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CURRENT REPORT
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| Item 8.01 | Other Events. |
On April 11, 2022, Bicycle Therapeutics plc (the “Company”) issued a press release announcing interim Phase I results from the Phase I/II trial of BT8009. A copy of the press release is filed as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated into this Item 8.01 by reference.
Also on April 11, 2022, the Company hosted a conference call and webcast to discuss the above-mentioned interim clinical trial results. A copy of the presentation used for the conference call and webcast is attached as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated into this Item 8.01 by reference.
Item 9.01 Financial Statements and Exhibits
| (a) | Exhibits |
| 99.1 | Press Release issued April 11, 2022 |
| 99.2 | Presentation dated April 11, 2022 |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Date: April 12, 2022 | BICYCLE THERAPEUTICS PLC | |
| By: | /s/ Lee Kalowski | |
| Name: | Lee Kalowski | |
| Title: | Chief Financial Officer | |
Exhibit 99.1
Bicycle Therapeutics Announces Interim BT8009 Phase I Clinical Trial Results at the 2022 AACR Annual Meeting
- 50% confirmed overall response rate, including one (13%) confirmed complete response in eight urothelial cancer patients dosed at 5.0mg/m2 weekly
- Median duration of response not yet reached in the 2.5mg/m2 and 5.0mg/m2 weekly cohorts; four of five responders in these cohorts still on therapy after at least 24 weeks
- Tolerability profile maintained over time, with low incidence of skin, ocular and neurological toxicities showing potential for differentiation from antibody-based approaches
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- Company to Host Conference Call Today at 8:30 a.m. ET
CAMBRIDGE, England, & BOSTON, April 11, 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, today announced interim Phase I results from the Phase I/II trial of BT8009, a second-generation BTC™ targeting Nectin-4. The results were presented in an oral presentation on Sunday, April 10 at the 2022 American Association for Cancer Research Annual Meeting in New Orleans, LA.
“Since our initial BT8009 Phase I/II trial interim results last year, we are encouraged to see BT8009’s promising profile endure over time. Over the last six months, the preliminary anti-tumor findings have been confirmed, the initial responses have deepened and remained durable, and the tolerability profile remains unchanged,” said Dominic Smethurst, MRCP, Chief Medical Officer of Bicycle Therapeutics. “We believe BT8009 has the potential to offer clinically meaningful differentiation compared to currently available therapies and we look forward to advancing the program once the escalation phase is complete.”
“As previously hypothesized, we believe that the differentiated pharmacokinetic profile of BTCs has the potential to deliver improved outcomes for patients and it is pleasing to see these clinical data mature and with it, the promise for a potentially industry-leading product profile,” said Kevin Lee, Ph.D., Chief Executive Officer. “We look forward to providing additional updates on BT8009 as well as updates from our broad Bicycle oncology pipeline this year.”
As of March 7, 2022, thirty-seven patients have been dosed in the Phase I/II trial of BT8009. A total of twelve response evaluable urothelial cancer (UC) patients have been dosed in monotherapy cohorts of 2.5mg/m2 and 5.0mg/m2 weekly in the ongoing trial.
| · | Four response evaluable UC patients were dosed at 2.5mg/m2 weekly. Among these four patients, one patient was observed to have tumor reductions constituting a confirmed partial response (PR) and two patients were observed to have stable disease (SD), reflecting a 25% overall response rate (ORR) and 75% disease control rate (DCR) in patients in this cohort. |
| · | Eight response evaluable UC patients were dosed at 5.0mg/m2 weekly. Among these eight patients, four patients were observed to have a confirmed complete response (CR) or PR, including one patient with a CR and three patients with a PR, and two patients with SD, reflecting a 50% ORR and a 75% DCR in UC patients for this cohort. Prior to enrollment, all patients in this cohort had previously received at least two prior lines of therapy, with a median of three. |
| · | The median duration of response has not yet been reached in either the 2.5 mg/m2 or 5.0mg/m2 cohort. Four of the five responders have ongoing Response Evaluation Criteria in Solid Tumors (RECIST) tumor responses. As of the March 7, 2022 data cutoff date, all four of these patients have a treatment duration of at least 24 weeks and all four remain on therapy. |
| · | Tolerability profile remains consistent with earlier results from this trial. No dose limiting toxicities have been observed in the 2.5mg/m2 or the 5.0mg/m2 cohorts, and with longer-term follow-up, incidence of skin and eye toxicity, neuropathy and hyperglycemia remains low. |
| · | Phase I dose escalation is ongoing. Exploration of additional doses and frequencies continues, and Bicycle intends to provide further updates this year. |
Conference Call Details
Bicycle Therapeutics will host a conference call and webcast today at 8:30 a.m. ET to review the data being presented. To access the call, please dial (800) 377-9118 (domestic) or (409) 937-8920 (international) and provide the Conference ID 2775710. A live webcast of the presentation will be available on the Investors & Media section of the Bicycle website, bicycletherapeutics.com.
About Bicycle Therapeutics
Bicycle Therapeutics (NASDAQ: BCYC) is a clinical-stage biopharmaceutical company developing a novel class of medicines, referred to as Bicycles, for diseases that are underserved by existing therapeutics. Bicycles 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 Bicycles attractive candidates for drug development. Bicycle is evaluating BT5528, a second-generation Bicycle Toxin Conjugate (BTC™) targeting EphA2; BT8009, a second-generation BTC targeting Nectin-4, a well-validated tumor antigen; and BT7480, a Bicycle TICA™ targeting Nectin-4 and agonizing CD137, in company-sponsored Phase I/II trials. In addition, BT1718, a BTC that targets MT1-MMP, is being investigated in an ongoing Phase I/IIa clinical trial sponsored by the Cancer Research UK Centre for Drug Development. Bicycle is headquartered in Cambridge, UK, with many key functions and members of its leadership team located in Lexington, Massachusetts. 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 advancement of its product candidates, including BT8009, and participation in the AACR Annual Meeting. 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 intentions disclosed in these forward-looking statements as a result of various factors, including: Bicycle’s abilities to meet other anticipated deadlines presented by the ongoing COVID-19 pandemic; uncertainties inherent in the initiation and completion of clinical trials and clinical development 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, and which are described in greater detail in the section entitled “Risk Factors” in Bicycle’s Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) on March 1, 2022, 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.
Investors:
David Borah, CFA
VP, Capital Markets & Investor Relations
david.borah@bicycletx.com
617-203-8300
Media:
Consilium Strategic Communications
Sukaina Virji or Mary-Jane Elliott
bicycle@consilium-comms.com
Exhibit 99.2
BT8009 clinical trial update NASDAQ: BCYC April 2022 Exhibit 992 SP1
This presentation 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 . All statements other than statements of historical facts contained in this presentation are forward - looking statements, including statements regarding our future financial or business performance, conditions, plans, prospects, trends or strategies and other financial and business matters ; our current and prospective product candidates, planned clinical trials and preclinical activities, current and prospective collaborations and the timing and success of our development of our anticipated product candidates . Forward - looking statements are neither historical facts nor assurances of future performance . Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our development plans, our preclinical and clinical results, our plans to initiate clinical trials and the designs of the planned trials and other future conditions, and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward - looking statements . These risks and uncertainties include, but are not limited to, risks related to the ongoing COVID - 19 pandemic, the risk that any one or more of our product candidates will not be successfully developed or commercialized, the risk of cessation or delay of any ongoing or planned clinical trials, the risk that we may not realize the intended benefits of our technology, including that we may not identify and develop additional product candidates for our pipeline, the risk that we may not maintain our current collaborations or enter into new collaborations in the future, or that we may not realize the intended benefits of these collaborations, the risk that our product candidates or procedures in connection with the administration thereof will not have the safety or efficacy profile that we anticipate, the risk that prior results will not be replicated or will not continue in ongoing or future studies or trials, the risk that we will be unable to obtain and maintain regulatory approval for our product candidates, the risk that the size and potential of the market for our product candidates will not materialize as expected, risks associated with our dependence on third - parties, risks regarding the accuracy of our estimates of expenses, risks relating to our capital requirements and needs for additional financing, and risks relating to our ability to obtain and maintain intellectual property protection for our product candidates . For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward - looking statements, see the section entitled “Risk Factors” in our Annual Report on Form 10 - K, filed with the Securities and Exchange Commission on March 1 , 2022 , as well as in other filings we may make with the SEC in the future, as well as discussions of potential risks, uncertainties and other important factors in our subsequent filings with the Securities and Exchange Commission . New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties . Except as required by applicable law, we do not plan to publicly update or revise any forward - looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise . 2 Forward - looking statements
Agenda 3 Introduction Kevin Lee Chief Executive Officer Technology overview Nick Keen Chief Scientific Officer BT8009 clinical experience to date Dominic Smethurst Chief Medical Officer Q&A Executive Management Team
Deeply experienced team Located Cambridge UK and Lexington, MA ~119 Employees * NASDAQ: BCYC Cash balance $438.7M * (expected cash runway into 2024) Clinical stage biopharma company pioneering Bicycles – a new differentiated class of innovative medicines 4 Focused on oncology and immuno - oncology with multiple Phase I/II clinical assets (BT5528, BT8009 and BT7480). BT5528 and BT8009 have shown preliminary signs of anti - tumor activity. Trial updates for BT5528 and BT8009 in 2022. * as of December 31, 2021 Extending the clinical utility of Bicycle ® platform into diverse range of therapeutic areas. Generating Bicycles – a novel synthetic peptide modality that enables complex previously undruggable targets to be drugged. Bicycle ® modular format platform based on Nobel Prize science. Strong intellectual property portfolio. Unique Platform Internal Programs Validating Partnerships Ambitious Company
Robust proprietary and partnered pipeline 5 Target / Product Partner / Sponsor Indication Modality Pre - clinical IND - enabling Phase I Phase II Internal programs BT5528 (EphA2) Oncology Bicycle ® Toxin Conjugate BT8009 (Nectin - 4) Oncology Bicycle ® Toxin Conjugate BT7480 (Nectin - 4/CD137) Immuno - oncology Bicycle TICA Œ BT7455 (EphA2/CD137) Immuno - oncology Bicycle TICA Œ Partnered programs THR - 149 (Kallikrein inhibitor Bicycle) Ophthalmology BT1718 (MT1 - MMP ) Oncology Bicycle ® Toxin Conjugate BT7401 (multivalent CD137 systemic agonist) Immuno - oncology Undisclosed Immuno - oncology Inhaled Bicycles Respiratory Novel anti - infectives Anti - infectives Novel CNS targets CNS Novel neuromuscular targets Neuromuscular
Bicycles are designed to combine the advantages of both small molecules and antibodies 6 Bicycle ® Small molecule Antibody Small size Yes – 1.5 - 2kDa Yes – <0.8kDa No – >150kDa Specificity High Low Multiple Chemical synthesis (NCEs) Yes Yes No Rapid tissue penetration Yes Yes No Complex protein targets druggable Yes Limited Yes Route of elimination Renal Liver Liver
MWt of 1.5 - 2kDa 50 - 100x smaller than antibodies High selectivity Allows more potent toxin to be delivered directly to tumor BTCs – preclinical data indicates higher potency and specificity with fewer side effects than ADCs 7 Antibody Bicycle ® 0.001 0.010 0.100 1.000 0 12 24 36 48 60 72 [Tissue] ( uM ) Time (h) BTC plasma Toxin tumor Toxin plasma Specificity Tumor targeting via antigen Toxin Large amount of cytotoxic payload can be delivered Linker Release of toxin directly into tumor via cleavable linker Bicycle ® Toxin Conjugate (BTC Œ ) PET Imaging 40 - 60min
BT8009 Monotherapy
Key takeaways from phase I dose escalation trial to date * 9 Promising clinical activity seen at 5mg/m 2 weekly; dose tolerated, with potential for differentiated and industry - leading product profile • 50% ORR and 75% disease control, including 1 (13%) complete response • Durable responses, with tumor reductions maintained over time • No DLTs, low incidence of skin toxicity, ocular toxicity and neuropathy 7.5mg/m 2 weekly cohort identified as a non - tolerated dose, with GI and fatigue related ‘soft DLTs’ being observed As predicted from preclinical data, BT8009 demonstrates linear pharmacokinetics. In contrast to ADCs, it also demonstrates a short terminal half - life. Alternative dosing frequencies being explored while nearing a recommended Phase 2 dose Expect to provide further updates on clinical progress later in 2022 * All BT8009 data as of 7Mar22
Dose escalation progress and strategy 10 Dose finding 2.5mg/m 2 QW (68%) 5mg/m 2 QW (135%) 7.5mg/m 2 Q2W (100%) 7.5mg/m 2 QW (200%) Further exploration of dosing and frequency MMAE equivalents of 1.25mg/kg Padcev/cycle Clinical activity seen at all weekly doses Soft DLTs Well tolerated Dose and regimen optimization 50% ORR; well - tolerated with low incidence of skin tox, neuropathy and ocular
Demographics Total N=37 Age, years, median (range) 66 (44 - 83) Sex, n (%) Male 22 (59%) Female 15 (41%) ECOG, n (%) 0 (Good performance status) 15 (41%) 1 22 (59%) Prior therapies, median 3 11 Overview of key demographics for all patients enrolled in BT8009 phase I dose escalation trial
Demographics Total N=37 Tumor type Breast 4 (11%) Esophageal 1 (3%) Head/Neck 2 (5%) Lung 5 (14%) Ovarian 1 (3%) Pancreatic 6 (16%) Urothelial 18 (49%) 12 Overview of disease history for all patients enrolled in BT8009 phase I dose escalation trial
Responses * observed in 2.5, 5 and 7.5mg/m 2 phase I dose escalation in response evaluable urothelial cancer patients 13 2.5mg/m 2 QW (N=4) • 1 of 4 responses (25% ORR) • 59% tumor reduction • Deepened from 37% at 30Sept21 • Remains on therapy; approaching 11 months • 2 of 4 stable disease • 75% disease control 5mg/m 2 QW (N=8) • 4 of 8 responses (50% ORR) • 1 complete response • 3 partial responses • 2 of 8 stable disease • 75% disease control • Greater detail on next slide 7.5mg/m 2 Q2W (N=2) • Well tolerated 7.5mg/m 2 QW (N=2) • 1 PR prior to dose reduction • 1 stable disease * Responses under response evaluation criteria in solid tumors (RECIST) version 1.1 Update of First Two Cohorts Newer Two Cohorts
Responses * observed in 5mg/m 2 QW cohort phase I dose escalation in response - evaluable urothelial patients 14 * Responses under response evaluation criteria in solid tumors (RECIST) version 1.1 Urothelial Responses • 4 responses in 8 patients • 1 Complete Response • 3 Partial Responses • 71% tumor reduction (100% reduction in target lesion) • 65% tumor reduction • 54% tumor reduction • Median DoR not reached • 3 responses ongoing • 1 progression at ~3 months
Comparison of complete responder pre - dose tumor images with tumor images after six months treatment (5mg/m 2 QW) 15 Lung lower lobe left Lung lower lobe right Baseline Follow - up 1 Follow - up 2 Follow - up 3 Target lesions were reduced by 100% after four months of BT8009 treatment Disappeared Disappeared Disappeared Disappeared
Phase I interim results from enfortumab vedotin (Padcev ® ) 16 100% patients pre - screened 60% patients ≥2 prior therapies ≥≥ Median PFS and DoR both 16 weeks ORR 10/33 or 30%
Data from BT8009 interim phase I dose escalation trial to date in response - evaluable urothelial cancer patients 17 2.5mg/m 2 5mg/m 2 No of patients 4 8 Median age 75 67 ≥2 prior lines (%) 4 (100%) 8 (100%) IHC pre - screen (%) 0 0 Partial or Complete Response (ORR %) 1 (25%) 4 (50%) Stable Disease or better (DCR %) 3 (75%) 6 (75%) Median duration of response (weeks) Not reached Not reached
Overview of adverse events observed in BT8009 phase I dose escalation trial across all patients 18 Preferred Term Incidence ( ≥ 15%) Fatigue 40.5% Nausea 37.8% Diarrhea 32.4% Pyrexia 32.4% Anemia 32.4% Decreased appetite 32.4% Constipation 29.7% Urinary tract infection 27.0% Neutrophil count decreased 24.3% Asthenia 24.3% Abdominal pain 21.6% Pruritus 18.9% Alopecia 18.9% Back pain 16.2% Hypokalemia 16.2% Hypomagnesmia 16.2%
Summary of adverse event information from Padcev ® FDA label 19 Adverse Event Median time to onset (months) * Padcev incidence * Padcev severity ( Gr≥3) * Which trial(s) N subjects Skin tox 0.6 55% 13% All 680 Neuropathy 4.6 52% 4% All 680 Ocular disorders 1.6 40% N/A EV - 201, EV - 101, EV - 102 384 Hyperglycemia 0.6 14% 7% All 680 Pneumonitis 2.9 3% 1% All 680 *Data from Padcev FDA approved product label
Overview of key adverse events observed in BT8009 phase I dose escalation trial across all cohorts 20 Adverse Event Incidence Severity ( Gr≥3) Related Skin tox 19% 0% 14% Neuropathy 24% 3% 19% Ocular disorders 3% 0% 3% Hyperglycemia 8% 0% 5% Febrile neutropenia 0% 0% 0% Pneumonitis 0% 0% 0%
Other adverse events of interest in BT8009 phase I dose escalation trial across all cohorts 21 Adverse Events Incidence Severity (Gr≥3) Related Neutropenia 30% 14% 30% Gastrointestinal Disorders: Nausea Diarrhea Vomiting 38% 32% 11% 3% 5% 3% 36% 24% 11%
Potential efficacy in other tumor types will be explored more thoroughly in Phase II expansion trial 22 Demographics Total N=37 Tumor type Breast 4 (11%) Esophageal 1 (3%) Head/Neck 2 (5%) Lung 5 (14%) Ovarian 1 (3%) Pancreatic 6 (16%) Urothelial 18 (49%) • 1 SD at 7.5mg Q2W. Disappearance of non - target lesions • 1 SD at 2.5mg. 9+ months on therapy • 1 SD at 7.5mg QW. 6+ months on therapy
Key takeaways from phase I dose escalation trial to date 23 Promising clinical activity seen at 5mg/m 2 weekly; dose tolerated, with potential for differentiated and industry - leading product profile • 50% ORR and 75% disease control, including 1 (13%) complete response • Durable responses, with tumor reductions maintained over time • No DLTs, low incidence of skin toxicity, ocular toxicity and neuropathy 7.5mg/m 2 weekly cohort identified as a non - tolerated dose, with GI and fatigue related ‘soft DLTs’ being observed As predicted from preclinical data, BT8009 demonstrates linear pharmacokinetics. In contrast to ADCs, it also demonstrates a short terminal half - life. Alternative dosing frequencies being explored while nearing a recommended Phase 2 dose Expect to provide further updates on clinical progress later in 2022