7 October 2021 - - UK-based biopharmaceutical company Bicycle Therapeutics plc (NASDAQ: BCYC) has provided a clinical update of its wholly-owned, next-generation Bicycle Toxin Conjugates, reporting interim Phase I trial results for BT5528 and preliminary findings from the ongoing dose escalation portion of the BT8009 clinical trial.

BT5528, a BTC targeting EphA2, a target for which prior antibody-based approaches have been unsuccessful, has demonstrated preliminary anti-tumor activity. Bicycle has established an RP2D range and is pursuing enrollment in expansion cohorts

Preliminary signs of anti-tumor activity observed. A total of 24 patients were dosed both prior to, and after, the implementation of the EphA2 immunohistochemistry assay, with a median of seven prior lines of therapy. Amongst these patients, preliminary anti-tumor activity was observed in urothelial and ovarian cancer patients.

A total of two BT5528 monotherapy urothelial patients were dosed. Both were observed to have tumor reductions constituting a partial response under Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The administered doses in these patients ranged from 6.5mg/m2 to 10 mg/m2 every other week.

A total of eight BT5528 monotherapy ovarian cancer patients were dosed. Of these eight, five were determined to be EphA2-positive based on the IHC assay.

Anti-tumor activity was observed in four of the five patients, including one that constituted a partial response under RECIST version 1.1 criteria. The range of administered doses in these patients was 6.5- 8.5mg/m2 every other week.

Doses of BT5528 administered to date have been tolerated in the ongoing Phase I portion of the Phase I/II trial, the company said.

In addition, and in contrast to the toxicities observed with MedImmune's EphA2 antibody-drug conjugate MEDI-547, Bicycle has observed no signs of coagulopathy to date.

Based on the Phase I results, Bicycle has established an RP2D range. BT5528 has been dosed up to 8.5mg/m2 every week and 10mg/m2 every other week.

Some mild and transient neutropenia was observed at 8.5mg/m2 every week, although this did not constitute a DLT. At 10mg/m2 every other week, two DLTs were observed (Grade 3 fatigue and Grade 3 pneumonitis).

The most common Grade 3 and above events were neutropenia, anemia and pneumonitis and there were two Grade 5 events: tumor lysis syndrome and renal failure caused by GI-related dehydration.

Based on the totality of the findings, the RP2D is expected to be in the range of 6.5 mg/m2 to 8.5mg/m2 every other week, a dose that is believed to be within the therapeutic range based on both preclinical studies and preliminary clinical anti-tumor activity.

Based on the findings from the Phase I trial, Bicycle plans to initiate expansion cohorts in urothelial and ovarian cancers as well as a basket that includes head and neck, non-small cell lung, gastroesophageal and triple negative breast cancers in 2022.

The trial will enroll up to 56 patients in the initial expansion cohorts, with the ability to further expand enrollment based on the results of the initial expansion cohorts.

BT8009, a Nectin-4 targeting BTC with a potentially differentiated profile as compared to a Nectin-4 targeting ADC has shown preliminary anti-tumor activity in the ongoing Phase I portion of its Phase I/II trial.

Preliminary signs of anti-tumor activity in urothelial patients observed. As of September 30, a total of 11 response evaluable urothelial cancer patients have been dosed in monotherapy cohorts of 2.5mg/m2 and 5.0mg/m2 weekly in the ongoing trial.

Of these, four patients were in the 2.5mg/m2 dose cohort and seven in the 5.0mg/m2 dose cohort. Prior to enrollment, all patients had previously received at least two prior lines of therapy, with a median of two and a range of two-to-six prior therapies.

A total of four patients were observed to have tumor reductions that constituted partial responses under RECIST 1.1, with a range in tumor reductions from 37% to 89% among these patients.

Four response evaluable patients were dosed at 2.5mg/m2 weekly. Among these four patients, three patients were observed to have at least stable disease, with a disease control rate of 75% and one patient was observed to have a tumor reduction of 37%, meeting the criteria of a partial response under RECIST 1.1.

Seven response evaluable patients were dosed at 5.0mg/m2 weekly. Among these seven patients, five were observed to have at least stable disease, with a disease control rate of 71% and three patients were observed to have tumor reductions meeting the criteria of a partial response under RECIST 1.1. The magnitude of tumor reductions ranged from 44% to 89%.

Dose escalation remains ongoing. At both 2.5mg/m2 weekly and 5.0mg/m2 weekly, BT8009 has been tolerated, with no DLTs observed to-date.

At 5.0mg/m2 weekly, BT8009 is estimated to administer over 35% more MMAE per four-week dosing cycle compared to the antibody-based drug conjugate, enfortumab vedotin. The escalation remains ongoing, and patients are currently being enrolled in 7.5mg/m2 weekly and every other week cohorts.

BT8009 enrollment ongoing. A total of 14 clinical sites are active globally, including nine outside of the United States. Bicycle said it expects to have up to 21 sites active this year.