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.

On September 12, 2022 Invitae (NYSE: NVTA), a leading medical genetics company, reported a collaboration with Simons Searchlight, an international research program with a goal of accelerating research and improving lives for people with rare genetic neurodevelopmental disorders (Press release, Invitae, SEP 12, 2022, View Source [SID1234619420]). This partnership will connect two sets of data – the longitudinal clinical data extracted from medical records through Invitae’s Ciitizen, a patient-consented, digital natural history data platform and patient reported outcomes and biospecimens collected by Simons Searchlight. The partnership breaks down data silos and provides a rich and deep dataset that will help accelerate research for rare neurodevelopmental diseases.

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Invitae’s (NVTA) mission is to bring comprehensive genetic information into mainstream medical practice to improve the quality of healthcare for billions of people. www.invitae.com (PRNewsFoto/Invitae Corporation)

"We are excited about this collaboration that will allow researchers to get deep, rich longitudinal data on rare disease patients," said Farid Vij, president and general manager of data for Invitae. "This is intended to help improve treatment, with a goal of ultimately finding a cure for these rare diseases."

Rare disease patients and caregivers are often asked to participate in many different stand- alone studies to help advance research. Through the combined clinical and patient-reported data in these two datasets, researchers get a deeper understanding of the etiology and progression of disease, sparing additional time, effort and data collection from the patient.

"Joining forces with Invitae is incredibly powerful for patients with rare diseases," said Jennifer Tjernagel, M.S., senior project manager at Simons Searchlight, Simons Foundation. "Our partnership and the resulting datasets will help improve understanding, diagnosis and treatment of neurodevelopmental disorders, such as STXBP1, SYNGAP1 and others. Having the support of Invitae’s Ciitizen platform will help pair patient-reported data with clinical information for in depth data analysis."

Charlene Son Rigby, president and co-founder of STXBP1 Foundation shared, "We are thrilled to partner with Invitae and Simons Searchlight on this initiative. We believe in the power of data and how important sharing that data can be in the journey to finding a cure for STXBP1 Disorder. Having this kind of collaboration in our toolkit is opening up an entirely new approach for our foundation and our patient community. The combination of Invitae’s existing clinical data which will be transitioned into a readily usable format, and Simons’ deep information from patients and caregivers, will provide doctors and scientists with an innovative way to accelerate understanding of natural history, while allowing patients and their loved ones to focus on what’s most important – their health."

Mike Graglia, Managing Director and Co-Founder of the SynGAP Research Fund stated, "Invitae’s Ciitizen is a powerful digital natural history study data platform in the rare disease space. The technology, execution and clinical expertise behind it are exceptional. Simons Searchlight is the most established clinician-led registry in autism and related disorders. The accomplishment of connecting these two platforms is a testament to their collective focus on helping patients. Every single patient who has access to Invitae’s Ciitizen platform and Searchlight should consent to join their profiles now."

This agreement expands upon a partnership that was originally launched as a pilot for STXBP1 patients and the STXBP1 Foundation. The relationship allowed consenting patients to link their de-identified Invitae Ciitizen data with the Simons Searchlight database to accelerate understanding of patients with STXBP1 disorder. By expanding focus to additional rare neurological disorders, such as SYNGAP1, SCN2A, SLC6A1 and more, researchers are one step closer to finding the needle in the haystack for patients with these conditions. To learn more about Invitae’s Ciitizen data platform and request access to the consented dataset for research, email [email protected].

On September 12, 2022 Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company that aims to develop the world’s most potent vaccines, reported that positive safety, immunogenicity, and early efficacy data from its SLATE program, an "off-the-shelf" vaccine program targeting shared neoantigens, in combination with immune checkpoint blockade, for patients with advanced solid tumors at the 2022 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, Gritstone Oncology, SEP 12, 2022, View Source [SID1234619419]). The presentation included initial data with SLATE-KRAS, a shared mutant KRAS-specific neoantigen vaccine candidate, in addition to updated data using the first version of the vaccine candidate (SLATE v1), which contains both KRAS and non-KRAS neoantigens. The data were presented by Chrisann Kyi, MD of Memorial Sloan Kettering Cancer Center during a mini-oral presentation on Saturday, September 10th.

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This Phase 1/2 study (NCT03953235) is evaluating the safety, immunogenicity, and early clinical activity of both SLATE v1 and SLATE-KRAS in combination with PD-1 checkpoint inhibitor Opdivo (nivolumab) and subcutaneous anti-CTLA-4 antibody Yervoy (ipilimumab) in patients with metastatic solid tumors harboring select KRAS mutations. SLATE v1 targets 20 shared neoantigens from KRAS, TP53, β-catenin, and BRAF genes, while SLATE-KRAS is optimized to exclusively target KRAS neoantigens including the highly prevalent G12C, G12D, G12V and Q61H driver mutations. Gritstone developed the KRAS-optimized candidate (SLATE-KRAS) after initial testing of SLATE v1 suggested non-KRAS neoantigens (including TP53) might exhibit immunodominance over KRASmut, thus attenuating efficacy.

A total of 38 patients with advanced solid tumors have been enrolled in the study across cohorts using SLATE v1 (n=26) or SLATE-KRAS (n=12). The majority of patients enrolled (31/38) had either advanced non-small cell lung cancer (NSCLC; n=18) or microsatellite stable colorectal cancer (MSS-CRC; n=13).

In the Phase 1/2 study, both SLATE-KRAS and SLATE v1 vaccine-based immunotherapies demonstrated:

A favorable safety and tolerability profile
Majority of treatment-related adverse events were Grade 1/2, with three ≥ Grade 3 events reported with SLATE v1 and no ≥ Grade 3 events reported with SLATE-KRAS
Consistent and potent immunogenicity
Induction of KRAS-specific CD8+ T cells: 55% of patients treated with SLATE-KRAS versus 31% of patients treated with v1 (by ex vivo ELISpot assay)
Early objective evidence of efficacy as measured by reduction in ctDNA (molecular response)
39% (7/18) molecular response rate in evaluable patients with MSS-CRC and NSCLC. Evaluable subjects had detectable KRASmut ctDNA at baseline and a post-baseline sample. All patients with NSCLC had progressed on prior (chemo)immunotherapy.
In 18 patients with NSCLC, a molecular response was correlated with extended OS. NSCLC patients with a molecular response demonstrated a median OS (9.6 months) more than double those without (4.5 months). The OS analysis included patients with no detectable ctDNA or no data at baseline (n=7) in the "no molecular response group." At the time of data cut-off, there were insufficient evaluable patients in the CRC patient set to support a similar analysis.
Additionally, treatment with SLATE-KRAS induced a molecular response (normalization of tumor markers and reduction in ctDNA) and clinical benefit were observed in a patient with Stage IV KRAS G12V mutant MSS-CRC and multiple liver metastases who had progressed on two prior therapies.

"We are highly encouraged by the early signs of efficacy from the SLATE immunotherapy program, in particular, from our product candidate targeting multiple KRAS oncogenic mutations in patients with advanced, treatment-refractory disease (SLATE-KRAS)," said Andrew Allen, M.D., Ph.D., Co-founder, President, and Chief Executive Officer of Gritstone. "We observe molecular responses in approximately 40% of all evaluable subjects receiving SLATE, and those seen in our NSCLC patients are correlating nicely with extended overall survival, which has been described in recent publications with checkpoint inhibitors. This relationship between OS and ctDNA response was also observed in our GRANITE individualized immunotherapy study in patients with advanced CRC, as published recently in Nature Medicine. Patients with NSCLC without a molecular response had a median overall survival of just 4.5 months, underscoring the encouraging efficacy signal with SLATE in this challenging context with high unmet need for alternative treatment options. The clinical and mechanistic observations across our shared and individualized neoantigen vaccine programs is strikingly consistent, as is the favorable safety and tolerability profile, reinforcing the therapeutic potential of our oncology vaccine programs."

Karin Jooss, Ph.D., Head of R&D, added, "SLATE-KRAS was optimized to simultaneously target multiple KRAS mutations with the aim of driving robust immunity across a broad array of KRAS positive tumor types. Vaccines targeting neoantigens identified from common oncogenic driver mutations are of increasing interest. The results shared at ESMO (Free ESMO Whitepaper) highlight our ability to develop and deliver differentiated, targeted vaccine candidates that can generate robust and durable immune responses in patients with late-line cancer. These data also support moving SLATE-KRAS into earlier lines of therapy to allow the immune system more opportunity to mount a robust immune response to neoantigens after multiple vaccination boosts before progression. We look forward to providing additional data and longer follow-up from the SLATE program in 2023."

Opdivo and Yervoy are trademarks of Bristol-Myers Squibb Company.

About SLATE
Gritstone’s neoantigen-based immunotherapy candidates are engineered to elicit a significant T cell response (particularly CD8+ cytotoxic T cells) against mutation-derived tumor-specific neoantigens, or TSNA, that are identified by Gritstone using its proprietary EDGE artificial intelligence platform and tumor HLA peptide sequencing. Gritstone’s SLATE "off-the-shelf" immunotherapy program uses a priming adenoviral vector and a self-amplifying mRNA (samRNA) vector to deliver a cassette of shared TSNA, representing mutated gene sequences that are found in multiple patients (such as KRAS mutations). A KRAS-specific product candidate, SLATE-KRAS, is being evaluated in combination with immune checkpoint blockade in the Phase 2 portion of its clinical study (NCT03953235). The SLATE program represents the potential to develop a suite of "off-the-shelf" product candidates that target tumor-specific mutations across a number of patient populations and cancer types.

On September 12, 2022 Fore Biotherapeutics (Fore Bio), a precision oncology company dedicated to developing innovative treatments that provide a better outcome for cancer patients, reported the presentation of new data demonstrating that FORE8394, a next-generation BRAF inhibitor, provides evidence of durable anti-tumor activity and patient benefit in BRAF-mutated (V600+) cancers (Press release, Fore Biotherapeutics, SEP 12, 2022, View Source [SID1234619418]). Data from the ongoing Phase 1/2a study evaluating FORE8394 for the treatment of advanced solid and central nervous system (CNS) tumors with activating BRAF alterations were presented in a poster session at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (ESMO) (Free ESMO Whitepaper) taking place in Paris, France.

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"I am extremely proud of the progress this team has made in advancing our next-generation, and potential best-in-class BRAF-inhibitor to address the limitations of the current standards of care and improve outcomes for patients with cancer," said Matthew Ros, Chief Executive Officer of Fore Biotherapeutics. "These results are very encouraging and reinforce our conviction that FORE8394 has the potential to provide meaningful benefit to patients with BRAF-mutated cancers with high unmet need. We are embarking upon developing this novel treatment and are on track to initiate our global Phase 2 trial next quarter."

As of the data cutoff date of July 31, 2022, 108 adults and children have received ≥1 dose of FORE8394 and are included in the safety population; 51 adults (≥18 years) met the criteria for the V600+ efficacy analysis; overall response rate (ORR) was 25.5% and median duration of response: 17.8 months. An additional analysis was conducted in the MAPK-inhibitor naïve subset, excluding patients with colorectal cancer (CRC) (N=21). Patients received 900-3600 mg/day of oral FORE8394 alone or with cobicistat (CYP3A4 inhibitor) to increase exposure, with the majority having been treated with total daily doses of 900-1800 mg.

Key Findings from the Ongoing Phase 1/2a Study

In MAPK inhibitor-naïve adult V600+ patients (N=21, excluding CRC), confirmed responses and durable benefit was seen across multiple tumor types
Clinical activity observed in this population includes ORR= 42.9%, clinical benefit rate ≥ 24 weeks= 71.4%, median duration of response was 17.8 months and median progression free survival (PFS) was 28.6 months
In patients with primary CNS tumors, 4 of 4 patients with high grade glioma and 2 of 3 patients with low grade glioma experienced a partial response (PR) ; 1 had stable disease and remains on treatment after 15+ months
Of 6 patients with papillary thyroid cancer, median PFS was not reached (median follow-up 5.6 years)
Additional responses were observed in patients with V600+ ovarian cancer where 3 of 3 patients had PR; 2 having received prior MAPK-targeted treatments
FORE8394 demonstrated a favorable safety profile, with long-term tolerability, across the 108 patients
Adverse events were transient and manageable
Symptomatic adverse events (AEs) were low grade (Grade 1 or 2), mild and included fatigue, nausea, diarrhea & vomiting
Hepatic laboratory changes were manageable with dose interruption or modification
No secondary cutaneous skin malignancies or acanthomas occurred
Only 1 participant discontinued treatment due to treatment related adverse event
"In this heterogeneous and heavily pre-treated patient population, the overall response rate and meaningful durations of response demonstrates the potential of FORE8394 to uniquely target tumors with BRAF alterations," said Stacie Shepherd, MD, PhD, Chief Medical Officer of Fore Biotherapeutics. "We’re excited that the majority of gliomas demonstrated response and the prolonged benefit and tolerability experienced by some patients receiving FORE8394. Based on the strength of these findings, our Phase 2 study will further evaluate FORE8394 in patients with both solid and CNS tumors with BRAF fusions and recurrent primary CNS tumors with BRAF V600E mutations."

"There are several limitations with first-generation BRAF inhibitors, including treatment resistance leading to disease progression and the paradoxical activation of the MAPK pathway, leading to secondary cutaneous skin cancers. In addition, these agents are inactive against class II BRAF alteration," said Eric Sherman, MD, principal investigator and medical oncologist, Memorial Sloan Kettering Cancer Center. "These results suggest FORE8394 may provide meaningful benefit to patients, and we look forward to further exploring its potential in the upcoming Phase 2 study."

About FORE8394

FORE8394 is an investigational, novel, small-molecule, next-generation, orally available selective inhibitor of mutated BRAF. It was designed to target a wide range of BRAF mutations while sparing wild-type forms of RAF. Preclinical studies and clinical trials have shown that its unique mechanism of action effectively inhibits not only the constitutively active BRAFV600 monomers targeted by first-generation RAF inhibitors but also disrupts constitutively active dimeric BRAF class II mutants, fusions, splice variants and others. Unlike first-generation RAF inhibitors, FORE8394 does not induce paradoxical activation of the RAF/MEK/ERK pathway. As a "paradox breaker," FORE8394 could therefore treat acquired resistance to current RAF inhibitors and, more generally, yield improved safety and more durable efficacy than first-generation RAF inhibitors.

On September 12, 2022 EpiAxis Therapeutics and University Health Network (UHN) – Canada’s largest and leading research hospital – reported that they have entered into a collaboration to study a new approach to prostate cancer treatment (Press release, EpiAxis Therapeutics, SEP 12, 2022, View Source;utm_medium=rss&utm_campaign=epiaxis-enters-strategic-partnership-with-uhn [SID1234619417]).

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As part of the agreement, EpiAxis Therapeutics will supply its lead peptides candidates for assessment in UHN’s prostate cancer models, with the aim of dramatically enhancing the ability to improve treatment and survival of men with lethal prostate cancer (CaP).

EpiAxis Therapeutics CEO Dr Jeremy Chrisp said that while next generation genomic technologies have deepened the understanding of prostate cancer development and evolution, they have arguably reached a therapeutic plateau.

"Most FDA-approved indications are for established targets in earlier disease states, rather than novel targets," Dr Chrisp said. "Our first-in-class assets have dual action and target dormant chemotherapy resistant cells while also improving the immune response against the persisting cells. EpiAxis is very pleased to be supplying our lead peptides candidates to UHN in hope of accelerating innovation in the treatment of CaP."

Dr Hansen He, Senior Scientist at UHN’s Princess Margaret Cancer Centre, will be leading the project utilising EpiAxis’ lead peptide candidates.

Dr He’s research program focuses on understanding epigenetic mechanisms underlying cancer development, progression and therapy response, with the aim of identifying epigenetic biomarkers and therapeutic targets to improve treatment outcomes for cancer patients.

"We are excited to collaborate with EpiAxis to target epigenetic regulator LSD1 in advanced prostate cancer. This leverages our deep understanding of the epigenetic mechanisms and the potent effect of LSD1 peptide inhibitors developed by EpiAxis," Dr He said.