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2024 | Annual Report
April 2025 To Our Shareholders, 2024 was a year of significant progress for Bicycle Therapeutics as we advanced our pipeline and strategic priorities. Encouraging clinical data across our pipeline of oncology, radiopharmaceutical and partnered programs continue to validate our approach to developing next-generation precision-guided therapeutics that have the potential to help patients live longer and live well. With our proprietary bicyclic peptide (Bicycle ) technology, multiple clinical trials, a disciplined strategic focus, a healthy balance sheet following our $555 million private placement and an experienced team, we look forward to another remarkable year. Realizing Patient Benefits Through The Bicycle Advantage Using our Bicycle technology, we are working to create medicines that can deliver practically any payload to any target. Our Bicycle molecules are highly selective to their intended target and have minimal systemic exposure and off-target activity, which we believe will lead to enhanced patient benefit due to potentially longer, deeper and broader responses. We call this The Bicycle Advantage. The Bicycle Advantage continues to be demonstrated in the clinical trial data from more than 500 patients treated with our various molecules. We believe the unique features of Bicycle molecules make them advantageous for oncology therapeutics as well as radiopharmaceuticals. Advancing the Development of Zelenectide Pevedotin for Metastatic Urothelial Cancer Our lead therapeutic candidate zelenectide pevedotin is a Bicycle Toxin Conjugate (BTC ) targeting Nectin-4, a well-validated tumor antigen, that continues to advance in clinical testing. Zelenectide s promising anti-tumor activity and differentiated safety profile in metastatic urothelial cancer (mUC) continues to be supported by updated monotherapy data in previously treated (second-line) patients and combination data with pembrolizumab in untreated (first-line) cisplatin-ineligible patients from our Phase 1/2 Duravelo-1 trial. We look forward to sharing longer-term data from these patients later this year. This past year, we were pleased to initiate the Phase 2/3 Duravelo-2 registrational trial evaluating zelenectide plus pembrolizumab versus chemotherapy in first-line mUC patients (Cohort 1), and zelenectide monotherapy and in combination with pembrolizumab in second-line mUC patients (Cohort 2), providing multiple opportunities for potential accelerated approval. In each cohort, two doses of zelenectide are being initially assessed, and we remain on track for dose selection for both cohorts in the second half of this year. Leveraging NECTIN4 Gene Amplification to Develop Zelenectide Pevedotin for Additional Solid Tumors Beyond mUC, we are utilizing a NECTIN4 gene amplification strategy to target patients with Nectin-4 associated cancers who we believe have the potential for significantly deeper responses to zelenectide. Several years ago, we identified that the NECTIN4 gene sits on a commonly amplified chromosomal site in cancer, creating more copies of the gene and often translating to more protein expression. Since zelenectide binds to Nectin-4, it was hypothesized that NECTIN4 gene amplification may predict response and could serve as a biomarker for therapy stratification. Post-hoc analyses in breast and lung cancer patients enrolled in our Duravelo-1 trial showed enhanced anti-tumor activity of zelenectide in patients with NECTIN4 gene amplification and/or polysomy. Based on these data, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to zelenectide for adults with previously treated, NECTIN4 gene-amplified advanced or metastatic triple-negative breast cancer and non-small cell lung cancer. We are in the process of initiating several additional Phase 1/2 trials evaluating zelenectide in NECTIN4 gene-amplified cancers, including breast cancer (Duravelo-3), lung cancer (Duravelo-4) and multiple tumors (Duravelo-5). Developing Next-Generation Radiopharmaceuticals Last year, we announced our plans to develop our own internal radiopharmaceuticals pipeline and outlined our strategy for leadership in this area. Our Bicycle Radionuclide Conjugate (BRC ) molecules are optimized for
enhanced radioisotope delivery, and in preclinical studies have shown high selectivity and tumor penetration with minimal systemic exposure. Essentially, The Bicycle Advantage for delivering cytotoxic payloads to the tumor is also an advantage for delivering radionuclide payloads. Additionally, the versatility and modularity of our Bicycle technology allow us to identify binders for practically any tumor antigen, putting us in an ideal position to develop new radiotherapeutics that have not been developed before. In October 2024, we presented first human imaging data for a BRC targeting MT1-MMP, our first radiopharmaceutical target. The data underscored the potential of MT1-MMP as a novel target in the treatment of cancer, demonstrated the translatability of BRC preclinical data and highlighted the potential of Bicycle molecules for targeted radionuclide therapy. We also selected Ephrin-A2 (EphA2), a novel tumor antigen that is widely expressed in many cancers, as our second BRC target and have partnered with leading isotope technology company Eckert & Ziegler to supply a range of radioisotopes and develop and manufacture our BRC molecules. As we continue to advance our emerging BRC pipeline, we look forward to sharing additional MT1-MMP human imaging data and initial EphA2 human imaging data, and to starting our first radiopharmaceuticals clinical trial in 2026. Drugging the Undruggable with BT5528 Historically, antibody-based approaches to targeting EphA2 have been unsuccessful due to safety issues. BT5528, an EphA2-targeting BTC molecule designed to overcome these historical safety challenges, continues to demonstrate a markedly differentiated profile thanks to The Bicycle Advantage. Updated results from the ongoing Phase 1/2 trial evaluating BT5528 monotherapy in patients with advanced solid tumors continue to support the molecule s promising safety and tolerability profile and anti-tumor activity. These data provide important information as we continue our dose optimization work and assess BT5528 in combination with nivolumab. Where We Are Headed With a clear strategy to build on our achievements, multiple anticipated catalysts and a healthy balance sheet, we are excited to continue our progress and move closer to bringing our innovative therapies to patients living with cancer. I deeply appreciate Team Bicycle for their dedication to our mission and commitment to the people we seek to help, as well as the patients and physicians who participate in our clinical trials, our partners and our shareholders. Sincerely, Kevin Lee, Ph.D., MBA Chief Executive Officer
 • shareholder letter icon 4/23/2025 Letter Continued (Full PDF)
 • stockholder letter icon 4/28/2023 BCYC Stockholder Letter
 • stockholder letter icon 4/15/2024 BCYC Stockholder Letter
 • stockholder letter icon More "Drugs & Pharmaceuticals" Category Stockholder Letters
 • Benford's Law Stocks icon BCYC Benford's Law Stock Score = 76


BCYC Shareholder/Stockholder Letter Transcript:

2024 | Annual Report


April 2025
To Our Shareholders,
2024 was a year of significant progress for Bicycle Therapeutics as we advanced our pipeline and strategic
priorities. Encouraging clinical data across our pipeline of oncology, radiopharmaceutical and partnered programs
continue to validate our approach to developing next-generation precision-guided therapeutics that have the potential
to help patients live longer and live well. With our proprietary bicyclic peptide (Bicycle  ) technology, multiple
clinical trials, a disciplined strategic focus, a healthy balance sheet following our $555 million private placement and
an experienced team, we look forward to another remarkable year.
Realizing Patient Benefits Through The Bicycle   Advantage
Using our Bicycle technology, we are working to create medicines that can deliver practically any payload to any
target. Our Bicycle   molecules are highly selective to their intended target and have minimal systemic exposure and
off-target activity, which we believe will lead to enhanced patient benefit due to potentially longer, deeper and
broader responses. We call this The Bicycle Advantage.
The Bicycle Advantage continues to be demonstrated in the clinical trial data from more than 500 patients treated
with our various molecules. We believe the unique features of Bicycle molecules make them advantageous for
oncology therapeutics as well as radiopharmaceuticals.
Advancing the Development of Zelenectide Pevedotin for Metastatic Urothelial Cancer
Our lead therapeutic candidate zelenectide pevedotin is a Bicycle   Toxin Conjugate (BTC  ) targeting Nectin-4, a
well-validated tumor antigen, that continues to advance in clinical testing. Zelenectide   s promising anti-tumor
activity and differentiated safety profile in metastatic urothelial cancer (mUC) continues to be supported by updated
monotherapy data in previously treated (second-line) patients and combination data with pembrolizumab in
untreated (first-line) cisplatin-ineligible patients from our Phase 1/2 Duravelo-1 trial. We look forward to sharing
longer-term data from these patients later this year.
This past year, we were pleased to initiate the Phase 2/3 Duravelo-2 registrational trial evaluating zelenectide plus
pembrolizumab versus chemotherapy in first-line mUC patients (Cohort 1), and zelenectide monotherapy and in
combination with pembrolizumab in second-line mUC patients (Cohort 2), providing multiple opportunities for
potential accelerated approval. In each cohort, two doses of zelenectide are being initially assessed, and we remain
on track for dose selection for both cohorts in the second half of this year.
Leveraging NECTIN4 Gene Amplification to Develop Zelenectide Pevedotin for Additional Solid Tumors
Beyond mUC, we are utilizing a NECTIN4 gene amplification strategy to target patients with Nectin-4 associated
cancers who we believe have the potential for significantly deeper responses to zelenectide. Several years ago, we
identified that the NECTIN4 gene sits on a commonly amplified chromosomal site in cancer, creating more copies
of the gene and often translating to more protein expression. Since zelenectide binds to Nectin-4, it was
hypothesized that NECTIN4 gene amplification may predict response and could serve as a biomarker for therapy
stratification.
Post-hoc analyses in breast and lung cancer patients enrolled in our Duravelo-1 trial showed enhanced anti-tumor
activity of zelenectide in patients with NECTIN4 gene amplification and/or polysomy. Based on these data, the U.S.
Food and Drug Administration (FDA) granted Fast Track designation to zelenectide for adults with previously
treated, NECTIN4 gene-amplified advanced or metastatic triple-negative breast cancer and non-small cell lung
cancer. We are in the process of initiating several additional Phase 1/2 trials evaluating zelenectide in NECTIN4
gene-amplified cancers, including breast cancer (Duravelo-3), lung cancer (Duravelo-4) and multiple tumors
(Duravelo-5).
Developing Next-Generation Radiopharmaceuticals
Last year, we announced our plans to develop our own internal radiopharmaceuticals pipeline and outlined our
strategy for leadership in this area. Our Bicycle Radionuclide Conjugate   (BRC  ) molecules are optimized for

enhanced radioisotope delivery, and in preclinical studies have shown high selectivity and tumor penetration with
minimal systemic exposure. Essentially, The Bicycle Advantage for delivering cytotoxic payloads to the tumor is
also an advantage for delivering radionuclide payloads. Additionally, the versatility and modularity of our Bicycle
technology allow us to identify binders for practically any tumor antigen, putting us in an ideal position to develop
new radiotherapeutics that have not been developed before.
In October 2024, we presented first human imaging data for a BRC targeting MT1-MMP, our first
radiopharmaceutical target. The data underscored the potential of MT1-MMP as a novel target in the treatment of
cancer, demonstrated the translatability of BRC preclinical data and highlighted the potential of Bicycle molecules
for targeted radionuclide therapy. We also selected Ephrin-A2 (EphA2), a novel tumor antigen that is widely
expressed in many cancers, as our second BRC target and have partnered with leading isotope technology company
Eckert & Ziegler to supply a range of radioisotopes and develop and manufacture our BRC molecules.
As we continue to advance our emerging BRC pipeline, we look forward to sharing additional MT1-MMP human
imaging data and initial EphA2 human imaging data, and to starting our first radiopharmaceuticals clinical trial in
2026.
Drugging the Undruggable with BT5528
Historically, antibody-based approaches to targeting EphA2 have been unsuccessful due to safety issues. BT5528,
an EphA2-targeting BTC molecule designed to overcome these historical safety challenges, continues to
demonstrate a markedly differentiated profile     thanks to The Bicycle Advantage.
Updated results from the ongoing Phase 1/2 trial evaluating BT5528 monotherapy in patients with advanced solid
tumors continue to support the molecule   s promising safety and tolerability profile and anti-tumor activity. These
data provide important information as we continue our dose optimization work and assess BT5528 in combination
with nivolumab.
Where We Are Headed
With a clear strategy to build on our achievements, multiple anticipated catalysts and a healthy balance sheet, we are
excited to continue our progress and move closer to bringing our innovative therapies to patients living with cancer.
I deeply appreciate Team Bicycle for their dedication to our mission and commitment to the people we seek to help,
as well as the patients and physicians who participate in our clinical trials, our partners and our shareholders.
Sincerely,
Kevin Lee, Ph.D., MBA
Chief Executive Officer



shareholder letter icon 4/23/2025 Letter Continued (Full PDF)
 

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