On October 4, 2023 AbbVie (NYSE: ABBV), the Broad Institute of MIT and Harvard, and Calico Life Sciences reported the publication in Nature of the discovery and preclinical data that demonstrate investigational ABBV-CLS-484 is a potential first-in-class, orally bioavailable, PTPN2/N1 phosphatase inhibitor that enhances anti-tumor immunity (Press release, AbbVie, OCT 4, 2023, View Source [SID1234635631]). The findings, based on research conducted by AbbVie in collaboration with the Broad Institute and Calico, support the development of ABBV-CLS-484 as a promising new strategy for cancer immunotherapy.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Titled "The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity," the paper highlights the novel structural insights and design that led to the discovery of ABBV-CLS-484 and its dual mechanism of action that targets tumor cells and suppresses their growth, as well as promotes the activation of several immune cell types to increase their anti-tumor activity.1

Researchers at the Broad previously identified protein tyrosine phosphatase non-receptor type 2 (PTPN2) and its closely related paralog PTPN1 as potential targets for cancer immunotherapy through an in vivo CRISPR screen.2 However, this challenging target class had previously been deemed "undruggable". AbbVie researchers overcame the challenges and discovered the dual PTPN2/N1 inhibitor, ABBV-CLS-484, through structure-based drug design and optimization of drug-like properties.

Discovery scientists at AbbVie, the Broad, and Calico further uncovered the biology and mechanism of action of ABBV-CLS-484. Preclinical findings presented demonstrate that ABBV-CLS-484 treatment amplifies the tumor intrinsic response to interferon and increases the activation and function of several immune cell subsets promoting cellular pathways including JAK-STAT signaling in animal models. In murine cancer models resistant to PD-1 blockade, monotherapy ABBV-CLS-484 treatment generates robust anti-tumor immunity. Through in vivo studies and single cell transcriptional profiling of tumor-infiltrating lymphocytes from ABBV-CLS-484 treated mice, the team revealed that ABBV-CLS-484 inflames the tumor microenvironment and promotes NK and CD8+ T-cell function. In T cells, mechanistically, ABBV-CLS-484 induces epigenetic and metabolic changes resulting in a unique functional state causing increased cytotoxicity and reduced T-cell exhaustion and dysfunction.

"Immunotherapies like PD-1 blockade have revolutionized cancer treatment; however, many patients do not respond well to them, and a significant unmet need remains," said Christina Baumgartner, Ph.D., co-first author and senior principal research scientist, AbbVie. "Through the extraordinary efforts of AbbVie’s medicinal chemistry team to drug the undruggable, we now have a potential first-in-class PTPN2/N1 inhibitor. We’re excited to share its biology and mechanism of action, and look forward to further evaluating it in the clinic."

"This study is a powerful demonstration of how collaboration can bring together diverse expertise to advance our understanding of disease biology and lead to discoveries that support new treatment strategies for people living with cancer," said Marcia Paddock, M.D., Ph.D., co-author and director of oncology new target development at Calico. "We are proud to be working with both AbbVie and the Broad Institute and look forward to sharing additional progress from our clinical studies of this novel immunotherapy."

ABBV-CLS-484 is the first active-site phosphatase inhibitor to enter clinical evaluation as a cancer therapy and is currently in an AbbVie and Calico-led Phase 1 clinical trial in solid tumors (NCT04777994).

"This is an unprecedented opportunity to evaluate how immune responses work," said Robert Manguso, Ph.D., co-senior author on the study, associate member at the Broad, and assistant professor at the Massachusetts General Hospital Center for Cancer Research and Harvard Medical School. "The ability to further explore this signaling pathway in clinical studies is really important."

On October 3, 2023 Oxford BioTherapeutics (OBT), a clinical stage oncology company with a pipeline of immuno-oncology and Antibody Drug Conjugate (ADC)-based therapies, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to BI 764532 for the treatment of extensive stage small cell lung cancer (ES-SCLC) whose disease has progressed following at least two prior lines of treatment including platinum-based chemotherapy, and of advanced or metastatic extrapulmonary neuroendocrine carcinomas (epNEC) whose disease has progressed following at least one prior line of treatment including platinum-based chemotherapy (Press release, Oxford BioTherapeutics, OCT 3, 2023, View Source [SID1234656435]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

BI 764532 is an investigational DLL3/CD3 IgG-like T-cell engager for treatment of patients with SCLC and other neuroendocrine tumors that is being developed by Boehringer Ingelheim. The discovery of BI 764532 was enabled through a successful partnership initiated in 2013, leveraging OBT’s proprietary OGAP drug discovery platform for identification of the DLL3 antigen and Boehringer Ingelheim’s longstanding expertise in oncology and development of biotherapeutics.

Encouraging data were presented from the Phase I first-in-human dose-escalation trial at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2023 Annual Meeting. These Phase I data demonstrated a clinically acceptable safety profile and early efficacy in patients with DLL3-positive ES-SCLC and epNECs.

Christian Rohlff, Chief Executive Officer of OBT, commented: "We are delighted about the accelerated clinical development of BI 764532, for which the DLL3 antigen was discovered using our OGAP technology platform. This is tremendously exciting for OBT, as it shows the real impact this partnership has for patients in need. Receiving an ES-SCLC or epNEC diagnosis can be life changing and there is an urgent, unmet need for additional targeted immunotherapeutics to ensure that individuals impacted by these aggressive cancers get the care they need."

FDA’s Fast Track designation is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious or life-threatening diseases and that demonstrate the potential to address unmet medical needs.

On October 3, 2023 Pacylex Pharmaceuticals, a clinical stage pharmaceutical company focused on the development of therapies for hematologic and solid cancers, reported recent results generated at NIH using its lead drug, zelenirstat, presented at the Canadian Association of Radiation Oncology Annual Meeting in Montreal, Canada, on September 23, 2023 (Press release, Pacylex Pharmaceuticals, OCT 3, 2023, View Source [SID1234645056]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The presentation, titled "Radiosensitization with Glioblastoma using Targeted Inhibition of N-Myristoylation" highlighted that:

Zelenirstat was more effective than clinically used radiosensitizers, which generally augment the effects of radiation by 10% to 30%, increasing the effects of radiation by 40% – 140%;
Orally administered zelenirstat is also predicted to cross the blood brain barrier more efficiently than temozolomide, the current standard of care radiosensitizer for aggressive brain cancers.
Dr. Deepak Dinakaran, MD, PhD, a radiation oncologist and clinician scientist who conducted this research at the US National Institute of Health, said, "Our results show that zelenirstat is a potent radiosensitizer in preclinical models of glioblastoma, and that it works through pathways that differ from available radiosensitizers, including temozolomide."

"Dr. Dinakaran’s exciting mechanistic work and the magnitude of the radiosensitization effect he identified suggests that zelenirstat, which has a broad spectrum of preclinical anticancer activity, might also be added to radiation for a variety of non-brain cancers, including cancers of the head and neck, lung, rectum, and uterine cervix." said John Mackey, CMO of Pacylex. "This opens up many new opportunities to benefit patients with common solid cancers."

On October 3, 2023 Iambic Therapeutics (formerly known as Entos), a biotechnology company developing novel therapeutics from its unique generative AI discovery platform, reported the closing of an oversubscribed $100 million Series B financing co-led by Ascenta Capital and Abingworth, and also including new investors NVIDIA, Illumina Ventures, Gradiant Corporation, Shanda, and independent board member Bill Rastetter (Press release, Iambic Therapeutics, OCT 3, 2023, View Source [SID1234637229]). Existing investors also participated, including Nexus Ventures, Catalio Capital Management, Coatue, FreeFlow, OrbiMed, Sequoia Capital, and Tao Capital. As part of the Series B, Iambic is delighted to welcome two new board members, Evan Rachlin, M.D., from Ascenta Capital and Kurt von Emster from Abingworth.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"At Iambic, our world-class team has combined physics and AI to create a differentiated drug discovery platform that achieves a step-change in the speed and success rate for delivering best-in-class and first-in-class development candidates to clinic. With the Series B funding, we intend to advance multiple AI-discovered candidates into the clinic and expand our pipeline, demonstrating how the Iambic platform can deliver better therapeutics to patients in less time, with optimized target product profiles for greater likelihood of clinical success."
– Tom Miller, Ph.D., Co-founder and CEO of Iambic

"We were struck by the originality of these molecules, offering distinctive approaches in both deeply validated and more novel biological pathways," added Evan Rachlin, M.D., Co-founder and Managing Partner of Ascenta Capital. "Iambic’s platform enables a more creative and expansive exploration of how to treat diseases with profound unmet needs. We are delighted to partner with Tom and his extraordinary team in translating these thoroughly tested medicines into humans."

"Abingworth is proud to support the remarkably talented team at Iambic in its drive to revolutionize drug discovery and speed to the market with highly selective drugs" said Kurt von Emster, Managing Partner and Head of Life Sciences at Abingworth.

"AI-driven technologies, including methods that Iambic and NVIDIA researchers have built together, are charting a new path for researchers in the discovery of new therapeutic candidates," said Rory Kelleher, Director of Healthcare and Life Sciences at NVIDIA. "NVIDIA-accelerated computing and software are helping industry pioneers like Iambic drive scientific breakthroughs and our continued collaboration aims to speed innovation in drug discovery."

"We believe technology innovations powered by advanced computing and omics-derived data insights will transform drug discovery and pave the way for the next wave of groundbreaking medicines," said Ron Mazumder, Ph.D., MBA, Partner of Illumina Ventures. "Iambic’s physics-informed machine learning approach has yielded promising lead candidates with superior profiles in record time."

Since its 2021 Series A financing, Iambic has rapidly built its AI-driven discovery platform, which unifies state-of-the-art, physics-informed machine learning and experimental automation, and has demonstrated the platform’s success in identifying therapeutic candidates with differentiated drug profiles. In addition to building out a deep bench of AI and drug-discovery experts, Iambic has discovered two candidates to advance into the clinic: IAM-H1, a highly selective and brain-penetrant inhibitor of HER2 and its oncogenic mutants, and IAM-C1, a potential first-in-class selective dual CDK2/4 inhibitor to address unmet needs in terms of therapeutic window and treatment resistance in cell-cycle-driven cancers. Further, Iambic has extended its leadership position in the AI community, creating methods such as NeuralPLexer and OrbNet to drive its discovery platform.

With the funds raised in the Series B, Iambic intends to advance multiple candidates into clinical development, expand its pipeline with additional candidates with best-in-class and first-in-class potential, and continue to innovate and build next-generation AI and automation technologies for drug discovery. It plans to leverage NVIDIA technology such as the NVIDIA DGX Cloud AI supercomputing platform and the NVIDIA BioNeMo cloud service to accelerate discovery.

The company retains the technology created under its prior name of Entos Inc., adopting the new name of Iambic Therapeutics to reflect its transition to a company with the additional capability of clinical development of candidates identified through its AI-driven discovery platform.

About the Iambic Therapeutics Physics-Informed AI-Driven Discovery Platform

The Iambic Therapeutics AI-driven platform was created to address the most challenging design problems in drug discovery, incorporating the most current AI technologies and purpose-built tools from Iambic. The integration of physics principles into the platform’s AI architectures improves data efficiency and allows molecular models to venture widely across the space of possible chemical structures. The platform’s algorithms enable identification of new chemical mechanisms for engaging difficult-to-address biological targets, discovery of defined product profiles that optimize therapeutic window, and exploration of the chemical space to discover candidates for development with highly differentiated properties. Through close integration of AI-generated molecular designs with automated experimental execution, Iambic completes design-make-test cycles on a weekly cadence.

On October 3, 2023, Vaccinex, Inc. (the "Company") sold in a public offering an aggregate of 9,600,000 common share equivalents together with accompanying common stock warrants ("Common Warrants"), comprised of (i) 7,600,000 shares ("Shares") of the Company’s common stock ("Common Stock") together with Common Warrants to purchase up to 7,600,000 shares of Common Stock ("Warrant Shares") and (ii) in lieu of Shares, pre-funded warrants ("Pre-Funded Warrants" and together with the Common Warrants, the "Warrants") to purchase up to 2,000,000 Warrant Shares together with Common Warrants to purchase up to 2,000,000 Warrant Shares (the "Offering") (Filing, 8-K, Vaccinex, OCT 3, 2023, View Source [SID1234635650]). The Shares and accompanying Common Warrants were sold at a combined public offering price of $1.00 per Share and accompanying Common Warrant, and the Pre-Funded Warrants and accompanying Common Warrants were sold at a combined public offering price of $0.999 per Pre-Funded Warrant and accompanying Common Warrant. The Offering was made pursuant to the Company’s registration statement on Form S-1, as amended (File No. 333-274520), which was declared effective by the Securities and Exchange Commission (the "SEC") on September 28, 2023. In connection with the Offering, on September 28, 2023, the Company entered into a securities purchase agreement (the "Purchase Agreement") with some of the purchasers in the Offering.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

FCMI Parent Co., an entity controlled by Albert D. Friedberg, chairman of the Company’s board of directors (the "Board"), purchased 3,000,000 Shares and accompanying Common Warrants in the Offering for a purchase price of $3.0 million and Maurice Zauderer, the Company’s President, Chief Executive Officer, and a member of the Board (FCMI Parent Co. and Dr. Zauderer, together, the "Related Parties"), purchased 500,000 Shares and accompanying Common Warrants in the Offering for a purchase price of $500,000.

Each Pre-Funded Warrant sold in the Offering has an initial exercise price equal to $0.0001 per share, and each Common Warrant has an initial exercise price equal to $1.00 per share. The Warrants were immediately exercisable. The Pre-Funded Warrants may be exercised at any time until they are exercised in full, and the Common Warrants will expire five years from the date of issuance. No Warrant holder (together with its affiliates) may exercise any portion of its Warrants to the extent that the holder would own more than 4.99% (or, at the election of the purchaser, 9.99%) of the outstanding Common Stock immediately after exercise (the "Beneficial Ownership Limitation"), except that (i) upon at least 61 days’ prior notice from the holder to the Company, the holder may increase the Beneficial Ownership Limitation to a percentage not to exceed 9.99%, (ii) Dr. Zauderer is not subject to the Beneficial Ownership Limitation, and (iii) the Beneficial Ownership Limitation with respect to FCMI Parent Co. is 39.99%.

The Company has the right to "call" any portion of a holder’s Common Warrants by delivering a call notice to the holder within 30 days after Company publicly announces an increase in pepinemab-treated patients relative to placebo-treated patients, with statistical significance having a p-value of less than or equal to 0.05, in the change of the FDG-PET standard uptake value ratio for brain metabolism between baseline and month 18 as assessed by [18F]fluorodeoxyglucose (FDG)-PET in the resting state following administration of 40 mg/kg pepinemab or placebo, as applicable, as described in the protocol for the Company’s SIGNAL-AD Alzheimer’s disease study. After delivery of a call notice, the Common Warrants will continue to be exercisable. Each Common Warrant will be canceled and no longer exercisable to the extent the holder fails to timely exercise the Common Warrant for the called portion thereof within 20 trading days following the Company’s issuance of a call notice.

The net proceeds to the Company from the Offering are expected to be approximately $8.7 million after deducting placement agent fees and other estimated offering expenses, but excluding the proceeds, if any, from the exercise of Warrants issued in the Offering. The Company intends to use the net proceeds from the Offering to fund the ongoing development and clinical trials of its lead drug candidate, pepinemab, in Alzheimer’s disease and cancer and for working capital and other general corporate purposes.

The Purchase Agreement prohibits the Company, until January 1, 2024, from issuing, agreeing to issue, or announcing the issuance or proposed issuance of any Shares or common stock equivalents, other than (i) equity awards granted pursuant to an equity incentive plan, (ii) upon the exercise of Warrants or the exercise, exchange, or conversion of other securities outstanding on September 28, 2023, (iii) sales to employees, directors, consultants, or their affiliated entities in the ordinary course of business or pursuant to or in connection with commitments in place as of September 28, 2023, (iv) pursuant to acquisitions, joint ventures, strategic alliances, or other strategic transactions approved by the Company’s Board of Directors, and (v) the issuance of warrants to purchase Shares, or Shares underlying such warrants, to purchasers of Common Stock in private placements conducted by the Company between July 30, 2023 and September 27, 2023. The Purchase Agreement also prohibits the Company, until January 1, 2024, from filing any registration statement or amendment or supplement thereto, subject to certain exceptions. In addition, pursuant to the Purchase Agreement, the Company’s executive officers and directors and beneficial owners of 5% or more of the Company’s outstanding Common Stock entered into customary lock-up agreements pursuant to which they agreed until December 2, 2023 not to sell or transfer any shares of Common Stock beneficially owned by them or securities that are convertible into, or exchangeable or exercisable for, shares of Common Stock, subject to certain exceptions.

A.G.P./Alliance Global Partners ("A.G.P.") acted as the exclusive placement agent for the Offering on a reasonable best efforts basis pursuant to the terms of a placement agency agreement entered into between the Company and A.G.P. on September 28, 2023 (the "Placement Agency Agreement"). The Company agreed to pay A.G.P. an aggregate fee of 7.0% of the aggregate gross proceeds received in the Offering and to reimburse A.G.P. for up to $75,000 for A.G.P.’s legal fees and up to 1.0% of the aggregate gross proceeds of the offering for non-accountable fees and expenses, except that the Company agreed to pay an aggregate fee of 2.0% of the gross proceeds received from sales to the Related Parties and the parties agreed that A.G.P. will not be paid for non-accountable expenses with respect to such sales.

The descriptions of the terms and conditions of the Placement Agency Agreement, the form of Pre-Funded Warrant, the form of Warrant, and the form of Purchase Agreement are qualified by reference to the full text of such documents, which are attached hereto as Exhibits 1.1, 4.1, 4.2 and 10.1, respectively.