On November 9, 2022 Aadi Bioscience, Inc. (NASDAQ: AADI), a biopharmaceutical company focused on developing and commercializing precision therapies for genetically defined cancers with alterations in mTOR pathway genes, reported financial results for the third quarter of 2022 (Press release, Aadi Bioscience, NOV 9, 2022, View Source [SID1234623592]).

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"The last several months have been transformational for Aadi, most recently having strengthened our balance sheet with a $72.5 million PIPE financing. In addition, we saw continued progress in patient enrollment for the PRECISION 1 trial targeting TSC1 and TSC2 inactivating alterations, and we anticipate providing preliminary data on a meaningful number of patients from PRECISION 1 in the first half of 2023," said Neil Desai, Ph.D., Founder and Chief Executive Officer of Aadi. "We also expanded our pipeline through the recent clinical collaboration with Mirati to explore the combination of nab-sirolimus with the KRAS inhibitor adagrasib, which we believe could potentially overcome tumor resistance."

"We have made great progress in the last year, positioning us well for the next phase of growth. In preparation for the advancements to come, we are also realigning our management structure. We announced last evening that I am moving into the role of Executive Chairman while our current COO, Brendan Delaney, will transition to President and CEO," continued Desai. "Brendan’s proven expertise, committed leadership and broad strategic vision have been key drivers of our success. Going forward, Brendan will assume leadership of the Company while my personal focus will turn toward advancement of our scientific initiatives."

Brendan Delaney, current Chief Operating Officer of Aadi commented, "It’s such an exciting time at Aadi, and I couldn’t be more pleased with the execution our team has demonstrated. I am honored to have been selected to lead this organization as we move forward and execute on the strategies that will support further growth. Our oncology franchise is growing, and I believe we are well-positioned to achieve our goal of becoming a leading precision oncology company that delivers on providing therapeutic benefit to patients in need."

Corporate Updates for the Third Quarter 2022 and Recent Highlights

Closed on a $72.5M financing and extended cash runway into 2025. The proceeds from the financing will be used to support the continued advancement of the PRECISION 1 trial and growing FYARRO commercial efforts, and to fund research and development of additional clinical opportunities with FYARRO and for working capital and general corporate purposes.

Continued advancement of the PRECISION 1 registrational-directed trial. The PRECISION 1 Phase 2 trial in patients with tumor agnostic TSC 1 and 2 inactivating mutations is advancing and on track to deliver preliminary data in the first half of 2023.

Grew FYARRO net product sales. For the three months ended September 30, 2022, net product sales of FYARRO showed continued growth, ending with $4.2 million in sales in the third quarter, a 24% increase over the second quarter.

Leadership transition. Current CEO, Dr. Neil Desai, has been appointed Executive Chairman, effective January 1, 2023. Current COO, Brendan Delaney, will transition to President and CEO, and will be joining the board of directors, effective January 1, 2023.

Signed a clinical collaboration agreement with Mirati Therapeutics on combination of adagrasib with nab-sirolimus. The companies will conduct an open-label Phase 1/2 trial to determine the optimal dose and recommended Phase 2 dose for the combination of adagrasib and nab-sirolimus in patients with KRASG12C – mutant solid tumors. The trial builds on preclinical data showing enhanced anti-tumor efficacy with the combination of adagrasib and nab-sirolimus relative to either agent alone. Initiation of the Phase 1/2 trial is expected in the first half of 2023.

Presented combination data of KRAS inhibitors and nab-sirolimus at the 34th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium. The results of these studies showed that combining nab-sirolimus with either of the KRASG12C inhibitors sotorasib or adagrasib significantly improved response against KRASG12C mutant lung cancer and bladder cancer tumors in vivo and nab-sirolimus also showed significantly greater potency in the combination compared to everolimus.
Third Quarter 2022 Financial Results

Cash, cash equivalents and short-term investments as of September 30, 2022 were $183.0 million as compared to $149.0 million as of December 31, 2021, which is expected to fund operations into 2025 based on current plans.

Total revenue for the quarter ended September 30, 2022 was $4.2 million resulting from sales of FYARRO.

Net loss for the three months ended September 30, 2022 was $14.5 million as compared to $87.1 million for the three months ended September 30, 2021. The prior year quarter included the non-cash impairment charge of $74.2 million related to the acquired contract intangible asset incurred in conjunction with the Aerpio merger.
Conference Call Information

The Aadi management team is hosting a conference call and webcast today at 8:30 am ET (5:30 am PT) to provide a corporate update and discuss results for the third quarter of 2022.

Participants may access a live webcast of the call on the "Investors & News" page of the Aadi Biosciences website at aadibio.com. To participate via telephone, please register in advance at this link. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. A replay of the conference call and webcast will be archived on the Company’s website for at least 30 days.

About FYARRO
FYARRO is an mTOR inhibitor indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).

About the PRECISION 1 Trial
The PRECISION 1 trial is a multi-center, open-label, tumor-agnostic pivotal study, of nab-sirolimus designed as a basket trial that will evaluate approximately 120 adult and adolescent patients with solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes. The trial will have two independent arms of 60 patients each to separately evaluate patients with either TSC1 or TSC2 inactivating alterations. Aadi has received Fast Track designation to evaluate nab-sirolimus in this indication from the FDA. The first patient in the PRECISION 1 trial was dosed in March 2022.

On November 9, 2022 Citius Pharmaceuticals, Inc. ("Citius" or the "Company") (Nasdaq: CTXR), a biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products reported that abstracts for I/ONTAK (E7777) for the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL) have been accepted for presentations at the prestigious 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, to be held in New Orleans, December 10-13, 2022 (Press release, Citius Pharmaceuticals, NOV 9, 2022, View Source [SID1234623591]).

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Dr. Francine Foss, Professor of Medicine in the Section of Medical Oncology at the Yale Cancer Center, and world-renowned expert in T-cell lymphomas, will deliver an oral presentation reviewing the efficacy and safety results of the completed I/ONTAK (E7777) Phase 3 study.

Dr. Christiane Querfeld, Professor of Dermatology and Dermatopathology at City of Hope Cancer Center, and Director of City of Hope’s multidisciplinary Cutaneous Lymphoma Program will present a poster highlighting the safety and tolerability data of I/ONTAK (E7777) in patients with relapsed or refractory cutaneous T-cell lymphoma from Study 302. Dr. Querfeld is one of the world’s foremost experts in the diagnosis and management of cutaneous lymphomas.

Oral Presentation:

Efficacy and Safety of E7777 (improved purity denileukin diftitox [ONTAK]) in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma: Results from Pivotal Study 302

Safety and Tolerability of E7777 (improved purity denileukin diftitox [ONTAK]) in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma: Results from Pivotal Study 302

"We look forward to sharing additional efficacy and safety data for I/ONTAK with the medical community at this year’s ASH (Free ASH Whitepaper) meeting. With I/ONTAK’s differentiated mechanism-of-action, we believe CTCL patients could benefit from this promising therapeutic option, if approved. Based on the clinical data from our recently completed Phase 3 trial, we submitted a biologics license application (BLA) with the U.S. Food and Drug Administration (FDA) in late September 2022, and look forward to engaging with the FDA during their review process," stated Dr. Czuczman, Chief Medical Officer and Executive Vice President of Citius Pharmaceuticals, Inc.

The oral presentation and poster will be available on Citius’ website once the event commences.

About I/ONTAK
I/ONTAK is a recombinant fusion protein that combines the interleukin-2 (IL-2) receptor binding domain with diphtheria toxin fragments. The agent specifically binds to IL-2 receptors on the cell surface, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis. I/ONTAK, a purified version of denileukin diftitox, is a reformulation of previously FDA-approved oncology treatment ONTAK. ONTAK was marketed in the U.S. from 1999 to 2014, when it was voluntarily withdrawn from the market. Manufacturing improvements resulted in a new formulation, which maintains the same amino acid sequence but features improved purity and bioactivity. The new formulation received regulatory approval in Japan in 2021 for the treatment of CTCL and peripheral T-cell lymphoma (PTCL). In 2011 and 2013, the FDA granted orphan drug designation (ODD) to I/ONTAK for the treatment of PTCL and CTCL, respectively.

About Cutaneous T-cell Lymphoma
Cutaneous T-cell lymphoma is a type of cutaneous non-Hodgkin lymphoma (NHL) that comes in a variety of forms and is the most common type of cutaneous lymphoma. In CTCL, T-cells, a type of lymphocyte that plays a role in the immune system, become cancerous and develop into skin lesions, leading to a decrease in the quality of life of patients with this disease due to severe pain and pruritus. Mycosis Fungoides (MF) and Sézary Syndrome (SS) comprise the majority of CTCL cases. Depending on the type of CTCL, the disease may progress slowly and can take anywhere from several years to upwards of ten to potentially reach tumor stage. However, once the disease reaches this stage, the cancer is highly malignant and can spread to the lymph nodes and internal organs, resulting in a poor prognosis. Given the duration of the disease, patients typically cycle through multiple systemic agents to control disease progression. CTCL affects men twice as often as women and is typically first diagnosed in patients between the ages of 50 and 60 years of age. Other than allogeneic stem cell transplantation, for which only a small fraction of patients qualify, there is currently no curative therapy for advanced CTCL.

On November 9, 2022 Nektar Therapeutics (Nasdaq: NKTR) reported the publication of preclinical data in Blood Advances, the open-access journal of the American Society of Hematology (ASH) (Free ASH Whitepaper), highlighting the effects of NKTR-255, a novel polymer-conjugated human IL-15, on the efficacy of human CD19 CAR-T cells in a xenogeneic lymphoma model and on CD8+ T effector cell (Tcell) and natural killer (NK) cell proliferation in non-human primates (Press release, Nektar Therapeutics, NOV 9, 2022, View Source [SID1234623590]).

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"The findings published today reinforce the foundational rationale behind the clinical development program we’re pursuing of NKTR-255 enhancing CAR-T cell therapies," said Jonathan Zalevsky, Ph.D., Chief Research & Development Officer at Nektar. "We are looking forward to progressing our research in combination with cell therapies and are excited to launch our Phase 2/3 clinical trial of NKTR-255 following approved CAR-T cell therapies in patients with relapsed or refractory diffuse large B-cell Lymphoma."

The data from this publication demonstrate that NKTR-255 not only enhanced in vivo proliferation and accumulation of T and NK cells in non-human primates, but also demonstrated enhanced in vivo antitumor efficacy of human CD19 CAR-T in lymphoma-bearing immunodeficient mice.

"In contrast to mice treated with CAR-T alone, those that received CAR-T and NKTR-255 had markedly higher CAR-T counts in blood and marrow that were sustained after tumor clearance, without evidence of persistent proliferation or ongoing activation/exhaustion assessed by Ki-67 and inhibitory receptor co-expression," said Dr. Cameron Turtle, senior author on the publication and CLEARbridge Chair of Cancer Immunotherapy at Sydney Medical School. "These data support the ongoing clinical research of combined CAR-T and NKTR-255 for B-cell malignancies."

Key findings are summarized below:

Serum IL-15 concentration is independently associated with longer CD19 CAR-T persistence in humans
NKTR-255 promotes CD8+ effector and memory T and NK cell accumulation in non-human primates
NKTR-255 enhances proliferation and survival of human CD19 CAR-T at low target cell abundance
NKTR-255 enhances accumulation and efficacy of human CD19 CAR-T in lymphoma bearing immunodeficient mice
The full citation of this article can be accessed at: View Source

About NKTR-255
NKTR-255 is a biologic that targets the IL-15 pathway in order to activate the body’s innate and adaptive immunity. Through optimal engagement of the IL-15 receptor complex, NKTR-255 is designed to enhance functional NK cell populations and formation of long-term immunological memory, which may lead to sustained and durable anti-tumor immune response.

Preclinical findings suggest NKTR-255 has the potential to synergistically combine with antibody-dependent cellular cytotoxicity molecules as well as to enhance CAR-T therapies.

There are two ongoing investigator sponsor trials evaluating NKTR-255 following treatment with a CAR-T cell therapy. Fred Hutchinson Cancer Center is conducting a Phase 1 study evaluating NKTR-255 in combination with CD19 CAR-T cell therapy in patients with relapsed or refractory large B-cell lymphoma (NCT05359211), and Stanford University is conducting a Phase 1 study evaluating NKTR-255 in combination with CD19/22 CAR-T cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (NCT03233854).

Nektar is also currently designing a Nektar-sponsored Phase 2/3 study combining NKTR-255 with approved CAR-T cell therapies in diffuse large B-cell lymphoma, which it aims to initiate in the first quarter of 2023.

On November 9, 2022 Kintor Pharmaceutical Limited ("KintorPharma", HKEX: 9939), a clinical-stage biotechnology company developing innovative small molecules and biological therapeutics, reported that the results from the novel dual c-Myc/GSPT1 degrader GT19715 have been selected for oral presentation at the annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) 2022 (ASH 2022), and the abstract is available on ASH (Free ASH Whitepaper)’s official website (Press release, Suzhou Kintor Pharmaceuticals, NOV 9, 2022, View Source [SID1234623589]).

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The ASH (Free ASH Whitepaper) annual meeting is the largest conference worldwide of hematology, bringing together basic, translational and clinical researchers in hematology. ASH (Free ASH Whitepaper) 2022 will be held from Saturday, December 10, to Tuesday, December 13, 2022, in New Orleans, Louisiana.

The oncoprotein c-Myc is dysregulated in 70% of all human cancers, mostly with amplified expression levels and enhanced activities to promote progression of cancers and leukemias. Rearrangements of MYC are best known in the translocation in Burkitt’s lymphomas, however, increased expression levels are also observed in acute myeloid leukemias (AML), including those with TP53 mutations or venetoclax (ven) resistance, both of which have devastating clinical outcomes despite recent advances in AML therapies.

The senior author Michael Andreeff, M.D., Ph.D., professor of Leukemia at The University of Texas MD Anderson Cancer Center, together with his team and Kintor Pharma, evaluated preclinical activities of the first-in-class c-Myc protein degrader GT19715 in therapy resistant AML models.

Utilizing single cell mass cytometry, researchers found increased c-Myc protein levels in immature CD34+ AML cells compared to normal bone marrow CD34+ cells. GT19715 demonstrated promising anti-leukemia efficacy in patient-derived AML cells with TP53 mutations, especially in immature CD34+ fractions; and treatment of GT19715 in mice eradicated lymphoma and leukemia cells in Daudi Burkitt’s lymphoma and Venetoclax-resistant AML models. Presentation will include updates and results will be presented by the first author Yuki Nishida, M.D., Ph.D. on Dec 10, 2022.

"We are really thrilled to present the data of encouraging preclinical activities of the first degrader of MYC proteins especially in MYC-driven leukemias and lymphomas at ASH (Free ASH Whitepaper) this year. MYC governs various oncogenic programs for cancer initiation and progression and has long been one of the "undruggable" targets in cancer therapy despite numerous attempts to target MYC or its pathways. Actually, we reported MYC inhibition by p53 reactivation at the ASH (Free ASH Whitepaper) last year, but now we have the first compound that successfully degrades MYC itself, demonstrating very promising early activity, which should also be applicable to other MYC-driven malignancies." Dr. Andreeff commented.

Dr. Youzhi Tong, founder, Chairman, and Chief Executive Officer of Kintor Pharma, commented, "We are very excited that the results of the novel dual c-Myc/GSPT1 degrader GT19715 were selected for oral presentation at the ASH (Free ASH Whitepaper) annual meeting, which indicates the international hematology community’s recognition of GT19715’s therapeutic potential. We will accelerate the progress of GT19715 into the clinical stage and hope to bring more innovative treatment options for patients with unmet needs."

On November 9, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that its novel inhibitor of the embryonic ectoderm development (EED) protein, APG-5918, has been approved by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA) to enter a Phase I study in patients with advanced solid tumors or hematologic malignancies (Press release, Ascentage Pharma, NOV 9, 2022, View Source [SID1234623587]). Following the recent clearance for the study in the US, this approval in China marks another milestone for the company’s strategy of simultaneous clinical development in the two countries. APG-5918 is the first domestically developed novel EED inhibitor entering clinical development in China.

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This multicenter, open-label Phase I dose-escalation and dose-expansion study is designed to assess the safety, pharmacokinetics, and efficacy of orally administered APG-5918 in patients with advanced solid tumors or hematologic malignancies. Prof. Ruihua Xu, President and Director of Sun Yat-Sen University Cancer Center, and President of the Chinese Society of Clinical Oncology, will be the principal investigator of this study.

EZH2, which is highly expressed in multiple tumors in humans, was found to promote the development and progression of tumors, and targeted inhibition of EZH2’s methyltransferase activity has already proved to be an effective mechanistic approach for cancer treatment. However, the secondary mutation of EZH2 may lead to acquired drug resistances, while the homologous EZH1 also has methyltransferase (MTase) activity that could limit the effects of EZH2 inhibitors. Studies have shown that the PRC2 complex’s component proteins and EZH2’s histone (MTase; HMTase) activities are highly dependent on the scaffold and modulating effects of EED. Compounds with inhibitory effects on EED, a subunit of PRC2, can disrupt the protein-to-protein interaction between EED and EZH2, culminating in damaged PRC2 functions, H3K27me3-induced silencing of PRC2 expressions, and blockade of the triple-methylation of H3K27.1 Therefore, allosteric targeting of EED has in recent years gained a great deal of traction as a promising approach for inhibiting the replacement of inactivated PRC2.

Discovered and developed by Ascentage Pharma, APG-5918 is an orally active, potent, selective, small-molecule EED inhibitor with high binding affinity. APG-5918 can regulate the epigenetics of tumors and the tumor microenvironment, and therefore has broad therapeutic potential for the treatment of hematologic malignancies, solid tumors, and nononcologic conditions. APG-5918 can selectively bind to the H3K27me3 domain of the EED protein, leading to the conformational changes to H3K27me3’s binding pockets in the EED protein, which can then block EED from interacting with the histone methyltransferase EZH2. Preliminary data showed that APG-5918 has in vitro antiproliferative activity in various tumor cell lines and antitumor activity in patient-derived xenograft (PDX)/cell line-derived xenograft (CDX) models of EZH1-mutant B-cell non-Hodgkin lymphoma, IN1-negative malignant rhabdoid tumor, BAP1-mutant mesothelioma and prostate cancer.

Prof. Ruihua Xu commented, "Targeting PRC2 complex proteins, especially the EED, may be an effective mechanistic approach for treating cancer patients with certain genetic profiles. In both in vitro studies and in vivo studies in animal models, the EED inhibitor APG-5918 has shown clear targeted binding and target-based antitumor activity, thus warranting further clinical evaluations."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "This approval of the clinical study of APG-5918 in China came shortly after the clearance for the study in the US, hence signals major progress in Ascentage Pharma’s efforts to simultaneously advance clinical programs in China and the US, and is also a strong testament to our global innovation capabilities. We look forward to closely collaborating with Prof. Xu to advance the clinical development of APG-5918, which we hope will offer a novel therapeutic to patients in need."

Reference

1. Erokhin M, Chetverina O, Győrffy B, Tatarskiy V V, Mogila V, Shtil AA, et al. Clinical correlations of polycomb repressive complex 2 in different tumor types. Cancers 2021;13:3155.