On October 28, 2022 Marengo Therapeutics, Inc., a company pioneering novel therapeutics targeting the T cell receptor Vβ chain (TCR Vβ) to selectively activate the right T cell subsets to fight cancer, reoorted the first preclinical proof-of-concept data on STAR0602, its novel TCR agonist antibody, during the 34th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on molecular targets and cancer therapeutics (ENA) in Barcelona, Spain (Press release, Marengo Therapeutics, OCT 28, 2022, View Source [SID1234622588]). The data presented showed potent anti-tumor activity of STAR0602 in a range of solid tumor models, including those refractory to check point inhibitors like PD-1/PD-L1.

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The plenary oral presentation was given by James Gulley, M.D., Ph.D., Co-Director of the Center of Immuno-Oncology (CIO), Deputy Director of the Center for Cancer Research (CCR) at the National Cancer Institute (NCI), and acting Clinical Director, NCI.

"STAR0602 offers an entirely new mechanism of selective T cell activation that increases both the quantity and quality of T cell responses to the tumor via a mechanism that is distinct to checkpoint inhibitors," said Zhen Su, M.D., MBA, Chief Executive Officer of Marengo. "These results strongly suggest our lead asset has the potential to become a next-generation IO backbone treatment against a range of solid tumors representing a novel therapeutic strategy for patients."

"We are pleased to share the first data for our STAR0602 program," added Andrew Bayliffe, Ph.D., Chief Scientific Officer of Marengo. "These studies show that our selective Vβ T cell activators access novel T cell immunology that has the potential to fundamentally remodel the adaptive immune response to solid tumors and install long-term tumor immunity."

Across a range of refractory murine syngeneic solid tumor models, mSTAR0602 (the murine surrogate of STAR0602) monotherapy at moderate dose levels either eradicated tumors or led to substantial regressions – effects that were durable over the long term. mSTAR0602-cured mice also showed long-term protection from tumor re-challenge. This anti-tumor activity was shown to be dependent on the accumulation of a specific subset of Vβ T cells in tumors that adopt a novel effector memory phenotype and a striking increase in TCR diversity. The expansion of these effector memory Vβ T cells was accompanied by a reduction in exhausted T cells and regulatory T cells. Similar potent expansion of human TILs and tumor killing was observed in primary syngeneic human ex vivo tumor models derived from several patient samples. The anti-tumor activity of STAR0602 in these ex vivo human tumor models was superior to pembrolizumab when tested in parallel at therapeutic concentrations.

Additional presentation details are outlined below:

Title: STAR0602, a novel TCR agonist antibody, demonstrates potent anti-tumor activity in refractory solid tumor models through the expansion of a novel, polyclonal effector memory T cell subset
Abstract Number: ENA22-0183
Session Day/Time: Friday, October 28; 12:40 pm, CET
Location: Barcelona International Convention Center, Barcelona, Spain
Presenter: James Gulley, M.D., Ph.D.
Research Highlights:
Non-human primate and patient organoid studies were conducted to confirm translation of STAR0602 target immunology to support planned human clinical trials.
The START-001 clinical study will assess the safety, tolerability, and preliminary clinical activity of STAR0602 as a single agent in patients with advanced antigen-rich solid tumors including PD-1 refractory patients. This open label, multicenter Phase 1/2 study consists of two parts: Phase 1 dose escalation and Phase 2 dose expansion. For more information, please visit clinicaltrials.gov (trial identifier: NCT05592626)

On October 28, 2022 Hinova Pharmaceuticals Inc. (STAR: 688302), a clinical-stage biopharmaceutical company focused on developing novel therapeutics for cancers and metabolic diseases through targeted protein degradation technologies, reported their preclinical results of HP518, an orally bioavailable chimeric degrader targeting androgen receptor (AR) for prostate cancer treatment, at the 5th Annual TPD Summit (Press release, Hinova Pharmaceuticals, OCT 28, 2022, View Source [SID1234622587]).

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Discovered and developed by Hinova, HP518 showed high degradation activity against fl-AR and most enzalutamide resistant AR point mutants, and demonstrated excellent antiproliferation activities against prostate cancer cell lines. Meanwhile, HP518 exhibited good metabolic stability and is stable in human plasma. HP518 showed excellent antitumor efficacy in xenograft model by oral dosing. HP518 was also well tolerated in preclinical tox studies.

HP518 is currently in Phase-I clinical trials in Australia. The ongoing open-label clinical study will evaluate the safety, pharmacokinetics, and anti-tumor activity of HP518 in patients with metastatic castration-resistant prostate cancer (mCRPC).

"Existing data makes us more confident that HP518 has the potential to be an innovative clinical option to patients with mCRPC," said Xinghai Li, MD/Ph.D., Chief Science Officer of Hinova, "Considering prostate cancer is a progressive disease, we have established a strong pipeline targeting the androgen receptor pathway for prostate cancer treatment. Based on our targeted protein degradation drug discovery platform, we are committed to develop best-in-class and first-in-class medicines to address unmet medical needs."

Hinova has established a targeted protein degradation drug discovery platform, which allows Hinova to integrate TPD biology and medicinal chemistry and to identify and optimize chimeric degraders with high efficiency. Furthermore, Hinova has accumulated much experience in development of Chimeric degrader.

On October 28, 2022 Flare Therapeutics, a biotechnology company targeting transcription factors to discover precision medicines for cancer and other diseases, reported that translational insights from a retrospective advanced urothelial cancer (UC) cohort in a poster titled, "Peroxisome Proliferator-Activated Receptor Gamma (PPARG) status defines the luminal lineage in molecular profiles of advanced urothelial cancers (UC)" at the 34th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium, being held in Barcelona, Spain (Press release, Flare Therapeutics, OCT 28, 2022, View Source [SID1234622586]). Molecular RWD, comprising of more than 3,000 genomic and transcriptomic profiles from advanced UC tissue, were utilized to evaluate the transcription factor PPARG, and its role as a master regulator of the luminal lineage associated with its expression and mutational status.

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"To the best of our knowledge, this represents the largest RWD from patients with advanced and metastatic urothelial cancer, providing unique insights into the persistence of PPARG signaling through disease progression, independent of the treatment paradigm," said Michaela Bowden, Ph.D., Senior Vice President of Biology and Translation at Flare Therapeutics. "Stratification of patients based upon their PPARG status serves as the foundation for our precision approach in identifying individuals most likely to respond to PPARG inhibition."

Flare presented its novel PPARG program demonstrating robust preclinical activity in a poster presentation titled, "Novel inhibitors of the luminal lineage transcription factor peroxisome proliferator-activated receptor gamma (PPARG) durably eradicate tumors in urothelial cancer animal models" on Wednesday, October 26th at same symposium.

Data highlights:

65% of advanced urothelial cancers evaluated were classified as luminal, of which one in three were enriched for genetic alterations in PPARG, RXRA or FGFR3
PPARG amplification, including a gain of only one copy number, is associated with higher PPARG expression
PPARG expression levels were sustained in metastatic lesions compared locally advanced tissues and did not significantly vary by metastatic tissue site
Flare is advancing a novel PPARG inhibitor through Investigational New Drug (IND)-enabling studies and expects to initiate its Phase 1 clinical trial in 2023 in individuals with locally advanced or metastatic UC.

About Advanced Urothelial Cancer
Muscle-invasive UC is a common type of bladder cancer, with about 20,000 individuals diagnosed each year in the United States alone, and significantly higher incidence rates in other regions of the world. This disease has high rates of recurrence and the five-year survival rate is approximately 5% in metastatic cases. The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is associated with the luminal lineage subtype reflecting approximately 65% of all advanced UC patients. Recurrent genetic alterations in PPARG, including focal amplification, missense mutations, and fusions, as well as hotspot mutations in its binding partner, retinoid X receptor alpha (RXRA) are characteristic of this molecular subtype.

On October 28, 2022 Exscientia plc (Nasdaq: EXAI) reported that the company has won the Prix Galien USA 2022 Award for Best Digital Health Solution in recognition of its AI-driven precision medicine platform (Press release, Exscientia, OCT 28, 2022, View Source [SID1234622585]). The award was presented Thursday at the Prix Galien Forum in New York City. Worldwide, the Prix Galien, which recognizes excellence in scientific innovation that improves the state of human health, is regarded as the most coveted prize in biopharmaceutical research.

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Exscientia is focused on designing fundamentally better drugs – faster. The company’s artificial intelligence (AI)-driven functional precision medicine platform enables a "patient-first" approach by integrating primary human tissue samples into early target and drug discovery research. Earlier this year, the next-generation platform, which aims to reinvent the way drugs are discovered and developed, was clinically proven to guide treatment selection and improve cancer treatment outcomes, in the landmark EXALT-1 study.

EXALT-1 demonstrated the ability of one of Exscientia’s AI-discovered medicines to improve cancer treatment outcomes, marking the first time a functional precision oncology platform improved patient outcomes in an interventional clinical study. Today, the live tissue technology used in that study is a core component underpinning Exscientia’s end-to-end platform, which has discovered the first three AI-designed molecules to enter clinical trials, dramatically cutting the time and cost required to generate novel molecules with the potential to become approved medicines.

"Sincere thanks to the Galien Foundation and Business France for this incredible honour. Exscientia is humbled to receive this recognition and grateful to our incredible team whose vision made it possible," said Exscientia founder and CEO Andrew Hopkins, DPhil. "This award is a recognition of the enormous potential that AI holds to transform how our industry discovers and develops the right drug for the right patient. This award recognized the potential of our AI driven precision medicine platform to truly bring the vision of personalised medicine to the benefit of the patient. The day is coming when all medicines will be discovered and developed by harnessing the power of AI. At Exscientia, we are proud to be pioneering the way forward."

On October 28, 2022 AC Immune SA (NASDAQ: ACIU), a clinical-stage biopharmaceutical company pioneering precision medicine for neurodegenerative diseases, reported that results for the third quarter ended September 30, 2022, and provided a corporate update (Press release, AC Immune, OCT 28, 2022, View Source [SID1234622584]).

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Prof. Andrea Pfeifer, CEO of AC Immune SA, commented: "With the recent positive data for an anti-Abeta antibody, lecanemab, further supporting the amyloid hypothesis in Alzheimer’s disease (AD), we are advancing towards year-end with strong momentum and renewed enthusiasm for the amazing potential of our development programs. The recent data also highlight the importance of intervening early in AD, further underlining the fundamental need for precision medicine in neurodegenerative diseases. This bodes well for our wholly owned vaccine ACI-24.060, which targets the two most toxic forms of Abeta, soluble toxic Abeta oligomers and pyroglu-Abeta. Because ACI-24.060 is a vaccine, it also has the potential to offer safety, efficacy, and logistical advantages compared to monoclonal antibodies. A key Phase 1b readout from ACI-24.060’s translational, biomarker-based trial is planned later this year, and is expected to inform our advancement into Phase 2 cohorts in AD and Down syndrome-related AD."

"Our cutting-edge diagnostic programs also received key external validation last quarter, with our partner Life Molecular Imaging announcing initiation of late-stage clinical development of our Tau PET tracer – triggering a milestone payment. The Michael J. Fox Foundation (MJFF) also recognized our alpha-synuclein (a-syn) tracer with a follow-on grant to develop a-syn PET tracers that could accelerate clinical development. These accomplishments affirm our leadership and commitment to leveraging precision medicine to enable earlier diagnosis, treatment, and ultimately prevention of neurodegenerative disease."

Q3 2022 and Subsequent Highlights

Detailed results from the Phase 2 Alzheimer’s Prevention Initiative (API) study evaluating the anti-Abeta monoclonal antibody crenezumab in autosomal dominant Alzheimer’s disease (ADAD) were presented at the 2022 Alzheimer’s Association International Conference (AAIC) by AC Immune’s partner Genentech, a member of the Roche group, and the Banner Alzheimer’s Institute. Numerical differences favoring crenezumab were observed across both co-primary endpoints, as well as multiple secondary and exploratory endpoints, though none were statistically significant. Demographic and baseline biomarker data indicate a confluence of factors may have led the study to have lower than expected statistical power. All mutation carriers in the study may continue to receive crenezumab while the data are further analyzed.
Provided an update on the Phase 1b/2 ABATE study of the anti-Abeta vaccine ACI-24.060 in patients with prodromal AD and individuals with Down syndrome (DS). Clinical sites in the UK and Spain are now open and recruiting following regulatory clearances in both countries. Interim results are expected around year end 2022 with plans to submit a U.S. Investigational New Drug (IND) application in Q1 2023.
Received clearance for a clinical trial application to initiate an adaptive, biomarker-based Phase 2 study of the anti-a-syn vaccine ACI-7104 in patients with early Parkinson’s disease (PD). Initiation of the trial is expected in Q4 2022.
The Tau PET tracer, PI-2620, is being advanced into late-stage development in AD by our partner, Life Molecular Imaging, following supportive results from an investigator-sponsored Phase 2 AD trial that showed its suitability as a targeted radiopharmaceutical for the detection of Tau deposits and for measuring longitudinal changes in subjects with mild cognitive impairment (MCI) as well as in patients with AD.
Received a MJFF follow-on grant to support the continued development of ACI-12589, AC Immune’s wholly-owned a-syn PET tracer. The new grant brings the total MJFF funding for this program up to USD 3.7 million.
Showcased pipeline of potentially first- and best-in-class therapeutic and diagnostic candidates with 10 presentations at the AAIC.
First-time presentation at AAIC of a biomarker-based, translational clinical trial of AC Immune’s wholly owned anti-Abeta vaccine, ACI-24.060, in patients with AD and individuals with DS.
Hosted a key opinion leader webinar on the potential benefits of vaccines for Alzheimer’s and Parkinson’s diseases. The webinar featured a presentation by Cynthia A. Lemere, Ph.D., of the Ann Romney Center for Neurologic Diseases at Brigham & Women’s Hospital and Harvard Medical School. To view a replay of the webinar, click here.
Achieved and Anticipated 2022 Clinical Milestones

ACI-24.060
anti-Abeta vaccine Dosed first patient in Phase 1b/2 ABATE study of ACI-24.060 in patients with AD and individuals with DS.
Phase 1b safety and immunogenicity data readout in AD and decision to move into DS expected in Q4 2022. Submission of U.S. Investigational New Drug (IND) application planned in Q1 2023.
ACI-35.030
anti-pTau vaccine Reported Phase 1b/2a interim analysis from highest dose group.
Expect the decision to move into late-stage development in Q4 2022.
ACI-7104
anti-a-syn vaccine Initiation of Phase 2 trial in early PD expected in Q4 2022.
Crenezumab
anti-Abeta antibody Reported detailed results from Phase 2 API-ADAD study in autosomal dominant AD.
Additional fluid biomarker data to be presented at CTAD 2022 Conference
Semorinemab
anti-Tau antibody Additional biomarker data from the Phase 2 Lauriet study in mild-to-moderate AD expected at CTAD 2022 Conference.
ACI-12589
a-syn-PET tracer Reported breakthrough results from first-in-human study at AD/PD 2022 conference.
PI-2620
Tau-PET tracer Reported Phase 2 results in AD enabling entry into late-stage development connected to a milestone payment.
Clinical PET study data in orphan indication in Q4 2022.

Analysis of Financial Statements for the Quarter Ended September 30, 2022

Cash Position: The Company had a total cash balance of CHF 140.5 million, composed of CHF 44.5 million in cash and cash equivalents and CHF 96.0 million in short-term financial assets. This compares to a total cash balance of CHF 198.2 million as of December 31, 2021. The Company’s cash balance provides cash for operations into Q3 2024 without consideration of potential incoming milestone payments.

R&D Expenditures: R&D expenses decreased by CHF 0.7 million for the three months ended September 30, 2022, to CHF 14.4 million.

Discovery and preclinical expenses (- CHF 0.8 million): The Company decreased expenditures across a variety of its discovery and preclinical programs.

Clinical expenses (- CHF 0.6 million): The Company’s increased expenditures for the accelerated clinical development programs of ACI-7104 and ACI-24.060 were offset by lower costs in various other clinical programs as they achieved anticipated goals.

Other non-allocated (+ CHF 0.5 million): The Company’s other non-allocated R&D expenditure increased by CHF 0.5 million mostly related to the reallocation of certain IT and facilities costs and IT investments.

G&A Expenditures: For the three months ended September 30, 2022, G&A decreased by CHF 2.1 million to CHF 3.3 million. This decrease is mostly related to the reallocation of certain IT and facilities expenditures made in Q3 2022 that were not reclassified in the prior period and the reversal of certain share-based compensation expenses.

Other Operating Income: The Company recognized CHF 0.3 million in grant income for R&D activities performed under our Michael J. Fox Foundation for Parkinson’s Research (MJFF) and Target ALS grants, an increase of less than CHF 0.1 million compared to the prior period.

IFRS Loss for the Period: The Company reported a net loss after taxes of CHF 13.5 million for the three months ended September 30, 2022, compared with a net loss of CHF 15.9 million for the comparable period in 2021.