On September 20, 2021 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM: HCM; HKEX: 13) reported that it has initiated a Japan registration-enabling bridging study for surufatinib to support the registration of surufatinib in the treatment of patients with advanced neuroendocrine tumors ("NETs") (Press release, Hutchison China MediTech, SEP 20, 2021, View Source [SID1234587947]). The first patient was dosed on September 15, 2021.

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Based on dialogue with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), it was agreed that the surufatinib Japanese new drug application ("NDA") for the treatment of advanced NETs include results from a pivotal study to be conducted in Japan, to complement the registration data package supporting the NDA to the U.S. Food and Drug Administration ("FDA") (accepted for review in June 2021) and the Marketing Authorization Application ("MAA") to the European Medicines Agency ("EMA") (validated in July 2021). The basis for the NDA and the MAA includes data from a U.S. Phase I/II study, as well as the completed Phase III SANET-ep and SANET-p studies used to support marketing authorization in China in advanced NETs, where surufatinib is currently marketed under the brand name SULANDA.

This Japan study is a two-stage, open label study of surufatinib where approximately 34 patients are expected to be recruited. In Part 1 of the study, the safety and tolerability of surufatinib 300mg once daily after 28 days of treatment will be assessed in patients with relapsed/refractory non-hematological malignancies; pharmacokinetics ("PK") and anti-tumor activity of surufatinib are secondary endpoints. In Part 2 of the study, efficacy will be assessed in patients with locally advanced or metastatic NETs; the primary outcome measure is objective response rate (ORR). The secondary outcome measures include disease control rate (DCR), progression free survival ("PFS"), duration of response (DoR), safety, and PK.

Surufatinib is the third potential new medicine discovered by HUTCHMED to enter into clinical development in Japan. A global Phase III registration study for fruquintinib, known as the FRESCO-2 study, is ongoing in patients with refractory metastatic colorectal cancer and is expected to enroll over 680 patients from over 150 sites in 14 countries, including Japan. A global single-arm, open-label study, known as the SAVANNAH study, is ongoing for savolitinib (partnered with AstraZeneca PLC) in combination with TAGRISSO in non-small cell lung cancer patients whose disease progressed following TAGRISSO due to MET amplification or overexpression.

About NETs

NETs form in cells that interact with the nervous system or in glands that produce hormones. They can originate in various parts of the body, most often in the gut or the lungs and can be benign or malignant. NETs are typically classified as pancreatic NET ("pNET") or extra-pancreatic (non-pancreatic) NET ("epNET").

According to Frost & Sullivan, there were 19,000 newly diagnosed cases of NET in the U.S. in 2020. Rates across the European Union (E.U.) appear largely similar to the U.S. This is supported by an analysis of global epidemiologic trends, which also show growth in the incidence of NETs worldwide.1 Importantly, NETs are associated with a relatively long duration of survival compared to other tumors. As a result, there were approximately 140,000 estimated patients living with NET in France, Germany, Italy, Spain, and the United Kingdom in 2020.2 In Japan, approximately 6,700 people were diagnosed with gastro-entero-pancreatic neuroendocrine neoplasms in 2016.3

About Surufatinib

Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects.

HUTCHMED currently retains all rights to surufatinib worldwide.

About Surufatinib Development

epNETs in China: On December 29, 2020, surufatinib was granted drug registration approval by the National Medical Products Administration of China ("NMPA") for the treatment of epNET. Surufatinib is marketed in China under the brand name SULANDA. The approval was based on results from the SANET-ep study, a Phase III trial (clinicaltrials.gov identifier: NCT02588170) in patients with advanced epNETs conducted in China. The study met the pre-defined primary endpoint of PFS at a preplanned interim analysis, and was published in The Lancet Oncology4. Median PFS was significantly longer for patients treated with surufatinib at 9.2 months, compared to 3.8 months for patients in the placebo group (HR 0.334; 95% CI: 0.223-0.499; p<0.0001). Surufatinib had an acceptable safety profile, with the most common treatment related adverse events of grade 3 or worse being hypertension (36% of surufatinib patients vs. 13% of placebo patients), proteinuria (19% vs. 0%) and anemia (5% vs. 3%).

pNETs in China: On June 16, 2021, surufatinib was granted drug registration approval by the NMPA for the treatment of pNET. The approval was based on results from the SANET-p study, a Phase III trial (clinicaltrials.gov identifier: NCT02589821) in patients with advanced pNET in China. The pre-defined primary endpoint of PFS was met at a preplanned interim analysis and was published in The Lancet Oncology5, demonstrating that surufatinib reduces the risk of disease progression or death by 51% in patients, with a median PFS of 10.9 months compared to 3.7 months on placebo (HR 0.491; 95% CI: 0.391-0.755; p=0.0011). The safety profile of surufatinib was manageable and consistent with observations in prior studies.

Immunotherapy combinations: HUTCHMED entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with anti-PD-1 monoclonal antibodies, including with tislelizumab (BGB-A317), TUOYI (toripalimab) and TYVYT (sintilimab), which are approved as monotherapies in China.

NETs in the U.S. and Europe: A FDA NDA submission was accepted in June 2021, followed by a MAA submission to the EMA validated in July 2021. The basis to support these filings includes the completed SANET-ep and SANET-p studies, along with existing data from surufatinib in U.S. epNET and pNET patients (clinicaltrials.gov identifier: NCT02549937). In the U.S., surufatinib was granted Fast Track Designations for development in pNET and epNET in April 2020, and Orphan Drug Designation for pNET in November 2019.

HUTCHMED has initiated an Expanded Access Protocol (EAP) in the U.S. to ensure patients with NET with limited therapeutic options have access to this treatment. Regulatory clearance of this protocol has been granted by the FDA and this program is open for site activation (clinicaltrials.gov identifier: NCT04814732).

On September 20, 2021 Oncternal Therapeutics, Inc. ("Oncternal") (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, and Celularity Inc. ("Celularity") (Nasdaq: CELU), a clinical-stage biotechnology company developing off-the-shelf placental-derived allogeneic therapies, reported they have entered into a research collaboration to evaluate placental derived-cellular therapies targeting receptor-tyrosine kinase-like Orphan Receptor 1 (ROR1) (Press release, Oncternal Therapeutics, SEP 20, 2021, View Source [SID1234588001]). As part of the collaboration, Celularity will explore the use of Oncternal’s ROR1-targeted monoclonal antibody, cirmtuzumab, in combination with Celularity’s natural killer cells. ROR1 targeted chimeric antigen receptor (CAR) gene modification will also be explored in Celularity’s CYNK natural killer cell and CyCART T cell platforms in preclinical studies.

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ROR1 is highly expressed by multiple solid tumors and hematological malignancies and confers both an aggressive phenotype and survival advantage to the tumor cells. Cirmtuzumab binding to ROR1 on leukemia and lymphoma cells decreases tumor cell proliferation and survival by blocking Wnt5a-induced activation, while it does not bind to adult tissues. Celularity will evaluate the use of cirmtuzumab in combination with CYNK-101, a placental derived-allogeneic NK cell therapy that has been genetically engineered to synergize with therapeutic antibodies. As part of the collaboration, Celularity will also evaluate ROR1-targeted CAR-NK and CAR-T cell therapies as extensions of its CYNK and CyCART programs, respectively.

"Our research studying ROR1 suggests the potential for a range of new targeted therapeutics, capable of addressing a wide variety of both solid tumors and hematological malignancies," said James Breitmeyer, M.D., Ph.D., founder, President and CEO of Oncternal. "We believe that targeted cellular therapies have the potential to extend the clinical benefit of our research and improve the standard of care for patients. However, the current limitations in efficacy, safety and availability of cellular therapies hinders their broader use. Celularity’s approach, leveraging the ability of placental-derived cells to differentiate and expand, has the potential to overcome these obstacles and could potentially offer more potent, tolerable and accessible cellular medicines and, in combination with our ROR1 targeting antibodies, address the significant unmet needs of patients."

Robert J. Hariri, M.D., Ph.D., founder, Chairperson and Chief Executive Officer of Celularity, added, "We are thrilled to enter this partnership with Oncternal to forge new therapeutic strategies for both solid tumors and hematological malignancies using our allogeneic placental-derived cell therapy product candidates with their innate stemness. Oncternal’s work has established ROR1 as an exciting target that could be utilized for the development of new and novel cellular medicines, and there is an immense potential for synergy combining two novel approaches to create exciting new pipeline candidates targeting a wide range of cancers. We look forward to working closely together to lead the next evolution of cellular medicines."

On September 20, 2021 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported that company management will present at the Cantor Virtual Global Healthcare Conference on Monday, September 27, 2021 at 4:00 p.m. ET / 1:00 p.m. PT (Press release, Xencor, SEP 20, 2021, View Source [SID1234588033]).

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A live webcast will be available under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com. Following the webcast, a replay will be archived on the website for at least 30 days.

On September 20, 2021 Redx Pharma (AIM: REDX), the drug discovery and development company focused on cancer and fibrosis, reported data from the monotherapy module of its Phase 1 clinical study of RXC004 for the first time (Press release, Redx Pharma, SEP 20, 2021, View Source [SID1234588078]). The data was presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 by the study’s lead investigator, Dr Natalie Cook, from the University of Manchester and Christie NHS Foundation Trust.

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The Phase 1 trial (clinicaltrials.gov NCT03447470) is evaluating RXC004, a wholly owned small-molecule Porcupine inhibitor as a monotherapy (Module 1) and in combination with nivolumab (Module 2) in unselected patients with advanced solid tumours for whom no standard therapy is available. The primary objective of the open label, ‘3+3’ dose escalation Phase 1 study is to assess the safety and tolerability of RXC004 with secondary endpoints including pharmacokinetics (PK) and anti-tumour activity, as measured by Response Evaluation Criteria in Solid Tumours (RECIST 1.1). The data presented are from 25 patients in the completed monotherapy module of the trial and informed the selection of 2mg as the dose for the planned Phase 2 monotherapy trials testing RXC004 in three different Wnt-ligand dependent cancers.

D r Natalie Cook, Lead Investigator of the Study, from the University of Manchester and Christie NHS Trust, commented: "This Phase 1 study provides encouraging evidence of the potential of Porcupine inhibition as a targeted treatment approach and supports the progression of RXC004 into Phase 2 development in selected patients with Wnt-ligand driven cancers." Lisa Anson, Chief Executive Officer of Redx Pharma, added: "The first clinical data on our Porcupine inhibitor, presented at the prestigious ESMO (Free ESMO Whitepaper) Congress, illustrate RXC004’s potential to improve outcomes in patients with Wnt-ligand driven advanced solid tumours who have limited treatment options. RXC004 demonstrated a well-tolerated profile at the selected dose and showed differentiated signs of efficacy in Wnt-ligand dependent tumours. We are excited to move to Phase 2 later this year, with a larger number of patients with Wnt-ligand driven cancers, who represent those most likely to benefit from treatment with RXC004."

Key results presented at ESMO (Free ESMO Whitepaper) highlighted:
· RXC004 was safe and well tolerated as a single agent at doses up to 2mg. No grade 4 or 5 adverse events (AEs) were reported at these dose levels and the most common treatment-related AEs across all patients were fatigue (52% of patients), nausea (44%), decreased appetite (40%), dysgeusia (‘altered taste’) (40%) and vomiting (24%). RXC004, given at doses up to 2mg alongside denosumab prophylaxis, averted the bone toxicity traditionally associated with Wnt-pathway inhibition, as evidenced by the absence of both increases in the bone turnover marker βCTX and spontaneous fractures.
· An oral dose of 2mg once daily is selected as the Phase 2 dose of RXC004 in monotherapy. The 2mg once-daily dose demonstrated high plasma exposure levels, while minimising adverse events. RXC004 exposures were dose proportional and median half-life was 14.5 hours. In addition, the pharmacodynamic marker of Axin-2 levels in skin showed active target engagement. · Efficacy data supports further investigation of RXC004 use in Wnt-ligand dependent tumours.

Although the study was not designed to assess efficacy as a primary endpoint, 18 patients had RECIST-evaluable disease. Of these patients: o 7 patients had Wnt-ligand dependent tumours, defined as those having detectable ring-finger protein 43 (RNF43) Loss of Function or R-spondin (RSPO) fusion, biliary-tract cancers or thymus cancers; 6 patients had Wnt-ligand independent tumours, defined as those having no detectable RNF43 Loss of Function or RSPO fusion, or colorectal tumours with detectable downstream adenomatous polyposis coli (APC) mutations; 5 patients were of unknown Wnt-ligand status. o At the data cut-off date on 30 July 2021, 5 of 7 patients (71%) with Wnt-ligand dependent tumours had durable RECIST stable disease (SD) versus 0 of 11 (0%) patients with independent or unknown Wnt-ligand status. o Median treatment duration was 13.1 weeks (6.4-25.4 weeks) for patients with Wnt-ligand dependent tumours versus 6.6 weeks (5.4-7.3 weeks) for patients with either Wnt-ligand independent tumours or tumours of unknown Wnt-ligand status.

The results from the second module in the Phase 1 study testing RXC004 in combination with nivolumab (OPDIVO-Bristol Myers Squibb, an anti-PD-1 antibody) are expected in H2 2021 and will be used to define a dose of RXC004 to be used in combination with standard dose nivolumab in a Phase 2 study in patients with genetically selected MSS mCRC. A link to the presentation can be found here: View Source Redx to host R&D Event Today’s data will be discussed by Medical Experts during Redx’s online R&D Event to be held on Monday 11 October 2021 at 1:00pm BST / 8.00am EDT. The event will also cover the Company’s pipeline beyond RXC004. To register for the event, please email [email protected] About the Phase 2 programme for RXC004 Redx plans to commence a global Phase 2 monotherapy programme in three tumour types to assess RXC004 efficacy in patients with Wnt-ligand driven cancers. For patients with microsatellite stable metastatic colorectal cancer (MSS mCRC) only those with RNF43 mutations or RSPO fusions will be enrolled. For pancreatic cancer patients only those with RNF43 mutations will be enrolled. The third tumour type to be studied will be biliary-tract cancer, a tumour known to have high Wnt-ligand dependency which will enrol unselected patients. All three of these cancer types have high unmet need with limited treatment options and poor 5-year survival rates of less than 3% for biliary and pancreatic cancer and 14% for MSS mCRC. All three studies are planned to commence in H2 2021 and initial results are expected in 2022.

About RXC004
RXC004 is a wholly owned, potent, selective, oral, small-molecule inhibitor of the Porcupine enzyme, a key activator of Wnt ligands in the Wnt-signalling pathway. The Wnt pathway is well established as a driver of both tumour growth and immune evasion. Aberrant Wnt signalling contributes directly to tumour growth and plays an important role in immune evasion, which has also been linked to resistance to immune-checkpoint inhibitors (ICIs) such as nivolumab. By selecting patients with tumours that have high Wnt-ligand dependency, such as tumours with mutations in the RNF43 gene and fusions in the RSPO gene family, RXC004 has an opportunity to both directly inhibit the tumour growth and have an immune-enhancing effect to allow the patient’s immune system to better recognise and attack the tumour. ICIs such as anti-PD-1 antibodies have revolutionised the treatment of cancer, but do not work in all patients. Wnt-pathway activation can enhance the ability of the tumour to evade destruction by the immune system and has been linked to lack of response to ICIs in these tumours. Redx scientists have demonstrated preclinically that RXC004 can block activation of the Wnt pathway and restore the ability of the immune system to fight the tumour. Thus, RXC004 offers potential as a monotherapy or combination therapy with ICIs.

On September 20, 2021 PharmaMar (MSE:PHM) reported that new data on Yondelis (trabectedin) in patients with metastatic or inoperable leiomyosarcoma will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) congress, which is being held virtually from 16th to 21st September (Press release, PharmaMar, SEP 20, 2021, View Source [SID1234596669]).

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Under the title "LMS-04 study: a randomised, multicenter phase-III study comparing doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin in nonprogressive patients as first-line therapy, in patients with metastatic or unresectable leiomyosarcoma. A French Sarcoma Group study," the French Sarcoma Group will present data from a phase III study comparing first-line treatment with trabectedin in combination with doxorubicin versus standard-o-care single-agent doxorubicin for the first-line treatment of patients with metastatic or unresectable leiomyosarcoma.

The study achieved its primary endpoint of Progression Free Survival (PFS), progression RECIST (Response Evaluation Criteria In Solid Tumors)1 , supplemented by central review. In the combination arm of trabectedin with doxorubicin, median PFS reached 12.2 months, compared to 6.2 months with single-agent doxorubicin (HR = 0.41; 95% CI 0.29-0.58; P<0.0001).

In addition, the Overall Response Rate (ORR) was 38% using the combination, compared to 13% in the comparator arm. Overall Survival (OS) was 30.5 months in patients who received trabectedin in combination with doxorubicin, compared to 24.1 months in patients who received doxorubicin alone.

Patricia Pautier, M.D., oncologist, head of the multidisciplinary committee of gynecologic oncology at Gustave-Roussy and lead author of the study, said: "Leiomyosarcoma has been classically reported as the most frequent soft tissue sarcoma subtype together with liposarcoma, a third of them have a uterine location. Patients have a poor prognosis when leiomyosarcomas are metastatic. In prospective clinical trials, a median PFS of about 6 months and overall survival of around 12–15 months are usually reported for patients treated with any first-line chemotherapy, representing a true unmet medical need. In general, Doxorubicin and Ifosfamide are the backbone of sarcoma treatment, but nor other association nor new therapies are superior to doxorubicin in terms of overall survival." She added: "Trabectedin is known to be active in second line treatment for leiomyosarcomas.

The previous phase II of the trabectedin-doxorubicin combination in metastatic or advanced LMS in first line therapy (LMS02) share very encouraging results in terms of ORR, PFS and OS. The results of the LMS04 study have confirmed that this combination is superior in terms of PFS to doxorubicin alone with a 6 months statistical benefit; the impact on PFS2 also is in favor of the use of the association in combination rather than in a sequential way. There is a clinical impact on overall survival and a longer follow-up will let us know if this therapy will impact overall survival and will be the new standard of treatment in this indication.