On May 23, 2024 Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported that the company has entered into a securities purchase agreement with certain existing and new accredited investors to issue and sell an aggregate of 25,933,706 American Depositary Shares ("ADSs"), each representing one ordinary share, and in lieu of ADSs to investors that so choose, non-voting ordinary shares, each at a price of $21.42 per share, through a private investment in public equity ("PIPE") financing (Press release, Bicycle Therapeutics, MAY 23, 2024, View Source [SID1234643580]). Bicycle anticipates the gross proceeds from the PIPE to be approximately $555 million. The financing is expected to close on May 28, 2024, subject to customary closing conditions.

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The financing was led by a U.S.-based healthcare focused investor with participation from Deep Track Capital, EcoR1 Capital, Fairmount, Forbion, Perceptive Advisors and RA Capital Management. Bicycle plans to use the net proceeds to fund the continued development of its proprietary pipeline and for other research and development, as well as for general corporate purposes.

"We are excited to announce today’s financing as it underscores the increasing conviction that our investors have in the Bicycle platform and team to create novel precision-guided therapeutics, which we believe have the potential to offer patients a significantly improved quality of life over other treatments," said Kevin Lee, Ph.D., CEO of Bicycle Therapeutics. "This financing will support our progress across multiple high-value programs and earlier discovery pipeline, both of which have multiple catalysts in the second half of 2024, as we develop innovative medicines that could help patients with cancer and other diseases live longer and live well."

Subsequent to the closing of this financing, Bicycle expects its pro forma cash and cash equivalents will be approximately $1.0 billion as of May 23, 2024. This cash estimate is a preliminary estimate and based on information currently available to management, and these estimates could change.

Jefferies is acting as sole placement agent for the financing.

The offer and sale of the securities to be sold in the PIPE are being made in a transaction not involving a public offering, and the securities have not been registered under the Securities Act of 1933, as amended (the "Securities Act"), or applicable state securities laws, and will be sold in a private placement pursuant to Section 4(a)(2) of the Securities Act and Rule 506 of Regulation D as promulgated by the Securities and Exchange Commission ("SEC") under the Securities Act. Accordingly, the securities may not be offered or sold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements of the Securities Act. Pursuant to the securities purchase agreement, Bicycle has agreed to file a registration statement with the SEC registering the resale of the ADSs and ordinary shares or ADSs issued upon the re-designation of the non-voting ordinary shares issued in the PIPE.

This press release shall not constitute an offer to sell, or a solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On May 23, 2024 Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported that emerging Phase 1/2 clinical pharmacokinetic (PK) and safety data for Bicycle Toxin Conjugates (BTC molecules) BT8009 and BT5528 demonstrating differentiated safety and tolerability profiles will be presented at the 2024 American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, taking place May 31-June 4 in Chicago (Press release, Bicycle Therapeutics, MAY 23, 2024, View Source [SID1234643579]). The company also announced zelenectide pevedotin as the International Nonproprietary Name (INN) for BT8009, and U.S. Food and Drug Administration (FDA) Fast Track Designation granted to BT5528 for the treatment of adult patients with previously treated, locally advanced or metastatic urothelial cancer (mUC).

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"As we advance the development of our investigational therapies, we are pleased to see the underlying characteristics of Bicycle molecules developed using our platform technology — small size for rapid tissue penetration, tunable pharmacokinetics and high target selectivity — are leading to emerging differentiated clinical profiles that we believe have the potential to provide enhanced benefits and quality of life for cancer patients who have advanced disease," said Kevin Lee, Ph.D., CEO of Bicycle Therapeutics. "At ASCO (Free ASCO Whitepaper), we look forward to presenting preliminary clinical pharmacokinetic and safety data for our Bicycle Toxin Conjugates zelenectide pevedotin, formerly BT8009, and BT5528 that show substantial differences in their pharmacokinetic profiles compared to antibody drug conjugates. Additionally, we continue to advance enrollment and site activation for our Phase 2/3 Duravelo-2 registrational trial of zelenectide pevedotin in mUC and prepare for multiple clinical and program updates in the second half of 2024. These include updates from the Phase 1/2 clinical trials of zelenectide pevedotin and BT5528, for which the newly awarded FDA Fast Track Designation demonstrates the continued need for targeted therapies for patients living with advanced bladder cancer."

PK and Safety Data from BTC Molecules
Title: Breaking from the paradigm of antibody-drug conjugates: Evaluation of clinical pharmacokinetics and safety of Bicycle Toxin Conjugates (BTCs)
Poster Session Title: Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology
Date and Time: Saturday, June 1, at 9 a.m. CT
Abstract Number: 3088
Speaker/Lead Author: Justin Bader, Pharm.D., MBA, Bicycle Therapeutics

Bicycle Therapeutics researchers and collaborators sought to compare PK behavior for BTC molecules to MMAE-containing antibody drug conjugate (ADC) enfortumab vedotin (EV). To do this, the researchers developed PK models and simulated PK exposures over a 28-day cycle for zelenectide pevedotin (5 mg/m2 once weekly) and BT5528 (5 mg/m2 once weekly) and compared them to published PK parameters for EV (1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle). Results showed:

BTC molecule half-life is substantially shorter than that of EV (<1 hour vs 3.6 days), resulting in extensive elimination of the BTC molecule within hours of dose administration rather than weeks. MMAE half-life is also shorter following BTC molecule administration relative to EV (1.9 days vs 2.6 days)​, potentially due to a slower rate of MMAE release from the ADC.
Relative to EV, BTC molecules achieved similar unconjugated MMAE PK exposure over a ​28-day cycle while maximum serum concentration (Cmax) was elevated for unconjugated MMAE, potentially driving rapid penetration into tumor tissue.
Relative to EV, conjugated MMAE PK exposure from BTC molecules was substantially lower, potentially limiting toxicities.
Zelenectide pevedotin and BT5528 continued to show promising emerging safety and tolerability profiles, with data to be presented from all patients dosed at Cycle 1 Day 1 with zelenectide pevedotin 5 mg/m2 once weekly monotherapy (data as of March 22, 2024) and with BT5528 6.5 mg/m2 every two weeks monotherapy (data as of March 14, 2024). The findings:

Zelenectide pevedotin-related adverse events (AEs) occurred in 84% of patients, of which 31% were Grade ≥3.
BT5528-related AEs occurred in 91% of patients, of which 22% were Grade ≥3.
In contrast to ADCs, treatment-related AEs of interest such as peripheral neuropathy, skin reactions, ocular disorders and hyperglycemia occurred at relatively low frequency and severity with both BTC molecules.
Trial-in-Progress: Registrational Phase 2/3 Duravelo-2 Study
Title: A phase 2/3 study of Bicycle Toxin Conjugate BT8009 targeting Nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC): Duravelo-2
Poster Session Title: Genitourinary Cancer – Kidney and Bladder
Date and Time: Sunday, June 2, at 9 a.m. CT
Abstract Number: TPS4619
Speaker/Lead Author: Yohann Loriot, M.D., Ph.D., Institut de Cancérologie Gustave Roussy, Université Paris-Saclay

The posters will be made available in the Publications section of bicycletherapeutics.com following the presentations.

On May 23, 2024 Bicycle Therapeutics plc (the "Company") reported to have entered into a securities purchase agreement (the "Purchase Agreement") with the purchasers named therein (the "Investors") (Filing, 8-K, Bicycle Therapeutics, MAY 23, 2024, View Source [SID1234643578]). Pursuant to the Purchase Agreement, the Company agreed to sell an aggregate of 25,933,706 of its American Depositary Shares ("ADSs"), each representing one of the Company’s ordinary shares, nominal value £0.01 per share (the "Ordinary Shares"), and in lieu of ADSs to Investors that so choose, non-voting ordinary shares (the "Non-Voting Ordinary Shares"), each at a purchase price equal to $21.42 per share (the "Private Placement"). The Purchase Agreement contained customary representations and warranties from the Company and the Investors and customary closing conditions. The closing of the Private Placement is expected to occur on May 28, 2024 (the "Closing Date"). The Company anticipates the aggregate gross proceeds of the Private Placement will be approximately $555 million before deducting placement agent fees and other expenses.

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Pursuant to the Purchase Agreement, the Company has agreed to prepare and file a registration statement with the Securities and Exchange Commission no later than 30 calendar days following the Closing Date, or a prospectus supplement to its registration statement on Form S-3ASR (File No. 333-272248) (if such registration statement is then effective) no later than 15 business days following the Closing Date, for purposes of registering the Registrable Securities (as defined in the Purchase Agreement). The ADSs are registered on registration statements on Form F-6 (File Nos. 333-231422 and 333-279465).

The Company has also agreed, among other things, to indemnify the Investors, their officers, directors, and constituent partners, legal counsel, and each person who controls such Investors from certain liabilities and to pay certain legal fees and other expenses reasonably incurred by the Investors in connection therewith.

The foregoing description of the Purchase Agreement does not purport to be complete and is qualified in its entirety by reference to the Purchase Agreement filed as Exhibit 10.1 to this report and incorporated by reference herein.

On May 23, 2024 Arvinas, Inc. (Nasdaq: ARVN) reported that two abstracts, including one for ARV-766 in prostate cancer and one for TACTIVE-K, a Phase 1b/2 clinical trial with vepdegestrant, a novel investigational oral PROteolysis Targeting Chimera (PROTAC) ER degrader, in combination with Pfizer’s atirmociclib (PF-07220060), an investigational CDK4 inhibitor, were accepted for presentation at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Congress held May 31 to June 4, 2024, in Chicago, IL (Press release, Arvinas, MAY 23, 2024, View Source [SID1234643576]).

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Presentation details are as follows:

Title: ARV-766, a PROteolysis TArgeting Chimera (PROTAC) androgen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC): initial results of a phase 1/2 study
Presentation Type and Abstract Number: Rapid Oral Abstract, 5011
Date: Monday, June 3, 2024
Time: 1:15 p.m. — 2:45 p.m. CDT
Category: Genitourinary Cancer—Prostate, Testicular, and Penile

Title: TACTIVE-K: phase 1b/2 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in combination with PF-07220060, a cyclin-dependent kinase (CDK)4 inhibitor, in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer
Presentation Type and Abstract Number: Trial-in-Progress (TiP) TPS1131, Poster 103b
Date: Sunday, June 2, 2024
Time: 9:00 a.m. — 12:00 p.m. CDT
Category: Session Type and Title: Poster Session – Breast Cancer—Metastatic

Abstracts are now available via the official ASCO (Free ASCO Whitepaper) Annual Congress website here.

About ARV-766
ARV-766 is an investigational, orally bioavailable PROTAC protein degrader designed to selectively target and degrade the androgen receptor (AR). Preclinically, ARV-766 has demonstrated activity in models of wild type androgen receptor tumors in addition to tumors with AR mutations or amplification, both common potential mechanisms of resistance to currently available AR-targeted therapies.

In April 2024, Arvinas entered into a transaction with Novartis that included an exclusive license agreement for the worldwide development and commercialization of ARV-766. Closing of the transaction is subject to customary closing conditions, including the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976.

About Vepdegestrant
Vepdegestrant is an investigational, orally bioavailable PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with ER positive human epidermal growth factor receptor 2 (HER2) negative (ER+/HER2-) breast cancer. Vepdegestrant is being developed as a potential monotherapy and as part of combination therapy across multiple treatment settings for ER+/HER2- metastatic breast cancer.

In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer share worldwide development costs, commercialization expenses, and profits.

The U.S. Food and Drug Administration (FDA) has granted vepdegestrant Fast Track designation as a monotherapy in the treatment of adults with ER+/HER2- locally advanced or metastatic breast cancer previously treated with endocrine-based therapy.

On May 23, 2024 Amphista Therapeutics ("Amphista"), a leader in next generation targeted protein degradation (TPD) approaches, reported the unveiling of a new mechanism of action for the degradation of BRD9, an emerging target in oncology, that is differentiated from cereblon- or VHL-based PROTACs, during an oral presentation at the 2024 Protein Degradation in Focus Symposium held in Dundee, UK (Press release, Amphista Therapeutics, MAY 23, 2024, View Source [SID1234643575]).

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This significant news for the TPD field builds upon an earlier announcement by Amphista of two compelling data sets demonstrating in vivo efficacy and central nervous system (CNS) activity of its mechanistically differentiated protein degraders. At today’s presentation titled "Degradation of BRD9 by a novel targeted glue", Dr Andrea Testa, Scientific Co-Founder and Senior Director, Discovery Chemistry showed data from proteomic and genetic validation studies which demonstrate that Amphista’s bifunctional degraders induced degradation of BRD9 by target-assisted E3 ligase recruitment. This novel mechanism selectively induces the proximity of BRD9 to DCAF16 and serves as a molecular glue. DCAF16 is a cullin-RING E3 ligase which can facilitate degradation of proteins of interest via ternary complex formation. Induction of this complex leads to deep and rapid degradation of BRD9 in vivo.

Louise Modis, Chief Scientific Officer of Amphista Therapeutics, said: "The discovery of a novel mechanism for BRD9 degradation, differentiated from cereblon- or VHL-based PROTACs, is a testament to Amphista’s proprietary chemistry and know-how. Our ability to translate this novel approach into high-quality, drug-like compounds with oral bioavailability and activity in vivo is truly exciting. As we continue to spearhead our efforts to advance new TPD approaches, our goal remains clear – to expand the offering of TPD medicines beyond CRBN and VHL-based agents and bring effective treatments to patients in areas of high unmet need."

In the results presented, Amphista’s sub-nanomolar BRD9 degraders showed activity in both solid and liquid cancer cell lines and demonstrated a high degree of selectivity over 8,000 proteins quantified by proteomics, including the closely related proteins BRD7 and BRD4. Notably, these compounds induced BRD9 degradation in a mouse xenograft model illustrating Amphista’s BRD9 degraders are orally bioavailable and active in vivo. This is the first-time in vivo degradation of BRD9 has been demonstrated via DCAF16, underscoring the potential therapeutic application of Amphista’s bifunctional degraders.

Building on this knowledge, Amphista is applying its proprietary scientific know-how and expertise to the development of targeted glues which induce degradation of different targets, expanding the opportunity beyond BRD9. Future announcements will provide details of additional pipeline targets as part of Amphista’s ambitions to develop a first- and/or best-in-class portfolio of degraders with leading physicochemical properties.