On January 14, 2021 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 progress updates for its wholly owned, next-generation Bicycle Toxin Conjugates (BTCs) targeting oncological indications, as well as its novel, fully synthetic Bicycle tumor-targeted immune cell agonists (TICAs) (Press release, Bicycle Therapeutics, JAN 14, 2021, View Source [SID1234573993]).

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"We are excited to start 2021 by announcing clinical progress across our internal oncology pipeline, with both our next-generation Bicycle Toxin Conjugates (BTCs) and our Bicycle tumor-targeted immune cell agonists (TICAs), positioning us for multiple inflection points over the coming year," said Kevin Lee, Ph.D., Chief Executive Officer of Bicycle Therapeutics. "Our lead program, BT1718, remains on track in the Cancer Research UK sponsored Phase IIa trial, and notably, we have observed preliminary signs of anti-tumor activity in the Phase I monotherapy portion of our trial of BT5528, including one partial response and additional evidence of tumor reductions. We continue to make strong progress with BT8009 as we expect to begin recruiting at our first clinical site outside of the US shortly, and we are encouraged by its initial pharmacokinetic (PK) profile. In our immuno-oncology pipeline, we expect BT7480, for which preclinical data has indicated a potential unique anti-tumor killing mechanism, to enter the clinic this year, and we have identified new TICAs targeting natural killer (NK) cells, which we are moving into lead optimization. Overall, we are pleased with our progress as we pursue our goal of realizing the full potential of our disruptive Bicycle technology, and we look forward to providing additional updates on our oncology pipeline, as well as our partnered programs beyond oncology, throughout the year."

BT1718, a potential first-in-class BTC targeting a key tumor antigen MT1-MMP, is progressing in the Phase IIa portion of the Cancer Research UK sponsored Phase I/IIa clinical trial in patients with advanced solid tumors

Patient enrollment in the Phase IIa portion of the Phase I/IIa trial sponsored by Cancer Research UK’s Center for Drug Development remains ongoing and is proceeding according to schedule. In this Phase IIa portion of the trial, all patients are MT1-MMP-positive based on a prespecified tumor membrane H-score. To date, the percentage of patients determined to be MT1-MMP-positive at the pre-specified cutoff is consistent with previous translational research findings. Enrollment is ongoing at four clinical sites, with additional sites expected to begin enrolling patients during the first half of 2021. Patients are currently being enrolled into two solid tumor cohorts, one in squamous non-small cell lung cancer (NSCLC) and the other in an all-comers "basket" cohort. Depending on results from these first two cohorts, Cancer Research UK may initiate up to two additional cohorts.
In the Phase I portion of the Phase I/IIa trial, BT1718 was generally well-tolerated. As previously announced, based on the Phase I trial results, 20 mg/m2 of BT1718 administered once weekly was selected as the Phase IIa dose. This dose is within the efficacious dose range predicted by preclinical models, in which an equivalent dose level was associated with complete responses. With once-weekly dosing, BT1718 appeared tolerable, with manageable adverse events. Though the primary objective of the Phase I portion of the BT1718 trial was evaluating safety and tolerability in an unselected group of patients with advanced solid tumors, some signs of anti-tumor activity were observed:

At doses of between 9.6 mg/m2 and 32.0 mg/m2 administered once-weekly, 13 out of 24 response evaluable patients at the eight week timepoint exhibited best response of at least stable disease. Ten of these 13 patients had a greater than 10% reduction in at least one target lesion, including a tumor reduction of 68% observed in one patient, a reduction that meets the RECIST Version 1.1 criteria of a partial response.
BT5528, a BTC targeting EphA2, a target for which prior antibody-based approaches have been unsuccessful, is currently being administered at doses within the predicted therapeutic range, with preliminary signs of anti-tumor activity

Doses of BT5528 administered to date appear well-tolerated in the ongoing Phase I portion of the Phase I/II trial. BT5528 has been tolerated up to 8.5mg/m2 weekly, which Bicycle believes, based on pre-clinical studies, is toward the top of the therapeutic range, with transient neutropenia observed at that dose. Dose finding for the Phase II portion of the trial remains ongoing and additional weekly and every other week doses are currently being explored. Currently administered doses are in the predicted therapeutic range, delivering over 15-fold more toxin than MedImmune’s EphA2 antibody-drug conjugate (ADC) MEDI-547. In addition, and in contrast to the toxicities observed with MEDI-547, no signs of coagulopathy have been observed to date.
Clinical PK profile of BT5528 is consistent with preclinical predictions. Early data received from tumor biopsies reveal that 24 hours after infusion of BT5528, tumor levels of the MMAE cytotoxin payload are approximately 10-fold greater than the corresponding plasma levels. Emerging, qualitative metabolite identification data from the clinical trial supports the hypothesis that BTCs undergo reduced hepatic metabolism and are eliminated renally.
Preliminary signs of anti-tumor activity have been observed. Although dosing continues to be refined, Bicycle has observed preliminary findings consistent with anti-tumor activity. An EphA2 immunohistochemistry (IHC) assay was deployed during 2020, enabling pre-selection of patients in the Phase I portion of the trial. Since implementation of the IHC assay, patients are prospectively screened and are eligible for enrollment based on a prespecified H-score. To date, two EphA2 selected patients have enrolled in the trial, one of whom was response evaluable.

In the response evaluable prospectively screened EphA2 positive patient, a urothelial patient currently receiving 6.5mg/m2 of BT5528 every other week, whose prior lines of therapies included both a PD-1 inhibitor and enfortumab vedotin, a 43% reduction in target lesions was observed at the first radiologic response assessment, constituting a partial response under RECIST version 1.1 criteria. Reductions in non-target lesions were also observed, and the patient remains enrolled in the trial.

In addition, an ovarian cancer patient, enrolled prior to implementation of the EphA2 assay, currently receiving 4.4mg/m2 of BT5528 every week, who had been previously treated with chemotherapy, a vascular endothelial growth factor (VEGF) inhibitor and a poly ADP ribose polymerase (PARP) inhibitor, has achieved an ongoing 25% reduction in target lesions, constituting stable disease. The patient, first dosed in May 2020, has completed eight cycles of BT5528 and remains enrolled in the trial. Subsequently the patient was retrospectively analyzed for EphA2 status and determined to be positive, but below the current enrollment H-score cutoff.
Enrollment in the Phase I/II trial of BT5528 remains on track and additional sites are expected to begin enrolling patients in 2021. Enrollment continues to track to plan, with five clinical sites currently active, including four in the United States and one now recruiting patients in the United Kingdom. Bicycle expects that up to five additional sites will be opened in the first half of this year, primarily in the United Kingdom and Europe. A planned total of up to 17 worldwide sites is expected to be active in 2021, with sites prioritizing the enrollment of eligible EphA2-positive patients in the monotherapy cohorts.
BT8009, a Nectin-4 targeting BTC with a potentially differentiated profile as compared to a Nectin-4 targeting antibody-drug conjugate (ADC) is progressing in the Phase I/II trial, with the first clinical site outside of the United States expected to open for patient recruitment this quarter

BT8009 is advancing in the Phase I portion of the Phase I/II clinical trial. Early clinical data supports a PK profile that is consistent with both preclinical predictions and data to date from Bicycle’s ongoing Phase I trial of BT5528, which utilizes the same linker and toxin payload.
Enrollment in the Phase I/II trial of BT8009 remains on schedule. As planned, sites in the United States opened first, with two sites initially recruiting patients. The first clinical site outside of the United States is expected to open for patient recruitment this quarter. During the first half of 2021, Bicycle expects up to nine additional sites to open, primarily in Canada and the United Kingdom, with further geographic expansion during the year. In total, Bicycle expects up to 21 clinical sites to be open, with prioritization given to enrolling appropriate Nectin-4-positive patients in the monotherapy cohorts.
Further clinical updates for all three BTC programs – BT1718, BT5528, and BT8009 – are expected during 2021

Novel, fully synthetic TICAs continue to advance, with BT7480 expected to enter the clinic this year and new TICA programs targeting natural killer (NK) cells identified and moving into lead optimization

IND preparation for BT7480, a novel TICA, remains on track, for a potential clinical start during the second half of 2021. BT7480 is a fully synthetic TICA that contains Bicycles targeting Nectin-4 and the key immune cell receptor CD137. BT7480 has been shown in preclinical models to rapidly penetrate tumors, have anti-tumor activity, and induce immune memory specific to the implanted tumor. IND-enabling activities for BT7480 are ongoing and the Phase I clinical trial is on track to commence in the second half of the year.
Early immuno-oncology (I-O) discovery efforts have resulted in the identification of TICA candidates targeting NK cells. Bicycle Therapeutics is moving these programs into lead optimization and will focus its early I-O development efforts in 2021 on advancing these novel Bicycles.