, physicians and patients will have access to the first FDA-cleared MRD assay, providing them with another important tool to make informed decisions about treatments to help achieve MRD negativity. We look forward to continuing our collaboration with Adaptive Biotechnologies to further explore MRD and deliver on our mission to serve patients through transformative science."

The recent FDA review and approval of drugs with MRD included as a clinical endpoint, as well as the agency’s inclusion of MRD on the recently released list of surrogate endpoints that can serve as the basis of drug approvals, demonstrate the clinical actionability of MRD and reinforce the need for an accurate and standardized, FDA-cleared method like clonoSEQ.3,4

"The clearance of the clonoSEQ Assay is an exciting advance for MM and ALL patients and physicians; as MRD is increasingly used to inform treatment decisions, the importance of having an accurate and standardized assessment method becomes paramount," said Chad Robins, chief executive officer and co-founder of Adaptive Biotechnologies. "NGS MRD testing is already part of National Comprehensive Cancer Network (NCCN) treatment guidelines for patients with MM, ALL, and CLL, and clonoSEQ is already in use for patient management in the majority of NCCN cancer centers, further demonstrating the clinical importance of MRD and acceptance of NGS MRD testing by the oncology community. Adaptive is working diligently with public and private payers to make clonoSEQ broadly available to patients in need."

About Minimal Residual Disease

Minimal residual disease (MRD), also referred to as measurable residual disease, refers to cancer cells that remain in the body after treatment for patients with lymphoid cancers. These cells can be present at levels undetectable by traditional morphologic methods, microscopic examination of blood, or a bone marrow or a lymph node biopsy.

MRD is used by physicians to detect and monitor disease burden in patients and to inform their treatment decisions. Clinical practice guidelines recommend assessing MRD at multiple time points during treatment and maintenance in MM and ALL, and guidelines for both diseases include NGS as a recommended testing method.5,6 The prognostic value of MRD assessment has been demonstrated in multiple lymphoid cancers.7,8 Controlled trials have shown that even small amounts of disease are profoundly significant for predicting a patient’s long-term clinical outcomes.1,9,10,11,12 Therefore, highly sensitive, standardized molecular technologies are needed for reliable detection of MRD.

Measurement of MRD is currently being evaluated as a way to measure efficacy in drug trials, with the potential to expedite the approval of emerging therapies.13

About the clonoSEQ Assay

The Adaptive Biotechnologies clonoSEQ Assay has been granted De Novo designation by the FDA as an in vitro diagnostic (IVD) to detect and monitor minimal residual disease (MRD) in patients with multiple myeloma (MM) and B-cell acute lymphoblastic leukemia (ALL) using DNA from bone marrow samples. It identifies and quantifies specific DNA sequences found in malignant cells, allowing clinicians to monitor patients for changes in disease burden during and after treatment. This robust assay provides sensitive and accurate measurement of residual disease that allows physicians to predict patient outcomes, assess response to therapy over time, monitor patients during remission and detect potential relapse. The clonoSEQ Assay is a single-site assay performed at Adaptive Biotechnologies. It is also available as a CLIA-regulated laboratory developed test (LDT) service for use in other lymphoid cancers.

clonoSEQ was reviewed under the FDA’s De Novo premarket review pathway, a regulatory pathway for some low- to moderate-risk novel devices for which there is no legally marketed predicate device.

For important information about the FDA-cleared uses of clonoSEQ, including the full intended use, limitations, and detailed performance characteristics, please visit www.clonoSEQ.com/technical-summary.

On October 1, 2018 AVEO Oncology (NASDAQ: AVEO) reported that it has initiated topline analysis of the phase 3 TIVO-3 clinical trial on the unanimous recommendation of the independent TIVO-3 Study Steering Committee, and after notice to the FDA (Press release, AVEO, OCT 1, 2018, View Source [SID1234529690]). The TIVO-3 trial is the Company’s randomized, controlled, multi-center, open-label study to compare FOTIVDA (tivozanib) to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). The Company expects to complete data analysis and report topline results from the study in approximately 6 weeks.

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The Steering Committee recommendation was preceded by a slowing in the rate of progression free survival (PFS) events in the trial over the last 4-6 months. The reasons given by the Steering Committee for the unanimous recommendation were that current patients have been on study for at least one year and may not progress for some time, and that the small reduction in events at the time of final analysis was unlikely to materially affect the clinical interpretation of the results. As of September 26, 2018, the last review of events, a total of 242 PFS events had occurred in the trial. The Company plans to set the data cutoff date for the primary analysis at October 4, 2018. Performing the primary analysis at 242 events reduces the power of the study from 90% (based on the prior target of 255 PFS events) to 88%.

Following the last review of events, 42 patients remain on treatment in the TIVO-3 study with 28 of the remaining patients yet to have a PFS event as determined by the independent radiology committee. All patients still enrolled in the study will continue to receive treatment per study protocol. The Company will remain blinded to study data until data analysis is complete.

"Initiation of the topline analysis of the TIVO-3 trial brings us one step closer to potentially realizing the strategy we laid out in 2015, which included commercialization of tivozanib in the United States and Europe, and exploration of tivozanib’s clinical potential in immunotherapy combinations," said Michael Bailey, president and chief executive officer of AVEO. "With the introduction of immunotherapy as a treatment for earlier-line RCC, survival among patients is extending well beyond disease progression on first- and second-line treatment, which we believe may substantially increase the third-plus-line opportunity for tivozanib. TIVO-3 has the potential to serve as the first prospective Phase 3 randomized dataset in this setting, creating an evidence-based guidepost for sequencing therapies in refractory disease. We look forward to announcing the topline results of TIVO-3 in the coming weeks."

The TIVO-3 trial was designed to enroll patients with RCC who have failed at least two prior regimens, including VEGFR-TKI therapy. Eligible patients may also have received checkpoint inhibitor therapy in earlier lines of treatment. Patients are randomized 1:1 to receive either tivozanib or sorafenib, with no crossover between arms. The primary endpoint of the study is PFS. Secondary endpoints include overall survival (OS), overall response rate, and safety and tolerability. TIVO-3, together with the previously completed TIVO-1 trial of tivozanib in the first-line treatment of RCC, is designed to support a regulatory submission of tivozanib in the U.S. as a treatment for RCC, if the data are positive. TIVO-3 patients were exclusively enrolled in North America, Western Europe, and Central Europe.

About Tivozanib (FOTIVDA)

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Hakko Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.1,2 Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models, enabling potentially enhanced activity when used in combination with immune modulating therapy.3 As part of a North American registration plan, tivozanib is currently being studied in the Phase 3 TIVO-3 trial, a randomized, controlled, multi-center, open-label study to compare tivozanib to sorafenib in subjects with refractory RCC. Tivozanib has been investigated in several tumors types, including renal cell, hepatocellular, colorectal and breast cancers.

On October 1, 2018 Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) reported that it earned a $22 million payment from Verastem Oncology under the license agreement between the Company and Verastem for COPIKTRA (duvelisib) (Press release, Infinity Pharmaceuticals, OCT 1, 2018, View Source [SID1234530645]). The payment was earned upon the approval by the U.S. Food and Drug Administration (FDA) on September 24, 2018 of duvelisib for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies, as well as accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies.

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"We are really pleased that duvelisib is now available for patients with CLL/SLL and follicular lymphoma and are proud of the role Infinity played in its development," said Adelene Perkins, Chief Executive Officer and Chair of Infinity. "This $22 million FDA approval payment from Verastem supports Infinity’s continued expansion of the development of IPI-549, our first-in-class, oral, immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase-gamma (PI3K-gamma), including in doublet and triplet combination trials to identify the best combination regimens to treat patients with specific types of cancer."

In 2016, Infinity entered into a license agreement granting Verastem an exclusive worldwide license for the research, development, commercialization, and manufacture of duvelisib and products containing duvelisib in oncology. Pursuant to the terms of the license agreement, Verastem has notified Infinity of its election to make the $22 million payment in cash, which Infinity expects to receive later this year. Infinity also is eligible for royalties on worldwide net sales of duvelisib ranging from the mid-to-high single digits, shared equally with Takeda.

Infinity’s updated 2018 financial guidance is:

Net Loss: Infinity expects net loss for 2018 to range from $10 million to $20 million.

Cash and Investments: Infinity expects to end 2018 with a year-end cash, cash equivalents and available-for-sale securities balance ranging from $50 million to $60 million.

Cash Runway: Based on its current operational plans, Infinity expects that its existing cash, cash equivalents and available-for-sale securities will be adequate to satisfy the company’s capital needs into 2020. Infinity’s financial guidance excludes additional funding or business development activities and does not include a potential $2 million payment from PellePharm, a private company, upon initiation of a Phase 3 study for the hedgehog inhibitor program, which Infinity licensed to PellePharm in 2013.

On September 30, 2018 Tocagen Inc. (Nasdaq: TOCA), a clinical-stage, cancer-selective gene therapy company, today is presenting data describing the tumor microenvironment and immunogenicity of Toca 511 (vocimagene amiretrorepvec) & Toca FC (flucytosine, extended-release) in patients with solid tumor malignancies at the International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper) hosted by The Cancer Research Institute (CRI), the Association for Cancer Immunotherapy (CIMT) (Free CIMT Whitepaper), the European Academy of Tumor Immunology (EATI), and the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in New York City (Press release, Tocagen, SEP 30, 2018, View Source;p=RssLanding&cat=news&id=2369481 [SID1234529699]). The lead author is Jaime Merchan, M.D., director, Phase 1 clinical trials program at Sylvester Comprehensive Cancer Center; associate professor of medicine at the University of Miami Miller School of Medicine.

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The poster describes data available as of August 31st for 20 patients with advanced solid tumors, including colorectal, sarcoma, pancreas and non-small cell lung cancer, treated with intravenous Toca 511 followed by oral Toca FC in the Phase 1b Toca 6 clinical trial. Among these patients, 15 also received Toca 511 via intratumoral administration.

In this preliminary analysis of immune activation in patients with advanced solid tumors, analysis of peripheral blood shows immune cell modulation that is consistent with what has been observed in preclinical studies and in patients with recurrent high grade glioma treated with Toca 511 & Toca FC in previous clinical trials. In addition, available tumor samples from three patients show Toca 511 infected both "hot" (T cells present) and "cold" (T cells low or absent) areas of metastatic tumor, suggesting Toca 511 can penetrate multiple tumor microenvironments. Toca 511 & Toca FC treatment was well tolerated.

"The encouraging preliminary immune activity data from the Toca 6 trial continue to support the proposed mechanism of action for Toca 511 & Toca FC and its potentbiial in the treatment of multiple cancers," said Asha Das, M.D., chief medical officer of Tocagen. "We look forward to advancing expansion opportunities for our lead product in patients with solid tumors."

CRI-CIMT-EATI-AACR Abstract/Poster Number: A018
Abstract Title: Effects of Toca 511 & Toca FC on tumor microenvironment and peripheral blood populations in patients with advanced malignancies
Date: Sunday, September 30, 2018
Time: 11:45 a.m. – 2:15 p.m. ET
The poster is available on Tocagen’s website.

About Toca 6
Toca 6 is a multi-center, open-label Phase 1b study evaluating Toca 511 & Toca FC in patients with advanced solid tumors. The study will evaluate the safety and presence of Toca 511 genes in tumors of patients with widely disseminated disease, immunologic activity in blood and tumor, and clinical activity such as tumor response and clinical benefit. More information can be found at www.tocagen.com/toca6 or by searching clinicaltrials.gov using the clinical trial identifier NCT02576665.

About Toca 511 & Toca FC
Tocagen’s lead product candidate is a two-part cancer-selective immunotherapy comprising an investigational biologic, Toca 511, and an investigational small molecule, Toca FC. Toca 511 is a retroviral replicating vector (RRV) that selectively infects cancer cells and delivers a gene for the enzyme, cytosine deaminase (CD). Through this targeted delivery, only infected cancer cells carry the CD gene and produce CD. Toca FC is an orally administered prodrug, 5-fluorocytosine (5-FC), which is converted into an anti-cancer drug, 5-fluorouracil (5-FU), when it encounters CD. 5-FU kills cancer cells and immune-suppressive myeloid cells resulting in anti-cancer immune activation and subsequent tumor killing.