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Upthera Inc. Signs “Collaboration Agreement for Joint Research and Development and Early Technology Export” with Boryung Inc. for Novel Multiple Myeloma (MM) Treatment

On February 6, 2024 Upthera Co., Ltd. (CEO Choi Si-woo), a company specializing in the development of innovative new drugs based on Targeted Protein Degradation (TPD) technology, reported that it had signed a collaboration agreement with Boryung Co., Ltd. (CEOs Kim Jeong-gyun and Jang Du-hyeon), a leader in the domestic anticancer drug field, for the joint research and development and early commercialization of a new drug candidate for Multiple Myeloma (MM).

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The core objective of this collaboration agreement is to license Upthera’s early discovery-stage pipeline of transcription factor proteolytic compounds to licensees, including multinational pharmaceutical companies. To this end, Upthera plans to collaborate by focusing on research and development to rapidly identify nonclinical candidates, while Boryung will carry out proactive business development activities from the early stages of research and development.

Through this agreement, Uptera is scheduled to receive a fixed upfront payment from Boryung and milestone payments upon the achievement of specific results by the time the candidate substance is identified. If this protein degradation compound achieves a technology export to a third party, Boryung will receive a certain percentage of the generated profits and retain exclusive domestic rights upon successful commercialization. The amounts of the upfront payment and milestone payments under the agreement between the two companies have agreed not to be disclosed.

Multiple myeloma is a disease characterized by the abnormal proliferation of plasma cells, resulting in multiple symptoms throughout the body; it is classified as one of the three major blood cancers, along with leukemia and lymphoma. Due to population growth and aging, the number of patients with the disease is continuously increasing, and it is an intractable cancer with a very high recurrence rate, meaning there is virtually no concept of a cure. Currently, various treatments and options for multiple myeloma exist, including Revlimid (Lenalidomide), Darzalex (Daratumumab), and Pomalist; however, the consensus among clinicians is that more new drugs and treatment options are needed, considering the characteristics of multiple myeloma, such as the very high recurrence rate and the large number of patients who are refractory to existing treatments.

The transcription factor protein in question was already well known through many prior studies as a very promising drug target for the treatment of multiple myeloma. However, transcription factor proteins are generally small in size, have few binding pockets, and contain many cofactors, making them representative undruggable targets for which new drug development was difficult using the existing small molecule inhibitor modality.

However, targeted protein degradation technology, including PROTACs that selectively degrade disease-causing proteins through the body’s ubiquitin proteasome system (UPS), enables degradation as long as the disease-causing protein is ubiquitinated in any way; based on this specific advantage, it is possible to develop new drugs that inhibit (degrade) transcription factor proteins. Upthera is currently developing a new drug candidate that degrades a specific transcription factor protein, which plays a key role in the differentiation of B cells into antibody-producing plasma cells, using targeted protein degradation technology.

Since the transcription factor proteins targeted by Upthera are representative undetectable targets, there is no history of developing inhibitors or binder compounds that bind to these proteins. Therefore, Upthera is discovering novel hit binder compounds that bind to these transcription factor proteins through DEL screening (DNA encoded library screening) via external partners and its own chemoproteomics-based covalent binder screening platform (UPPBEAT), and is currently developing targeted proteolytic compounds.

Regarding multiple myeloma treatments, Boryung possesses Revlikin Capsules (active ingredient: Lenalidomide) and Belkin Injection (active ingredient: Bortezomib), which are currently marketed in Korea, as well as Aplidin (active ingredient: Plitidepsin), for which Boryung holds exclusive commercial rights after introducing it to the domestic market from the Spanish pharmaceutical company PharmaMar. Furthermore, having successfully avoided the patent for Pomalist (active ingredient: Pomalidomide), a multiple myeloma treatment, in 2021, Boryung is eligible to apply for generic approval in 2023. Consequently, Boryung plans to build a diverse portfolio of multiple myeloma treatments ranging from first-line to third-line standard therapies. Leveraging its marketing experience with multiple myeloma treatments and a network of relevant experts and clinicians, Boryung possesses a deep understanding and expertise regarding the multiple myeloma and related treatment market. Through this, the company intends to effectively carry out proactive business development activities regarding this transcription factor proteolytic compound.

Boryung CEO Jang Doo-hyun stated, "We expect excellent results from the combination of Uptera’s R&D capabilities and Boryung’s know-how in the anticancer drug business," adding, "We will focus on the early development of the new drug to provide hope to multiple myeloma patients with a new treatment option."

Uptera CEO Choi Si-woo stated, "I am very pleased to be able to collaborate with Boryung, a leader in the domestic anticancer drug field. We will strive to achieve research and development and commercialization results as soon as possible by combining the technological and commercialization capabilities of both companies."

(Press release, Uppthera, FEB 6, 2024, View Source [SID1234664779])

The Results of Phase II Clinical Study of KN046 in Combination with Nab-paclitaxel in TNBC were Published in Nature Communications

On February 6, 2024 Alphamab Oncology (stock code: 9966.HK) reportedKN046-203 is a phase II, open label, multi-center, multi-cohorts clinical study, evaluating the efficacy, safety, and tolerability of KN046 in combination with nab-paclitaxel in patients with TNBC as first-line treatment. A total of 27 female patients who were systemic treatment naïve for locally advanced inoperable or metastatic TNBC were enrolled.

As of August 21, 2022, based on the Independent Review Committee (IRC) evaluation, the objective response rate (ORR) from 25 efficacy evaluable TNBC patients was 44.0% (95% CI: 24.4~65.1%), the disease control rate (DCR) was 96.0% (95% CI: 79.7~99.9%), the clinical benefit rate (CBR) was 52.0% (95% CI: 31.1~72.2%) and the median DOR was not mature. The progression-free survival (PFS) and overall survival (OS) was analyzed on intention-to treat (ITT) population. The median PFS was 7.33 months (95%CI: 3.68~11.07 months). Among the patients with PD-L1 expression ≥1%, the median PFS was 8.61 months (95%CI, 1.61 – NE months). The median OS result was 30.92 months (95% CI, 14.75 – NE months), and the 2-year OS rate was 60.1% (95%CI, 37.2~76.9%). Both PD-L1 negative and positive patients could derive OS benefit from the therapy.

Among the 27 evaluable patients, Grade 3-4 treatment-related adverse events (TRAEs) occurred in 18 patients (66.7%). Treatment-related serious adverse events (TRSAEs) occurred in 6 patients (22.2%). Immune-related adverse events (irAEs) occurred in 13 patients (48.1%). Most irAEs were Grade 1 or 2. Grade ≥3 irAEs were reported in 3 patients, 2 patients with Grade 3 immune-mediated liver disease, and 1 patient with Grade 3 rash.

Conclusion: KN046 combined with nab-paclitaxel in the first-line treatment of TNBC showed encouraging PFS and OS. Patients received combination therapy were well tolerated and the safety profile was manageable.

About KN046

KN046 is PD-L1/CTLA-4 bispecific antibody independently developed by Alphamab. Its innovative designs include: a novel mechanism – CTLA-4 fused with PD-L1 single domain antibody; engineered to target the tumor microenvironment with high PD-L1 expression, and Treg (suppress tumor immunity) clearing function.

There are about 20 clinical trials of KN046 in different stages covering more than 10 types of tumors including NSCLC, pancreatic cancer, thymic cancer, HCC, ESCC and TNBC in Australia, the US and China. The results of these clinical trials have shown an advantage in survival for patients. Alphamab Oncology has received FDA clearance to enter phase II trial of KN046 based on the clinical results in China and Australia. Moreover, KN046 has obtained the U.S. FDA’s orphan drug designation for thymic epithelial tumor in September 2020. Several pivotal clinical trials are currently being conducted, among which the interim analysis of the phase III clinical study of KN046 combined with chemotherapy as the first-line treatment of NSCLC successfully met the prespecified PFS endpoint. that the phase Ⅱclinical research results of anti- PD-L1/CTLA-4 bispecific antibody KN046 in combination with nab-paclitaxel as first-line treatment in advanced triple-negative breast cancer (TNBC) were published online in the renowned journal Nature Communications (IF: 16.6, JCR Q1). Professor Binghe Xu from Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College is the corresponding author of this paper.

(Press release, Alphamab, FEB 6, 2024, View Source [SID1234657016])

Consolidated Financial Results for the Nine-Month Period Ended December 31, 2023

On February 6, 2024 reported its Consolidated Financial Results for the Nine-Month Period Ended December 31, 2023 (Presentation, Eisai, FEB 6, 2024, View Source [SID1234642346]).

Triumvira Immunologics Pivots to Claudin 18.2-Targeted Cell Therapy, Pauses HER2 Program

On February 6, 2024 Triumvira Immunologics on Monday reported it began dosing patients in a Phase I/II trial or an autologous T-cell antigen coupler (TAC) therapy, TAC101-CLDN18.2, targeting claudin 18.2 (CLDN18.2)-positive solid tumors (Press release, Triumvira Immunologics, FEB 6, 2024, View Source [SID1234639946]).

At the same time, in an effort to optimize finite resources, the Austin, Texas-based company has paused clinical development of its HER2-targeted TAC agent, TAC 100-HER1 (formerly TAC01-HER2), and is focusing instead on the CLDN18.2 program, said Robert Williamson, Triumvira’s president and chief operating officer.

Vividion Therapeutics starts Phase I clinical trial in advanced solid and hematologic tumors with oral STAT3 inhibitor

On February 6, 2024 Vividion Therapeutics, Inc. (Vividion), reported that it has initiated dosing of patients in a Phase I clinical trial evaluating VVD-130850, an investigational oral STAT3 inhibitor for the treatment of advanced solid and hematologic tumors (Press release, Vividion Therapeutics, FEB 6, 2024, View Source [SID1234639895]). Vividion is a biopharmaceutical company, and a wholly owned and independently operated subsidiary of Bayer AG, utilizing innovative discovery technologies with the potential to unlock high value, traditionally undruggable targets with precision therapeutics for devastating cancers and immune disorders. The start of the trial represents another major milestone for Vividion’s innovative chemoproteomics platform.

"The initiation and dosing of the first clinical trial with our STAT3 inhibitor program marks a major inflection point for Vividion as this is the second program from our platform that we have advanced into the clinic in just a few months. We are proud of the progress we have made in a relatively short amount of time with a pipeline consisting of previously undruggable protein targets for prominent oncology and immunology diseases," said Aleksandra Rizo M.D., Ph.D., Chief Executive Officer of Vividion.

"We are leveraging Vividion’s innovative chemoproteomics drug discovery technology to develop new therapies that are addressing high profile cancer targets with the potential to stop or reverse the progression of disease," said Christian Rommel, Ph.D., Member of the Executive Committee of Bayer’s Pharmaceuticals Division and Head of Research and Development. "For millions of patients and their families, cancer continues to be a devastating disease, and new treatments are needed to address key drivers of tumor cell survival and growth. The start of the clinical development of Vividion’s STAT3 inhibitor program takes us one step closer to a potentially meaningful new treatment for cancer patients."

VVD-130850 is an oral small molecule inhibitor of STAT3 binding to a novel allosteric pocket leading to direct inhibition of DNA binding and expression of STAT3 target genes in cancer cells. The Phase I clinical trial will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of VVD-130850 in patients with advanced solid and hematologic tumors as a single-agent and in combination with immune checkpoint inhibition.

"We are excited to announce the initiation and dosing of this highly selective STAT3 inhibitor," said Jenna Goldberg, M.D., Chief Medical Officer of Vividion. "What makes this clinical candidate really outstanding in our minds is that it binds to STAT3 to inhibit the expression of downstream target genes without affecting the STAT3 protein levels. We believe the STAT3 pathway holds promise to shift the treatment paradigm for cancer patients and look forward to advancing VVD-130850 through clinical development."

The company is advancing multiple novel drug discovery programs toward the clinic and has more than a dozen similar pipeline opportunities emerging in early discovery in the fields of oncology and immunology. Following the company’s acquisition by Bayer in August 2021, Vividion is operating at arm’s length in a best-of-both-worlds’ model, preserving its innovative, entrepreneurial culture while also leveraging Bayer’s deep expertise in small molecule drug development, global capabilities and financial strength.

About STAT3

Signal transducer and activator of transcription 3 (STAT3) is a key regulatory protein, which become hyperactivated in certain human cancers where it can promote tumor progression, metastasis, and decreased immune responses. Owing to its role in tumor formation, metastasis as well as drug resistance and immunosuppression, the STAT3 pathway is recognized as a promising therapeutic target in a wide range of cancers.