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."

On October 12, 2021 Agilent Technologies Inc. (NYSE: A) reported its Ki-67 IHC MIB-1 pharmDx (Dako Omnis) is now FDA approved as an aid in identifying patients with early breast cancer (EBC) at high risk of disease recurrence, for whom adjuvant treatment with Verzenio (abemaciclib) in combination with endocrine therapy is being considered (Press release, Agilent, OCT 12, 2021, View Source [SID1234591195]). This is the first IHC assay measuring Ki-67 expression to receive FDA approval in the context of treatment with Verzenio and was developed in collaboration with Eli Lilly and Company.

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"Agilent’s Ki-67 IHC MIB-1 pharmDx (Dako Omnis) companion diagnostic assay for the Dako Omnis advanced staining platform has been designed and tested to aid in evaluating risk of recurrence in early breast cancer (EBC)"

Understanding the risk of recurrence in EBC is vital for informing disease management, as identifying patients at high risk can provide clarity for patients as well as facilitate treatment decisions to potentially improve outcomes. Conventional methods for evaluating the risk of recurrence in EBC are based on staging and are performed according to standard clinical and pathological features of the disease. However, these standard features may not capture the full risk of recurrence for individuals with EBC.

The American Joint Committee on Cancer has identified the Ki-67 biomarker as Level of Evidence III in diagnosing EBC due to its association with cellular proliferation. Ki-67 is thus an important component of comprehensive risk assessment, but it has been inconsistently applied in the past.1

"Agilent’s Ki-67 IHC MIB-1 pharmDx (Dako Omnis) companion diagnostic assay for the Dako Omnis advanced staining platform has been designed and tested to aid in evaluating risk of recurrence in early breast cancer (EBC)," said Sam Raha, president of Agilent’s Diagnostics and Genomics Group. "Its approval establishes a clinically relevant standard for recurrence risk assessment in EBC so that more high-risk patients who may experience clinical benefit from treatment with Verzenio are identified."

This approval builds on Agilent’s previous successes in expanding the clinical applicability of therapeutic biomarker analysis, further cementing the company’s position as a provider of diagnostic assays that deliver high quality and ease of implementation.