On October 12, 2021 The Case-Coulter Translational Research Partnership (CCTRP) at Case Western Reserve University, with support from JobsOhio as part of the Cleveland Innovation District initiative, reported more than $1.9 million in funding and support for 10 promising university-based biomedical technologies (Press release, Case Western Reserve University, OCT 12, 2021, View Source [SID1234591155]).

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"The infusion of resources from the JobsOhio program is part of a multiyear commitment from the State of Ohio and Case Western Reserve University to grow the local innovation economy," said Mitch Drumm, the university’s interim vice president for research and technology management.

Ten projects were selected for large program awards, which range from $50,000 to $200,000 each. Several additional pilot projects have or will be awarded pilot funding by year’s end. All projects involve partnerships between a clinician and a biomedical engineer, and focus on solving unmet health care needs.

The 15-year-old CCTRP program invests more than $1.1 million annually in direct funding and support services to help teams from Case Western Reserve and its partner institutions advance products from the laboratory to the marketplace, where they can improve patient care.

Funding focuses on preparing projects for commercialization and includes support for such efforts as demonstrating technical feasibility. So far, 69 full projects have been supported to date, leading to 38 licenses, 30 startup companies and the delivery of 38 technologies to patients. For each dollar invested by the program, the university technologies received an additional $25 investment, mostly as at-risk capital.

"The Case-Coulter Translational Research Partnership continues to be a cornerstone of our department, filling an essential gap to transition university biomedical technologies from research to products, where they can significantly improve the health of our society," said Robert Kirsch, the Allen H. and Constance T. Ford Professor and chair of the university’s Department of Biomedical Engineering.

The Case-Coulter oversight committee reviewed 25 proposals for 2021 funding and support. To be chosen, projects must have the potential to advance to a commercial entity within 12 to 30 months.

"As a group, the quality of the evaluated technologies continues to improve each year, demonstrating the robustness of the biomedical research-based technology pipeline," said Steve Fening, CCTRP managing director. "Even with the infusion of additional capital from JobsOhio, we still had many more proposals that deserved to be included in the program than we could accommodate, making the selection process as challenging as ever."

The 10 projects selected and their inventors are:

BAFF CAR-NK cells—an immunotherapy with less side effects
Reshmi Parameswaran, assistant professor of medicine, and Umut Gurkan, the Warrant E Rupp Associate Professor of mechanical engineering

B cell Activating Factor Chimeric Antigen Receptor-Natural Killer (BAFF CAR-NK) cells can specifically kill B cell cancers in a very effective manner with minimum side effects. This is a potential therapy to address patients not responding to current cancer treatments.

Safety and pharm-tox evaluation of Neutrostat: neutrophil-targeted nanomedicine for VTI
Evi Stavrou, assistant professor of medicine and staff physician at the Louis Stokes Cleveland VA Medical Center, and Anirban Sen Gupta, professor of biomedical engineering

The NeutroStat technology consists of a nanoparticle loaded with specific neutrophil signal inhibitory drugs. The nanoparticle can specifically target activated neutrophil-platelet complexes that are the hallmark of developing clot niche in venous thrombosis and weakens the clot growth by decreasing neutrophil-driven thrombotic mechanisms.

Pharmacokinetic-pharmacodynamic-efficacy and safety studies of humanized monoclonal antibodies to treat inflammatory and immune diseases
Yunmei Wang, associate professor of medicine, Xin Yu, the F. Alex Nason Professor of biomedical engineering, and Daniel Simon, professor of medicine and chief clinical and scientific officer and president of University Hospitals Cleveland Medical Center

They developed novel monoclonal antibodies (mAbs) against a key extracellular signaling protein, the myeloid-related protein-14 (MRP-14, aka S100A9), that acts as a potent driver of inflammation and thrombosis. MRP-14 has been implicated in the pathogenesis of several human diseases including SLE, thrombosis, atherosclerosis and acute lung injury.

Microfluidic impedance red cell diagnostic assay (MIRCA-Dx): a revolutionary new way to assess targeted and genetic therapies for inherited red cell disorders
Gurkan, Pedram Mohseni, the Goodrich Professor of Engineering Innovation and chair of electrical engineering and biomedical engineering, and Sanjay Ahuja, professor of pediatric hematology/oncology and staff physician at University Hospitals

New genetic therapies can correct unhealthy red blood cells, but can’t assess the health and functional properties of the newly made red cells in a patient. The researchers offer a novel reproducible, portable diagnostic test for physicians and pharmaceutical companies to measure how well the new genetic therapies work for a red blood-cell disorder, such as sickle cell disease.

Gastrointestinal liner for diversion of intestinal contents
Steve Schomisch, assistant professor of surgery, and Jeff Marks, professor of surgery

People sometimes develop a wound connecting their intestine to their skin. This complication is incredibly debilitating and costly. The intestinal contents leak out onto the skin causing injury to the skin and muscle, dehydration and malnutrition, and there is currently no way to stop it. The researchers are developing a novel management strategy to greatly reduce the leak, which reduces cost of care and helps patients recover faster.

3D-UBS for fast volumetric evaluation of ocular injuries and disease
David Wilson, professor of biomedical engineering, Faruk Orge, professor of ophthalmology and pediatrics and staff physician at University Hospitals, and Mahdi Bayat, assistant professor of electrical engineering

This technology will be the first high-resolution, 3D microscopic ultrasound system to provide novel visualizations of eye structures to better understand pathophysiology, plan treatments and assess treatment results. Ultrasound is an effective ophthalmic imaging method that allows structures behind the iris, including the lens and ciliary body, as well as key portions of the aqueous outflow system, to be seen. This region of the eye plays a critical role in glaucoma—which affects over 2.7 million people in the United States alone—and cataract, which are leading causes of reversible and irreversible blindness.

HXB-319 as an engineered mesenchymal stem cell (MSC) based treatment for the rare/orphan autoimmune disorder Goodpasture Syndrome
Hulya Bukulmez, associate professor of pediatrics and staff physician at MetroHealth, and John Chae, professor of biomedical engineering and vice president of research and sponsored programs at MetroHealth

They have developed a novel cell therapy (HXB-319) based on naked MSCs, engineered to enhance immune responses to reduce inflammation and its resulting organ damage. The work proposed will help to advance HXB-319 cell therapy toward clinical use by targeting systemic autoimmune inflammatory diseases that cause end-stage organ damage such as pulmonary hemorrhage and end-stage kidney disease.

Nanobubble contrast agents as an enabling technology to manage prostate cancer
Agata Exner, professor of radiology and biomedical engineering, Jim Basilion, professor of radiology and biomedical engineering, and Lee Ponsky, professor of urology and staff physician at University Hospitals

This project is a new ultrasound contrast agent (nanobubble) that can improve the detection and treatment of prostate cancer by targeting the prostate specific membrane antigen (PSMA)—a biomarker overexpressed on prostate cancer cells—to allow highly specific detection and focused therapy, which affects only cancer cells and leaves normal cells unaffected. The nanobubble is a versatile technology with several potential uses within prostate cancer management including improved delineation of tumors, guidance of focal therapies and targeted therapy.

Toxicokinetic (TK) analysis of BG34-200 immunotherapy
Mei Zhang, assistant professor of biomedical engineering, and Alex Huang, professor of pathology and staff physician at University Hospitals

A significant portion of patients with solid tumor cancers don’t respond to immunotherapies due to a lack of T-cell-inflamed tumor microenvironment. This novel plant-derived non-toxic BG34-200 molecule can be intravenously injected to modulate macrophages and create a tumor microenvironment that is vital for the generation of antitumor T-cell responses. The team is launching a clinical trial targeting canine metastatic osteosarcoma to collect key and gap data in preparation for a first human clinical trial targeting pediatric osteosarcoma.

Enabling closed-loop baroreflex activation in the treatment of refractory hypertension
Jonathan Baskin, associate professor of otology head and neck and staff physician at the Louis Stokes Cleveland VA Medical Center, Dustin Tyler, the Kent H. Smith Professor II of Biomedical Engineering, Gilles Pinault, assistant professor of surgery and staff physician at University Hospitals, and Steve Majerus, research scientist at the Louis Stokes Cleveland VA Medical Center

High blood pressure or hypertension is a serious health care problem associated with considerable morbidity and mortality. Physicians rely heavily on drugs to treat hypertension, but there is a significant and growing population that is drug-resistant. Their approach employs an implanted neuromodulatory system to address this unmet need. They have demonstrated efficacy of their novel stimulation system in an acute human model, however, a vital element in this treatment modality is sensing blood pressure.

On October 12, 2021 Bicycle Therapeutics plc (the "Company") reported that it entered into an underwriting agreement (the "Underwriting Agreement") with Goldman Sachs & Co. LLC, Morgan Stanley & Co. LLC and SVB Leerink LLC (the "Representatives"), as representatives of the several underwriters named therein (collectively, the "Underwriters"), pursuant to which the Company agreed to issue and sell 3,240,741 American Depositary Shares ("ADSs"), each representing one of the Company’s ordinary shares, nominal value £0.01 per share, at a public offering price of $54.00 per ADS (the "Offering") (Filing, 8-K, Bicycle Therapeutics, OCT 12, 2021, View Source [SID1234591239]). The net proceeds to the Company from the Offering are expected to be approximately $163.8 million, after deducting underwriting discounts and commissions and estimated offering expenses payable by the Company. The Company also granted the Underwriters an option to purchase 486,111 additional ADSs at the public offering price.

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The Offering is being made pursuant to the Company’s registration statement on Form S-3 (File No. 333-260179), which became effective upon filing with the Securities and Exchange Commission on October 12, 2021, a base prospectus dated October 12, 2021 and the related prospectus supplement dated October 12, 2021. The Offering is expected to close on October 15, 2021, subject to customary closing conditions.

The Underwriting Agreement contains customary representations, warranties and agreements by the Company, customary conditions to closing, indemnification obligations of the Company and the Underwriters, including for liabilities under the Securities Act of 1933, as amended, other obligations of the parties and termination provisions. The representations, warranties and covenants contained in the Underwriting Agreement were made only for purposes of such agreement and as of specific dates, were solely for the benefit of the parties to such agreement and may be subject to limitations agreed upon by the contracting parties, including being qualified by confidential disclosures exchanged between the parties in connection with the execution of the Underwriting Agreement. The Company’s directors and executive officers have agreed, subject to certain exceptions, not to sell or transfer any ordinary shares (including ADSs representing ordinary shares) for 60 days, and the Company has agreed not to sell or transfer any ordinary shares (including ADSs representing ordinary shares) for 60 days, in each case, after October 12, 2021, without first obtaining the written consent of the Representatives.

On October 12, 2021 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported updated results from the Company’s ongoing Phase 1 CARBON trial evaluating the safety and efficacy of CTX110, its wholly-owned allogeneic CAR-T cell therapy targeting CD19+ B-cell malignancies (Press release, CRISPR Therapeutics, OCT 12, 2021, View Source [SID1234591103]).

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"We are excited to share positive data from our CARBON trial, which show that CTX110 could offer patients with large B-cell lymphomas an immediately available ‘off-the-shelf’ therapy with efficacy similar to autologous CAR-T and a differentiated safety profile," said Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. "Furthermore, we have the potential to improve upon already observed efficacy with a consolidation dosing strategy. Based on these encouraging results, we are planning to expand CARBON into a potentially registrational trial in the first quarter of 2022."

CARBON Trial Overview

The Phase 1 CARBON trial is an open-label, multicenter clinical trial evaluating the safety and efficacy of CTX110 in adult patients with relapsed or refractory B-cell CD19+ malignancies who have received at least two prior lines of therapy. To date, enrollment has been focused on patients with the most aggressive disease presentations, including diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), high-grade double- or triple-hit lymphomas, and transformed follicular lymphoma. The majority of patients had Stage IV lymphoma and were refractory to their last line of therapy before entering the trial. Nine patients received prior autologous stem cell transplant. Patients who received prior autologous CAR-T therapy were not eligible.

As of the August 26, 2021 data cutoff, 30 patients with large B-cell lymphoma (LBCL) had been enrolled, of which 26 patients had received CTX110 with at least 28 days of follow-up and are included in the analysis. Only one enrolled patient did not receive CTX110. Three patients at the time of the data cut had less than 28 days of follow-up and were not evaluable for this analysis.

Patients were infused with a single CTX110 infusion following three days of a standard lymphodepletion regimen consisting of fludarabine (30mg/m2/day) and cyclophosphamide (500mg/m2/day). Patients could

be re-dosed with CTX110 following disease progression. The primary endpoints include safety as measured by the incidence of dose limiting toxicities (DLTs) and overall response rate (ORR). Key secondary endpoints include complete response (CR) rate, duration of response and overall survival.

Additional details may be found at clinicaltrials.gov, using identifier: NCT04035434.

Safety

CTX110 was well tolerated across all dose levels. The adverse events of interest for all evaluable patients are shown in the table below.

There were no cases of Graft versus Host Disease (GvHD) and no infusion reactions to either lymphodepleting chemotherapy or CTX110.

All cases of cytokine release syndrome (CRS) were Grade 1 or 2 per the American Society for Transplantation and Cellular Therapy (ASTCT) criteria and either required no specific intervention or resolved following standard CRS management. Neither the frequency nor severity of CRS has increased in patients who were re-dosed with CTX110.

The only case of Grade 3 or higher immune effector cell-associated neurotoxicity syndrome (ICANS) was in the patient with concurrent HHV-6 encephalitis who was previously disclosed. There have been no cases of ICANS in any other patients treated at Dose Level (DL3) through Dose Level (DL4).

Only two patients experienced Grade 3 or higher infections: the previously discussed patient with HHV-6 encephalitis, and one patient who developed pseudomonal sepsis that resolved in four days.

The emerging safety profile of CTX110 is positively differentiated from autologous CAR-T therapies that show high frequencies of severe CRS and ICANS, and from other allogeneic CAR-T therapies that require more toxic lymphodepletion regimens and can result in prolonged immunosuppression and increased risk of serious infections.

Clinical Activity

Data are shown below for the 26 patients that received CTX110 and had at least 28 days of follow-up. The ORR and CR rates for patients treated at DL2 and above are shown both on an intent-to-treat (ITT) and modified ITT (mITT) basis. ITT includes all enrolled patients (n=24 at DL2 and above) whereas mITT includes only those patients who received an infusion of CTX110 (n=23 at DL2 and above). Dose-dependent responses and durable complete responses were seen with CTX110. Disease assessment was performed by investigator review according to the 2014 Lugano response criteria.

A single dose of CTX110 at DL2 and above resulted in a 58% ORR and 38% CR rate on an ITT basis.
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Responses were seen in a variety of patients, including patients who had refractory disease, bulky disease, or who had progressed after prior autologous stem cell transplant.

The data demonstrate the potential for CTX110 to produce durable remissions, as evidenced by a 21% six-month CR rate (4 of the 9 patients who achieved CR at Day 28, remained in CR at 6 months; 5 patients had not reached their 6-month evaluation point), which is in the range of durable remissions observed with approved autologous CAR-T therapies on an ITT basis.

The data provide a strong rationale that consolidation dosing can improve on an already competitive profile for CTX110.

Based on this safety and efficacy profile, the Company plans to expand into a potential registrational trial that incorporates consolidation dosing in Q1 2022. In parallel, the Company continues to advance the rest of its immuno-oncology portfolio and scale its manufacturing capabilities in its new state-of-the-art manufacturing facility in Framingham, Massachusetts.

Conference Call and Webcast

To access the conference call, please dial +1 (866) 952-8559 (domestic) or +1 (785) 424-1743 (international) and reference the conference ID "CRISPR."

A live webcast of the event will be available on the "Events & Presentations" page in the Investors section of the Company’s website at View Source A webcast replay will be available on the CRISPR Therapeutics website after the event and will be archived for 14 days.

About CTX110

CTX110, a wholly owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR-T investigational therapy targeting Cluster of Differentiation 19, or CD19. CTX110 is being investigated in the ongoing CARBON trial.

About CARBON

The ongoing Phase 1 single-arm, multi-center, open label clinical trial, CARBON, is designed to assess the safety and efficacy of several dose levels of CTX110 for the treatment of relapsed or refractory B-cell malignancies.

On October 12, 2021 Deepcell, a life science company pioneering AI-powered cell classification and isolation for basic and translational research, reported a collaboration with the Levesque Lab at the University of Zurich (Press release, Deepcell, OCT 12, 2021, View Source [SID1234591119]). The goals of the collaboration are to use Deepcell’s technology to identify and sort rare melanoma cells, profile melanoma tissues to gain a deeper understanding about tumor microenvironment, and enable molecular analyses of the sorted cells.

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This collaboration brings together one of the leading scientific research institutions in Europe and one of the most innovative life science companies. Deepcell’s AI-powered platform analyzes, classifies and isolates viable cells in a label-free manner based on morphology alone. Through its deep learning-based algorithms and unique cell sorting approach, Deepcell supports a quantitative and mechanistic understanding of cell biology.

"Melanoma cells are difficult to isolate with conventional sorting methods because they lack reliable cell surface markers. By isolating and sorting cells using morphology, we may deepen our understanding of the biology of melanoma progression and, in particular, of cell phenotypes and molecular features of cancerous cells," said Dr Levesque, Associate Professor at the University of Zurich.

The Deepcell platform combines high-resolution imaging of cells in flow with real-time cell classification and sorting, using cell morphology as the only analyte. This label-free, target-agnostic approach overcomes some of the limitations of cell surface marker-based classification and enrichment, including the limited number of available markers and channels for detection, prior knowledge or guesswork required to select surface proteins, and availability of protein-specific antibodies. Importantly, the technology not only analyzes the cellular phenotype, but also enables the isolation of viable, unperturbed cells, allowing for the linkage of cell morphology with molecular data and functional assays.

"We continue to expand our collaborations with world-class researchers, such as teaming up with Dr Levesque and his team at the University of Zurich," said Maddison Masaeli, Co-founder and CEO of Deepcell. "Our unique AI-powered technology transforms cell morphology into a precise, reproducible and unbiased analyte that enables highly accurate cell classification while maintaining cell viability. With the researchers at the University of Zurich, we will be able to generate rich data to help elucidate the complex tumor microenvironment."

On October 12, 2021 Prokarium, a biopharmaceutical company pioneering the oncology field of microbial immunotherapy, and Wacker Biotech reported that they had signed a contract for the manufacturing of Prokarium’s microbial novel immunotherapy for bladder cancer (Press release, Prokarium, OCT 12, 2021, View Source [SID1234591157]). Under the terms of the initial agreement, Wacker Biotech will ramp up GMP (Good Manufacturing Practice) production of Prokarium’s Salmonella-based immunotherapy at its biotech site in Amsterdam using its LIBATEC technology.

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Preparations for the start of production, technology transfer and scale-up for a Phase 1 trial are already underway, as announced by the companies. "We are very pleased to work with Wacker Biotech given their deep expertise with live microbial products and GMP production," said Kristen Albright, PharmD, Prokarium’s Chief Executive Officer. "This marks an exciting milestone essential to progressing our lead microbial immunotherapy program into clinic."

As a CDMO (Contract Development and Manufacturing Organization), Wacker Biotech will use its LIBATEC technology platform for Live Microbial Products (LMPs) in the project. The company’s site in Amsterdam is a pioneer in the field of LMP production. "With our LIBATEC platform, Wacker Biotech offers its customers over 15 years’ experience in process development and manufacturing pharmaceutical’s that contain living microorganisms", said Jörg Lindemann, Managing Director of Wacker Biotech B.V. "The LIBATEC platform can be used for a wide range of Live Microbial Products and is perfectly suited to support Prokarium with their Salmonella-based immunotherapy."