On November 15, 2021 Benitec Biopharma Inc. (NASDAQ: BNTC) ("Benitec" or "the Company"), a development-stage, gene therapy-focused, biotechnology company developing novel genetic medicines based on the proprietary DNA-directed RNA interference ("ddRNAi") platform, reported the financial results for its Fiscal Year Q1 ended September 30, 2021 (Press release, Benitec Biopharma, NOV 15, 2021, View Source [SID1234595648]). The Company has filed its quarterly report on Form 10-Q for the quarter ended September 30, 2021, with the U.S. Securities and Exchange Commission.

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Operational Updates

The key milestones related to the investigational agents under development by the Company and other corporate updates are outlined below:

BB-301 (Oculopharyngeal Muscular Dystrophy Program)

On September 8, 2021, Benitec provided three key updates related to the progress of the BB-301 development program, including: updated results for the BB-301 Pilot Dosing Study in large animals, updates on European and North American regulatory interactions for the BB-301 development program, and a comprehensive overview of the design of, and key primary and secondary endpoints for, the Phase 1b/2a clinical trial which is planned for initiation in 2022. All of the updates were positive and demonstrated the significant progress that has been achieved for the BB-301 development program; below is a summary of each update:
BB-301 Pilot Dosing Study in Large Animals: On September 8th the Company disclosed updated analyses for the animal subjects dosed with BB-301 in the Pilot Dosing Study. The updated data continued to demonstrate dose-dependent transduction of the target pharyngeal muscle tissues by BB-301, dose-dependent gene expression for the three distinct components of the therapeutic BB-301 transgene, and biologically significant levels of gene silencing ("knock-down") of the target PABPN1 protein. These updated data provide continued support for the planned advancement of BB-301 into the Phase 1b/2a clinical study in 2022.
Regulatory Interactions in Europe: Following the disclosure in February 2021 of the positive interim data from the BB-301 Pilot Dosing Study in large animals, Benitec completed a Scientific Advice Meeting with The National Agency for the Safety of Medicines and Health Products in France (L’Agence nationale de sécurité du médicament et des produits de santé or "ANSM") in the first half of 2021. At the conclusion of the meeting:
The BB-301 Pilot Dosing Study in large animals was viewed as an appropriate dose range finding study.
The design of the ongoing GLP Toxicology and Biodistribution study was viewed as appropriate to support Phase 1b/2a testing of BB-301.
The manufacturing plan for clinical grade BB-301 drug product can be conducted under GMP conditions with a production process analogous to that employed in prior large-scale production runs for BB-301.
The design of the Phase 1b/2a clinical trial can support the evaluation of BB-301 safety and clinical efficacy in key populations of OPMD patients.
Regulatory Interactions in the United States: Benitec has been granted a Type C Meeting with the U.S. Food and Drug Administration ("FDA") in the fourth quarter of 2021.
Regulatory Interactions in Canada: Benitec has been granted a Pre-CTA Consultation Meeting with Health Canada in the fourth quarter of 2021.
BB-301 Phase 1b/2a Clinical Study Design: On September 8th the Company provided a comprehensive overview of the key design elements of the upcoming BB-301 Phase 1b/2a clinical trial. The Phase 1b/2a study is planned for 2022. In addition to the determination of the safety and tolerability profiles of BB-301, the secondary endpoints of the trial will facilitate the accurate and reproducible characterization of the key physiological processes underlying the successful completion of the pharyngeal phase of swallowing. The core analytical tools and methods that will be employed during the clinical study will focus on functional measures of swallowing efficiency for OPMD patients during the pharyngeal phase of swallowing.
Financial Highlights

Total Revenues for the quarter ended September 30, 2021 were $0 compared to fifty-five thousand dollars in total revenue for three months ended September 30, 2020. The decrease in revenues from customers is due to the decrease in licensing and royalty revenues in the current period.

Total Operating Expenses were $4.8 million for the quarter ended September 30, 2021 compared to $2.7 million for the comparable period in 2020. For the quarters ended September 30, 2021 and 2020, respectively, Benitec incurred $0 and $134 thousand in royalties and license fees. During the three months ended September 30, 2021 and 2020, respectively, the Company incurred $2.8 million and $0.8 million in research and development expenses. The increase in research and development expenses is primarily related to the commencement of the BB-301 GLP Toxicology and Biodistribution Study in large animals at Charles River Laboratories. Additionally, the Company incurred expenses related to the production of GMP-grade drug product to facilitate submissions of the Clinical Trial Applications outside of the United States and the Investigational New Drug Application in the United States, as these activities are critical to the planned initiation of the Phase 1b/2a clinical trial for BB-301 in 2022. General and administrative expenses were $2.0 million and $1.8 million for the three months ended September 30, 2021 and 2020, respectively. The increase during this three-month period was due to small increases in insurance costs, consultant fees, and legal and accounting fees.

Jerel A. Banks, M.D., Ph.D., Executive Chairman and Chief Executive Officer of Benitec Biopharma commented, "Our team continues to focus on the core development activities that will ensure the advancement of BB-301 into the first-in-human study. Our primary goal has been, and will continue to be, the improvement of the lives of patients suffering from genetic disorders for which no curative interventions exist. We believe that the initiation of the Phase 1b/2a study is critical for patients in the Oculopharyngeal Muscular Dystrophy community and represents an important milestone with respect to our long-term goals as a company."

On November 15, 2021 Ayala Pharmaceuticals, Inc. (Nasdaq: AYLA), a clinical-stage oncology company focused on developing and commercializing small molecule therapeutics for patients suffering from rare and aggressive cancers, primarily in genetically defined patient populations, reported financial results for the period ended September 30, 2021 and highlighted recent progress and upcoming milestones for its pipeline programs (Press release, Ayala Pharmaceuticals, NOV 15, 2021, View Source [SID1234595544]).

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"As we gear up for multiple important milestones in 2022 across all of our clinical-stage programs in various indications, including desmoid tumors, triple negative breast cancer, adenoid cystic carcinoma and potentially multiple myeloma, we remain steadfast in our approach to developing gamma secretase inhibitors to treat these genetically defined cancers," said Roni Mamluk, Ph.D., Chief Executive Officer of Ayala. "We are incredibly pleased with the safety and efficacy profile of AL101 for the treatment of recurrent/metastatic adenoid cystic carcinoma harboring Notch-activating mutations, as presented at ESMO (Free ESMO Whitepaper) in September, as well as the strong preclinical rationale for potential combination treatment in this indication and other tumor types. We also continued to progress our pivotal RINGSIDE trial evaluating AL102 for the treatment of desmoid tumors as enrollment continues across multiple sites globally and look forward to reporting preliminary results from this trial in mid-2022. In addition, we are very pleased with our ongoing collaboration with Novartis and the status of the study of our AL102 in combination with their anti BCMA agent for multiple myeloma."

Recent Business Highlights and Upcoming Milestones:

Published Two Case Studies Highlighting Clinical Activity of AL101 in Desmoid Tumors in Current Oncology: In September 2021, Ayala published two case studies of adult patients with desmoid tumors treated with AL101. Both patients experienced significant tumor burden and symptomatic and life-threatening disease due to disease bulk and location. With AL101 treatment, both subjects achieved long-lasting partial responses with a maximal decrease in tumor size from baseline of 41% after approximately 1 year (55 weeks) of treatment in Case One, and a maximal decrease in tumor size from baseline of 60% after about 1.6 years (82 weeks) of treatment in Case Two.

On Track to Report Initial Interim Data from Part A of the Pivotal Phase 2/3 RINGSIDE Trial for the Treatment of Desmoid Tumors in Mid-2022: Enrollment continues to progress globally in the Phase 2/3 RINGSIDE Trial of AL102. Ayala expects to report an initial interim data read-out from part A of the trial in mid-2022, with part B of the study commencing thereafter.

Phase 1 Trial of AL102 in Combination with Novartis’ BCMA Targeting Agent, WVT087 for the Treatment of Relapsed/Refractory Multiple Myeloma Continues to Progress: Enrollment progresses as planned in the Phase 1 combination trial of AL102 with Novartis’ investigational anti-B-cell maturation antigen (BCMA) agent, WVT078, for the treatment of relapsed and/or refractory (R/R) multiple myeloma (MM).

Presented Preliminary Clinical Data from the Ongoing Phase 2 ACCURACY Trial and ACC at European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2021: In September 2021, Ayala presented updated interim data from the 6mg cohort of its ongoing Phase 2 ACCURACY study of AL101 for the treatment of recurrent/metastatic adenoid cystic carcinoma (R/M ACC) harboring Notch activating mutations. The data demonstrated meaningful clinical activity of AL101 6mg monotherapy with a 70% disease control rate across 33 evaluable patients. Partial responses were observed in three subjects (9%) and stable disease was observed in 20 subjects (61%). The 6mg dose of AL101 was well tolerated with manageable side effects consistent with those observed in the 4mg cohort.

Presented Preclinical Proof of Concept Data of AL101 in Combination with Approved Cancer Therapies in ACC at ESMO (Free ESMO Whitepaper): In September 2021, Ayala also presented a preclinical study evaluating the potential of combination therapy of AL101 in PDX models of ACC, comparing the differential gene expression of ACC tumors versus normal matched tissue regardless of Notch activation status. AL101 in combination demonstrated significant tumor growth inhibition, including regressions, compared to each drug alone, and the study indicated that crosstalk between signaling pathways may increase the efficacy of AL101 in R/M ACC regardless of Notch mutational status.

Phase 2 TENACITY Trial of AL101 for the Treatment of Triple Negative Breast Cancer Continues to Progress: Ayala continues to enroll patients in the Phase 2 TENACITY clinical trial of AL101, for the treatment of patients with Notch-activated recurrent or metastatic (R/M) triple negative breast cancer (TNBC). The Company expects to report preliminary data from this ongoing trial in 2022.

Third Quarter 2021 Financial Results

Cash Position: Cash and cash equivalents were $40.8 million as of September 30, 2021, as compared to $42.0 million as of December 31, 2020.
Collaboration Revenue: Collaboration revenue was $0.6 million for the third quarter of 2021, as compared to $0.7 million for the same period in 2020.
R&D Expenses: Research and development expenses were $7.4 million for the third quarter of 2021, compared to $5.4 million for the same period in 2020. The increase was primarily driven by the advancement in our clinical trials.
G&A Expenses: General and administrative expenses were $2.2 million for the third quarter of 2021, compared to $1.9 million for the same period in 2020.
Net Loss: Net loss was $9.8 million for the third quarter of 2021, resulting in a basic and diluted net loss per share of $0.68. Net loss was $7.4 million for the same period in 2020, resulting in a basic and diluted net loss per share of $0.59.

On November 15, 2021 Kintara a biopharmaceutical company focused on the development of new solid tumor cancer therapies, reported financial results for its fiscal first quarter ended September 30, 2021 and provided a corporate update (Press release, Kintara Therapeutics, NOV 15, 2021, View Source [SID1234595587]).

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CORPORATE HIGHLIGHTS AND RECENT DEVELOPMENTS

Positioned our management team for our next stage of development by announcing that Robert E. Hoffman, our current Chairman, succeeded Saiid Zarrabian as our President and Chief Executive Officer. Mr. Hoffman will continue in his capacity as our Chairman and Mr. Zarrabian has transitioned to heading up our strategic partnerships initiative and will remain a member of our Board of Directors (November).
Activated additional clinical trial sites for glioblastoma (GBM) patients for the VAL-083 arm of the GBM AGILE registrational study sponsored by the Global Coalition for Adaptive Research (GCAR). There are over 26 activated clinical sites (August).
Reported topline results from the Phase 2 study conducted at the MD Anderson Cancer Center that affirm the safety and efficacy of VAL-083 in two different GBM patient subtypes and support continued evaluation of VAL-083 in the GBM AGILE registrational study.
Topline Phase 2 clinical study results for VAL-083 as adjuvant therapy for newly-diagnosed GBM patients were reported demonstrating progression free survival and overall survival of 10.0 months and 16.5 months, respectively, in efficacy evaluable patients (September).
Topline Phase 2 clinical study results for VAL-083 for recurrent GBM were reported demonstrating median overall survival of 8.0 months for the 48 efficacy evaluable patients initially receiving the GBM AGILE treatment dose of 30 mg/m2/day (July).
Entered into securities purchase agreements with healthcare-focused institutional investors to raise approximately $15.0 million in gross proceeds. Funding from this registered direct offering provides cash for ongoing clinical studies and corporate working capital needs (September).
Continued to advance development of REM-001 for the treatment of Cutaneous Metastatic Breast Cancer (CMBC), including taking critical steps toward manufacturing sufficient quantity of drug to allow for initiation and completion of the 15-patient confirmatory study. Enrollment of first patient is expected in the second quarter of calendar 2022.
"Our focus this past quarter was purely on executing the clinical strategy for VAL-083, our first-in-class, potentially transformational therapy for multiple oncology indications, and REM-001, our late-stage photodynamic therapeutic platform," commented Robert E. Hoffman, Kintara’s President and Chief Executive Officer. "I’m particularly pleased to report that we have exceeded our expectations regarding the pace of enrollment for the GBM AGILE study and as such, remain confident that we’ll meet the goal of advancing to the final registration stage of the study in the third quarter of calendar 2022."

SUMMARY OF FINANCIAL RESULTS FOR FISCAL YEAR 2022 FIRST QUARTER ENDED SEPTEMBER 30, 2021

At September 30, 2021, the Company had cash and cash equivalents of approximately $19.3 million. For the three months ended September 30, 2021, the Company reported a net loss of approximately $6.0 million, or $0.25 per share, compared to a net loss of approximately $19.5 million, or $1.33 per share, for the three months ended September 30, 2020. The decrease in the net loss for the three months ended September 30, 2021 compared to the three months ended September 30, 2020 was largely due to the recognition of $16.1 million of non-cash expenses related to the acquisition of in-process research and development costs associated with the merger with Adgero Biopharmaceuticals Holdings, Inc. in August 2020.

On November 15, 2021 Roivant Sciences Ltd. (Nasdaq: ROIV), a next-generation biopharmaceutical company dedicated to improving the delivery of healthcare to patients, reported its financial results for the second fiscal quarter ended September 30, 2021 and provided an update on the Company’s operations (Press release, Roivant Sciences, NOV 15, 2021, View Source [SID1234595619]).

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Roivant’s Chief Executive Officer, Matt Gline, noted: "We are looking forward to this new phase of growth as we prepare to launch potential blockbuster tapinarof in psoriasis, with registrational studies in atopic dermatitis also underway. In addition to the studies underway at Dermavant, we expect at least four other programs will enter Phase 2 or Phase 3 trials in 2022, and we are excited to continue advancing our protein degrader programs towards the clinic, as well."

Recent Developments

Roivant: Roivant closed its business combination with Montes Archimedes Acquisition Corp. ("MAAC") and concurrent PIPE financing, and Roivant began trading on Nasdaq under the ticker "ROIV." Roivant also announced the appointment of its new Chief Financial Officer, Richard Pulik, who previously served as the Global Head of Business Development & Licensing and Portfolio Management, Oncology at Novartis.
Dermavant: At the 30th EADV Virtual Congress, Dermavant presented final results from the Phase 3 PSOARING 3 long-term extension study of tapinarof in patients with plaque psoriasis. The study results demonstrated that tapinarof was generally well tolerated long term, with a safety profile consistent with the pivotal studies and previously reported interim analysis of data from PSOARING 3. The study demonstrated a high rate of complete disease clearance, with 58.2% of patients who entered the study with a PGA score ≥2 achieving a PGA score of 0 or 1. The study also demonstrated improved and durable results for up to 52 weeks and a median remittive effect off-therapy of approximately four months for patients entering with a PGA score of 0.
Aruvant: At Roivant’s Annual R&D Day, Aruvant released clinical data from the third and fourth patients dosed in its ongoing Phase 1/2 trial of ARU-1801 in sickle cell disease. These patients, the first to be dosed with Aruvant’s updated manufacturing process, have had zero vaso-occlusive events 18 and 12 months after dosing, respectively. Punam Malik, M.D., Director of the Cincinnati Comprehensive Sickle Cell Center and Program Leader of the Hematology and Gene Therapy Program at the Cincinnati Children’s Hospital Medical Center, will present ARU-1801 data at 6:00 to 8:00 PM ET on December 13, 2021 at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.
Sio Gene Therapies: Sio Gene Therapies announced positive interim safety and biomarker data from its ongoing Phase 1/2 clinical trial of AXO-AAV-GM1 in GM1 gangliosidosis, showing consistent dose-dependent improvements across biomarker measures and no overt disease progression in six out of seven patients treated across low- and high-dose cohorts.
Major Upcoming Milestones

Dermavant: We expect a decision from the FDA on the approval of tapinarof for the treatment of adults with plaque psoriasis in the second quarter of calendar year 2022. We also expect to report topline data from Dermavant’s Phase 3 clinical trial of tapinarof for the treatment of atopic dermatitis in the first half of calendar year 2023.
Immunovant: Contingent upon FDA feedback, Immunovant plans to initiate a pivotal trial evaluating batoclimab for the treatment of myasthenia gravis in the early part of calendar year 2022, and re-initiate its programs in thyroid eye disease and warm autoimmune hemolytic anemia. Immunovant also plans to announce at least two new indications and submit INDs with their trial designs to the FDA by August 2022.
Aruvant: We expect Aruvant to report additional clinical data from its ongoing Phase 1/2 trial of ARU-1801 in sickle cell disease patients at ASH (Free ASH Whitepaper), including data that demonstrates how the potent anti-sickling effect of ARU-1801 can translate into robust clinical outcomes.
Kinevant: Kinevant remains on track to initiate its Phase 2 trial evaluating namilumab for the treatment of pulmonary sarcoidosis in the first half of calendar year 2022.
Lysovant: Lysovant remains on track to initiate its multiple ascending dose study of LSVT-1701 in patients with complicated Staph aureus bacteremia including infective endocarditis in the first half of calendar year 2022.
Fiscal Quarter Ended September 30, 2021 Financial Summary

Cash Position

As of September 30, 2021, we had cash and cash equivalents of approximately $2.5 billion. The increase from cash and cash equivalents of approximately $2.0 billion as of June 30, 2021 reflects net cash proceeds of $213.4 million received at the closing of the business combination with MAAC and concurrent PIPE financing, approximately $320 million in cash proceeds from Datavant’s merger with Ciox Health (the "Datavant Merger") and funding of the second $100.0 million payment to Proteovant Sciences under a subscription agreement entered into with SK, Inc. in December 2020.

Research and Development Expenses

Research and development (R&D) expenses were $254.3 million for the three months ended September 30, 2021 compared to $97.4 million for the three months ended September 30, 2020. The increase was primarily due to an increase in program-specific costs relating to our product candidates, one-time consideration for the purchase of in-process R&D related to an asset acquisition, and an increase in share-based compensation expense due to the achievement of the liquidity event vesting condition for restricted stock units, performance options and capped value appreciation rights upon the closing of the business combination with MAAC, resulting in the recognition of a one-time catch-up expense of $22.9 million. Non-GAAP R&D expenses were $103.9 million for the three months ended September 30, 2021 compared to $50.2 million for the three months ended September 30, 2020.

General and Administrative Expenses

General and administrative (G&A) expenses were $437.8 million for the three months ended September 30, 2021 compared to $59.7 million for the three months ended September 30, 2020. The increase was largely due to an increase in share-based compensation expense, primarily as a result of the achievement of the liquidity event vesting condition for restricted stock units, performance options and capped value appreciation rights upon the closing of the business combination with MAAC, resulting in the recognition of a one-time catch-up expense of $350.0 million. Non-GAAP G&A expenses were $68.6 million for the three months ended September 30, 2021 compared to $47.7 million for the three months ended September 30, 2020.

Gain on Sale of Investment

Gain on sale of investment resulted from the Datavant Merger in July 2021. At closing of the Datavant Merger, we received approximately $320 million in cash and a minority equity interest in the combined company, which resulted in a gain of $443.8 million.

Net Loss

Net loss for the three months ended September 30, 2021 was $225.6 million compared to $53.5 million for three months ended September 30, 2020. On a per common share basis, net loss was $0.32 and $0.06 for the three months ended September 30, 2021 and 2020, respectively. Non-GAAP net loss was $169.2 million for the three months ended September 30, 2021 compared to $96.9 million for the three months ended September 30, 2020.

(1) Represents non-cash share-based compensation expense.
(2) Represents one-time development milestone payments.
(3) Represents one-time in-process research and development expense.
(4) Represents a one-time gain on sale of investment resulting from the merger of Datavant and CIOX Health in July 2021.
(5) Represents the unrealized loss (gain) on equity investments in unconsolidated entities that are accounted for at fair value with changes in value reported in earnings. This is a non-cash loss (gain) that has no direct correlation to the operation of Roivant’s business.
(6) Represents the change in fair value of debt and liability instruments, which is non-cash and primarily includes the unrealized loss (gain) relating to the measurement and recognition of fair value on a recurring basis of certain liabilities.
(7) Represents the one-time gain on termination of the options held by Sumitomo Dainippon Pharma Co., Ltd. to purchase Roivant’s ownership interest in certain Vants (the "Sumitomo Options").
(8) Represents one-time gain on deconsolidation of a subsidiary and the remeasurement of a previously held interest in an unconsolidated entity upon its consolidation.
(9) Represents the estimated tax effect of the adjustments.

The information presented in this document has been prepared in accordance with U.S. generally accepted accounting principles ("GAAP"), unless otherwise noted as non-GAAP. Roivant believes that its presentation of non-GAAP financial measures provides useful supplementary information to and facilitates additional analysis by investors. Management uses certain non-GAAP information internally for its operating, budgeting and financial planning purposes. Non-GAAP information is not prepared under a comprehensive set of accounting rules and should only be used to supplement an understanding of Roivant’s operating results as reported under GAAP. Non-GAAP financial information generally excludes (i) non-cash items, including share-based compensation expense and the change in fair value of debt and liability instruments, (ii) consideration for the purchase of in-process research and development through asset acquisitions and license agreements, including upfront cash payments, the fair value of equity liability instruments issued, and the fair value of certain future contingent consideration payments, and (iii) other items that are considered unusual or not representative of underlying trends of Roivant’s business. Non-GAAP measures may be defined and calculated differently by other companies in the same industry. Reconciliations of the non-GAAP financial measures to the most directly comparable GAAP financial measures are provided in the tables above.

Investor Conference Call Information

Roivant will host a live conference call and webcast at 8:00 a.m. ET on Monday, November 15, 2021 to report its second quarter 2021 financial results, and provide a corporate update.

To access the live conference call, please dial +1-844-224-1923 (domestic) or +1-214-989-7105 (international) and use conference ID 3545615. A webcast of the call will also be available under "Events & Presentations" in the Investors section of the Roivant website at https://investor.roivant.com/news-events/events. The archived webcast will be available on Roivant’s website after the conference call.

Upcoming Investor Events

Jefferies London Healthcare Conference on Wednesday, November 17, 2021 at 12:20 p.m. GMT
Evercore ISI HealthCONx Conference on Tuesday, November 30, 2021 at 2:15 p.m. ET

On November 15, 2021 ImmunoGenesis, a clinical-stage biotechnology company developing science-driven immune therapies, reported that preclinical data from its lead development programs were presented in six scientific posters at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36th Annual Meeting (SITC 2021), which was held November 10-14, 2021, in Washington, DC. The preclinical results presented advance the development of ImmunoGenesis’ immunotherapy programs (Press release, ImmunoGenesis, NOV 15, 2021, View Source [SID1234595649]).

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"We are very pleased to have data from our programs presented at SITC (Free SITC Whitepaper)," said James Barlow, ImmunoGenesis President and CEO. "These strong study findings support our development programs focused on creating therapies that target cold cancers—including pancreatic cancers—refractory to currently available immunotherapy. We look forward to further building upon these successful results with the advancement of our drug candidates as we look to enter clinical trials next year."

Posters Related to IMGS-001: PD-L1/PD-L2 Dual-Specific Antibody with Effector Function

Human PD-L2 triggers a unique T cell inhibitory program through PD-1 engagement distinct from that of PD-L1

Using a T cell line with an NFAT reporter, this study validated that human PD-L2, unlike murine PD-L2, generates a purely co-inhibitory signal in human T cells, albeit with a reduced inhibitory potential relative to PD-L1. Further, preliminary data in a syngeneic murine model of EL4 showed that antibody dependent cellular cytotoxicity capable PD-L2 blocking antibodies are therapeutically superior to PD-L1 or PD-L2 blockade alone. The study was the first demonstration of T cell immunoregulatory functions of PD-L2, which are distinct from those of PD-L1, and demonstrate that the more tumor-selective expression pattern of PD-L2 relative to PD-L1 provides a therapeutic advantage to effector-function capable PD-L2 antibodies.

Dual-specific antibodies blocking both PD-L1 and PD-L2 engagement of PD-1 restore anti-tumor immunity

This study investigated the capacity of monoclonal antibodies capable of bivalent binding to both PD-L1 and PD-L2 to restore the function of PD-1-suppressed T cells in vitro. The study also evaluated whether enhancing the cytotoxic effector function of these bispecific antibodies might further enhance their efficacy through the depletion of tumor cells and supportive stroma. Results indicated that these bispecific antibodies restore the function of PD-1-suppressed T cells with equivalent efficiency to pembrolizumab. ADCC-capable PD-Ligand bispecific antibodies suppress the growth of U2940 lymphoma in immunodeficient mice more efficiently than Rituximab, and in a syngeneic model of PD-L1/PD-L2 double positive colon carcinoma, these antibodies demonstrate superiority to PD-1 blocking antibodies to limit tumor growth and increase survival. This study showed that ADCC-capable PD-Ligand bispecific antibodies display higher therapeutic potential than existing anti-PD-1 antibodies and represent a new class of PD-1 pathway therapeutics with significant potential for the treatment of a variety of human cancers.

Posters Related to IMGS-501: STING Immune Stimulating Antibody Conjugate (STING-ISAC)

High-potency synthetic STING agonists rewire the myeloid stroma in the tumor microenvironment to amplify immune checkpoint blockade efficacy in refractory pancreatic ductal adenocarcinoma

This study profiled myeloid-derived suppressor cell (MDSC) and M2 macrophage function following stimulation with cyclic dinucleotides (CDNs) of ascending potency using RNA sequencing and protein arrays to uncover molecular and cellular mechanisms by which stimulator of interferon genes (STING) agonists reprogram the suppressive myeloid stroma to drive proinflammatory conversion of tumor myeloid stroma to sensitize tumors to immune checkpoint blockade. For the first time, this study concluded that synthetic CDN STING agonists affect MDSC and M2 macrophage repolarization, in part through altering metabolism and c-Myc signaling. Lastly, the study demonstrated the potential for high-potency STING agonists to overcome resistance to checkpoint blockade in an aggressive orthotopic tumor model of pancreatic ductal adenocarcinoma.

Intratumoral delivery of high potency STING agonists modulates the immunosuppressive myeloid compartment and induces curative responses in checkpoint-refractory glioblastoma models

This study utilized the synthetic cyclic di-nucleotide STING agonists IACS-8803 (8803) and ML-RR-S2-CDA (MLRR) to assess survival and tumor immune infiltrate functional reprogramming in two orthotopic transplantable human and murine glioblastoma tumor models, U87 and the recently developed QPP8 (QKi-/- Pten-/- P53-/-). The study concluded that STING agonists prolong survival in human and murine orthotopic models of glioblastoma. This prolonged survival is associated with a decrease in immunosuppressive M2 functional markers in human tumor infiltrating myeloid populations. Additionally, M2-polarized microglia demonstrated a reduction in M2 functional markers and upregulation of proinflammatory M1 markers following treatment with STING agonists. Together these results indicate that delivery of STING agonists can induce proinflammatory repolarization of the glioblastoma myeloid stroma, including both infiltrating myeloid populations and brain-resident microglia, to drive prolonged survival in refractory models of glioblastoma.

Posters Related to Evofosfamide Hypoxia-Reversal Agent in Combination with Checkpoint Inhibitors

Disrupted oxygen supply and tumor hyper-oxygen consumption contribute independently to prostate cancer immune privilege

This study investigated the capacity of two mitochondrial complex I inhibitors to reduce tumor oxidative metabolism, diminish myeloid suppressive capacity, and improve anti-tumor T cell immunity, alone and in combination with evofosfamide and checkpoint blockade to sensitize unresponsive tumors to immunotherapy. This study found that while evofosfamide or inhibition of oxidative metabolism alone did not significantly impact tumor regression, dual combination and triple combination with checkpoint blockade led to a significant reduction in tumor burden. Conclusions indicate that tumor hypoxia and associated immune suppressive programming can be reduced through both local tissue remodeling and limitation of tumor oxygen metabolism. Complex I inhibition selectively inhibits tumor and myeloid cell function, while sparing T cells. This provides opportunities to craft synergistic immuno-metabolic therapies with the potential to treat cold tumor patients refractory to current FDA approved immunotherapeutics.

Hypoxia reduction in tandem with anti-angiogenic therapy remodels the PDAC microenvironment and potentiates CD40 agonist therapy

In this study, evofosfamide (TH-302, IMGS-101) and a vascular endothelial growth factor receptor-2 (VEGFR-2) blocking antibody were used to treat several syngeneic murine models, including orthotopic pancreatic cancer and a transplantable model of prostate cancer. The researchers concluded that evofosfamide and DC101 utilize unique yet complementary mechanisms to improve the survival of mice challenged with pancreatic or prostate tumors. This combination relieves hypoxic stress and simultaneously reinvigorates T cell function and reduces macrophage mediated immunosuppression. In this setting, CD40 agonist therapy provides an additive benefit in prolonging mouse survival. Put together, these data indicate that targeted reduction of hypoxia with anti-angiogenic therapy remodels the tumor microenvironment and enhances immunotherapy responses in PDAC.

About IMGS-001 PD-L1/PD-L2
ImmunoGenesis’ lead program is IMGS–001, a PD-L1/PD-L2 dual-specific inhibitor with an engineered cytotoxic effector function. As the first molecule to target PD-L2 in addition to PD-L1, IMGS-001 has the potential to shut down the entire PD-1 pathway, potentially providing superior blockade compared to other PD-1 or PD-L1 inhibitors. The built-in engineered effector function allows IMGS-001 to kill immunosuppressive cells that express PD-L1 and/or PD-L2. Preclinical data showed that IMGS–001 offered five times the response rate in cold tumors than currently available immunotherapies. Additionally, IMGS–001 can provide a foundation for add-on therapies.

About IMGS-501 STING-ISAC
STING-ISAC builds on ImmunoGenesis’ novel platform PD-L1/PD-L2 inhibitor by conjugating a STING agonist to the antibody, combining an optimal PD-1 pathway blockade with a powerful immune agonist. ImmunoGenesis is developing this agent to effectively and systemically transport the intravenously delivered STING agonist to all tumor sites and targets within the tumor microenvironment. This therapeutic advance pushes through an important barrier seen with traditional STING agonists, which consistently produce an effect only at the site of the intratumoral injection. ImmunoGenesis’ STING-ISAC, delivered intravenously, could precisely target where it is most effective across tumor sites.

About Evofosfamide
ImmunoGenesis has extended its program to include the hypoxia-reversal agent evofosfamide. Hypoxia predicts poor outcomes in patients across tumor types, as it suppresses T-cell immunity in the tumor microenvironment. Evofosfamide reduces hypoxia by a tissue-remodeling process that includes replacement of disrupted tumor vasculature with fully functional new vessels, allowing for restoration of T-cell infiltration into previously hypoxic zones. Prior Phase 1 data of evofosfamide in combination with ipilimumab resulted in an overall response rate of 17% and a disease control rate of 83% across four dose levels in 21 heavily pre-treated patients with advanced cancer. While not the primary target, this hypoxia-reversal agent sensitizes tumors for checkpoint inhibition and is on target to be in clinic in combination with immune checkpoint blockades in 2022.