On December 12, 2024 RemeGen Co. Ltd. ("RemeGen") (9995.HK, 688331.SH) at the Poster Spotlight Session "Novel HER2 Therapeutics" of the 47th San Antonio Breast Cancer Symposium (SABCS), reported for the first time the data from a phase III study (RC48-C006, NCT03500380) of Disitamab Vedotin (DV) in treating patients with HER2-positive advanced breast cancer with liver metastasis (BCLM) (Press release, RemeGen, DEC 12, 2024, View Source [SID1234649086]). This is the first prospective randomized phase III study globally on a HER2-targeting ADC that demonstrated significant efficacy in patients with HER2-positive advanced BCLM. Professor Jiayu Wang from the Cancer Hospital, Chinese Academy of Medical Sciences presented and discussed the study. SABCS is one of the largest and most influential annual conferences focusing on advances in breast cancer clinical research, and this RemeGen sponsored study attracted the attention of experts worldwide.

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Data shows that about 45% of patients with HER2-positive advanced breast cancer have liver metastasis. This subset has a poor prognosis with a 5-year survival rate of only 8% to 12%, for whom no satisfactory therapies are available now.

This is a randomized, open-label, multicenter phase III study comparing the efficacy and safety of DV versus Lapatinib plus Capecitabine in patients with HER2-positive advanced BCLM. A total of 104 patients were enrolled, of whom 53 received DV and 50 received Lapatinib plus Capecitabine. All patients had previously been treated with Trastuzumab and Taxanes.

As of data cutoff date (December 31, 2023), according to the assessment by the Independent Review Committee (IRC), DV significantly improved progression-free survival (PFS) versus Lapatinib plus Capecitabine (median: 9.9 months vs. 4.9 months; hazard ratio [HR]: 0.56 [95% CI: 0.35-0.90]), which is consistent with the investigator-assessed PFS (HR: 0.62 [95% CI: 0.39-0.98]). The overall survival (OS) data, though immature, indicated a benefit trend in favor of DV. The safety profile was consistent with past DV use experience, with no new safety signals detected.

"This is the first confirmatory phase III study that demonstrated promising efficacy of an HER2-targeting ADC in patients with HER2-positive advanced BCLM," observed Professor Jiayu Wang. DV demonstrated clinically meaningful benefit compared with Lapatinib plus Capecitabine and a manageable safety profile, potentially offering a promising new treatment option for patients with HER2-positive advanced BCLM previously treated with Trastuzumab and Taxanes. The Biologics License Application (BLA) filing for this indication of DV has been accepted by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration in October 2024 and priority review was granted based on the breakthrough therapy designation.

On December 12, 2024 Transcenta Holding Limited ("Transcenta") (HKEX: 06628), a global clinical stage biopharmaceutical company with fully-integrated capabilities in discovery, research, development and manufacturing of antibody-based therapeutics, reported late-breaking presentation of preclinical study results of novel humanized LIV-1 antibody based ADCs at 2024 San Antonio Breast Cancer Symposium (SABCS) (Press release, Transcenta, DEC 12, 2024, View Source [SID1234649085]). The ADCs (ADC-1 and ADC-2) were engineered using Transcenta’s proprietary antibody with site-specifical conjugation of Topoisomerase I Inhibitor payloads and these ADCs demonstrated significantly higher tumor regression activities than MMAE based ADCs in triple-negative breast cancer (TNBC) tumor models.

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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, the responses are typically short lived. Thus, there is an urgent need to develop more effective treatments [1].

LIV-1, a member of the zinc transporter family and an estrogen-regulated gene in metastatic breast cancer, is overexpressed in a high prevalence in breast cancer (93%), including both TNBC and hormone receptor positive breast cancer, as well as in melanoma (82%), prostate (72%), ovarian (48%) and uterine (30%) cancer. This makes LIV-1 an attractive cell surface target for developing ADC therapeutics.

To develop next generation LIV-1 targeting ADC, Transcenta generated a proprietary novel humanized anti-LIV-1 mAb, 48D6, which displayed unique epitope form benchmark antibody, high binding affinity, specificity, excellent internalization ability. The conjugation method also eliminated FcR binding which resulted in significantly reduced non-specific FcR mediated binding and clearance, and improved pharmacokinetics profile in mice.

In vitro studies indicated that breast tumor cells, such as MDA-MB-468 and MCF-7, are more sensitive to Topo I inhibitor than MMAE. Consequently, Transcenta developed two Topo I inhibitor-based ADCs (ADC-1 and ADC-2) using glycotransferase mediated site-specific conjugation. Both ADC-1 and ADC-2 have a drug-to-antibody ratio (DAR) of 4 but with two different Topo I inhibitor payloads. A MMAE based ADC (ADC-3) with the same site-specific conjugation and DAR4 was also synthesized as the control.

Although ADC-1 and ADC-2 displayed similar and specific cytotoxic activities against human LIV-1-expressing tumor cells in vitro, as compared to SGN-LIV1A analog (DAR4) or ADC-3, they exhibited much higher maximal tumor cell killing than SGN-LIV1A analog in vivo. In addition, both ADC-1 and ADC-2 demonstrated a strong bystander effect which is important to overcome tumor heterogeneity.

In vivo pharmacology study revealed that ADC-1 or ADC-2 exhibited dose-dependent and more potent anti-tumor activities than the SGN-LIV1A analog or ADC-3 in the human LIV-1 transfected MDA-MB-468, a TNBC tumor model.

At 3 mg/kg the tumor growth inhibition (TGI)% were: ADC-1 92.4%, ADC-2 94.7%, ADC-3 68.5% and SGN-LIV1A analog 57.0% on Day 30. However, the overall response rate (ORR, 50% reduction of tumor volume from baseline) at 3mg/kg for SGN-LIV1A analog or ADC-3 was 0%, while ORRs of ADC-1 and ADC-2 were 40% and 70%, respectively. At 6 mg/kg, on Day 42, ORRs of ADC-1 and ADC-2 were 90% and 100%, respectively, and complete response (CR) rates were 90% and 100% respectively. The body weight of mice didn’t change significantly at either 3 or 6 mg/kg for ADC-1 or ADC-2.

"The significantly enhanced anti-tumor activities of ADC-1 and ADC-2 are likely due to the high affinity binding of 48D6 to LIV-1 and the high cytotoxicity of Topo I inhibitor for breast tumor cells." said Dr. Xueming Qian, Chairman of the Board and CEO at Transcenta, "These data warrant further investigation of the lead LIV-1 targeting ADCs (ADC-1 and ADC-2) as potential next-generation therapeutic agent in LIV-1 positive breast cancer and other solid tumors."

The 47th San Antonio Breast Cancer Symposium (SABCS) held from December 10 to 13, 2024, in San Antonio, Texas, USA. This Symposium is designed to provide state-of-the-art information on the experimental biology, etiology, prevention, diagnosis, and therapy of breast cancer and premalignant breast disease to an international audience of academic and private physicians and researchers.

On December 12, 2024 Candel Therapeutics, Inc. ("Candel") (Nasdaq: CADL), a clinical stage biopharmaceutical company focused on developing multimodal biological immunotherapies to help patients fight cancer, reported the pricing of an underwritten public offering of 10,000,001 shares of its common stock at a price to the public of $6.00 per share and pre-funded warrants to purchase up to an aggregate of 3,333,333 shares of its common stock at a price to the public of $5.99 per pre-funded warrant to purchase one share of the common stock, which represents the per share public offering price for the common stock less the $0.01 per share exercise price for each such pre-funded warrant (Press release, Candel Therapeutics, DEC 12, 2024, View Source [SID1234649084]). The gross proceeds from the offering to Candel are expected to be approximately $80 million, before deducting underwriting discounts and commissions and other offering expenses. The offering is expected to close on or about December 16, 2024, subject to customary closing conditions. In addition, Candel has granted the underwriters a 30-day option to purchase up to 2,000,000 additional shares of common stock at the public offering price, less the underwriting discount.

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Candel intends to use the net proceeds from the offering to continue the development of its product candidates, including preparing submission of a Biologics License Application for CAN-2409 in prostate cancer and for general corporate purposes.

Citigroup, BofA Securities and Canaccord Genuity are acting as joint bookrunning managers for the offering. H.C. Wainwright & Co. is acting as lead manager for the offering.

A shelf registration statement relating to the shares of common stock offered in the public offering described above was filed with the Securities and Exchange Commission (the "SEC") on August 5, 2022 and declared effective by the SEC on August 12, 2022. The offering is being made only by means of a written prospectus and prospectus supplement that form a part of the registration statement. A preliminary prospectus supplement and accompanying prospectus relating to the offering has been filed with the SEC and is available on the SEC’s website at www.sec.gov. A final prospectus supplement and accompanying prospectus will be filed with the SEC. When available, copies of the final prospectus supplement and the accompanying prospectus may also be obtained by contacting Citigroup Global Markets Inc., c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, New York 11717, or telephone: 1-800-831-9146; BofA Securities, NC1-022-02-25, 201 North Tryon Street, Charlotte, North Carolina 28255-0001, Attention: Prospectus Department, email: [email protected]; or Canaccord Genuity LLC, Attention: Syndication Department, 1 Post Office Square, 30th Floor, Boston, MA 02109, or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy the securities being offered, nor shall there be any sale of the securities being offered in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.

On December 12, 2024 iTeos Therapeutics, Inc. (Nasdaq: ITOS), a clinical-stage biopharmaceutical company pioneering the discovery and development of a new generation of immuno-oncology therapeutics for patients, reported the presentation of clinical, translational, and preclinical data from its adenosine A2A receptor (A2AR) antagonist program, inupadenant, including interim data from the dose escalation portion of A2A-005, the Phase 2 trial assessing inupadenant and platinum-doublet chemotherapy in post-immunotherapy metastatic non-small cell lung cancer (NSCLC) patients, at the European Society for Medical Oncology Immuno-Oncology (ESMO IO) Congress 2024 (Press release, iTeos Therapeutics, DEC 12, 2024, View Source [SID1234649083]).

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"We believe our presentations at ESMO (Free ESMO Whitepaper) IO on the adenosine pathway demonstrate the strong efforts our research and discovery team have put into understanding this immunosuppressive mechanism," said Michel Detheux, Ph.D., president and chief executive officer of iTeos. "While the initial signal for inupadenant’s RP2D in the A2A-005 trial compared to chemotherapy alone is encouraging and supports its differentiated, insurmountable profile, we as well as our scientific and clinical advisory boards believe it does not meet sufficient level of clinical activity to warrant further investment. We remain committed to focusing our resources on developing differentiated, first- or best-in-class therapies and look forward to providing updates on our pipeline in 2025."

Mini Oral Sessions
Title: Inupadenant Combined with Chemotherapy in Patients with Non-Squamous NSCLC Progressing On or After Immune Checkpoint Inhibitor Therapy: Results from Dose-Finding Part of the A2A-005 Trial
Summary: As of the October 29, 2024 data cutoff, the topline data from the dose escalation portion of A2A-005 presented at the ESMO (Free ESMO Whitepaper) IO Congress were based on 36 patients eligible for safety and efficacy evaluation. Patients received inupadenant at 40mg, 60mg, or 80mg twice daily (BID) in combination with carboplatin/pemetrexed. All patients had a minimum follow-up of 6 months. Patient baseline characteristics were balanced across arms, with a slight imbalance of more patients with brain metastases in the 40mg and 80mg cohorts and ECOG status 0 favoring the 80mg cohort.

The primary endpoint of the safety of inupadenant in combination with carboplatin/pemetrexed was observed to be manageable and tolerable, with no dose dependent toxicities.
The secondary endpoint of ORR was 63.9% across all patients (53.3% at 40mg, 66.7% at 60mg, and 73.3% at 80mg).
The secondary endpoint of mPFS was 7.7 months across all patients (5.6 months at 40mg and 6.6 months at 60mg; mPFS remains unreached at 80mg).
The exploratory biomarker of CXCL13, a B-cell chemokine and lymphoid structure marker associated with clinical activity, was observed to be restored by inupadenant after depletion by chemotherapy, with quicker restoration kinetics in patients with PFS greater than 6 months.
As of the data cutoff, 8 patients remained on treatment (1 at 40mg, 1 at 60mg, and 6 at 80mg). The median follow-up was 9.7 months (10.6 months at 40mg, 13.1 months at 60mg, and 8.2 months at 80mg).

Response Measure Inupadenant 40mg + carboplatin / pemetrexed BID Inupadenant 60mg + carboplatin / pemetrexed BID Inupadenant 80mg + carboplatin / pemetrexed BID Overall
(N=15) (N=6) (N=15) (N=36)
ORR, % 53.3% 66.7% 73.3% 63.9%
n
(95% CI) n=8
(26.6–78.7) n=6
(22.3–95.7) n=15
(44.9–92.2) n=36
(46.2–79.2)
Complete response, n (%) 0 0 2 (13.3%) 2 (5.6%)
Partial response, n (%) 8 (53.3%) 4 (66.7%) 9 (60.0%) 21 (58.3%)
Stable disease, n (%) 7 (46.7%) 1 (16.7%) 3 (20.0%) 11 (30.6%)
Progressive disease, n (%) 0 0 1 (6.7%) 1 (2.8%)
Not evaluable/no assessment, n (%) 0 1 (16.7%) 0 1 (2.8%)
mPFS, months 5.6 6.6 NC 7.7
Event n (%)
(95% CI) 13 (86.7%)
(4.1-8.3) 5 (83.3%)
(0.4-NC) 6 (40.0%)
(4.9-NC) 24 (66.7%)
(5.1-11.0)
Landmark 6-Month PFS % 46.7%
(21.2-68.7) 50.0%
(11.1-80.4) 64.6%
(34.7-83.5) 54.5%
(36.8-69.1)
CI, confidence interval; NC, not calculable

Title: The A2AR Antagonist Inupadenant Promotes Humoral Responses in Patients
Summary: Based on monotherapy clinical and translational data, inupadenant demonstrated modulation of humoral responses in patient blood and tumor tissue, supporting our previous finding that expression of antibody-secreting cells (ASCs) in tumor tissue is associated with non-progression in patient disease. Furthermore, CXCL13 expression, a protein involved in immune cell recruitment, activation, and adaptive immune response regulation, increased in patients treated with inupadenant and more rapidly and extensively in non-progressors compared to progressors. These findings confirm inupadenant plays a key role in B cell maturation restoration and may play a substantial role in delaying progression in end-stage patients.

Poster Sessions
Title: The A2AR Antagonist Inupadenant Promotes Humoral Responses in Preclinical Models
Summary: In preclinical models, inupadenant counteracted the A2AR-mediated inhibition of B cell maturation into ASCs and immunoglobulin production in both in vitro and ex vivo systems by modulating B cells at the level of the germinal center (GC). These findings suggest that inupadenant restores or even enhances B cell maturation towards ASCs and GC reactions in both secondary lymphoid organs as well as the tumor in the presence of A2AR signaling. Furthermore, this process is essential for producing high-affinity antibodies and potentially for sustained anti-tumor immunity.

Title: A Novel Tumor Adenosine Signature to Guide Indication Selection for Adenosine Pathway inhibitor
Summary: Based on the spatial quantification of adenosine in human tumors, we developed the first adenosine gene signature, demonstrating its potential for indication selection. This new signature, derived from 249 differentially expressed genes (DEGs) associated with metabolism and immune activation, showed high predictive power across tumor types. Furthermore, the adenosine signature was higher in tumors compared to healthy tissue and exhibited variable expression and prognostic value across tumor subtypes. These findings suggest that the adenosine signature represents a powerful tool for prioritizing tumor types which may benefit most from adenosine-targeting therapies and for understanding the mechanisms of adenosine-mediated immunosuppression.

On December 12, 2024 Phio Pharmaceuticals Corp. (NASDAQ: PHIO) is a clinical-stage biotechnology company developing therapeutics that use its INTASYL siRNA gene silencing technology designed to make the body’s immune cells more effective in killing cancer cells reported its manuscript, Self-delivering RNAi Immunotherapeutic PH-762 Silences PD-1 to Generate Local and Abscopal Anti-tumor Efficacy, has been published in the December, 2024 issue of Frontiers in Immunology (Press release, Phio Pharmaceuticals, DEC 12, 2024, View Source [SID1234649082]).

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The article presents preclinical proof-of-concept data for PH-762, an INTASYL compound designed to silence PD-1, is currently in clinical development for advanced cutaneous malignancies. Phio recently presented data from its second cohort in its on-going Phase 1b clinical trial showing one patient with cutaneous squamous cell carcinoma in the 2nd cohort achieved a complete response (100% tumor clearance) while a second patient with squamous cell carcinoma achieved a partial response (90% tumor clearance).

Frontiers in Immunology is dedicated to propelling advancements in the field of Immunology. The Editor-in-Chief is Luigi Daniele Notarangelo, Director of the Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIH), and Senior Researcher at Boston Children’s Hospital, Harvard Medical School.

"We are delighted to see this publication which presents a comprehensive summary of INTASYL’s uniqueness addressing its selective gene targeting, potent silencing, and is a promising candidate for treatment of solid tumors," said Robert Bitterman, CEO, Phio Pharmaceuticals.