Updated monotherapy data for Nectin-4 targeting
zelenectide pevedotin in metastatic urothelial cancer (mUC) showed
a promising 45% overall response rate (ORR), 11.1 months median
duration of response and a generally well-tolerated safety
profile
EphA2-targeting BT5528 demonstrated an emerging
differentiated safety profile and antitumor activity in patients
with advanced solid tumors, including a 45% ORR in mUC 6.5 mg/m2
every two weeks dose expansion cohort
Relatively low frequency and severity of
treatment-related peripheral neuropathy following monotherapy with
Bicycle Toxin Conjugates® zelenectide pevedotin and BT5528, with
patients often able to continue therapy without modification
BT7480 demonstrated a favorable safety profile
and preliminary antitumor activity in advanced Nectin-4-associated
solid tumors
Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical
company pioneering a new and differentiated class of therapeutics
based on its proprietary bicyclic peptide (Bicycle®) technology,
today announced updated Phase 1/2 clinical results for Bicycle
Toxin Conjugate (BTC®) zelenectide pevedotin (formerly BT8009) in
metastatic urothelial cancer (mUC); BTC molecule BT5528 in advanced
solid tumors, such as mUC and ovarian; and Bicycle Tumor-Targeted
Immune Cell Agonist® (Bicycle TICA®) BT7480 in advanced solid
tumors. The company also shared an analysis of peripheral
neuropathy, a key adverse event of interest associated with
monomethyl auristatin E (MMAE)-based drug conjugates, in patients
treated with BTC molecules. These data will be presented during a
poster session at the European Society for Medical Oncology (ESMO)
Congress 2024 in Barcelona today.
“We are pleased that the data presented at ESMO continue to
support the promising response and differentiated safety profiles
of our Bicycle molecules. Importantly, our lead investigational
therapy zelenectide pevedotin continues to demonstrate an overall
response rate that is in line with other drug conjugates used to
treat metastatic urothelial cancer, but with a marked improvement
in tolerability. Overall, we believe the data continue to
demonstrate the potential of our Bicycle technology platform to
create differentiated medicines designed to help patients not only
to live longer but also to live well,” said Kevin Lee, Ph.D., CEO
of Bicycle Therapeutics. “These clinical data are just the first
set of updates that we have guided to delivering this year. In the
coming months, we look forward to sharing initial imaging data from
our growing radiopharmaceutical pipeline and additional data for
zelenectide pevedotin in bladder, breast and lung cancer.”
ESMO 2024 Data Highlights
Zelenectide pevedotin is a BTC® molecule targeting
Nectin-4, a well-validated tumor antigen, designed to overcome the
significant toxicity associated with other drug conjugate
approaches. Updated results from the ongoing Phase 1/2 Duravelo-1
trial evaluating 5 mg/m2 weekly of zelenectide pevedotin
monotherapy in 45 mUC patients who had not previously been treated
with enfortumab vedotin showed:
- Among 38 efficacy-evaluable patients, a 45% overall response
rate (ORR), including 1 confirmed complete response and 16 partial
responses (13 confirmed). Stable disease was maintained in 9
patients, and 12 patients experienced progressive disease.
- A median duration of response of 11.1 months among the 14
patients with confirmed responses.
- An emerging differentiated safety profile, particularly around
adverse events of interest such as peripheral neuropathy, skin
reactions and eye disorders. Notably, there were no Grade ≥3
treatment-related adverse events (TRAEs) of peripheral neuropathy
(any kind), skin reactions or eye disorders, and patients with
pre-existing peripheral neuropathy were unlikely to develop
worsening peripheral neuropathy during treatment with zelenectide
pevedotin.
The global Phase 2/3 Duravelo-2 registrational trial of
zelenectide pevedotin in patients with mUC is currently enrolling.
Additional data updates for zelenectide pevedotin in combination
with pembrolizumab in first line mUC and monotherapy in late line
triple-negative breast cancer and non-small cell lung cancer
(NSCLC) are planned for later this year.
BT5528 is a BTC molecule targeting EphA2, a tumor antigen
that is widely expressed in many cancers and has historically been
difficult to target using other drug conjugate approaches. Updated
results from the ongoing Phase 1/2 trial evaluating 6.5 mg/m2 every
two weeks and 5 mg/m2 weekly of BT5528 monotherapy in patients with
advanced solid tumors showed:
- Among 113 efficacy-evaluable patients, a 12% ORR in patients
with advanced solid tumors.
- The highest anti-tumor activity in mUC, with a 34% ORR in all
efficacy-evaluable patients enrolled in the dose escalation and
expansion cohorts. Among patients receiving 6.5 mg/m2 every two
weeks, a 31% ORR was observed in the dose escalation and expansion
cohort and a 45% ORR was observed in the expansion cohort only. A
lower but acceptable ORR of 27% was observed in patients receiving
5 mg/m2 weekly.
- No objective responses in patients with ovarian cancer who
received 5 mg/m2 weekly. However, 5 patients maintained stable
disease.
- A suggested correlation between EphA2 expression and response.
Among 14 patients with mUC who had available immunohistochemistry
and response data, a 43% ORR was observed in EphA2-positive
patients compared to a 20% ORR in EphA2-negative patients.
- A clearly differentiated emerging safety profile, with none of
the hemorrhage events or hematological toxicities that have been
associated with other EphA2-targeting drug conjugates.
The company has begun assessing BT5528 at 6.5 mg/m2 every two
weeks in combination with nivolumab. Results from this cohort are
expected in 2025.
Low rates of treatment-related peripheral neuropathy (TRPN)
following monotherapy treatment with BTC molecules zelenectide
pevedotin or BT5528. In 149 patients treated with zelenectide
pevedotin and 74 patients treated with BT5528 from ongoing Phase
1/2 studies, results showed:
- TRPN in 28% of patients treated with zelenectide pevedotin and
19% of patients treated with BT5528, nearly all of which were low
grade (1-2). One Grade 3 event (neuralgia) was reported in a
patient treated with zelenectide pevedotin following prior therapy
with enfortumab vedotin. No Grade 3-4 events were observed for
BT5528.
- Among zelenectide pevedotin-treated patients with peripheral
neuropathy at baseline, 80% did not develop TRPN during
treatment.
- TRPN resulted in few dose modifications across the overall
patient populations for zelenectide pevedotin and BT5528, and no
drug withdrawals were necessary for either BTC molecule.
- TRPN had completely resolved in 14% (zelenectide pevedotin) and
21% (BT5528) of patients, and 26% and 21%, respectively, had some
resolution or improvement at time of reporting, though
post-treatment follow-up was limited. Median time to resolution or
improvement of TRPN was 2.2 weeks for zelenectide pevedotin and 1.7
weeks for BT5528.
The data support the hypothesis that the antibody-drug construct
may be a primary driver of peripheral neuropathy rather than MMAE
toxicity as was previously believed.
BT7480 is a Nectin-4 targeted CD137 agonist designed to
overcome immune agonist toxicities and activate the immune system
in Nectin-4 expressing tumors. Initial data from the Phase 1/2 dose
escalation trial evaluating BT7480 in patients with advanced solid
tumors showed:
- Among 39 patients assigned to receive one of 10 different doses
(0.002-3.5 mg/kg weekly) of BT7480, an emerging differentiated
safety and tolerability profile with a low number of severe adverse
events. Low rates of Grade ≥3 TRAEs (5%) and of treatment-related
severe adverse events (TRSAEs) (8%) were reported, with no such
events among those receiving the highest dose of 3.5 mg/kg.
- Best overall response of stable disease in 13 patients, 5 of
whom had NSCLC. Stable disease was prolonged (>8 months) in 3
patients, 2 with NSCLC and 1 with anal cancer. There were 2
unconfirmed partial responses, both in patients with cervical
cancer.
- Preliminary biomarker analyses that support BT7480 dual
targeting of CD137 and Nectin-4 as demonstrated by enhanced immune
cell activation, aligned with the proposed mechanism of action of
BT7480.
As the maximum tolerated dose for BT7480 has not yet been
reached, the company is continuing dose exploration in combination
studies, starting with nivolumab.
The posters are available in the Publications section of the
Bicycle Therapeutics website.
About Bicycle Therapeutics Bicycle Therapeutics is a
clinical-stage pharmaceutical company developing a novel class of
medicines, referred to as Bicycle® molecules, for diseases that are
underserved by existing therapeutics. Bicycle molecules are fully
synthetic short peptides constrained with small molecule scaffolds
to form two loops that stabilize their structural geometry. This
constraint facilitates target binding with high affinity and
selectivity, making Bicycle molecules attractive candidates for
drug development. The company is evaluating zelenectide pevedotin
(formerly BT8009), a Bicycle® Toxin Conjugate (BTC®) targeting
Nectin-4, a well-validated tumor antigen; BT5528, a BTC molecule
targeting EphA2, a historically undruggable target; and BT7480, a
Bicycle Tumor-Targeted Immune Cell Agonist® (Bicycle TICA®)
targeting Nectin-4 and agonizing CD137, in company-sponsored
clinical trials. Additionally, the company is developing Bicycle®
Radio Conjugates (BRC™) for radiopharmaceutical use and, through
various partnerships, is exploring the use of Bicycle® technology
to develop therapies for diseases beyond oncology.
Bicycle Therapeutics is headquartered in Cambridge, UK, with
many key functions and members of its leadership team located in
Cambridge, Mass. For more information, visit
bicycletherapeutics.com.
Forward Looking Statements This press release may contain
forward-looking statements made pursuant to the safe harbor
provisions of the Private Securities Litigation Reform Act of 1995.
These statements may be identified by words such as “aims,”
“anticipates,” “believes,” “could,” “estimates,” “expects,”
“forecasts,” “goal,” “intends,” “may,” “plans,” “possible,”
“potential,” “seeks,” “will” and variations of these words or
similar expressions that are intended to identify forward-looking
statements, although not all forward-looking statements contain
these words. Forward-looking statements in this press release
include, but are not limited to, statements regarding Bicycle’s
anticipated progress across its R&D pipeline and the
advancement of its product candidates, including zelenectide
pevedotin, BT5528 and BT7480; the anticipated progression of
Bicycle’s clinical trials and the method and timing of announcement
of data from clinical trials and program updates for clinical
candidates; the potential of the Bicycle technology platform to
create differentiated medicines; the development of potential
radiopharmaceutical or other product candidates using Bicycle’s
technology through various partnerships; and the therapeutic
potential for Bicycles in oncology and other applications. Bicycle
may not actually achieve the plans, intentions or expectations
disclosed in these forward-looking statements, and you should not
place undue reliance on these forward-looking statements. Actual
results or events could differ materially from the plans,
intentions and expectations disclosed in these forward-looking
statements as a result of various factors, including: uncertainties
inherent in research and development and in the initiation,
progress and completion of clinical trials and clinical development
of Bicycle’s product candidates; the risk that Bicycle may not
realize the intended benefits of its technology or partnerships;
timing of results from clinical trials; whether the outcomes of
preclinical studies will be predictive of clinical trial results;
the risk that trials may have unsatisfactory outcomes; potential
adverse effects arising from the testing or use of Bicycle’s
product candidates; and other important factors, any of which could
cause Bicycle’s actual results to differ from those contained in
the forward-looking statements, are described in greater detail in
the section entitled “Risk Factors” in Bicycle’s Quarterly Report
on Form 10-Q filed with the Securities and Exchange Commission
(SEC) on August 6, 2024, as well as in other filings Bicycle may
make with the SEC in the future. Any forward-looking statements
contained in this press release speak only as of the date hereof,
and Bicycle expressly disclaims any obligation to update any
forward-looking statements contained herein, whether because of any
new information, future events, changed circumstances or otherwise,
except as otherwise required by law.
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version on businesswire.com: https://www.businesswire.com/news/home/20240914550368/en/
Investors and media: Stephanie Yao SVP, Investor
Relations and Corporate Communications ir@bicycletx.com
857-523-8544
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