On April 19, 2023 InnoCare Pharma (HKEX: 09969; SSE: 688428), a leading biopharmaceutical company, reported that its BTK inhibitor orelabrutinib received approval from the China National Medical Products Administration (NMPA) in the treatment of patients with relapsed/refractory (r/r) marginal zone lymphoma (MZL) (Press release, InnoCare Pharma, APR 19, 2023, View Source [SID1234630331]). Orelabrutinib has thus become the first and the only approved BTK inhibitor for the treatment r/r MZL in China, which was also orelabrutinib’s third indication approved in China.

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Jun Zhu, Professor of the Peking University Cancer Hospital said, "MZL is considered incurable at the relapsed/refractory stage with limited therapeutic options. Orelabrutinib demonstrated a high response with durable disease remission and was well tolerated in Chinese patients with r/r MZL. The results of this study support the use of orelabrutinib as an effective and tolerable oral treatment option for r/r MZL patients."

Dr. Jasmine Cui, the co-founder, chairwoman and CEO of InnoCare said, "MZL is a lymphoma with high incidence rate in China. We would like to thank all the principal investigators and patients who participated in this study, as well as our partners for their strong support and employees for their unremitting efforts. The approval of the third indication of orelabrutinib will not only fill the gap in China, but also benefit more lymphoma patients."

Marginal zone lymphoma (MZL) is an inert B-cell non-Hodgkin’s lymphoma (NHL). It is the second most prevalent lymphoma in China, accounting for 8.3% of all lymphomas. It mainly affects the middle-aged and elderly people. The annual incidence of MZL has increased globally. After first-line treatment, the r/r MZL patients lack effective treatment options.

BTK, as a key target for MZL treatment, has attracted widespread attention, and only orelabrutinib has been approved for the treatment of MZL in China. With high target selectivity and well-tolerated safety profile, orelabrutinib has been approved in China for the treatment of r/r chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and r/r mantle cell lymphoma (MCL).

About Orelabrutinib

Orelabrutinib is a highly selective BTK inhibitor developed by InnoCare for the treatment of cancers and autoimmune diseases.

On Dec. 25, 2020, orelabrutinib received conditional approval from the China National Medical Products Administration (NMPA) in two indications: the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL), and the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL). At the end of 2021, orelabrutinib was included into National Reimbursement Drug list to benefit more lymphoma patients.

Orelabrutinib’s supplemental New Drug Application (sNDA) was under priority review by the China National Medical Products Administration (NMPA) for the treatment of patients with relapsed or refractory Marginal Zone Lymphoma (R/R MZL).

In addition to the approved indications, multi-center, multi-indication clinical trials are underway in the US and China with orelabrutinib as monotherapy or in combination therapies, such as first line treatment of MCD subtype of diffuse large B-cell lymphoma (DLBCL).

Orelabrutinib was granted as Breakthrough Therapy Designation for the treatment of r/r MCL by U.S. Food and Drug Administration (FDA). Phase II registrational trial for R/R MCL was completed in the U.S.

In addition, orelabrutinib’s global phase II studies for the treatment of Multiple Sclerosis (MS), and clinical trials for the treatment of SLE, Primary Immune Thrombocytopenia (ITP) achieved proof of concept (PoC), and orelabrutinib’s phase II study for the treatment of Neuromyelitis Optica Spectrum Disorder (NMOSD) is ongoing in China.

On April 19, 2023 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies for the treatment of cancer and autoimmune diseases, reported the presentation of additional preclinical data on the Company’s casitas B-lineage lymphoma-B (CBL-B) program in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, HotSpot Therapeutics, APR 19, 2023, View Source [SID1234630330]).

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"We believe the targeting of CBL-B, a master regulator of immune cell activation, represents a promising therapeutic approach given preclinical data that indicated CBL-B’s ability to lower the threshold for both T cell and natural killer (NK) cell activation, which has the potential to drive benefit for patients with tumors that respond poorly or do not respond to standard-of-care immunotherapies," said Geraldine Harriman, Ph.D., Co-Founder and Chief Scientific Officer of HotSpot. "These data lend strong support to the ability of CBL-B inhibition to affect change to the tumor microenvironment through the enhancement of NK cell proliferation and activity. We look forward to continuing to advance HST-1011, our lead CBL-B inhibitor clinical candidate, through our ongoing Phase 1 clinical study in patients."

The presentation describes preclinical data for a HotSpot compound that is designed as a novel, allosteric, small molecule inhibitor of CBL-B E3 ubiquitin ligase activity:

In in vitro studies, HotSpot’s CBL-B inhibitor demonstrated an ability to increase the single-cell polyfunctionality of NK cells and to enhance the activation of NK cells, NK cell proliferation, and NK cell-mediated cytotoxic activity against K562 cells. Additionally, HotSpot’s CBL-B inhibitor enhanced NK cell function in tumor models in vivo. Collectively, we believe these data demonstrated that inhibition of CBL-B can enhance the effector function of NK cells and, in turn, promote NK cell-mediated killing of cancer cells.
About HST-1011

HST-1011 is an investigational orally bioavailable, selective, small molecule allosteric inhibitor of CBL-B, an E3 ubiquitin protein ligase critically involved in immune cell response. Because CBL-B functions as a master regulator of effector cell (T cell and natural killer cell) immunity, its inactivation removes its endogenous negative regulatory functions to substantially enhance anti-tumor immunity. Preclinical data has demonstrated HST-1011’s ability to bind to and inhibit a natural hotspot on CBL-B, yielding the activation and propagation of a targeted anti-tumor immune response. Enabled by HotSpot’s proprietary Smart Allostery platform, HST-1011 is designed with tight binding, low nanomolar potency, a slow dissociation rate from the target to enable sustained pharmacology, and greater selectivity for CBL-B relative to C-CBL.

On April 19, 2023 IDEAYA Biosciences, Inc. (NASDAQ: IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported achievement of First-Patient-In in the Phase 1 clinical trial evaluating IDE161 (NCT 05787587) and release of a poster presentation profiling IDE161 at AACR (Free AACR Whitepaper) 2023 (Press release, Ideaya Biosciences, APR 19, 2023, View Source [SID1234630329]). IDE161 is a potent, selective, small-molecule inhibitor of PARG, a novel and mechanistically-differentiated target in the same clinically validated pathway as poly (ADP-ribose) polymerase (PARP).

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"We are excited to clinically investigate IDE161 as a potential first-in-class synthetic lethality treatment for cancer patients with homologous recombination deficiencies (HRD). We believe IDE161 may be impactful for ER+ / Her2- breast cancer patients with HRD, as well as for patients having ovarian cancer and other solid tumors with HRD, for whom current treatment options are limited," said Dr. Darrin M. Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences. "Based on its preclinical tolerability profile, IDE161 may also be suitable for evaluation with several distinct classes of combination agents, providing multiple paths to demonstrate patient benefit in these populations," continued Dr. Beaupre.

Dr. Timothy Yap, M.D., Ph.D., Associate Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston, the site which dosed the first patient, is a leading principal investigator for the Phase 1 clinical trial evaluating IDE161.

IDEAYA’s Phase 1 clinical trial will evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of IDE161 as monotherapy in patients having tumors with homologous recombination deficiency (HRD). The clinical protocol includes dose escalation in solid tumors with HRD. Subject to selection of an expansion dose, the company is planning expansion in cohorts for patients having HRD tumors in breast cancer, ovarian cancer, and a basket of other solid tumors. The breast cancer cohort will focus on estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (Her2-) tumors with HRD, which represent approximately 10% to 14% of breast cancer patients.

IDEAYA is planning to present a poster with preclinical data profiling IDE161 at the 2023 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) on Wednesday, April 19, 2023:

Abstract 6093: "IDE161, a potential first-in-class clinical candidate PARG inhibitor, selectively targets Homologous-Recombination-Deficient and PARP inhibitor resistant breast and ovarian tumors" (Abed, M. et al.)
Date/Time: Wednesday April 19, 2023 at 9:00 am – 12:30 pm ET
Session / Location: Molecular/Cellular Biology and Genetics, Targeting DNA Damage Response and Novel Pathways; Poster Section 13, Poster Board 1
The IDE161 abstract is available online at View Source in connection with the 2023 Annual Meeting of AACR (Free AACR Whitepaper), and the poster will be available online at View Source following the presentation.

An updated corporate presentation, reflecting updates from AACR (Free AACR Whitepaper) 2023 for IDE161 (PARG), as well as for IDE397 (MAT2A), co-published with Amgen, and Werner Helicase, co-published with GSK, will also be available on the IDEAYA website at its Investor Relations page: View Source

IDEAYA owns or controls all commercial rights in IDE161, subject to certain economic obligations under its exclusive, worldwide license with Cancer Research UK and University of Manchester.

On April 19, 2023 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported that James Porter, Ph.D., Chief Executive Officer, and Alexandra Balcom, Chief Financial Officer, will participate in a fireside chat during the Stifel 2023 Virtual Targeted Oncology Days on Wednesday, April 26, 2023, at 1:30 p.m. ET (Press release, Nuvalent, APR 19, 2023, View Source [SID1234630328]).

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A live webcast will be available in the Investors section of the company’s website at www.nuvalent.com, and archived for 30 days following the presentation.

On April 19, 2023 Replicate Bioscience, a company pioneering novel self-replicating RNA (srRNA) technology for use in infectious disease, oncology, autoimmune disease, and more, reported new preclinical data underscoring the strength of Replicate’s srRNA platform and its potential for oncology applications at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Replicate Bioscience, APR 19, 2023, View Source [SID1234630327]).

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"Taken together, the results of these studies demonstrate the activity, versatility, and durability of Replicate’s srRNA vectors and their potential for treating cancer," said Zelanna Goldberg, M.D., Chief Medical Officer at Replicate, and poster presenter. "Our srRNAs are designed to produce higher bioactivity at low doses compared to linear mRNA therapeutics. These unique characteristics enable flexible co-administration with existing therapies and better tolerability. We are pleased to share these promising results with the oncology community and look forward to advancing our programs towards clinical trials."

The poster presented today by Dr. Goldberg, titled "A self-replicating RNA precision medicine approach to overcoming resistance to endocrine therapy in ER+ breast cancer," underscores the therapeutic potential of Replicate’s lead immuno-oncology candidate, RBI-1000, to address acquired resistance mutations, a major factor behind the clinical failure of existing endocrine therapy.

RBI-1000 encodes high frequency, clinically characterized pervasive and predictable acquired resistance mutations found in estrogen-receptor expressing breast cancer, representing about 80% of all ER+ breast cancers. RBI-1000 primes T cells to respond to these mutations as they arise and is designed to act synergistically with standard of care treatments.
In a mouse model expressing the targeted acquired resistance mutations, RBI-1000 successfully primed CD4+ and CD8+ T cells leading to significant tumor growth inhibition and improved survival at a 100-fold lower dose than linear mRNA approaches in other tumor models.
"This study contributes to our growing body of preclinical data indicating that when coupled with a standard of care therapy, RBI-1000 forces tumors into a lose-lose situation and ultimately, destruction," said Parinaz Aliahmad, Ph.D., head of Research and Development at Replicate. "Our team is proud to pave the way in unlocking broader applications for RNA to realize therapeutic breakthroughs for large and diverse patient populations."

The second poster, titled "A self-replicating RNA precision medicine approach to therapeutic protein delivery of narrow therapeutic index biomolecules," was presented on April 17 by Dr. Goldberg. The study is the first demonstration of Replicate’s srRNAs to encode multiple biotherapeutic molecules in a single vector backbone for better bioactivity at lower doses than linear mRNA approaches. Multiple encoded proteins also allow for durable tumor immunotherapy, and applications such as the expression of cytokines, other biologics, protein replacement, or secreted proteins.

RBI-2000 encodes two distinct proteins on one RNA strand: one multimeric protein to promote generation of new immune cells, and another monomeric to prevent sterile inflammation, aberrant angiogenesis, and tumor invasiveness. RBI-2000 utilizes a novel self-replicating RNA vector with an enhanced pharmacokinetic profile and pharmacodynamic effects at very low doses capable of controlling tumors as a monotherapy or in combination with checkpoint inhibition.
Mice who had complete responses were rechallenged with tumor cells at 70 days post-treatment and successfully rejected the challenge, indicating robust immunological memory.