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.

On September 12, 2022 Kineta, Inc. ("Kineta" or the "Company"), a clinical-stage biotechnology company focused on the development of novel immunotherapies in oncology, reported that it will be featured as a presenting company at the H.C. Wainwright 24th Annual Global Investment Conference (Press release, Kineta, SEP 12, 2022, View Source;utm_medium=rss&utm_campaign=kineta-announces-participation-in-the-h-c-wainwright-24th-annual-global-healthcare-conference [SID1234619422]). The conference is being held as a hybrid event on September 12-14, 2022. The in-person venue for the event is the Lotte New York Palace Hotel in New York City. Virtual participation will be staged simultaneously with over 500 company presentations scheduled as live feed or available on-demand.

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Shawn Iadonato, Ph.D., Kineta’s Chief Executive Officer, will provide a corporate update and overview of KVA12.1, Kineta’s IND-ready VISTA blocking immunotherapy that is scheduled to initiate a Phase 1 clinical trial in the fourth quarter of 2022.

Event: H.C. Wainwright 24th Annual Global Investment Conference (Hybrid Conference)
Date: September 12-14, 2022
Time: 7:00 A.M. Eastern Time
Location: Virtual webcast to start on-demand on September 12, 2022 at 7:00 A.M. Eastern Time

Participants may access the webcast of the event through the following link:

View Source

The webcast can also be accessed in the Investors section of the Kineta website at www.kinetabio.com. The webcast replay will be available shortly after the conclusion of the event for 30 days.

On September 12, 2022 Keros Therapeutics, Inc. ("Keros") (Nasdaq: KROS), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel treatments for patients suffering from hematological, pulmonary, and musculoskeletal disorders with high unmet medical need, reported that it presented preliminary clinical data from the Part 2 multiple ascending dose ("MAD") portion of its Phase 1 clinical trial of KER-012 in healthy postmenopausal women at the American Society of Bone and Mineral Research 2022 Annual Meeting on Sunday, September 11, 2022 (Press release, Keros Therapeutics, SEP 12, 2022, View Source [SID1234619421]). In addition, Keros also announced preclinical data evaluating the bone anabolic activity of RKER-050, a research form of KER-050, in a mouse model of myelodysplastic syndromes ("MDS").

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"We reported data from Part 2 of our Phase 1 clinical trial of KER-012, which continues to support the potential of KER-012 to correct dysfunctional activin signaling in multiple diseases," said Jasbir S. Seehra, Ph.D., President and Chief Executive Officer of Keros. "We observed evidence of maximal inhibition of activin signaling as demonstrated by the reduction in follicle-stimulating hormone as well as increases in bone-specific alkaline phosphatase levels, which is a marker of osteoblast activity. Importantly, no clinically meaningful changes were seen in hemoglobin or red blood cells. We believe these results are supportive of the potential of KER-012 to treat diseases like pulmonary arterial hypertension and bone disorders characterized by increased activin signaling. With the completion of this Phase 1 clinical trial, we are preparing to initiate a Phase 2 clinical trial in early 2023 evaluating KER-012 in patients with pulmonary arterial hypertension."

Clinical Presentation

KER-012, a Modified ActRIIB Ligand Trap, Administered to Healthy Postmenopausal Women was Generally Well Tolerated and Increased Biomarkers of Bone Formation, Supportive of a Bone Anabolic Mechanism
This Phase 1 clinical trial was a randomized, double-blind, placebo-controlled, two-part trial to assess the safety, tolerability and pharmacokinetics of KER-012. Preliminary topline data from the Part 1 single ascending dose ("SAD") portion of the trial was reported in May 2022. In Part 2 of the trial, subjects received three subcutaneous doses of either 0.75, 1.5 or 4.5 mg/kg of KER-012 or placebo administered 28 days apart with a 16-week safety follow-up. A total of 26 subjects were enrolled in three sequential multiple-ascending dose escalation cohorts, with eight subjects in the 0.75 mg/kg cohort and six subjects in each of the 1.5 mg/kg and 4.5 mg/kg cohorts receiving KER-012. Six subjects enrolled in Part 2 of this trial received placebo doses.

As of the data cut-off date of August 4, 2022, KER-012 was generally well tolerated at all dose levels tested. One subject discontinued after receiving two doses of placebo due to a serious adverse event unrelated to treatment. Another subject withdrew consent after receiving two 1.5 mg/kg doses of KER-012. There were no discontinuations due to treatment-related adverse events, and the majority of the adverse events that were observed were mild in severity and resolved.

Preliminary results from Part 2 of this trial include the following:

Maximal target engagement was observed in the 4.5 mg/kg dose cohort, with a mean (standard deviation, "SD") 52.0 (19.32)% reduction in follicle-stimulating hormone ("FSH"). Five out of six subjects who received a 4.5 mg/kg dose of KER-012 achieved a >40% reduction in serum FSH levels from baseline.
Robust dose-dependent and sustained increases in markers of bone formation were observed:
Dose-dependent increases in serum levels of bone specific alkaline phosphatase ("BSAP"), a marker of osteoblast activity, were observed starting at the lowest dose of 0.75 mg/kg. The highest increase in BSAP was observed in the 4.5 mg/kg dose cohort, with mean (SD) maximum increases from baseline of 76.5 (20.33)%.
Repeat administration of KER-012 at 28-day intervals resulted in increases in BSAP after each dose, which is supportive of activation of osteoblasts after each dose potentially due to increased bone morphogenic protein signaling.
Treatment with three doses of KER-012 at 28-day intervals did not elicit changes in hemoglobin or red blood cells in any of the multiple-dose cohorts evaluated in Part 2 of this trial.
Preclinical Presentation

RKER-050, a Novel Activin Receptor Type II Ligand Trap, Improved Bone Loss in a Myelodysplastic Syndrome Mouse Model
A research form of KER-050 ("RKER-050") was tested in a mouse model of MDS. Male MDS mice were administered either vehicle or 7.5 mg/kg of RKER-050 once weekly for six weeks. Healthy male mice received only vehicle.

Vehicle-treated MDS mice had reduced bone volume, lower bone volume fraction, increased trabecular separation and reduced trabecular number relative to healthy controls. However, treatment with RKER-050 prevented loss of bone volume, bone volume fraction and trabecular number and reduced trabecular separation in MDS mice relative to vehicle-treated MDS mice.

These data suggest that KER-050 has the potential to restore hematopoiesis and bone health, which may lead to the regeneration of a healthier bone marrow microenvironment in patients with MDS.

About KER-012
KER-012 is designed to bind to and inhibit the signaling of transforming growth factor-beta ("TGF-β") ligands that suppress bone growth, including activin A and activin B. Keros believes that KER-012 has the potential to increase the signaling of bone morphogenic protein ("BMP") pathways through this inhibition of activin A and activin B signaling, and consequently treat diseases such as pulmonary arterial hypertension ("PAH") that are associated with reduced BMP signaling due to inactivating mutations in the BMP receptors. KER-012 is being developed for the treatment of PAH and for the treatment of disorders associated with bone loss, such as osteogenesis imperfecta and osteoporosis.

About KER-050
Keros’ lead protein therapeutic product candidate, KER-050, is an engineered ligand trap comprised of a modified ligand-binding domain of the TGF-β receptor known as activin receptor type IIA that is fused to the portion of the human antibody known as the Fc domain. KER-050 is being developed for the treatment of low blood cell counts, or cytopenias, including anemia and thrombocytopenia, in patients with MDS, and in patients with myelofibrosis.