On November 12, 2021 CatalYm, reported the presentation of expanded clinical and new preclinical data for its lead candidate CTL-002, an antibody targeting the novel cancer target GDF-15, at the 36th Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (Press release, Catalym, NOV 12, 2021, View Source [SID1234595386]). The results will be presented in two poster presentations on November 13, 2021 and will include data from the ongoing first-in-human trial "GDFather" (GDF-15 Antibody-mediated Effector cell Relocation) as well as preclinical data characterizing the potential of GDF-15 as a therapeutic target for the treatment of multiple solid tumor indications. The conference is taking place, both in person (Washington, D.C.) and virtually, from November 10 – 14, 2021.

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"Based on GDF-15’s overexpression in a wide variety of tumors and strong correlation with poor survival, we are making it our mission to develop a therapy to neutralize GDF-15 to make a positive impact for the large population of patients unresponsive to checkpoint inhibitors. The data presented today are really interesting based on the demonstration of CTL-002-mediated GDF-15 neutralization and T cell activity in patients, further strengthening our therapeutic concept," commented Prof. Dr. Eugen Leo, Chief Medical Officer at CatalYm.

Dr. Phil L’Huillier, Chief Executive Officer at CatalYm added, "GDFather is the most advanced clinical trial of a GDF-15-targeting therapeutic, and we are delighted to further update the scientific community on our rapid progress with our unique approach. With the enrollment in all dose levels of the escalation part now completed, we look forward to providing first efficacy read-outs in the near term."

The poster titled "A phase I, first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in subjects with advanced stage solid tumors (Acronym: GDFATHER)" provides an update on the ongoing Phase 1 trial assessing CTL-002 as a monotherapy or in combination with nivolumab. Dose levels 1-4 have been completed safely with excellent tolerability and no adverse effects. Preliminary pharmacodynamics for dose levels 1-3 are indicative of CTL-002-mediated GDF-15 neutralization, as well as a tumor-selective influx of T cells in the majority of enrolled patients.

The second poster, "Tumor-derived GDF-15 prevents therapy success of checkpoint inhibitors by blocking T-lymphocyte recruitment", describes the preclinical validation of GDF-15 as a druggable therapeutic target and CatalYm’s lead candidate CTL-002, a monoclonal antibody designed to neutralize GDF-15. The results further strengthen the pivotal role GDF-15 plays in preventing effective immune cell infiltration. CTL-002 is shown to restore the ability of immune cells to enter the tumor microenvironment in vivo validating the GDF-15-specific antibody as a strong candidate for cancer treatment.

All posters presented in the poster hall will be made available as virtual ePosters throughout the SITC (Free SITC Whitepaper) 36th Annual Meeting and can be accessed in the "Science" section on CatalYm’s website under publications.

About the GDFather Trial

The GDFather trial (GDF-15 antibody-mediated effector cell relocation) is an ongoing first-in-human study and consists of two parts. In the dose escalation phase (Part A), up to 24 patients will receive escalating doses of CTL-002 in a "3+3" manner with the lead candidate given as a monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In the second dose expansion phase (Part B, phase 2a), several cohorts with tumors identified to be GDF-15-dependent will be treated to further evaluate safety and preliminary efficacy of CTL-002 treatment.

About CTL-002

CTL-002 is a humanized, monoclonal antibody designed to neutralize the tumor-produced Growth Differentiation Factor-15 (GDF-15). GDF-15 secretion by the tumor has been shown to prevent T cell migration into the tumor and suppresses T cell function and the adaptive immune response in the tumor microenvironment. This enables the tumor to evade the immune system and become resistant to standard of care and current immunotherapy approaches such as checkpoint inhibitors. CTL-002 counteracts these immuno-suppressive mechanisms by neutralizing GDF-15, enhancing the infiltration of immune cells into the tumor, improving both priming of T cells by dendritic cells and tumor killing by T cells and NK cells

On November 12, 2021 Nimbus Therapeutics, a biotechnology company designing and developing breakthrough medicines through structure-based drug discovery, reported the first patient dosed in the first-in-human Phase 1/2 study of their small-molecule hematopoietic progenitor kinase 1 (HPK1) inhibitor, NDI-101150 (Press release, Nimbus Therapeutics, NOV 12, 2021, View Source [SID1234595402]). HPK1 is a key regulator of T cell, B cell and dendritic cell-mediated immune responses, making it a high-priority target in immuno-oncology.

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"We are proud to expand our clinical development program with the initiation of this first-in-human trial. The preclinical evidence we’ve seen for our HPK1 inhibitors to date, including in vivo data shared at the 2021 AACR (Free AACR Whitepaper) Annual Meeting, has shown significant tumor growth inhibition, both as a single agent and in combination with anti-PD1, and robust and durable effects on immune memory," said Jeb Keiper, M.S., MBA, Chief Executive Officer of Nimbus. "New approaches to expand the promise of immuno-oncology to solid tumors are greatly needed and we’re eager to explore the potential of NDI-101150 to help address this unmet need."

The Phase 1/2 trial is a multicenter, open-label study that will assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of NDI-101150 given as monotherapy or in combination with pembrolizumab in adults with advanced solid tumors. It is planned to enroll approximately 106 subjects.

"HPK1 is an important therapeutic target in immuno-oncology because of its role in multiple adaptive immune system components, including T cell, B cell and dendritic cell-mediated immune responses. We are pleased to have progressed a highly-selective HPK1 inhibitor into the clinic," said Peter Tummino, Ph.D., Chief Scientific Officer of Nimbus. "Development of this agent was made possible by Nimbus’ computational drug discovery approach, which continues to provide opportunities to develop new medicines in diseases with high unmet medical need."

On November 12, 2021 Agenus (NASDAQ: AGEN), an immuno-oncology company with an extensive pipeline of checkpoint antibodies, adjuvants, and vaccines designed to activate immune response to cancers and infections, reported the presentation of new clinical data for AGEN1181 (Fc-enhanced anti-CTLA-4) as monotherapy and in combination with balstilimab (anti-PD-1) at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36th Annual Meeting (Press release, Agenus, NOV 12, 2021, View Source [SID1234595440]).

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"AGEN1181 as monotherapy and in combination with balstilimab has shown durable responses in heavily pre-treated, poorly immunogenic ‘cold’ cancers, as well as those who have failed to respond to prior PD-1 inhibition," said Steven O’Day, MD, Chief Medical Officer of Agenus. "This regimen is well tolerated, with no hypophysitis, pneumonitis, or high-grade hepatitis observed to date. The clinical performance of AGEN1181 is consistent with its Fc-enhanced design, safely expanding the benefit of immunotherapy to a broader patient population."

Evidence of single agent activity
As of the data cut-off date of September 17, 2021, one hundred and sixteen patients received AGEN1181 in a dose escalation study to determine the optimal monotherapy dose and combination dose with balstilimab. Of note, this population was heavily pre-treated, with over half of these patients receiving at least 3 prior lines of therapy and nearly a third of patients receiving prior anti-PD-1 therapy. There were four cases of confirmed objective responses to AGEN1181 monotherapy. These include a complete response (CR) in MSS endometrial cancer, and partial responses (PR) in pancreatic cancer, as well as PD-1 refractory cervical cancer. These are the first reported responses to CTLA-4 monotherapy in these disease settings. The fourth response was in a patient with PD-1 refractory melanoma. Of note, three of the monotherapy responders expressed the low affinity FcγRIIIA receptor, which is associated with lack of response to first-generation CTLA-4 inhibitors1.

Balstilimab combination benefits >60% of patients
Significant benefit was also observed with the combination of AGEN1181 and balstilimab across multiple "cold" cancers studied, with >60% of evaluable patients receiving at least 1 mg/kg AGEN1181 experiencing disease control. Among 20 evaluable patients with microsatellite stable colorectal cancer (MSS-CRC), where PD-1 inhibitors have historically shown limited to no activity2-5, there were three confirmed PRs and one unconfirmed PR. In addition, ten cases of stable disease (SD) were observed, with one patient’s tumor burden reduced by 27%. The disease control rate (DCR) among these MSS CRC patients was 70%.

Among 9 evaluable ovarian cancer patients receiving at least 1 mg/kg of AGEN1181 in combination with balstilimab, there were three confirmed PRs and two cases of SD (one of the patients with SD had a 28% reduction of tumor burden). Compelling clinical activity was also seen in MSS-endometrial cancer as both patients treated with combination therapy demonstrated PRs; all three patients with MSS endometrial cancer treated with AGEN1181 (one with monotherapy, two in combination with balstilimab) had objective responses. Additional responders to combination therapy include 1 confirmed PR in a NSCLC patient who failed prior PD-1 therapy, 2 confirmed PRs in visceral angiosarcoma, and 1 unconfirmed PR in leiomyosarcoma.

Responses in this Phase 1 trial have been durable, with half lasting at least 24 weeks and the majority ongoing.

"AGEN1181 as monotherapy and in combination with balstilimab has shown promising activity in patients with poorly immunogenic tumors such as MSS-CRC, endometrial and ovarian cancers; these are tumor types that do not traditionally respond well to single agent anti PD-1/PD-L1 therapy," said Anthony El-Khoueiry, MD, Phase I Program Director and Associate Professor of Clinical Medicine at Keck School of Medicine of University of Southern California (USC). Dr. El-Khoueiry is also an oncologist at the USC Norris Comprehensive Cancer Center, part of Keck Medicine of USC. "Importantly, multiple responders expressed the low affinity FcγRIIIA receptor, a feature that makes them less likely to respond to first-generation CTLA-4 antibodies. Together, this highlights the potential of AGEN1181 to fulfill unmet medical needs in the current treatment landscape by overcoming limitations of approved immunotherapies."

Differentiated safety profile versus first generation CTLA-4 inhibitors
AGEN1181 was well tolerated with no hypophysitis, pneumonitis, or high-grade hepatitis. Rates of gastrointestinal and skin toxicities were comparable to those observed with first-generation CTLA-4 inhibitors.

Phase 2/3 trials to be initiated in colorectal and gynecological cancers
Based on these data, multi-arm, randomized phase 2/3 trials investigating AGEN1181 as monotherapy and in combination with balstilimab in MSS-CRC and gynecological cancers (ovarian and MSS-endometrial cancer) are being initiated. The design of these trials may support a potential filing for full and/or accelerated approval based on the magnitude of benefit demonstrated in the studies. Combination studies of AGEN1181 with AGEN2373, a conditionally active CD137 agonist, are expected to begin later this year in PD-1 refractory melanoma.

Presentation Details:
Abstract Title: AGEN1181, an Fc-enhanced anti-CTLA-4 antibody, alone and in combination with balstilimab (anti-PD-1) in patients with advanced solid tumors: Initial phase I results (NCT03860272)
Abstract Number: 479
Presenting Author: Dr. Anthony El-Khoueiry

The poster presentation can be accessed in the investor section of our website at View Source

In addition, Dr. Steven O’Day, Chief Medical Officer at Agenus and Dr. Manuel Hidalgo, Chief of the Division of Hematology and Medical Oncology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, will participate in a webcast hosted by Dr. Matt Phipps, biotechnology analyst at William Blair on Friday, November 12, 2021 at 12:00 p.m. ET.

Registration for the webinar can be done in advance at View Source

A replay will be available after the call for 30 days on the Events & Presentations page of the Agenus website at View Source

Disclosures:
Dr. El-Khoueiry has served as a consultant for Agenus.

About AGEN1181
AGEN1181 is a next-generation, Fc-enhanced, immunoglobulin G1 (IgG1) antibody designed to block CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) from interacting with its ligands CD80 and CD86. The Fc region of the antibody was engineered to enhance potency, improve safety, and benefit a broader patient population versus first-generation anti CTLA-4 antibodies. CTLA-4 is a negative regulator of immune activation that is considered a foundational target within the immuno-oncology market.

About Balstilimab
Balstilimab is a novel, fully human monoclonal immunoglobulin G4 (IgG4) designed to block PD-1 (programmed cell death protein 1) from interacting with its ligands PD-L1 and PD-L2. PD-1 is a negative regulator of immune activation that is considered a foundational target within the immuno-oncology market.

On November 12, 2021 Savara Inc. (Nasdaq: SVRA), a clinical stage biopharmaceutical company focused on rare respiratory diseases, reported financial results for the third quarter ending September 30, 2021 and provided a business update (Press release, Savara, NOV 12, 2021, View Source [SID1234595457]).

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"The team is focused and driving hard on advancing the pivotal Phase 3 IMPALA 2 trial," said Matt Pauls, Chair and Chief Executive Officer, Savara. "Given that an increasing number of sites are actively screening and enrolling patients, and we completed an important regulatory milestone with EMA’s acceptance of our proposed revised PIP, we are pleased with our progress over the last quarter. While the potential impact of COVID-19 and the flu over the winter is unknown, we remain confident in our guidance of a 20-month enrollment timeframe and top-line data by the end of Q2 2024. Finally, we significantly bolstered our inhalation delivery and biological product expertise in the manufacturing, regulatory, and quality functions with the addition of Peter Clarke and Charles LaPree."

Third Quarter Financial Results (Unaudited)
Savara’s net loss attributable to common stockholders for the three months ended September 30, 2021, was $10.5 million, or $(0.07) per share, compared with a net loss attributable to common stockholders of $11.1 million, or $(0.18) per share, for the three months ended September 30, 2020.

Research and development expenses increased by $0.9 million, or 16.6%, to $6.5 million for the three months ended September 30, 2021 from $5.6 million for the three months ended September 30, 2020. The increase was primarily attributable to an approximately $3.2 million increase in costs associated with the screening of patients and progression of the IMPALA-2 trial for the molgramostim development program. This was partially offset by a $2.1 million decrease in chemistry, manufacturing, and control ("CMC") and clinical operations activities associated with the wind down of the vancomycin study in methicillin-resistant Staphylococcus aureus (MRSA) lung infection.

General and administrative expenses decreased by $2.0 million, or 36.7%, to $3.4 million for the three months ended September 30, 2021 from $5.4 million for the three months ended September 30, 2020. The decrease was primarily due to the recognition of a one-time non-recurring charge of $0.8 million for non-cash stock-based compensation and approximately $1.5 million of paid and accrued severance payments to former members of executive management during the three months ended September 30, 2020.

As of September 30, 2021, Savara had cash, cash equivalents, and short-term investments of approximately $171 million and debt of approximately $25 million.

On November 12, 2021 Epizyme, Inc. (Nasdaq: EPZM), a fully integrated, commercial-stage biopharmaceutical company developing and delivering novel epigenetic therapies, reported that Grant Bogle, President and Chief Executive Officer of Epizyme, will present at the Jefferies London Healthcare Conference (Press release, Epizyme, NOV 12, 2021, View Source [SID1234595473]). A pre-recorded fireside chat will be available to play on demand starting at 3:00am EST (8:00am GMT) on November 18, 2021.

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A live webcast of the fireside chat will be available in the investor section of the Company’s website at www.epizyme.com and will be archived for 60 days following the presentation.