On June 22, 2020 RGENIX, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported it is presenting an abstract on RGX-104, RGENIX’s lead therapy in development (Press release, Rgenix, JUN 22, 2020, View Source [SID1234561349]). RGENIX’s abstract, "Correlative analysis of pharmacokinetics and pharmacodynamics of RGX-104, a first-in-class Liver-X-Receptor (LXR) agonist, and clinical outcomes in patients with advanced solid tumors" was accepted for the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, which this year was scheduled as two virtual meetings. The abstract results will be presented as a virtual poster presentation (#LB-133/7) in the Late-Breaking Research: Clinical Research 1 session on June 22, by clinical investigator Dr. Monica Mita, Co-Director, Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, who is lead author on the study.

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RGX-104 is a small-molecule LXR agonist that modulates innate immunity via transcriptional activation of the ApoE gene. RGX-104 inhibits tumor angiogenesis and depletes myeloid derived suppressor cells (MDSC), thereby activating cytotoxic T-lymphocytes. MDSCs are associated with resistance to both checkpoint inhibitors (CPI) and chemotherapy, providing a rationale for combination therapy with RGX-104.

For the dose escalation stage of the Phase 1 study, RGX-104 was tested as a monotherapy or in combination with either nivolumab, ipilimumab, or docetaxel in heavily pre-treated patients with refractory or relapsed solid tumors, including patients who had progression on prior checkpoint inhibitors (CPI). As outlined in the presentation, objective clinical activity was observed in all treatment arms, including the monotherapy arm, with partial responses achieved in patients with NSCLC, SCLC, melanoma, SCCHN, and endometrial cancer.

Of note, in the combination arms, a 28.6% objective response rate was observed in all evaluable patients who had previously progressed on CPI, with 4 of 14 evaluable patients achieving PRs. Responses included ongoing durable PRs – some exceeding 11 months – in CPI refractory/resistant patients whose tumors were PD-L1 low/negative.

Importantly, clinical activity across all treatment arms was associated with RGX-104 related pharmacodynamic effects, including ApoE activation, MDSC depletion, and CD8 T cell activation with associated induction of IFNγ. Robust ApoE induction was achieved with BID dosing of RGX-104 and was correlated with the magnitude of MDSC depletion. Additionally, in comparison to PD-L1 positive tumors, PD-L1 negative tumors were found to have significantly lower baseline (pre-treatment) levels of ApoE, a feature associated with higher likelihood of clinical benefit to RGX-104. The data demonstrate that MDSC depletion via ApoE induction with RGX-104 can overcome resistance to CPI or chemotherapy, resulting in durable clinical activity.

As a result, RGX-104 is being evaluated in combination with the front-line standard-of-care regimen of pembrolizumab plus carboplatin/pemetrexed in a phase 1b/2 study currently enrolling patients with advanced non-squamous non-small cell lung cancer (NSCLC) whose tumors are PD-L1 negative. RGX-104 is also being evaluated in combination with docetaxel in a phase 1b/2 expansion study that has begun enrolling patients with relapsed/refractory extensive stage small-cell lung cancer (ES-SCLC) or high grade-neuroendocrine tumors (HG-NET).

Monica Mita, M.D., principal investigator from Cedars-Sinai Medical Center and lead author and presenter of the poster, said, "These exciting results provide clinical validation of the novel MDSC-targeting mechanism of RGX-104. The durable clinical responses observed in patients who have previously progressed on checkpoint inhibitors are very promising."

Masoud Tavazoie, M.D., Ph.D., and Chief Executive Officer of RGENIX, said, "We are very encouraged by the results presented today as they demonstrate that our first-in-class drug candidate RGX-104 can robustly target MDSCs, a key drug resistance mechanism, to provide durable clinical benefit to patients. The findings further strengthen the foundation for our ongoing Phase 1b/2 studies. We look forward to sharing results from these ongoing studies."

On June 22, 2020 BERG, a clinical-stage biotech that employs artificial intelligence (AI) to research diseases and develop innovative treatments, reported five presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting, being held from June 22- 24, 2020 (Press release, Berg, JUN 22, 2020, View Source [SID1234561365]).

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Two presentations feature outputs of the BERG Interrogative Biology platform. One focuses on BERG’s Interrogative Biology discovered oncology target BPM 42522, its lead molecule, and mechanism of action leading to its anti-cancer properties. The other highlights validation of the BERG pan-cancer model by an independent study (Behan FM et al., (Nature, 2019 Apr 10). Three other presentations demonstrate the translational impact from current collaborations with institutions including BIDMC/Harvard, Stanford University and Uniformed Services University of the Health Sciences along with Walter Reed National Military Medical Center.

"We are making significant advances with BERG’s Interrogative Biology platform, by partnering with several thought leaders in the field of oncology at the upcoming AACR (Free AACR Whitepaper) meeting," said Dr. Niven R. Narain, BERG Co-founder, President and Chief Executive Officer. "This week, we will present the preliminary results of a lead molecule that modulates BPM 42522, as a direct result from BERG’s platform as well. None of this would be possible without the continued support of our partners around the world."

"BERG’s pioneering work in analyzing large molecular datasets with Bayesian Artificial Intelligence for identification of therapeutic targets with high translational potential, clearly illustrates the impact of our work in improving drug discovery as well as the success rates of our developments," said Professor Vikas P. Sukhatme, M.D., Sc.D., Dean of the Emory School of Medicine, Chief Academic Officer of Emory Healthcare, and a member of BERG’s Scientific Advisory Board.

Presentation Details at the AACR (Free AACR Whitepaper) Virtual Meeting:

Presentation title

Abstract title/number

Presenters

Date/time

Identification of Molecular Targets 2

Interrogative Biology platform identifies a ubiquitin pathway and its utility in cancer is supported by small molecule modulators

Abstract # 2943/17

Stephane Gesta, Shefali Sharma, Pragalath Sundararajan, Mingshu Huang, Kayleigh Gray, Maria Nastke, Arcan Guven, Anne Diers, Shiva Kazerounian, Suwagmani Hazarika, Eric M. Grund, Vivek K. Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan

June 22, 2020

9:00am-6:00pm

Virtual Meeting II: E-Posters

Mechanisms of Drug Action 3

BPM31510, a Coenzyme Q10 (CoQ10) containing lipid nanodispersion, enhances radiation effects to prolong survival in a rodent glioblastoma model

Abstract # 2968/15

Jiaxin Sun, Milton Merchant, Anne R. Diers, Shiva Kazerounian, Stephane Gesta, Niven R. Narain, Rangaprasad Sarangarajan, Seema Nagpal, Lawrence Recht

June 22, 2020

9:00am-6:00pm

Virtual Meeting II: E-Posters

Recent Biomarker Discovery Techniques

Impact of hemolysis on multi-omic pancreatic cancer biomarker discovery: Derisking precision medicine biomarker development

Abstract # 2860/14

Michael A. Kiebish, Punit Shah, Valerie Bussberg, Vladimir Tolstikov, Rick Searfoss, Kennedy Ofori-Mensa, Eric M. Grund, Abena Darkway, Emily Y. Chen, Bennett Greenwood, Ellaine Adu Ntoso, Leonardo Rodrigues, Mia Liu, Elder Granger, Chas Bountra, Rangaprasad Sarangarajan, A J. Moser, Niven R. Narain

June 22, 2020

9:00am-6:00pm

Virtual Meeting II: E-Posters

Molecular Classification of Tumors for Diagnostics, Prognostics, and Therapeutic Outcomes 2

Integrated proteomic and informatic assessment of ER+HER2- and ER-/HER2-breast tumors

Abstract # 5311/20

Guisong Wang, Punit Shah, Vladimir Tolstikov, Praveen-Kumar Raj-Kumar, Jiafang Liu, Lori A. Sturtz, J. Leigh Fantacone-Campbell, Rebecca Zingmark, Jeffrey A. Hooke, Mary L. Cutler, Kris Richardson, Leonardo Rodrigues, Valerie Bussberg, Rangaprasad Sarangarajan, Niven R. Narain, Hai Hu, Michael A. Kiebish, Albert J. Kovatich, Craig D. Shriver

June 22, 2020

9:00am-6:00pm

Virtual Meeting II: E-Posters

Identification of Molecular Targets 2

Benchmarking targets from cancer models using causal interference based drug-target and phenotype identification (Interrogative Biology) cross-validates "high-priority" targets identified in CRISPR-CAS9 screen

Abstract #2929/3

Leonardo O. Rodrigues, Lixia Zhang, Poornima Tekumalla, Stephane Gesta, Vivek K. Vishnudos, Michael A. Kiebish, Niven R. Narain, Rangaprasad Sarangarajan

June 22, 2020

9:00am-6:00 pm

Virtual Meeting II: E-Posters

Full abstracts of the posters are available on the AACR (Free AACR Whitepaper) web site at View Source!/9045.

On June 22, 2020 Tetraphase Pharmaceuticals, Inc. (Nasdaq:TTPH), a biopharmaceutical company focused on commercializing its novel tetracycline XERAVATM (eravacycline for injection) to treat serious and life-threatening infections, reported that on June 19, 2020, its Board of Directors received an unsolicited proposal from La Jolla Pharmaceutical Company ("La Jolla") to acquire Tetraphase for $43.0 million in cash, plus an additional aggregate amount of $16.0 million in cash potentially payable under contingent value rights ("CVRs") to be issued in the transaction (the "La Jolla Proposal"), and that on June 21, 2020 the Board determined that the La Jolla Proposal is a "Superior Offer" under the terms of the Agreement and Plan of Merger, dated June 4, 2020, to which the Company is a party with Melinta Therapeutics, Inc. ("Melinta") and Toronto Transaction Corp., a wholly-owned subsidiary of Melinta (the "Melinta Merger Agreement") (Press release, Tetraphase, JUN 22, 2020, View Source [SID1234561274]). In connection with this determination and in accordance with the terms of the Melinta Merger Agreement, the Company has given notice to Melinta of such determination and of its intention to consider changing its recommendation of the tender offer under the Melinta Merger Agreement or terminating the Melinta Merger Agreement unless Melinta proposes revisions to the terms of the Melinta Merger Agreement or makes another proposal on or prior to Friday, June 26, 2020 that, if accepted, would result in the La Jolla Proposal ceasing to be a Superior Offer.

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Under the Melinta Merger Agreement, Melinta would acquire Tetraphase through a cash tender offer by its subsidiary for all of Tetraphase’s outstanding shares of common stock, for an aggregate of $39.0 million in cash (representing consideration of $1.79 per share of Tetraphase common stock), plus CVRs representing the right to receive cash consideration based on the achievement of certain net sales milestones, in an aggregate amount of up to $16.0 million.

Under the La Jolla Proposal, La Jolla would acquire Tetraphase through a cash tender offer for all of Tetraphase’s outstanding shares of common stock. The upfront cash consideration under the La Jolla Proposal would be as follows: (i) $2.00 per share of Tetraphase common stock (including common stock underlying restricted stock units, performance-based stock units and pre-funded warrants), (ii) $2.68 per share of Tetraphase common stock underlying the common stock warrants issued by the Company in November 2019, and (iii) $2.69 per share of Tetraphase common stock underlying the common stock warrants issued by the Company in January 2020. The total upfront consideration to be received by Tetraphase equityholders under the La Jolla Proposal at closing is approximately $43.0 million, with approximately $21.4 million of this amount allocated to the Company’s outstanding common stock warrants. The La Jolla Proposal is not subject to any financing contingencies. The definitive terms and conditions of a merger agreement detailing the La Jolla Proposal have been fully negotiated. If the La Jolla Proposal continues to constitute a Superior Offer through Friday, June 26, 2020, the Tetraphase Board will consider terminating the Melinta Merger Agreement and entering into the merger agreement with La Jolla.

At this time, the Tetraphase Board (1) continues to recommend the offer under the Melinta Merger Agreement, (2) is not modifying or withdrawing its recommendation with respect to the offer under the Melinta Merger Agreement, or proposing to do so, and (3) is not making any recommendation with respect to the La Jolla Proposal or the offer under the proposed merger agreement with La Jolla.

Janney Montgomery Scott LLC is acting as financial advisor to Tetraphase and Wilmer Cutler Pickering Hale and Dorr LLP is acting as legal advisor.

On June 22, 2020 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported that preclinical data from the company’s glucocorticoid receptor (GR) antagonist and CD73 inhibitor programs in five poster presentations during the ongoing American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II (Press release, ORIC Pharmaceuticals, JUN 22, 2020, https://investors.oricpharma.com/news-releases/news-release-details/oric-pharmaceuticals-presents-preclinical-data-glucocorticoid-1 [SID1234561301]).

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"We are pleased to be able to present these compelling preclinical data from our ORIC-101 and CD73 programs, which continue to validate our scientific platform focused on overcoming therapeutic resistance in cancer," said Lori Friedman, chief scientific officer. "In particular, we are encouraged to see ORIC-101 reversing GR-mediated resistance in a variety of tumor models, and preliminary evidence of differentiation of ORIC-533 versus competitor compounds in preclinical studies. We look forward to the continued advancements of these programs and our discovery research pipeline as we work to improve patients’ lives."

ORIC-101 (GR Antagonist):
ORIC-101 is a potent and selective small molecule antagonist of GR, which has been linked with resistance to multiple classes of cancer therapeutics across a variety of solid tumors. ORIC-101 is currently being investigated in two separate Phase 1b combination trials, with enzalutamide in prostate cancer and with nab-paclitaxel in solid tumors.

Key findings of the presentations:

A transcriptional signature of GR activity was identified in a panel of 32 cell lines across triple negative breast cancer, non-small cell lung cancer and pancreatic ductal adenocarcinoma, which translated from preclinical models to human tumors
ORIC-101 overcame GR-mediated resistance to chemotherapeutic agents including taxanes, antimetabolites and platinums, in both in vitro and in vivo efficacy studies spanning a variety of solid tumor types
Transcriptional and histological profiling showed that ORIC-101 reversed GR-activated pathways involved in drug resistance, and reversed in vivo markers of epithelial-to-mesenchymal transition, antiapoptosis, and hypoxia
The company is further assessing the GR activation signature and mechanistic findings in an ongoing Phase 1b trial of ORIC-101 in combination with nab-paclitaxel in adults with advanced or metastatic solid tumors
Poster Presentations:

ORIC-101 comprehensively inhibits glucocorticoid pathways to overcome therapeutic resistance in pan-cancer models (Poster #4120)
ORIC-101 overcomes resistance to diverse chemotherapeutics across cancer types (Poster #4121)
ORIC-101 overcomes glucocorticoid receptor-mediated chemoresistance in pancreatic cancer models (Poster #4123)
ORIC-533 (CD73 Inhibitor):
CD73 is a key node in the adenosine pathway believed to play a central role in resistance to chemotherapy and immunotherapy. ORIC discovered and characterized differentiated orally bioavailable small molecule inhibitors of CD73, including clinical candidate ORIC-533, that revert immunosuppression and promote anti-tumor responses in vivo.

Key findings of the presentations:

ORIC’s CD73 inhibitors demonstrated suppression of adenosine production in vitro across multiple cell types and rescued activation of CD8+ T cells exposed to AMP with greater potency than competitor compounds
ORIC-533 was shown to result in sustained inhibition of adenosine production after drug washout, consistent with its slow off-rate, and differentiating from other CD73 inhibitors
ORIC-533 potency in high AMP environments distinguishes it from other compounds, with activity in AMP concentrations as high as 1 millimolar, which may better reflect certain tumor microenvironments
Daily oral delivery of ORIC’s CD73 inhibitors significantly inhibited tumor growth, with corresponding in vivo reduction of adenosine levels in tumors, and immune modulation consistent with decreased immunosuppression
Poster Presentations:

CD73 inhibition with a novel orally bioavailable small molecule blocks adenosine production and rescues T-cell activation (Poster #1023)
An orally bioavailable inhibitor of CD73 reverts intratumoral immunosuppression and promotes anti-tumor response (Poster #LB-115)

On June 22, 2020 Heat Biologics, Inc. ("Heat") (NASDAQ:HTBX), a clinical-stage biopharmaceutical company focused on developing first-in-class therapies to modulate the immune system, including multiple oncology product candidates and a novel COVID-19 vaccine, reported that the first patient has been treated in the Company’s first-in-human Phase 1 clinical trial evaluating PTX-35, the first antibody product candidate developed by Heat Biologics’ Pelican Therapeutics subsidiary (Press release, Heat Biologics, JUN 22, 2020, View Source [SID1234561318]).

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This first-in-human study is expected to enroll up to 30 patients with advanced solid tumors refractory to standard of care. Eligible patients will be enrolled to receive PTX-35 every two weeks until disease progression. Escalating dose levels of PTX-35 will be explored until optimal immunological dose or maximum tolerated dose is established. The objectives of the study include safety evaluation, determination of the recommended Phase 2 dose as well as exploratory analyses of clinical benefit and immunological effect of PTX-35. This trial is supported by a $15.2 million grant from the Cancer Prevention and Research Institute of Texas (CPRIT).

Jeff Wolf, CEO of Heat Biologics, commented, "This is an important milestone as we advance our first antibody product candidate into clinical development. I am very pleased with our team’s effort in accelerating the development of PTX-35 as well as the speed of execution to initiate our first-in-human study following FDA clearance of our Investigational New Drug (IND) Application. I believe that PTX-35, our potential first-in-class T-cell co-stimulatory antibody, will offer a differentiated approach to benefit cancer patients."

About PTX-35

PTX-35 is a novel, potential first-in-class antibody T-cell co-stimulator targeting TNFRSF25 (death receptor 3), a receptor that is preferentially expressed by antigen-experienced T cells. TNFRSF25 agonism leads to activation of antigen-experienced memory CD8+ T cells, which are instrumental for tumor destruction. Preclinical studies have demonstrated that PTX-35, in combination with antigen-driven immunotherapies, resulted in enhanced anti-tumor properties, including potent proliferation of antigen-specific T cells, production of effector cytokines and augmented effector immune function. A favorable safety profile was demonstrated in preclinical studies, with no deleterious cytokine release in mice, non-human primates or in vitro human immune cells.

A $15.2 million grant has been awarded by Cancer Prevention and Research Institute of Texas (CPRIT) to support the pre-clinical development, manufacturing and Phase 1 clinical development for PTX-35.