On December 11, 2024 CatalYm reported that data of the first-in-human Phase 1/2a study of its lead drug candidate visugromab were published in Nature (Press release, Catalym, DEC 11, 2024, View Source [SID1234649062]). The paper titled "Neutralizing GDF-15 can overcome anti-PD-(L)1 resistance in solid tumors" emphasizes the significant potential of visugromab to induce unprecedented cancer remission depth and durability across multiple solid tumor indications as well as in combination with nivolumab in late- to last-line solid tumors. Visugromab is a humanized, monoclonal antibody that counteracts GDF-15, a critical immunosuppressant used by tumor cells to survive.

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The publication provides a mature data set of the GDFATHER Phase 1/2a trial (NCT04725474), demonstrating that the company’s anti-GDF-15 antibody visugromab in combination with the PD-1-inhibitor nivolumab delivers deep and durable responses in by strict RECIST 1.1 criteria anti-PD-(L)1 relapsed/refractory solid tumor patients. Building on interim data presented at ASCO (Free ASCO Whitepaper) earlier this year, the additional findings extend the durability profile of the anti-tumor responses seen in these late- to last-line metastatic non-small cell lung cancer (NSCLC), urothelial cancer (UCC) and hepatocellular cancer (HCC) patients. The publication further provides a wealth of translational research data that demonstrate the detailed proof-of-mechanism (POM) for visugromab, which induces T-cell influx, T-cell proliferation, and Interferon-γ signature induction in the tumor microenvironment both in monotherapy and in combination with nivolumab. Furthermore, pan-cancer immunogenomic analyses demonstrate the impact of GDF-15 on the tumor microenvironment and its immune cell landscape.

The full publication can be accessed and downloaded via the following link.

"The publication of our data in Nature confirms the high significance and novelty the scientific community has ascribed to GDF-15 as an immuno-oncology target, as well as the potential of visugromab to transform the cancer immunotherapy treatment landscape," said Eugen Leo MD PhD MBA, Chief Medical Officer at CatalYm. "We observed both robust proof-of-mechanism and clinical proof-of-concept in this first-in-human trial for visugromab, with more than half of our responders achieving deeper RECIST 1.1 responses than seen with their initial checkpoint inhibitor treatment. Notably, we see a growing number of lasting complete responses in late- to last-line patients who had no further therapeutic alternatives anymore. This is a significant outcome not seen with other exploratory I/O treatments in this setting. We are now rapidly advancing visugromab into earlier lines of treatment, with several trials planned for 2025 in high unmet medical need solid tumor indications."

Summary of Key Clinical Results from the ongoing GDFATHER Phase 1/2a trial (GDF-15 Antibody-mediaTed Human Effector T Cell Relocation Phase 1/2a Trial):

The matured results from the Phase 2a indication-specific cohorts for NSCLC, UC, and all HCC so far treated show the following Objective Response Rates (ORR) based on strict RECIST 1.1 criteria:
non-squamous NSCLC: ORR of 19.0% (4/21), with 2 partial responses (PR) and 2 complete responses (CR)
UC: ORR of 18.5% (5/27), with 4 PR and 1 CR
HCC: interim ORR of 20.0% (4/20), with 3 PR and 1 CR
The current mean duration of response (DoR) for UC and NSCLC surpassed 15 and 16 months with 7/9 responses ongoing.
More than half of all responders in the NSCLC and UC cohorts of the trial experienced a response depth on study treatment as per RECIST 1.1 criteria that had not been reached on their prior anti-PD1/PD-L1 treatment that was mostly administered as first-line treatment and in combination with chemotherapy.
Among the NSCLC and UC responders, 3 out of 4 complete responders had not achieved a complete response on any prior line of systemic treatment, including their initial anti-PD1/PD-L1 therapy.
Additionally, biomarker analyses revealed promising potential for patient stratification, with elevated levels of serum GDF-15 correlating with reduced immune cell infiltration in tumors.
The combination of visugromab with nivolumab was overall well-tolerated, with a safety profile comparable to nivolumab treatment alone.
In a subgroup of patients that had combined manifest cachexia, a similar effect on weight gain was observed as demonstrated for another GDF-15 inhibitor in a recent cachexia trial.
Cachexia, a syndrome characterized by severe weight loss and muscle wasting is driven by elevated GDF-15 levels in certain cancer types. By neutralizing GDF-15, visugromab can help mitigate these effects, potentially improving the quality of life for patients undergoing intensive cancer treatments.

Based on these encouraging data, CatalYm is currently preparing for a broad Phase 2b program in earlier treatment settings for non-squamous NSCLC and additional tumor indications. These developments highlight the company’s commitment to tackling cancer resistance and improving treatment outcomes for patients across multiple tumor types.

About Visugromab (CTL-002)

Visugromab is a monoclonal antibody that neutralizes the tumor-derived Growth Differentiation Factor-15 (GDF-15), a locally acting immunosuppressant fostering immunotherapy resistance. Neutralizing GDF-15 with visugromab reverses key cancer resistance mechanisms to reinstate an efficient anti-tumor response by reenabling immune cell activation, proliferation and Interferon-γ signature induction. Visugromab has demonstrated a good safety profile and potent and durable anti-tumor efficacy in combination with anti-PD-1 treatment in advanced cancer patients. The antibody will now be investigated in Phase 2b studies in multiple solid tumor indications.

On December 11, 2024 SystImmune, Inc. (SystImmune), a clinical-stage biotechnology company, reported that a poster for BL-B01D1, a potentially first-in-class EGFRxHER3 bispecific antibody drug conjugate (ADC) will be presented at the San Antonio Breast Cancer Symposium (SABCS) 2024, taking place on December 10-13 in San Antonio, Texas. BL-B01D1 is being jointly developed by SystImmune and Bristol Myers Squibb under an exclusive license and collaboration agreement (Press release, SystImmune, DEC 11, 2024, View Source [SID1234649061]).

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Updated results from clinical trials of BL-B01D1 will include data from patients with advanced stage triple-negative, HR-positive / HER2-negative, and HER2-positive breast cancer. The data to be presented at SABCS highlights continued progress of BL-B01D1 clinical development and builds upon the previously reported clinical data in lung, breast and bladder cancer patients.

"These data substantially add to the body of evidence that shows encouraging signals of efficacy in main breast cancer subtypes and strengthens our conviction that BL-B01D1 has a manageable safety profile," said Jonathan Cheng, M.D., CMO of SystImmune. "We are committed to continuing the development of this therapy through clinical trials and exploring its potential both as a monotherapy and in combination with other agents, to improve outcomes for cancer patients globally."

Details on the presentations at SABCS are below:
‍BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate, in patients with Locally Advanced or Metastatic Breast Cancer and other Solid Tumor: Updated results from a Phase I study
Presentation Number: P5-07-27/Abstract SESS-630
Speaker: Jiong Wu, M.D.
Onsite Poster display date: Friday, December 13th, 2024

About BL-B01D1
The company is developing BL-B01D1, a bispecific antibody-drug conjugate (ADC) that targets both EGFR and HER3. These proteins are highly expressed in most epithelial tumors. The tetravalent BL-B01D1 has two binding domains for distinct Growth Factor Receptors that drive cancer cell proliferation and survival. Inheriting the SI-B001 mechanisms of action, BL-B01D1 blocks EGFR and HER3 signals to cancer cells, reducing proliferation and survival signals. Upon antibody mediated internalization, BL-B01D1 is trafficked to cancer cell lysosomes and liberates its therapeutic payload that induces genotoxic stress activating pathways leading to cancer cell death.

On December 11, 2024 Dizal (SSE:688192), a biopharmaceutical company committed to developing novel medicines for the treatment of cancer and immunological diseases, reported the publication of a pooled analysis evaluating sunvozertinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI)-resistant non-small cell lung cancer (NSCLC) in the official journal of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Lung Cancer (Press release, Dizal Pharma, DEC 11, 2024, View Source [SID1234649060]). The results of the analysis demonstrated that sunvozertinib exhibited promising antitumor activity and favorable safety profile, warranting future investigations into its potential in patients with EGFR mutated NSCLC who have developed resistance to EGFR TKIs.

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The analysis pooled data from three Phase 1 and 2 studies (WU-KONG1, WU-KONG2 and WU-KONG15). A total of 40 NSCLC patients with EGFR sensitizing mutations who had developed resistance to EGFR TKI treatment were enrolled, 90% of whom had received ≥ 3 prior lines of therapy. Eligible patients received sunvozertinib at doses ranging from 50 mg to 400 mg once daily. As of September 15, 2023, the key findings of the analysis were as follows:

The best objective response rate (ORR) was 27.5 %, and disease control rate (DCR) was 60 %.
The median duration of response (mDoR) and progression free survival (mPFS) were 6.5 months and 6 months, respectively.
Greater ORR of 55.6% was seen in patients with EGFR sensitizing and T790M double mutations (78% had received third-generation EGFR-TKI treatment in prior lines of therapy).
Sunvozertinib was well-tolerated, and the safety profile was consistent with previous reports.
"Resistance to chemotherapy or EGFR TKIs remains a major challenge in the management of EGFR mutated NSCLC. In clinical practice, EGFR-targeted therapeutic strategies are one of the main approaches to addressing EGFR-TKI resistance," said Mengzhao Wang, MD, PhD, at Peking Union Medical College Hospital, the first and corresponding author of the paper. "Sunvozertinib is an oral, irreversible EGFR TKI that targets a broad spectrum of EGFR mutations while maintaining high selectivity for wild-type EGFR. Previous studies suggested that sunvozertinib demonstrated anti-tumor activity in NSCLC patients with EGFR-sensitizing mutations, T790M mutations, and exon 20 insertion mutations. This new analysis further validated sunvozertinib’s potential in overcoming resistance to prior EGFR TKI treatments, warranting further investigation."

"Encouragingly, the pooled analysis has revealed the potential clinical value of sunvozertinib in EGFR TKI-resistant NSCLC," said Xiaolin Zhang, PhD, CEO of Dizal. "Confronted with the challenge of resistance to third-generation EGFR TKIs, we will continue to advance our exploration in this area, aiming to bring new treatment options to patients with EGFR mutated NSCLC."

About sunvozertinib (DZD9008)
Sunvozertinib is an irreversible EGFR inhibitor discovered by Dizal scientists targeting a wide spectrum of EGFR mutations with wild-type EGFR selectivity. In August 2023, sunvozertinib received approval from NMPA to treat advanced NSCLC with EGFR exon20ins after platinum-based chemotherapies. The approval is based on the results of WU-KONG6 study, the pivotal study of sunvozertinib in platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins. The primary endpoint of the study was the confirmed overall response rate (cORR) as assessed by the Independent Review Committee (IRC) reached 60.8%. Anti-tumor efficacy was observed across a broad range of EGFR exon20ins subtypes, and in patients with pretreated and stable brain metastasis. In addition, sunvozertinib also demonstrated encouraging anti-tumor activity in NSCLC patients with EGFR sensitizing, T790M, and uncommon mutations (such as G719X, L861Q, etc.), as well as HER2 exon20ins.

Sunvozertinib showed a well-tolerated and manageable safety profile in the clinic. The most common drug-related TEAEs (treatment-emergent adverse event) were Grade 1/2 in nature and clinically manageable.

Two global pivotal studies are ongoing in ≥ 2nd line (WU-KONG1 Part B) and 1st line setting (WU-KONG28), respectively, in NSCLC patients with EGFR exon20ins.

Pre-clinical and clinical results of sunvozertinib were published in peer-reviewed journals Cancer Discovery and The Lancet Respiratory Medicine.

On December 11, 2024 iOnctura, a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers, reported a clinical update on its lead asset, roginolisib. Results from the completed Phase I DIONE-01 study are due to be presented at the European Society for Medical Oncology Immuno-Oncology (ESMO-IO) annual congress tomorrow, 12 December at 12:30 CET (presentation 164P) (Press release, iOnctura, DEC 11, 2024, View Source [SID1234649059]).

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Allosteric modulator of PI3Kδ, roginolisib, has a unique chemical structure and binding mechanism which makes it highly specific for PI3Kδ, giving it an advantageous pharmacology profile and an unprecedented safety profile compared to previous generations of PI3Kδ inhibitors.

Roginolisib is being investigated in solid and hematological malignancies including uveal melanoma (UM), a rare cancer of the eye. Eye melanoma is a rapidly growing market which is projected to be worth USD 9.56B by 2032[1].

The two-part Phase I study DIONE-01, firstly evaluated continuous daily dosing of roginolisib [at 10, 20, 40 and 80 mg] in 24 patients with pretreated solid tumors and follicular lymphoma (FL), and secondly evaluated a dose confirmation cohort in 20 UM patients.

Results from DIONE-01 show:

Study met its primary objective to determine the safety of the anticipated optimal biologically effective dose (BED): Roginolisib was well tolerated at the recommended Phase II dose (RP2D) of 80mg, with <7% Grade 3/4 treatment-emergent adverse events (TEAEs) considered to be related to roginolisib. TEAEs did not result in immune-related toxicity, or dose-limiting toxicity, in either solid tumor or hematological patients. In contrast to prior PI3Kδ inhibitors, roginolisib dosing did not require dose modifications.
Roginolisib is well tolerated over long periods of treatment, up to 4.5 years.
Median overall survival (OS) was 16 months for the 29 patients with UM treated with roginolisib, who had previously received a median of two prior therapies. This exceeds the median OS of 7 months observed in historical controls in patients receiving immunotherapies as second line treatment[2].
Median progression free survival (PFS) was 5 months for patients treated with roginolisib versus less than 3 months for historical controls2.
Clinical findings validate the mechanism of action of roginolisib: roginolisib reduces immune-suppressive immune cells and chemokines, UM-related tumor clones (ctDNA) and PI3K-related signaling indicating a rebalancing of the immune system.
Catherine Pickering, Chief Executive Officer of iOnctura, said: "The Phase I DIONE-01 data highlight the benefits of roginolisib for patients with uveal melanoma and advanced cancers. Roginolisib’s unique allosteric binding mechanism has translated into a differentiated beneficial clinical profile, including a doubling of overall survival compared to historical controls in uveal melanoma. We are delighted to announce these data support progression of roginolisib into a randomized Phase II study."

Professor Michele Maio, University of Siena and Principal Investigator of the roginolisib studies, added: "Being able to continue to investigate roginolisib in a randomized Phase II study is a positive step to understand more about this already well tolerated molecule. Roginolisib has given prolonged disease stabilization to patients with uveal melanoma who have exhausted all other therapeutic options. So far, these patients have maintained a good quality of life without major limitations. I’m looking forward to seeing what the Phase II trial delivers over the coming months."

Activation of trial sites for the Phase II OCULE-01 study (NCT06717126) investigating roginolisib versus investigator’s choice in the second-line+ treatment of uveal melanoma is ongoing.

On December 11, 2024 TC BioPharm (Holdings) PLC ("TC BioPharm" or the "Company") (NASDAQ: TCBP) a clinical-stage biotechnology company developing platform allogeneic gamma-delta T cell therapies for cancer and other indications, reported a partnership with CareDx, Inc. (NASDAQ: CDNA) The Transplant Company who will perform pharmacokinetic analysis using its AlloCell solution in the ACHIEVE clinical trial (Press release, TC Biopharm, DEC 11, 2024, View Source [SID1234649058]).

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The ACHIEVE clinical trial is an adaptive, open-label, phase II study designed to evaluate the efficacy and effectiveness of TCB008, an allogeneic gamma delta T cell therapy for patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS).

CareDx is a leading precision medicine company focused on discovering, developing, and commercializing healthcare solutions for transplant patients and caregivers. CareDx’s AlloCell test, a sensitive solution for pharmacokinetic monitoring of allogeneic immune and stem cell therapies, will be used to evaluate the expansion and persistence of TCB008 in patients enrolled in the ACHIEVE trial.

It is expected that these expansion and persistence data will provide an understanding of the duration and effect of TCB008 Gamma Delta T-Cells in reconstituting the immune system of acute myeloid leukemia patients enrolled in the ACHIEVE trial.

"Our partnership with CareDx is a significant milestone," said Alison Bracchi, Executive Vice President of Clinical Operations at TC BioPharm. "The collaboration is pivotal to the development and optimization of TCB008 as a therapy for acute myeloid leukemia and other blood cancers."

"We are thrilled to continue to progress the science of allogeneic cell therapy for patients battling acute myeloid leukemia," said Marica Grskovic, PhD, CareDx Chief Strategy Officer. "This partnership builds upon our growth strategy to expand into hematology oncology with pharmacokinetic and monitoring assays for patients undergoing cell therapy."