• Nectin-4 portfolio comprised of BT8009 and BT7480 represents potential opportunity to become leader in treating Nectin-4-driven cancers, starting with metastatic urothelial cancer (mUC)
  • Updated BT8009 clinical data continue to support promising response and differentiated safety profile in mUC as well as emerging clinical activity in additional tumor types beyond bladder
  • EphA2 portfolio led by BT5528 could be the first to address a historically undruggable target widely expressed in many cancers
  • Additional work in oncology and beyond highlight the breadth of the Bicycle® platform and its potential to address a multitude of diseases

Bicycle Therapeutics (Nasdaq: BCYC), a biotechnology company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle®) technology, is today hosting a Research & Development (R&D) Day for investors and analysts in New York to provide clinical updates for BT8009, BT7480 and BT5528, and an overview of the company’s strategy and pipeline opportunities. The company will also highlight the broad capabilities of its novel Bicycle® platform technology. The event begins at 8 a.m. ET and will be available via webcast here.

“During our first R&D Day, we are excited to showcase the advantages of our Nobel Prize-winning science and our strategy to discover and develop therapies with greater tolerability that could provide enhanced benefit to a multitude of patients, starting with those who have cancer,” said Kevin Lee, Ph.D., CEO of Bicycle Therapeutics. “Through our Nectin-4 and EphA2 portfolios and the continued work on our platform, including through partnerships, we are building a leading precision-guided therapeutics company with the potential to address a wide range of diseases that affect millions of people around the world. We believe that our technology has the potential to not only help patients live longer but also to live well.”

“Today we are excited to provide clinical updates for our three lead programs,” said Santiago Arroyo, M.D., Ph.D., Chief Development Officer of Bicycle Therapeutics. “In totality, the data support the emerging differentiated profile of our Bicycle® molecules, paving the way to deliver best-in-class or first-in-class therapies for many cancers. Based on our clinical updates, we are taking important next steps with our development programs, setting up what we expect to be a catalyst-rich 2024.”

Key R&D Day Highlights

Nectin-4 Portfolio

Bicycle Therapeutics is advancing two clinical programs, BT8009 and BT7480, targeting Nectin-4, a well-validated tumor antigen with elevated levels of expression in multiple tumor types.

BT8009 is a Nectin-4 Bicycle toxin conjugate (BTC®) designed to overcome the significant toxicity associated with other toxin conjugate approaches. In the ongoing Phase 1/2 Duravelo-1 study involving heavily pre-treated patients, BT8009 showed:

  • A promising response profile with a 38% objective response rate (ORR) in 26 patients with metastatic urothelial cancer (mUC) receiving 5 mg/m2 weekly and who had not been treated with enfortumab vedotin (EV-naïve), and a median duration of response (mDOR) of 11.1 months in 10 patients with 5 responders still on therapy. This includes 1 complete response, 7 partial responses and 2 unconfirmed responses.
  • Encouraging initial data in other cancers such as ovarian, triple-negative breast (TNBC) and non-small cell lung (NSCLC) that support further expansion beyond mUC.
  • An emerging differentiated safety profile seen in 113 patients with various types of cancer receiving 5 mg/m2 weekly, with treatment-related adverse events being primarily low in frequency and severity.
    • Adverse events of interest such as ocular disorders, peripheral neuropathy and skin reactions were low in frequency and severity. Importantly, treatment-related peripheral neuropathy was low-grade and often reversible, including zero cases of severe (≥Grade 3) peripheral sensory neuropathy (damage to the nerves that carry sensations like pain to the brain).
    • In 34 EV-naïve mUC patients, treatment-related adverse events and adverse events of interest were also low, similar to the 5 mg/m2 weekly total safety study population. Notably, there were zero cases of severe (≥Grade 3) ocular disorders, peripheral neuropathy or skin reactions.
    • In 7 heavily pre-treated mUC patients receiving BT8009 5 mg/m2 weekly in combination with pembrolizumab, an acceptable tolerability profile was observed with limited severe treatment-related adverse events, including zero cases of severe (≥Grade 3) ocular disorders, peripheral neuropathy or skin reactions.

Bicycle Therapeutics plans to initiate the Phase 2/3 Duravelo-2 registrational trial of BT8009 in patients with mUC in 1Q 2024 and intends to complete the Phase 1/2 Duravelo-1 open-label study across multiple cancers.

BT7480 is a Nectin-4 targeted CD137 agonist designed to overcome immune agonist toxicities and activate the immune system in Nectin-4 expressing tumors. Clinical development has been guided by safety considerations observed with first-generation CD137 agonists, the novelty of the Bicycle® platform technology and the U.S. Food and Drug Administration’s (FDA) Project Optimus initiative. In a Phase 1 clinical trial, BT7480 showed:

  • In 33 patients assigned to receive one of 9 different doses of BT7480, an emerging differentiated safety and tolerability profile with a low number of severe adverse events. The majority of the patients studied had tumors that expressed Nectin-4 and CD137.
  • Two unconfirmed partial responses in heavily pre-treated patients with cervical cancer.
  • Three prolonged stable disease (≥7 months) in NSCLC and anal cancer.

Bicycle Therapeutics will continue to define the recommended Phase 2 dose (or maximum dose) and dose range for BT7480, with a view to enroll combination cohorts with checkpoint inhibitors in 2024. These data will inform the design of a Phase 2 trial that could support potential accelerated approval of BT7480.

Ephrin-A2 (EphA2) Portfolio

Bicycle Therapeutics is advancing one clinical program, BT5528, and one preclinical program, BT7455, targeting EphA2, a tumor antigen that is widely expressed in many cancers and has historically been difficult to target. BT7455 is an EphA2-targeted CD137 agonist whose Investigational New Drug-enabling work is ongoing.

BT5528 is an EphA2 BTC® designed to overcome the significant toxicity associated with other toxin conjugate approaches that have been unsuccessful. In an ongoing Phase 1/2 clinical trial enrolling patients with various solid tumors, BT5528 showed:

  • In 109 patients, an acceptable emerging tolerability profile with few severe adverse events. This was also seen in 74 patients receiving 6.5 mg/m2 every other week, the dose being studied in various tumors in the expansion cohorts. Importantly, unlike other EphA2-targeted agents, no bleeding events were observed in patients treated with BT5528 at any dose.
  • Encouraging early activity in mUC with a 39% ORR in 18 patients receiving 6.5 mg/m2, 8.5 mg/m2 or 10 mg/m2 every other week, and an mDOR of 4 months in 7 patients with one responder still on therapy. This includes 6 partial responses and 1 unconfirmed response.
  • Encouraging emerging data in other cancers such as ovarian, gastric/upper gastrointestinal and head and neck that are informing the dose optimization strategy and further development.

Given the promising tolerability profile of BT5528 at 6.5 mg/m2 every other week and in line with the FDA’s Project Optimus initiative, Bicycle Therapeutics has now commenced further cohorts in mUC and ovarian cancer to test 5 mg/m2 weekly, which will inform decisions about dose optimization, potential drug combinations and expansion into other tumor types. Data from these cohorts are expected to be available in the second half of 2024.

Platform Opportunities

The company will highlight its progress in developing its next generation of Bicycle® conjugates, including:

  • Next generation BTCs: Focusing on designing linkers specifically for BTCs, which may provide enhanced payload release into the tumor. The company plans to select a BTC® clinical candidate using next-generation technology in the second half of 2024.
  • Bicycle Radio Conjugates (BRC™): Developing a pipeline of novel binders with optimized properties for radioisotope delivery. For example, preclinical studies of a BRC targeting MT1-MMP, a high-value target in cancer treatment, showed potent anti-tumor activity and a favorable tolerability profile. Over 2024, Bicycle Therapeutics intends to generate early human imaging data from its wholly owned BRC pipeline.
  • Beyond Oncology: Successfully exploring other therapeutic applications of the Bicycle® platform technology using non-dilutive funding, demonstrating the platform’s plug-and-play approach to precision targeting. For example, through partnerships with Dementia Discovery Fund and Ionis Therapeutics, the company demonstrated that delivery of therapies to the central nervous system, including across the blood brain barrier, can be achieved with Bicycle® molecules. Bicycle Therapeutics will continue to develop Bicycle® molecules to address disease outside of oncology through innovative partnerships.