On September 13, 2024 Senhwa Biosciences, Inc. (TPEx: 6492), a new drug development company focusing on first-in-class therapeutics for oncology, rare diseases, and infectious diseases, reported that its new drug Silmitasertib (CX-4945) was granted a rare pediatric disease designation (RPDD) by US FDA for the treatment of neuroblastoma (Press release, Senhwa Biosciences, SEP 13, 2024, View Source [SID1234646581]). This is the recognition obtained again after Silmitasertib (CX-4945) received RPDD in medulloblastoma from the FDA in July 2020, demonstrating the great potential of Silmitasertib (CX-4945) in the development of treatments for rare pediatric cancers.

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Silmitasertib is a first-in-class small molecule drug that targets the CK2 protein and acts as a CK2 inhibitor that exhibited antitumor activity in pre-clinical study of neuroblastoma. The RPD designation will qualify the drug for the priority review voucher (PRV) program meant to encourage development of novel therapies for rare pediatric diseases. Silmitasetib has previously granted 1 RPD and 3 orphan drug designations (ODD) by the FDA.

"The RPD designation offers sponsors the additional incentive by requesting priority review vouchers (PRVs) for their future marketing applications, and this approach encourages the drug development for the treatment of rare pediatric diseases," said Jin-Ding Huang, PhD, CEO of Senhwa Biosciences, Inc.

Neuroblastoma, an embryonic tumor of the peripheral sympathetic nervous system, is the third most common pediatric cancer and the most common cancer in infants. It is mostly diagnosed in infancy at an average of 1 to 2 years old. There are an estimated 700 to 800 new cases of neuroblastoma each year in the United States.

While low and intermediate-risk neuroblastoma have a very high rate of survival, high-risk neuroblastoma has a 5-year survival rate of about 50%, and it has a high likelihood of recurrence even with intense multimodal treatments. There is currently no standard treatment for patients with relapsed/refractory neuroblastoma.

On September 13, 2024 ESSA Pharma Inc. ("ESSA", or the "Company") (NASDAQ: EPIX), a clinical-stage pharmaceutical company focused on developing novel therapies for the treatment of prostate cancer, reported the presentation of updated dose escalation data from its Phase 1/2 study evaluating masofaniten (formerly EPI-7386) in combination with enzalutamide at the 2024 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, taking place September 13-17, 2024, in Barcelona, Spain (Press release, ESSA, SEP 13, 2024, View Source [SID1234646580]). Masofaniten is a first-in-class N-terminal domain androgen receptor ("AR") inhibitor that suppresses androgen activity through a novel mechanism of action and is being developed for the treatment of prostate cancer. The poster presentation is available on the "Publications" section of the Company’s website at www.essapharma.com.

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"We are pleased to be sharing more mature data from the Phase 1 dose escalation study evaluating masofaniten in combination with enzalutamide today at ESMO (Free ESMO Whitepaper) 2024. The combination continues to be well tolerated with prolonged reductions in circulating prostate-specific antigen ("PSA") levels in patients with metastatic castration-resistant prostate cancer ("mCRPC"). After 15.2 months of follow up, neither median time to PSA progression nor radiographic progression free survival have been reached. These data compare favorably to historical data for single agent enzalutamide treatment in the mCRPC patient population," said David Parkinson, MD, President and CEO of ESSA. "We continue to focus on the enrollment of the Phase 2 dose expansion study evaluating masofaniten in combination with enzalutamide, with 33 sites activated in the US, Canada and Australia and an additional 22 sites anticipated in Europe. We look forward to providing further updates in 2025."

Poster presentation details:

Title: Phase 1/2 trial of oral EPI-7386 (masofaniten) in combination with enzalutamide (Enz) compared with Enz alone in subjects with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 results and Phase 2 design
Presenting Author: Christos Kyriakopoulos, MD, University of Wisconsin-Madison Carbone Cancer Center
Presentation #: 1641P
Date and time: Sunday, September 15, 2024; 12:00-1:30 p.m. CEST/ 6:00-7:30 a.m. ET

Data summary: This Phase 1/2 multicenter, open-label clinical trial enrolled patients with mCRPC who have received androgen deprivation therapy and who are naïve to second-generation antiandrogens but may have been treated previously with one line of prior chemotherapy in the metastatic hormone-sensitive prostate cancer setting. The data presented today includes 18 patients across four cohorts in the Phase 1 dose escalation portion of the study. Masofaniten has no effect on enzalutamide exposure, thus allowing the use of full dose per label (160mg) of enzalutamide in combination. Enzalutamide reduces masofaniten exposure but twice daily dosing of masofaniten appears to mitigate the reduction and maintains clinically relevant drug exposures.

In patients evaluable for safety (n=18), masofaniten combined with enzalutamide, continues to be well-tolerated at the dose levels tested through 32 cycles of dosing in some patients. Most frequent adverse events were Grades 1 and 2, related to either AR inhibition or gastrointestinal tract irritation. In Cohort 4, one patient experienced a Grade 3 rash, which was observed immediately following administration of masofaniten combined with enzalutamide and deemed probably related, resulting in the expansion of the cohort from four to seven patients. No additional dose-limiting toxicities (DLTs) were observed, therefore the maximum tolerated dose (MTD) was not reached. The recommended Phase 2 combination doses (RP2CDs) were identified as masofaniten 600 mg twice daily (BID) in combination with enzalutamide 160 mg once daily (QD).

In the patients evaluable for efficacy (n=16), rapid, deep and durable reductions in PSA were observed, regardless of previous chemotherapy status, including in patients who received lower than the full dose of enzalutamide (120 mg). Across all dose cohorts, 88% of patients (14 of 16) achieved PSA50, 88% of patients (14 of 16) achieved PSA90, 69% of patients (11 of 16) achieved PSA90 in less than 90 days, and 63% of patients (10 of 16) achieved PSA <0.2ng/mL. With a current median follow up of 15.2 months, the median time to PSA progression and radiographic progression free survival have not yet been reached.

The randomized, open-label, two arm, Phase 2 dose expansion portion of the study is underway and is designed to evaluate the combination of masofaniten and enzalutamide versus single agent enzalutamide in patients with mCRPC naïve to second generation anti-androgens. The study is currently enrolling at approximately 33 sites in the USA, Canada and Australia, and an additional 22 sites anticipated in Europe.

About Masofaniten

Masofaniten (formerly known as EPI-7386) is a first-in-class investigational, highly selective, oral, small molecule inhibitor of the N-terminal domain ("NTD") of the androgen receptor ("AR"). Masofaniten’s unique mechanism of action disrupts the AR signaling pathway, the primary pathway that drives prostate cancer growth, by selectively binding to the NTD, a region of the AR that is not currently targeted by other therapies. Masofaniten is currently being studied in an open-label, randomized Phase 2 clinical trial (NCT05075577) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) naïve to second-generation antiandrogens. ESSA is also conducting a Phase 1 monotherapy study (NCT04421222) in patients with mCRPC whose tumors have progressed on standard-of-care therapies. The U.S. Food and Drug Administration has granted Fast Track designation to masofaniten for the treatment of adult male patients with mCRPC resistant to standard-of-care treatment. ESSA retains all rights to masofaniten worldwide.

On September 13, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing and commercializing therapies to address global unmet medical needs primarily for malignancies, reported that it has released the clinical data of olverembatinib (HQP1351), the company’s novel drug candidate, in patients with succinate dehydrogenase- (SDH-) deficient gastrointestinal stromal tumor (GIST), in a Mini Oral at the 2024 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, Ascentage Pharma, SEP 13, 2024, View Source;ascentage-pharma-releases-latest-data-showing-sustained-clinical-efficacy-of-olverembatinib-in-sdh-deficient-gist-during-a-mini-oral-presentation-302248193.html [SID1234646579]).

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These data of olverembatinib, presented in the Mini Oral at ESMO (Free ESMO Whitepaper) 2024, showed sustained clinical benefit in patients with SDH-deficient GIST. As of March 12, 2024, six of the 26 patients with SDH-deficient GIST enrolled in the study achieved partial responses (PRs). The objective response rate (ORR) was 23.1%, and the median progression-free survival (PFS) was 22 months. Furthermore, studies on mechanism of action (MOA) revealed that olverembatinib exerts its antitumor activity by modulating multiple signaling pathways involved in angiogenesis, apoptosis, proliferation, and survival.

Olverembatinib, a novel orally-administered tyrosine kinase inhibitor (TKI) developed by Ascentage Pharma, is the first approved third-generation BCR-ABL inhibitor in China. To date, olverembatinib has been approved for two indications in China, including adult patients with TKI-resistant chronic-phase chronic myeloid leukemia (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation; and adult patients with CML-CP resistant to and/or intolerant of first-and second-generation TKIs. Olverembatinib is jointly commercialized in China by Ascentage Pharma and Innovent Biologics. This is a study of an investigational drug not yet approved by the US Food and Drug Administration (FDA).

In addition to hematologic indications, olverembatinib is also being clinically evaluated for the treatment of GIST. To date, olverembatinib has already been granted a Breakthrough Therapy Designation by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) for the treatment of patients with SDH-deficient GIST who had received first-line treatment. Recently, olverembatinib was cleared by the China CDE to enter a registrational Phase III study in patients with SDH-deficient GIST.

Prof. Haibo Qiu, of Sun Yat-Sen University Cancer Center, and the presenter of the report, commented, "SDH-deficient GIST is an extremely rare type of cancer. According to Chinese and International clinical guidelines, there are currently no standard treatment options for unresectable SDH-deficient GIST. In this Phase I study, we have observed encouraging clinical benefit data and further explored the MOA of olverembatinib. Supported by existing data, we will soon initiate a registrational Phase III study in efforts to bring a new treatment option to more patients with SDH-deficient GIST."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "Clinical data presented in the Mini Oral reaffirmed olverembatinib’s clinical benefit and favorable tolerability in patients with SDH-deficient GIST, thus indicated another potential breakthrough for an indication with a huge unmet medical need. We will actively advance this clinical development program which hopefully will soon offer patients a safe and effective new treatment option."

As one of the world’s leading and most influential oncology congresses, the ESMO (Free ESMO Whitepaper) Congress showcases the latest results in some of the most cutting-edge cancer research from around the world.

Highlights of the data on olverembatinib presented at this year’s ESMO (Free ESMO Whitepaper) Congress are as follows:

Updated efficacy results of olverembatinib (HQP1351) in patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST) and potential mechanisms of action (MOA)

Format: Mini oral
Presentation#: 1722MO
Category: Sarcoma
Date & Time: Friday September 13, 2024, 16:30 – 16:35 CEST
Speaker: Haibo Qiu, MD, PhD, Sun Yat-sen University Cancer Center
Highlights:

Background: SDH-deficient GIST is a rare disease with limited treatment options. The oncogenic mechanism of SDH deficiency has not been elucidated. Olverembatinib, already approved in China for the treatment of adult patients with TKI-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP), with or without the T315I mutation, has shown promising clinical efficacy in SDH-deficient GIST. This report provides the most updated Phase I efficacy data and translational data of olverembatinib in SDH-deficient GIST.
Methods: This study (HQP1351-SJ0003; NCT03594422) was designed to evaluate the safety and efficacy of olverembatinib in patients (≥12 years of age) with GIST or other solid tumors. Olverembatinib was administered orally every other day (QOD). The study evaluated the clinical efficacy of olverembatinib and analyzed the drug’s MOA using multiple in vitro and in vivo assays including a SDHB knock-down rat pheochromocytoma PC12 (#5F7)-derived mouse xenograft model.
Enrolled Patients: As of March 12, 2024, a total of 26 patients with SDH-deficient GIST (confirmed by IHC) were treated with olverembatinib, including 25 (96.2%) who had received 1 to 4 TKIs and 13 (50.0%) who had received ≥3 TKIs.
Efficacy and Safety Results: Olverembatinib was well tolerated at doses of 30 to 50 mg. In all, 6 (23.1%) patients achieved partial responses (PRs) and the median PFS was 22.0 months (range: 12.9-38.6).
Preclinical Results: Olverembatinib had superior antiproliferative activity (vs. other approved TKIs) in SDHB-deficient cell lines (IC50, 0.129-5.132 μM). In PC12#5F7 (SDHB knock-down) cells, olverembatinib decreased HIF 2α, VEGFA, and FGFR1 protein levels and inhibited phosphorylation of FGFR1, IGF 1R, SRC, AKT, and ERK1/2. In PC12#5F7-derived xenograft models, olverembatinib demonstrated dose dependent antitumor activity at 10 and 20 mg/kg (QOD).
Conclusions: Olverembatinib showed sustained clinical efficacy in SDH-deficient GIST, indicating potential benefit of this treatment as well as providing a benchmark for future studies in this rare subtype of GIST. MOA studies revealed that olverembatinib exerts antitumor activity by modulating multiple signaling pathways involved in angiogenesis, apoptosis, proliferation, and survival.

On September 13, 2024 MediLink Therapeutics (MediLink) reported clinical data for YL201, a novel B7H3-targeting antibody drug conjugate (ADC) developed based on MediLink’s Tumor Microenvironment Activable LINker-payload (TMALIN) platform, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, Suzhou Medilink Therapeutics, SEP 13, 2024, View Source [SID1234646573]). This is the first disclosure of clinical data for YL201 featured in an oral presentation.

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Presented results are from phase I studies (NCT05434234 & NCT06057922) conducted in China and the US to explore the safety and efficacy of YL201 in patients with advanced solid tumors. As shown in the abstract, by August 9 2024, a total of 312 patients were enrolled in the dose escalation and expansion studies with various tumor types, including small cell lung cancer (SCLC, n=79), nasopharyngeal carcinoma (NPC, n=75), and non-small cell lung cancer without actionable genomic alterations (NSCLC without AGAs, n=68). All enrolled patients have been treated with prior standard therapy, and 60% had at least 2 prior treatment lines.

During dose escalation stage, dose limiting toxicities were observed at 2.8 mg/kg (n=1) and 3.0 mg/kg (n=2). For dose expansion, 2.0 mg/kg and 2.4 mg/kg were selected as recommended expansion doses. As of 09 Aug 2024, 276 patients had at least one post-baseline tumor assessment per RECIST V1.1., The overall response rate (ORR) was 44.6%, the disease control rate (DCR) was 83.7%. The median follow-up duration was 5.4 months, and 46% of the patients are still on treatment.

Antitumor activity was observed in multiple solid tumor types. In extensive-stage SCLC patients, among 72 patients who had evaluable tumor assessment, all patients had prior treatment with platinum-based chemotherapy, and 95% had prior treatment with anti-PD-(L)1. The ORR was 68.1% (at dose levels >= 2.0 mg/kg: 70.0%) and the median progress-free survival (mPFS) was 6.2 months (at dose levels >= 2.0 mg/kg: 6.2 months). Also worth mentioning was that in patients with brain metastasis, the ORR was 52.2% and mPFS was 5.3 months, comparable to those of overall population.

In 70 NPC patients with evaluable tumor assessment, the ORR was 48.6% (at dose levels >= 2.0 mg/kg: 48.6%), and mPFS was 7.2 months (at dose levels >= 2.0 mg/kg: 7.2 months). In heavily-treated NPC patients receiving at least 2 prior lines of treatment, the efficacy was also comparable, with ORR of 51.0% and mPFS of 7.0 months.

In NSCLC without AGA, all patients had prior treatment with anti-PD-(L)1 and platinum-based chemotherapy. In the histological subtypes of adenocarcinoma and LELC, ORR were 29.2% and 60.9%, respectively, and mPFS were unmatured and 8.1 months, respectively.

In terms of safety, the grade 3 and higher treatment-related TEAEs (TRAEs) occurred in 51% of the patients, and serious TRAEs occurred in 28%. The most common TRAE were leukopenia (G≥3 29%), anemia (G≥3 22%) and neutropenia (G≥3 30%), while decreased appetite (G≥3 1%) and nausea (G≥3 1%) were the most common non-hematological TRAEs. Only 3 (1%) were reported as treatment related interstitial lung disease.

"We are excited to share the results of YL201 at the ESMO (Free ESMO Whitepaper) Congress," said Dr. Steve Chin, Chief Medical Officer of MediLink. "Clinical data accumulated from a sample size of over 300 patients has solidly demonstrated the antitumor activity of YL201 in multiple solid tumor types, especially in SCLC, NPC, and NSCLC without AGA. Significant improvement was shown in these population compared to historical data of existing standard treatment regimens. Also, YL201 is well tolerated with the most common TRAEs being hematological toxicities, which are deemed to be manageable. We were actively preparing Phase 3 studies of YL201 in SCLC, NPC, etc."

About YL201

YL201 is an innovative antibody-drug conjugate that specifically targets B7-H3. B7-H3 is overexpressed on differentiated malignant cells and cancer-initiating cells of various tumor types, but has a restricted expression in normal tissue, indicating its potential as ADC drug. YL201 has been developed by utilizing MediLink’s Tumor Microenvironment Activable LINker-payload (TMALIN) conjugated with a highly specific B7-H3 antibody. Currently, YL201 is being investigated in four Phase I or II studies, including one multi-national Phase I clinical study.

On September 13, 2024 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the publication of a manuscript in Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which describes the design and characterization of NVL-655 and details Nuvalent’s approach to rationally targeting ALK (Press release, Nuvalent, SEP 13, 2024, View Source [SID1234646572]). NVL-655 is currently being studied in the ongoing ALKOVE-1 Phase 1/2 clinical trial for patients with advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors.

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The manuscript, entitled "NVL-655 is a selective and brain-penetrant inhibitor of diverse ALK mutant oncoproteins, including lorlatinib-resistant compound mutations," is published online and can be accessed here: View Source

"Currently available ALK tyrosine kinase inhibitors (TKIs) are important treatment options for patients with ALK-driven lung cancer. However, limitations including treatment-emergent drug resistance, off-target neurological adverse events, and inadequate control of brain metastases, support the need for continued development in this disease," said senior author Alexander Drilon, MD, Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, and investigator in the ALKOVE-1 trial. "As detailed in this publication, preclinical characterization and preliminary clinical data provide a compelling rationale for the ongoing clinical investigation of NVL-655 and evaluation of its potential to address the limitations of available ALK TKIs for patients with ALK-positive NSCLC."

The manuscript details the design principles underlying the activity of NVL-655 against ALK single and compound resistance mutations, including the most commonly occurring resistance mutation, ALK G1202R. Additionally, it outlines a molecular rationale for the selectivity of NVL-655 for ALK over the structurally related tropomyosin receptor kinase (TRK) family, whose inhibition has been associated with neurological adverse events that can be dose limiting. Preclinical characterization of the activity and selectivity of NVL-655 is presented, including in vivo xenograft studies, preclinical assessments of brain penetrance and intracranial activity, and a comparison of eight ALK TKIs across multiple biochemical and cellular assays.

The manuscript further documents three case studies from the ALKOVE-1 trial of patients with ALK fusion-positive lung cancers who had received a range of ALK TKIs, including lorlatinib, and presented with brain metastases or with tumors that harbored ALK G1202R. NVL-655 elicited tumor responses in these patients without accompanying CNS effects attributed to off-target TRK inhibition. These findings support the potential for NVL-655 as a future treatment for these patient populations that may also enhance tolerability through improved selectivity for ALK.

"With this publication in Cancer Discovery, we are pleased to have now also elucidated our focused approach for ALK-positive NSCLC. Along with our parallel lead program for ROS1-positive NSCLC, these selective inhibitors form the foundation for our pipeline of precisely targeted therapies which aim to deliver potential best-in-class activity against recalcitrant targets through solving for multiple, and at times competing, challenges in structure-based drug design," said Joshua Horan, Ph.D., Vice President, Chemistry at Nuvalent. "We are grateful to our collaborators for their contributions to this manuscript and to the continued advancement of NVL-655."

Enrollment is ongoing in the global Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, designed with registrational intent. Updated data from the Phase 1 portion of the trial will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 in Barcelona, Spain during a Proffered paper session on Saturday September 14, 2024 from 9:30 – 9:40 a.m. CEST.

About NVL-655

NVL-655 is a novel brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations such as G1202R. In addition, NVL-655 is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. NVL-655 has received breakthrough therapy designation for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with two or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC. NVL-655 is currently being evaluated in the Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, a first-in-human study of NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors (NCT05384626).