On September 7, 2022 Bicycle Therapeutics plc (NASDAQ: BCYC), a biotechnology company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported Phase I dose escalation top-line results from its Phase I/II trial of BT5528, a BTC targeting EphA2, in patients with advanced solid tumors (Press release, Bicycle Therapeutics, SEP 7, 2022, View Source [SID1234619126]).

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"The therapeutic profile from the dose escalation portion of the Phase I/II trial of BT5528 in patients with late-line disease suggests both differentiated safety and promising activity, most notably in ovarian and urothelial cancers," said Dominic Smethurst, Chief Medical Officer of Bicycle Therapeutics. "Significant safety concerns seen with antibody drug conjugate (ADC) approaches have limited the ability to effectively address EphA2, a target which correlates with tumor progression and is overexpressed in many cancers. Based on BT5528’s promising and differentiated safety profile, we hope to demonstrate the true therapeutic potential of this target, this program and our broader Bicycle Toxin Conjugate (BTC) platform."

"Smaller size, tumor penetration, pharmacokinetic and other qualities distinguish BT5528 and other members of our BTC platform from traditional toxin delivery systems and may confer significant advantages," said Kevin Lee, Ph.D., Chief Executive Officer of Bicycle Therapeutics. "Clinical data emerging from our BT5528 study continues to elucidate these potential advantages, and supports the continued, rapid advancement of our Bicycle-targeted therapeutics platform, all with the ultimate goal of creating unique, impactful medicines that transform the lives of patients. Enrollment continues on schedule in the expansion portion of this trial, and we anticipate providing further updates next year."

BT5528, a BTC targeting EphA2, a target for which prior antibody-based approaches have been unsuccessful, has demonstrated anti-tumor activity and differentiated tolerability. Bicycle has established an RP2D dose (6.5mg/m2 every other week) and is enrolling ongoing expansion cohorts.

Preliminary signs of anti-tumor activity observed. A total of 45 patients (15 at RP2D 6.5mg/m2 every other week) were dosed with a median of four prior lines of therapy. Expression of EphA2 was evaluated retrospectively using an immunohistochemistry (IHC) assay.
Amongst these patients, anti-tumor activity was observed in urothelial and ovarian cancer patients.
A total of 21 ovarian cancer patients were dosed. Of these, nine response evaluable patients were determined to be EphA2-positive based on the IHC assay. The median prior lines of therapy for these nine patients was four.
Among these nine late-line ovarian cancer patients, six patients (67%) were observed to have a reduction in target lesions, including one patient with a complete response (CR) and one with a partial response (PR) under Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, resulting in a disease control rate (DCR) of 67% and an overall response rate (ORR) of 22%.
A total of eight urothelial patients were dosed. Of these, three response evaluable patients were determined to be EphA2-positive based on the IHC assay and of these three patients, two were observed to have tumor reductions constituting a PR under RECIST version 1.1 (ORR and DCR of 67%).
BT5528 well-tolerated at RP2D of 6.5mg/m2 every other week. Low, or no, levels of incidence of neutrophil count decrease, peripheral neuropathy, skin rash and eye disorders were reported. Low-grade GI treatment-related events were those most commonly reported amongst the 15 patients at this dose. There were three Grade 3 and above events at the RP2D: diarrhea (n=1, 7%) and anemia (n=2, 13%). In addition, and in contrast to the toxicities observed with EphA2 ADCs, Bicycle has observed no signs of treatment-related coagulopathy to date in any patient.
Bicycle advancing BT5528 in ongoing expansion cohorts. In June 2022, Bicycle announced the dosing of the first patient in the part B dose expansion portion of the Phase I/II trial. Up to 56 patients will be enrolled in the initial expansion cohorts, with the ability to further expand enrollment based on results from these cohorts. Dose expansion is taking place in urothelial (n=14) and ovarian (n=14) cancers as well as in a basket cohort of other solid tumors (n=28), including non-small cell lung, triple-negative breast, head and neck, and esophageal cancers.
Conference Call Details

Bicycle Therapeutics will host a conference call and webcast today, September 7, 2022, at 8:30 a.m. ET to review the BT5528 trial data. To access the call, please dial (877) 870-4263 (domestic) or (412) 317-0790 (international) at least 10 minutes prior to the start time and ask to be joined to the Bicycle Therapeutics call. A live webcast of the presentation will be available on the Investors & Media section of the Bicycle website, bicycletherapeutics.com.