On December 11, 2023 Laekna (2105.HK), a clinical-stage biotechnology company, reported the results of a phase Ib study to evaluate the efficacy and safety of afuresertib plus fulvestrant in patients with locally advanced or metastatic HR+/HER2- breast cancer who failed standard of care therapies at the 2023 San Antonio Breast Cancer Symposium (SABCS) on December 8 (Press release, Laekna Therapeutics, DEC 11, 2023, View Source;laekna-reports-afuresertib-phase-ib-breast-cancer-study-results-302011286.html [SID1234638464]).

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From May 2022 to April 2023, 20 patients (19 female and 1 male) with locally advanced or metastatic HR+/HER2- breast cancer who had failed 1-2 lines of endocrine therapy were enrolled in the Phase Ib study. The median duration of follow-up was 11 months.

As of October 16, 2023, the main study results are as follows:

– 70% of the patients were previously treated with CDK4/6 inhibitors.

– Among the total patient population, the confirmed ORR was 30% (95% CI, 11.9, 54.3), the median PFS was 7.3 months (95% CI, 3.7, NE). The disease control rate (DCR) was 80%.

– Among the 11 patients with specific biomarker alterations (PIK3CA/AKT1/PTEN), the confirmed objective response rate was 45.4% (95% CI, 16.7, 76.6), the disease control rate was 82%, and the median PFS was 7.3 months (95% CI, 3.6, 8.2).

– Among the 17 Chinese patients, the confirmed ORR was 29.4% (95% CI, 10.3, 60.0), the disease control rate was 82.4%, and the median PFS was 7.3 months (95% CI, 3.6, 8.2).

– The results demonstrated a well-tolerated safety profile of afuresertib plus fulvestrant. No dose modification was required during the safety run-in period. No patient discontinued treatment due to TEAE. No serious adverse event (SAE) was reported.

Investigators concluded that the combination therapy of afuresertib and fulvestrant has shown promising efficacy with a well-tolerated safety profile, supporting further evaluation in the upcoming Phase III part of the study.

Academician Binghe Xu, the lead investigator of the study, said: "While therapies for breast cancer are increasing, the treatment of drug resistance remains one of the clinical challenges. With the approval of the world’s first AKT inhibitor last month, patients with locally advanced or metastatic HR+/HER2- breast cancer now have new hope. The Phase Ib data of the combination therapy of afuresertib and fulvestrant are promising. I look forward to the next Phase III study of afuresertib in breast cancer."

"Biomarkers of response and/or resistance to endocrine-based therapies has become a prominent topic in the field of breast cancer treatment. It is also the central theme of the ‘Poster Spotlight Session’ in which our study was presented," said Dr. Yong Yue, Chief Medical Officer of Laekna. "Compared with the PFS data of 3-4 months for fulvestrant monotherapy[1], the median PFS of afuresertib plus fulvestrant is significantly increased to 7.3 months, with a favorable safety profile."

Lakena has initiated the Phase III pivotal trial of afuresertib plus fulvestrant in the treatment of HR+/HER2- breast cancer. The company strives to bring new hope to patients.

Notes

Breast cancer

The latest data released by the International Agency for Research on Cancer (IARC) of the World Health Organization show that the number of new cases of breast cancer in 2020 reached 2.26 million worldwide, surpassing lung cancer for the first time and becoming the world’s most prevalent cancer with 685,000 deaths. The latest epidemic data of malignant tumors in China also show that breast cancer has ranked first among women, with about 420,000 new cases each year[2].

Approximately 69% of breast cancer patients in the United States are considered HR+/HER2[3], and the proportion of this subtype among Chinese patients is 62%[4]. Although most patients with this type of breast cancer initially benefit from first/second-line endocrine ± CDK4/6 inhibitors and/or chemotherapy, most may develop drug resistance after a period, leading to treatment failure.

With further research on AKT, it has been demonstrated that factors such as PTEN loss and AKT/PIK3CA mutation can lead to excessive activation of the AKT signaling pathway, resulting in the occurrence, development, and drug resistance of tumors, especially prevalent in HR+ breast cancer. AKT has consequently emerged as a popular target for treating tumors.

Afuresertib

Afuresertib (LAE002) is an AKT inhibitor developed by Laekna. Laekna has initiated multiple clinical studies of combination therapies with Afuresertib in patients with PROC, HR+/HER2− breast cancer, mCRPC, TNBC, PD-1-resistant cervical cancer, and endometrial cancer.

On December 11, 2023 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported the presentation of preclinical data from the Company’s highly differentiated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) program in an oral presentation at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, HotSpot Therapeutics, DEC 11, 2023, View Source [SID1234638463]).

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MALT1 is a component of the CARD11-BCL10-MALT1 (CBM) protein complex, which serves as a key regulator of NFkB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies, including Non-Hodgkin’s lymphoma, as well as other lymphomas and selected solid tumors. Leveraging our proprietary Smart Allostery platform, HotSpot has developed potential first-in-class small molecules designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NFkB pathway, while sparing MALT1’s protease function.

"MALT1’s therapeutic potential rests in the role of its scaffolding function to regulate the NFkB pathway, which is implicated in a broad range of hematological and solid tumors," said Geraldine Harriman, Co-Founder and Chief Scientific Officer of HotSpot. "Using our Smart Allostery platform, HotSpot has delivered a potential first-in-class allosteric inhibitor, HST-1021, that is designed to potently and selectively inhibit MALT1’s scaffolding function. HST-1021’s pharmacological attributes suggest therapeutic potential, as these preclinical data demonstrated in vivo tumor growth inhibition without any observed negative impact on other immune functions. We look forward to providing additional updates as we advance our program, as we plan to file an Investigational New Drug (IND) application for HST-1021 in 2024."

The presentation describes preclinical data for HST-1021, HotSpot’s MALT1 inhibitor development candidate:

Using the Smart Allostery platform, HotSpot elucidated and drugged a natural hotspot on MALT1 that potently and selectively inhibited MALT1’s scaffolding function, while sparing MALT1’s protease function.
In several B-cell lymphoma xenograft models, HST-1021 demonstrated robust, dose-dependent tumor growth inhibition (TGI), including in both MALT1 protease-inhibitor sensitive ABC-DLBCL and MALT1 protease-resistant NFkB-driven DLBCL models.
In contrast to MALT1 protease inhibitors, HotSpot’s scaffolding inhibitor did not deplete Treg cells or suppress T-cell activation in vivo, which HotSpot believes supports the potential for clinical mitigation of the risk of autoimmune disease resulting from chronic MALT1 protease function inhibition and would allow for broad combination use.

On December 11, 2023 Shuttle Pharmaceuticals Holdings, Inc. (Nasdaq: SHPH) ("Shuttle Pharma") reported submission of an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) to support the next phase of development of Ropidoxuridine (Press release, Shuttle Pharmaceuticals, DEC 11, 2023, View Source [SID1234638462]). Ropidoxuridine is Shuttle Pharma’s lead radiation sensitizer candidate for use in combination with radiation therapy (RT) to treat brain tumors (glioblastoma), a deadly malignancy of the brain with no known cure.

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RT is a proven modality for treating cancers. However, there is a significant need in the market to make radiation more effective. By developing radiation sensitizers, Shuttle Pharma aims to increase cancer cure rates, prolong patient survival and improve quality of life when used as a primary treatment, or in combination with surgery, chemotherapy and immunotherapy.

"Today’s announcement is an important milestone for Shuttle Pharma and the thousands of patients with brain tumors who currently lack effective therapies," stated Shuttle Pharma’s Chairman and CEO, Anatoly Dritschilo, M.D. "The IND submission is the culmination of many years of clinical development by the Shuttle Pharma team, as well as support from the broader cancer community, including the National Institutes of Health’s National Cancer Institute and Small Business Innovation Research program, who have provided guidance and grant funding to bring this potentially important new radiation sensitizing therapy to market."

An IND submission is a request submitted to the regulatory authorities seeking permission to test a new drug or therapeutic substance in humans. The submission includes detailed information about the drug, its composition, pharmacology, toxicology data from preclinical studies, proposed clinical trial protocols, and information on manufacturing and quality control. With the IND application submission now complete, the FDA is expected to provide Shuttle Pharma with its decision to proceed with the Phase II trial within approximately 30 days.

The submission of the IND follows recent receipt of written responses to questions submitted for a Type B pre-Investigational New Drug Application (PIND) meeting with the FDA in September 2023. During the PIND meeting, the FDA provided positive feedback and guidance on the Company’s Chemistry, Manufacturing, and Controls (CMC) and clinical protocol design for Ropidoxuridine, thus providing the pathway to this IND submission.

The planned Phase II trial will investigate whether a new treatment, Ropidoxuridine, taken during radiation treatment, will be a safe and possibly effective for treatment of patients with newly diagnosed IDH-wildtype glioblastoma with unmethylated MGMT promoter.

Dr. Dritschilo added, "Our mission is to improve the lives of cancer patients by developing therapies that are designed to maximize the effectiveness of RT while limiting the side effects of radiation in cancer treatment. This IND submission is an important next step in making this mission a reality."

An estimated 800,000 patients in the US are treated with radiation therapy for their cancers yearly. According to the American Cancer Society and the American Society of Radiation Oncologists, about 50% are treated for curative purposes and the balance for therapeutic care. The market opportunity for radiation sensitizers lies with the 400,000 patients treated for curative purposes, with this number expected to grow by more than 22% over the next five years.

Shuttle Pharma has received Orphan Drug Designation from the FDA, providing potential marketing exclusivity upon first FDA approval for the disease.

On December 11, 2023 Telix Pharmaceuticals Limited (ASX: TLX, Telix, the Company) reported that the first patient has been dosed in a United States (U.S.) expanded access program (EAP, ClinicalTrials.gov ID: NCT06090331) for TLX250-CDx (89Zr-DFO-girentuximab) (Press release, Telix Pharmaceuticals, DEC 11, 2023, View Source [SID1234638461]). TLX250-CDx is the Company’s first-in-class, non-invasive investigational positron emission tomography (PET) imaging agent in clear cell renal cell carcinoma (ccRCC).

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The patient was dosed at ARA Diagnostic Imaging at Austin Radiological Association in Austin (TX, U.S.) following U.S. Food and Drug Administration (FDA) agreement to proceed.

FDA agreement for an EAP follows the completion of Telix’s successful global Phase III ZIRCON study (Zirconium in Renal Cancer Oncology, ClinicalTrials.gov ID: NCT03849118), which reported positive results in November 2022, meeting all co-primary and secondary endpoints.[1]

Dr John Leahy, molecular radiologist and nuclear medicine specialist at ARA Diagnostic Imaging and a Principal Investigator on the EAP stated, "With TLX250-CDx, for the first time, urologists and urologic oncologists may have a non-invasive way to determine the presence of ccRCC, the most common and aggressive form of kidney cancer. We are therefore extremely pleased to have been selected as the inaugural site for this national EAP, with patients in Austin and the surrounding area now able to benefit from greater confidence in their kidney cancer diagnosis and treatment planning."

Mary Jessel, Senior Vice President of Global Medical Affairs at Telix added: "Ahead of regulatory approval, this EAP provides continued access to TLX250-CDx to address a clear unmet patient need. ZIRCON results demonstrate that TLX250-CDx has potential to become a new standard of care in the diagnosis and staging of ccRCC, where existing imaging can be inconclusive."

Under its EAPs – sometimes called ‘compassionate use’ – the FDA works with companies to allow access to investigational products outside of a clinical trial to patients for whom there are no comparable or satisfactory alternate options.

Telix is progressing towards a Biologics License Application (BLA) submission for TLX250-CDx with the FDA and other equivalent applications with regulatory agencies in key commercial jurisdictions.

U.S. patients, or physicians who may have eligible patients in the U.S., can e-mail [email protected] for further information about the TLX250-CDx EAP.

Telix’s Policy on Offering Compassionate Use to Investigational Medicines can be downloaded at the following link.

For more information about ongoing clinical trials of TLX250-CDx, please visit View Source

On December 11, 2023 Mabwell (688062.SH), an innovative biopharmaceutical company with entire industry chain, reported that its submission to the Center for Drug Evaluation (CDE) of the National Medical Products Administration for the "A Randomized, Open-label, Controlled, Multicenter Phase III Clinical Trial of 9MW2821 versus Investigator’s Choice of Chemotherapy for Treating Unresectable Locally Advanced or Metastatic Urothelial Carcinoma in Patients Previously Treated with Platinum-Containing Chemotherapy and PD-(L)1 Inhibitors" has been approved (Press release, Mabwell Biotech, DEC 11, 2023, View Source [SID1234638460]). The company will now officially initiate the Phase III clinical study of 9MW2821 for treating locally advanced or metastatic urothelial carcinoma in patients previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors.

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9MW2821 is a novel Nectin-4 targeting ADC developed independently by Mabwell, marking the first of its kind among the products developed in China with the same target to enter clinical trials. As of December 5, 2023, more than 250 subjects were enrolled. In the Phase II clinical trial of 9MW2821, at a dose of 1.25 mg/kg, the monotherapy resulted in an objective response rate (ORR) of 62.2% (95% CI: 44.8%–77.5%) and a disease control rate (DCR) of 91.9% (95% CI: 78.1%–98.3%) in patients with advanced urothelial carcinoma. The median progression-free survival (PFS) was 6.7 months (95% CI: 3.8–NR), while the median overall survival (OS) has not been reached yet.

Currently, multiple clinical trials are being conducted simultaneously for this project. Clinical trials on combination therapy with other treatments, in addition to monotherapy, are also advancing. Promising antitumor activity coupled with favorable safety profiles has been observed across various cancer types.

About Urothelial Carcinoma
According to the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), bladder cancer is the ninth most common malignant tumor in terms of incidence and ranks thirteenth in mortality among malignant tumors. According to the 2016 Chinese national cancer statistics published by the National Cancer Center in February 2022, there were 82,300 new bladder cancer cases, with an incidence of 3.53 per 100,000 individuals. Urothelial carcinoma, ranking among the top ten most prevalent cancers in China, is characterized by its tendency toward metastasis and recurrence. Advanced urothelial carcinoma is associated with short survival, contributing to a substantial disease burden in China and seriously compromising patients’ survival and quality of life.

About 9MW2821
9MW2821 is a novel Nectin-4 targeting ADC developed by world-class ADC development platform and automated high-throughput antibody discovery platform of Mabwell. It achieves site-specific modification of antibody through proprietary conjugate technology linkers and optimized ADC conjugation process. 9MW2821 can specifically bind to Nectin-4 on the cell membrane surface, be internalized and release cytotoxic drug, and induce the apoptosis of tumor cells. The company is conducting several clinical trials on a range of indications, including urothelial carcinoma and cervical cancer. Currently, the R&D progress of 9MW2821 ranks first in China and second in the world. 9MW2821 is the first to read out preliminary clinical data in cervical cancer among the products with the same target in the world.