On September 12, 2022 NuCana plc (NASDAQ: NCNA) reported that data from the ongoing NuTide:701 study of NUC-7738 in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting (Press release, Nucana BioPharmaceuticals, SEP 12, 2022, View Source [SID1234619427]).

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Oral 455MO: NUC-7738 in Patients with Advanced Solid Tumors- Phase 1 results from the NuTide:701 Phase 1 / 2 Study

Data on NUC-7738 from the Phase 1 part of NuTide:701 showed encouraging signals of anti-tumor activity across a range of tumor types, particularly melanoma. Promising data were observed in a variety of solid tumors with numerous patients staying on treatment for extended periods, including one patient with metastatic melanoma who became eligible for complete surgical resection following eleven months of treatment with NUC-7738. NUC-7738 also had a favorable safety profile with low rates of treatment-related AEs (TRAEs), very few Grade 3 TRAEs and no patients experiencing Grade 4 or 5 TRAEs.

Dr. Stefan Symeonides, Senior Lecturer in Experimental Cancer Medicine at the Edinburgh Cancer Research Centre and lead author of the ESMO (Free ESMO Whitepaper) presentation, said: "NUC-7738 has shown an excellent safety profile and encouraging signals of anti-tumor activity in this study which is enrolling patients who have exhausted all standard therapies. We are excited to further investigate the activity of NUC-7738 in melanoma and other tumor types."

"We remain very encouraged by what we have observed with NUC-7738," said Hugh S. Griffith. "NUC-7738’s precise mode of action of disrupting RNA polyadenylation in cancer cells thereby altering the expression of genes associated with key cellular processes is very exciting. The positive signals observed in Part 1 of the NuTide:701 study, combined with NUC-7738’s differentiated mode of action, provide a strong scientific rationale to expedite its development and enrich the Phase 2 part of the study for patients with melanoma. This part of the study will also include a cohort combining NUC-7738 with pembrolizumab, which is a standard of care for melanoma patients. We have begun enrolling patients into the Phase 2 part of the study and look forward to sharing these data."

About NUC-7738
NUC-7738 is a phosphoramidate transformation of 3′-deoxyadenosine (3′-dA), also known as cordycepin. 3’-dA has demonstrated potent anti-cancer activity in non-clinical studies, but has not been successfully developed as an anti-cancer agent due to its rapid breakdown by adenosine deaminase (ADA). NUC-7738 is designed to generate the active anti-cancer metabolite of 3’-dA directly inside cancer cells, thus overcoming 3’-dA’s key limitations of breakdown, transportation and activation. The cytotoxic effect of NUC-7738 is largely attributed to the generation of the main active anti-cancer metabolite, 3′-dATP which interferes with RNA polyadenylation, causing changes in the expression of genes involved in various cellular processes, leading to cancer cell death.

On September 12, 2022 NANOBIOTIX (Euronext: NANO –– NASDAQ: NBTX – the ‘‘Company’’), a late-clinical stage biotechnology company pioneering physics-based approaches to expand treatment possibilities for patients with cancer, reported reaching an agreement in principle to restructure €30.7 million in outstanding debt obligations related to the Company’s 2018 loan agreement with the European Investment Bank ("EIB") (Press release, Nanobiotix, SEP 12, 2022, View Source [SID1234619426]).

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"The European Investment Bank has shown an unwavering commitment to supporting potentially disruptive healthcare innovation in the European Union and this agreement in principle is a testament to their strength as a strategic partner," said Bart Van Rhijn, chief financial officer, Nanobiotix. "In view of macroeconomic volatility and the impact on the overall biotechnology industry, Nanobiotix continues to prioritize lead registrational programs for NBTXR3 as a single agent activated by radiotherapy and in combination with checkpoint inhibitors for the treatment of head and neck cancer. Restructuring existing debt obligations to extend the maturity date of the loan will enable Nanobiotix to drive priority development programs in 2023 by extending operating runway an additional quarter. Combined with the committed access to capital available through our existing equity line, this provides Nanobiotix with the ability to extend its operating runway into the first quarter of 2024."

The finance contract and royalty agreement established with the EIB in July 2018 consisted of an initial tranche of €16.0 million drawn in October 2018 and repayable in a single installment at maturity in 2023 and a second tranche of €14.0 million granted in March 2019 and repayable in semi-annual installments of principal and interest after a two-year grace period. The 2018 agreement also included a commitment to pay low single-digit royalties annually over a six-year period beginning in January 2021.

The agreement in principle is structured around Nanobiotix expected cash inflow from future non-dilutive value drivers including planned commercialization1 of NBTXR3 and potential partnerships. The agreement in principle allows for deferment of approximately €25.3 million in principal repayments up to June 2029 and approximately €5.4 million in payment-in-kind (PIK) interest payments up to October 2024. It also includes an additional €20.0 million payment with a due date in 2029 which could be accelerated based on potential cash inflow. The outstanding debt obligations will continue to accrue interest until the new maturity dates. The six-year royalty period included in the 2018 agreement is also being revised to commence upon commercialization.

Execution by the Company and EIB of a definitive amendment, expected in Q4 2022, is subject to finalization of the necessary documents and agreements.

On September 12, 2022 Mersana Therapeutics, Inc. (NASDAQ: MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to XMT-1660 for the treatment of adult patients with advanced or metastatic triple-negative breast cancer (TNBC) (Press release, Mersana Therapeutics, SEP 12, 2022, View Source [SID1234619425]). XMT-1660 is a B7-H4-directed Dolasynthen antibody drug conjugate with a precise, target-optimized drug-to-antibody ratio (DAR 6) and Mersana’s clinically validated DolaLock microtubule inhibitor payload with controlled bystander effect.

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"While breast cancer remains an area of high unmet need, TNBC is associated with particularly poor outcomes and very limited treatment options," said Anna Protopapas, President and Chief Executive Officer of Mersana Therapeutics. "XMT-1660 has demonstrated promising anti-tumor effects in preclinical studies, and we are excited to have recently initiated our Phase 1 trial to investigate its safety and clinical activity. This Fast Track designation allows for a potentially accelerated regulatory review of XMT-1660 as we seek to offer a new therapy for patients living with a range of B7-H4 expressing tumors."

Mersana’s ongoing multicenter Phase 1 trial is investigating the safety, tolerability and anti-tumor activity of XMT-1660 in patients with solid tumors, including in breast, endometrial and ovarian cancers. The initial dose escalation portion of this trial will evaluate the safety and tolerability of XMT-1660. The dose expansion portion of the trial will evaluate the safety, tolerability and efficacy of XMT-1660.

The FDA’s Fast Track program is designed to facilitate the development and expedite the review of drug candidates to treat serious conditions and fill an unmet medical need. A product candidate that is granted Fast Track designation may be eligible for several benefits, including more frequent meetings and communications with the FDA and, if certain criteria are met, the potential for Accelerated Approval, Priority Review or Rolling Review of a Biologics License Application (BLA) by the FDA.

On September 12, 2022 Mereo BioPharma Group plc (NASDAQ: MREO) ("Mereo" or the "Company"), a clinical stage biopharmaceutical company focused on rare diseases and oncology, reported updated clinical data and promising biomarker data from ACTIVATE, a Phase 1b/ 2 study of anti-TIGIT antibody, etigilimab, in combination with nivolumab, in select recurrent advanced / metastatic solid tumors (Press release, Mereo BioPharma, SEP 12, 2022, View Source [SID1234619424]). These biomarker data were presented at a poster session at the 2022 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting on September 10, 2022.

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The multicenter ACTIVATE study is designed to evaluate the efficacy, safety, tolerability, PK, and pharmacodynamics of etigilimab, Mereo’s proprietary anti-TIGIT antibody, in combination with a PD-1 inhibitor, nivolumab, with dosing every two weeks. Biomarker analyses were included as exploratory endpoints.

As of September 12, 2022, there were 63 efficacy-evaluable checkpoint inhibitor-naïve (CPI-naive) subjects with a minimum of 1 staging scan at 8 (+/-1) weeks and RECIST 1.1 response assessment or documented clinical progression. Key updates:

Cervical cancer: 3/7 PD-L1 combined positive score CPS>1%, CPI-naïve cervical cancer subjects with confirmed complete responses (cCRs) ORR of 43%, 2 ongoing at >284 days and >142 days, and 1 withdrew consent with ongoing cCR at 163 days. Two additional patients had stable disease (SD) for a DCR rate of 71%. Of interest, biomarker analysis showed that the 2 cervical subjects with complete responses exhibited higher levels of PVR, TIGIT as well as high CD226+CD8+ co-expression. No evaluable tissue for biomarker analysis was available for the third patent with a complete response.

Uveal melanoma: 1/6 evaluable subjects, with confirmed partial response (cPR) at >347 days, ORR 17% and 2 patients were SD, for 175 and 294 days DCR 50%. The subject with cPR was noted to have high CD226+CD8+ co-expression, and was PVR positive and PD-L1 negative (CPS <1%).

Biomarker data presented at ESMO (Free ESMO Whitepaper) 2022 evaluated tumors for baseline expression of PVR, TIGIT, PD-L1 and CD226 by multiple modalities including validated IHC assays. Consistent with Mereo’s previously reported data (Mereo BioPharma webcast, November 30, 2021), high PVR expression was observed in subjects with decreases in target lesions (TL) from baseline and RECIST 1.1 responses. Additional noteworthy responses observed in subjects with cancer types not typically responsive to CPI monotherapy, with tumors that had high PVR expression and were either PD-L1 negative (CPS <1%), or PD-L1 low (CPS≤3%) include, (i) an ovarian PR (-80% target lesion (TL) decrease, ongoing >255 days, PD-L1 negative), (ii) an endometrial PR (-69% TL decrease, ongoing >150 days, MMR proficient, PD-L1 CPS=3%), (iii) a dedifferentiated liposarcoma PR (-80% TL decrease, ongoing cPR >267 days, high TIGIT, PD-L1 CPS=1%), and (iv) a recurrent/metastatic testicular GCT patient with stable, near normalization of elevated tumor marker alpha feto protein (doing well clinically on study >127 days), PD-L1 negative. The presentation at ESMO (Free ESMO Whitepaper) 2022 demonstrated robust target engagement in patients as evidenced by significant decreases in peripheral T regulatory cells while maintaining circulation levels of CD8 cells. Increases in proliferating T-cells subsets (CD8, CD4), proliferating NK cells, and intracellular cytokines (IFNg, IL2, and TNFα) were observed and sustained longitudinally. Additionally, etigilimab plus nivolumab reduced TPEX cells (CD8+CCR7+PD1+TIGIT+), progenitor cells believed to be committed to an exhausted-like fate. Further data was reported showing reductions in circulating tumor DNA (ctDNA) measured at ~5-6 weeks post-treatment correlated with clinical benefit.

These data support the role of dual checkpoint inhibition of the TIGIT/PVR and PD-(L)-1 pathways and further evaluation of these biomarkers, including PVR and CD226, as a potential enrichment strategy for the treatment of etigilimab plus anti-PD1.

"We are encouraged by the totality of biomarker data from the ACTIVATE study. These data have the potential to provide a roadmap for future clinical studies of etigilimab and nivolumab, including the opportunity to incorporate a patient enrichment strategy, that could help to provide a benefit to patients in need of additional treatment options," said Dr. Ann Kapoun, Senior Vice President Translational Research & Development at Mereo BioPharma.

"We continue to observe evidence of clinical benefit across a range of tumors being evaluated in the ACTIVATE study," said Dr. Suba Krishnan, Senior Vice President Clinical Development, at Mereo BioPharma. "At this time, we have paused the ongoing Phase 1b/2 ACTIVATE trial for further enrollment; 30 patients previously enrolled currently remain on study. The totality of emerging data from ACTIVATE and other trials targeting the TIGIT axis will direct next steps for the etigilimab program."

On September 12, 2022 Lyell Immunopharma, Inc. (Nasdaq: LYEL), a clinical‑stage T-cell reprogramming company dedicated to developing curative cell therapies for patients with solid tumors, reported that a poster describing the first-in-human Phase 1 trial design for LYL797, Lyell’s ROR1-targeted CAR T-cell therapy enhanced with genetic and epigenetic reprogramming for the treatment of solid tumors, is being presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022 in Paris, France (Press release, Lyell Immunopharma, SEP 12, 2022, View Source [SID1234619423]).

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"This first-in-human Phase 1 trial is designed to provide important data on the potential of Lyell’s innovative reprogramming technologies to endow T cells with durable anti-tumor functionality," stated Dr. Tina Albertson, chief medical officer of Lyell. "These reprogramming technologies are designed to overcome primary barriers to sustained response to adoptive cell therapy for patients with solid tumor cancers, namely T-cell exhaustion and lack of durable stemness."

Details on the presentation are below:

Phase 1 Study of LYL797, a ROR1-targeted CAR T-cell therapy with genetic and epigenetic reprogramming for the treatment of advanced solid tumors

Category: Investigational Immunotherapy
Date, Time & Location: September 12, 2022, 9 a.m. CET to 5 p.m. CET, Hall 4
Presentation number: 777TiP
About LYL797

LYL797 is an investigational chimeric antigen receptor (CAR) T-cell therapy for patients with receptor tyrosine kinase-like orphan receptor 1-positive (ROR1+) solid tumors. LYL797 incorporates Gen-R and Epi-R, Lyell’s novel reprogramming technologies designed to overcome primary barriers to successful adoptive cell therapy: T-cell exhaustion and lack of durable stemness. The Phase 1 trial will assess LYL797 in patients with relapsed/refractory triple-negative breast cancer (TNBC) or non-small cell lung cancer (NSCLC). More information can be found on ClinicalTrials.gov by searching NCT05274451.