On October 31, 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 recent business progress and financial results for the third quarter ended September 30, 2024 (Press release, Bicycle Therapeutics, OCT 31, 2024, View Source [SID1234647582]).

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"In the third quarter, we continued to make significant advancements across our business and pipeline. At ESMO (Free ESMO Whitepaper), we reported updated data for our clinical-stage molecules, further supporting their promising monotherapy response rates and differentiated safety profiles. Additionally, last week we shared exciting first human imaging data for our first radiopharmaceuticals molecule, validating the potential of MT1-MMP as a novel cancer target and providing important information on the ability of our Bicycle molecules to deliver radioisotopes to the tumor," said Kevin Lee, Ph.D., CEO of Bicycle Therapeutics. "Altogether, we believe these data demonstrate the power and broad capabilities of our Bicycle technology platform, and we look forward to providing additional updates later this year."

Third Quarter 2024 and Recent Events

· Announced first human imaging data for a Bicycle Radionuclide Conjugate (BRC) targeting MT1-MMP and outlined strategy for leadership in next-generation radiopharmaceuticals.

o Data presented at the European Association of Nuclear Medicine 2024 Congress validate the potential of MT1-MMP as a novel target in the treatment of cancer, demonstrate the translatability of BRC preclinical data and highlight the potential of Bicycle molecules for targeted radionuclide therapy.

§ In an oral presentation, the German Cancer Consortium shared results of fluorine-18-labelled FDG-PET/CT imaging and gallium-68-labelled BRC MT1-MMP PET/CT imaging in a 65-year-old male diagnosed with advanced pulmonary adenocarcinoma, the most common type of non-small cell lung cancer, in the lung and lymph nodes confirmed by endobronchial ultrasound biopsy. Both scans revealed multiple lymph node metastases and bone metastases in the sternum. MT1-MMP imaging demonstrated tracer uptake in the primary tumor in the lung and lymph node and bone metastases, consistent with FDG imaging. Additionally, the MT1-MMP BRC tracer showed renal excretion, with all other organs showing only a negligible tracer uptake. Clear imaging contrast was also observed at early time points.

§ In an e-poster presented by Bicycle Therapeutics, preclinical data demonstrate the suitability of Bicycle molecules to deliver indium to tumors in vivo due to their favorable properties including specific tumor uptake, rapid tumor penetration and rapid renal elimination. Additionally, imaging showed how the biodistribution profile of BRCs can be optimized to maintain high tumor uptake and retention while significantly reducing kidney levels. These data build on the body of preclinical data that the company has published in this area demonstrating the use of Bicycle molecules to effectively deliver various radioisotopes, such as lutetium and lead, to tumors.

o Bicycle Therapeutics’ strategy in radiopharmaceuticals focuses on pursuing novel targets with first-in-class potential and selecting the isotope that best aligns with the target biology and indication. In line with this strategy, the company selected EphA2, a novel tumor antigen that is widely expressed in many cancers, as its second BRC target and signed a letter of intent with leading isotope technology company Eckert & Ziegler to put in place an agreement to supply a range of radioisotopes and develop and manufacture BRC molecules.

· Presented updated clinical results across oncology pipeline at the European Society for Medical Oncology Congress 2024.

o Zelenectide pevedotin (formerly BT8009) is a Bicycle Toxin Conjugate (BTC) molecule targeting Nectin-4, a well-validated tumor antigen. Updated results from the ongoing Phase 1/2 Duravelo-1 trial evaluating 5 mg/m2 weekly of zelenectide pevedotin monotherapy in patients with metastatic urothelial cancer (mUC) who had not previously been treated with enfortumab vedotin showed a 45% overall response rate (ORR) in efficacy-evaluable patients (n=38), with a median duration of response of 11.1 months among patients with confirmed responses (n=14). Zelenectide pevedotin continued to demonstrate an emerging differentiated safety profile, particularly around adverse events of interest such as peripheral neuropathy, skin reactions and eye disorders.

The global Phase 2/3 Duravelo-2 registrational trial of zelenectide pevedotin in patients with mUC is currently enrolling. Additional data updates for zelenectide pevedotin monotherapy in other tumor types and in combination with pembrolizumab in first-line mUC are planned by year end.

o BT5528 is a BTC molecule targeting tumor antigen EphA2, which has historically been difficult to target using other drug conjugate approaches. Updated results from the ongoing Phase 1/2 trial evaluating 6.5 mg/m2 every two weeks and 5 mg/m2 weekly of BT5528 monotherapy in patients with advanced solid tumors showed an emerging differentiated safety profile and antitumor activity, including a 45% ORR in mUC patients enrolled in the dose expansion cohort (n=11) receiving 6.5 mg/m2 every two weeks.

Bicycle Therapeutics is currently assessing BT5528 at 6.5 mg/m2 every two weeks in combination with nivolumab, with results expected in 2025.

o An analysis of BTC clinical data showed that treatment-related peripheral neuropathy (TRPN) in patients receiving either zelenectide pevedotin or BT5528 occurred at low rates and were primarily low grade. In 223 patients from ongoing Phase 1/2 studies, TRPN occurred in 28% of zelenectide pevedotin-treated patients and in 19% of BT5528-treated patients, nearly all of which were low grade (Grade 1-2). One Grade 3 event (neuralgia) was reported in a patient treated with zelenectide pevedotin following prior therapy with enfortumab vedotin, while no Grade 3-4 events were observed for BT5528.

These data showing low rates of TRPN at primarily low severity with BTC molecules support the hypothesis that the antibody-drug construct may be a primary driver of peripheral neuropathy rather than monomethyl auristatin E (MMAE) toxicity as was previously believed.

o BT7480 is a Nectin-4 targeted CD137 agonist designed to overcome immune agonist toxicities and activate the immune system in Nectin-4 expressing tumors. Initial data from the Phase 1/2 dose escalation trial evaluating BT7480 in patients with advanced solid tumors showed an emerging differentiated safety and tolerability profile, with low rates of severe adverse events among 39 patients assigned to receive one of 10 different doses (0.002-3.5 mg/kg weekly). Preliminary biomarker analyses support BT7480 dual targeting of CD137 and Nectin-4 as demonstrated by enhanced immune cell activation, aligned with the proposed mechanism of action of BT7480.

As the maximum tolerated dose for BT7480 has not yet been reached, Bicycle Therapeutics is continuing dose exploration in combination studies, starting with nivolumab.

· Promoted Zafar Qadir to Chief Legal Officer and General Counsel. Since joining Bicycle Therapeutics in April 2020, Mr. Qadir has managed critical responsibilities to support the company’s growth by leading the legal, compliance and intellectual property functions. Over the course of his career, Mr. Qadir has more than a decade of corporate, legal, intellectual property, regulatory and compliance experience and has played a pivotal role in Bicycle Therapeutics’ key partnerships and transactions.

Third Quarter 2024 Financial Results

· Cash and cash equivalents were $890.9 million as of September 30, 2024, compared to $526.4 million as of December 31, 2023. The increase in cash and cash equivalents is primarily due to net proceeds from our PIPE financing in May 2024 and share option exercises, offset by the repayment of our debt facility with Hercules Capital, Inc. in July 2024 and cash used in operating activities.

· Research and Development (R&D) expenses were $48.3 million for the three months ended September 30, 2024, compared to $39.9 million for the three months ended September 30, 2023. The increase in expense of $8.4 million was primarily due to increased clinical program expenses for zelenectide pevedotin development and increased personnel-related expenses, including incremental share-based compensation of $1.1 million, offset by decreased clinical program expenses for Bicycle Tumor-Targeted Immune Cell Agonist molecule development, lower discovery, platform and other expenses, and higher U.K. R&D tax credits period over period.

· General and administrative expenses were $18.3 million for the three months ended September 30, 2024, compared to $16.3 million for the three months ended September 30, 2023. The increase of $2.0 million was primarily due to increased personnel-related expenses, including incremental share-based compensation expense of $0.7 million.

· Net loss was $50.8 million, or $(0.74) basic and diluted net loss per share, for the three months ended September 30, 2024, compared to net loss of $49.9 million, or $(1.26) basic and diluted net loss per share, for three months ended September 30, 2023.