Bicycle Therapeutics : April 2026 Corporate Presentation

Published: 2026-04-20 07:24:06 ET BCYC

Published on 04/20/2026 at 07:24 am EDT

April 2026

Unique Platform

Developing Bicycle® molecules - a novel synthetic peptide modality that can potentially deliver any payload to any target

Technology based on

Nobel Prize-winning science

Strong intellectual property portfolio

Internal Programs

Focused on oncology, with multiple clinical molecules

Nuzefatide pevedotin (formerly BT5528) targeting historically undruggable target with ADCs, progressing into Phase 2 in PDAC

Radioligand pipeline addressing novel cancer targets MT1-MMP and EphA2

Zelenectide pevedotin demonstrating differentiated safety profile and strong antitumor activity in mUC

Validating Partnerships

Extending use of platform into diverse range of therapeutic areas such as radioligands and non-core areas such as neurology

Ambitious Company

Deeply experienced team

Located in Cambridge, UK, and

Lexington, MA

NASDAQ: BCYC

Cash and cash equivalents of

$628.1M as of December 31, 2025, with expected financial runway into 2030

Bicycle® molecule

Short linear peptide

Scaffold

Chemical modification

with scaffold

Bicycle® Phage Display

Discovery

Peptide & Medicinal

Multi-specific Bicycle® molecules

Bicycle Drug Conjugates

Potential Bicycle® Medicines

Monomeric Bicycle® molecules

Bicycle

Radioligands

Chemistry

Diverse Bicycle® phage libraries (>1020)

Natural Amino Acids

Linear peptide

Bicycle® molecule

Optimize Bicycle® monomers

Non-natural Amino Acids

Build and Optimize Therapeutic Bicycle® molecules

Easy conjugation of Linkers and Payloads

Targeting and Effector

Bicycle® molecules

Bicycle® molecules are designed

to mimic an antibody's paratope

The Bicycle® Advantage:

Optimal properties for precision guided therapeutics

Tumor antigen

Small size for rapid tissue penetration

Tunable PK for optimized target vs. systemic exposure

Antibody Bicycle®

molecule

High affinity and selectivity for precision

targeting and tumor retention

Precision Guided Therapeutics

Greater Tolerability

Enhanced Patient Benefit

Rapid tumor penetration

Minimized systemic exposure

Minimal off-target activity Tumor retention

Improved adherence to optimized dosage regimen

Better combinability

Longer responses

Deeper/broader responses

Our goal: Help patients live longer and live well

We are building a robust pipeline of Bicycle therapeutics

Target

Molecule

Study

Indication

Preclinical

IND enabling/ human imaging

Early-Stage Development

Late-Stage Development

Internal oncology programs

nuzefatide pevedotin

Ph2 open label

PDAC

(BDC® molecule)

Ph1/2 combo with nivolumab

2L+ mUC

EphA2

68Ga BIA molecule

Utility study

All comers

EphA2 BRC®

molecule

Preclinical

MT1-MMP

68Ga BIA molecule

BT1702 (BRC®

molecule, 212Pb)

Utility study

IND enabling

All comers

zelenectide

Duravelo-2

Ph2 combo with pembrolizumab

Ph1/2 combo with nivolumab

1L mUC

2L+ mUC

All comers

pevedotin

Nectin-4

(BDC® molecule)

BT7480 (Bicycle

TICA®)

Additional targets

Undisclosed

Preclinical

Partnered programs

PLN

ION826/AZD4063

Phase 1

Cardiometabolic disease

1L: 1st line; 2L+: 2nd line or later; IND: Investigational New Drug; mUC: metastatic urothelial cancer; PDAC: pancreatic ductal adenocarcinoma; BIA: Bicycle® Imaging Agent; BDC®: Bicycle®

Drug Conjugate: BRC®: Bicycle® Radioconjugate; TICA® : Bicycle tumor-targeted immune cell agonist®; PLN: phospholamban gene

Nuzefatide pevedotin

Nuzefatide pevedotin (BT5528): a potential EphA2 targeted therapy

Selective Bicycle® molecule to EphA2 antigen

~4 kDa versus ~150+ kDa for ADCs

Toxin (MMAE), shielded when bound to BDC®

Protease cleavable linker

Novel, potent and selective small peptide Targets EphA2 without treatment limiting

toxicity seen with other modalities

Differentiated pharmacology to deliver validated payload

Lead tumor being studied (Ph2):

Pancreatic

Additional tumors of interest:

Head and neck, Urothelial

Generally well-tolerated at clinically active doses in Phase 1/2 trial

Potential for combinability and long mDOR

Nuzefatide is a differentiated candidate targeting the 'undruggable'

BDC: Bicycle drug conjugate; EphA2: ephrin type-A receptor 2; mDOR: median duration of response; MMAE: monomethyl auristatin E; Ph2: Phase 2

Multiple antibody-based approaches to target EphA2 have been unsuccessful due to toxicity or lack of efficacy

Molecule

MEDI-547

(Medimmune)

ATRC-301

(Atreca)

MM-310

(Merrimack)

DS-8895a

(Daiichi Sankyo)

Format

Antibody drug conjugate

scFv antibody fragments conjugated to docetaxel-based liposomes

Afucosylated antibody

Development status

Discontinued during phase 1

Discontinued preclinically

Discontinued during phase 1

Discontinued after phase 1

"The study was stopped before cohort 2 enrollment due to treatment-related bleeding and coagulation events"1

Non-human primate toxicology study "revealed safety signals, including bleeding"2

"Phase 1 study unable to reach optimal therapeutic index" due to "cumulative peripheral neuropathy"3

"Limited therapeutic efficacy at doses evaluated and 89Zr-DS-8895a demonstrated low tumour uptake."4,5

Successfully targeting EphA2 could provide new ways to address unmet need across tumor types

1Annunziata et al, Invest New Drugs. 2013, 31(1): 77-84; 2Atreca Inc., press release Nov 10, 2022; 3Merrimack Pharmaceuticals Inc., press release April 4, 2019; 4Gan et al, Invest New

Patient demographics and clinical characteristics for nuzefatide pevedotin in key dose range finding cohorts

Patient characteristic

All patients (N=161)

Nuzefa 6.5 mg/m2 Q2W (n=74)

Nuzefa 8.0 mg/m2 Q2W (n=12)

Nuzefa 6.5 mg/m2 Q2W

+ nivo 480 mg Q4W (n=14)

Age, median years (range)

63 (33-83)

63 (33-78)

61 (48-74)

69 (56-83)

Sex, n (%) Male Female

71 (44)

90 (56)

34 (46)

40 (54)

7 (58)

5 (42)

11 (79)

3 (21)

Race, n (%)

White

Black or African American Other

129 (80)

5 (3)

27 (17)

55 (74)

19 (26)

12 (100)

13 (93)

1 (7)

Baseline ECOG PS, n (%)

66 (41)

95 (59)

30 (40)

44 (60)

5 (42)

7 (58)

8 (57)

6 (43)

Tumor type, n (%)

Urothelial

Non-small cell lung Head and neck Pancreas

51 (32)

14 (9)

17 (11)

9 (6)

20 (27)

9 (12)

8 (11)

1 (1)

3 (25)

9 (75)

14 (100)

Prior lines of therapy in the locally advanced/metastatic setting, median (range)

3 (1-13)

2 (1-5)

2 (1-6)

Prior therapy, n (%) Checkpoint inhibitor Platinum Antimetabolite

Antibody-drug conjugate Taxane

Antineoplastic

FGFR inhibitor

95 (59)

146 (91)

115 (71)

36 (22)

100 (62)

49 (30)

6 (4)

44 (60)

66 (89)

53 (72)

16 (22)

50 (68)

23 (31)

2 (3)

11 (92)

8 (67)

2 (17)

8 (67)

3 (25)

14 (100)

13 (93)

12 (86)

11 (79)

1 (7)

2 (14)

Data as of 09Feb2026. ECOG PS: Eastern Cooperative Oncology Group performance status; FGFR: fibroblast growth factor receptor; nivo: nivolumab; nuzefa: nuzefatide pevedotin; Q2W: once every two weeks; Q4W: once every 4 weeks

Nuzefatide pevedotin is generally well tolerated at clinically active doses both as a monotherapy and in combination with nivolumab

Category, n (%)

All patients (N=161)

Nuzefa 6.5 mg/m2 Q2W (n=74)

Nuzefa 8 mg/m2 Q2W (n=12)

Nuzefa 6.5 mg/m2 Q2W

+ nivo 480 mg Q4W (n=14)

TEAEs

Grade ≥3

157 (98)

87 (54)

70 (95)

35 (47)

12 (100)

7 (58)

14 (100)

11 (79)

TESAEs

Grade ≥3

52 (32)

47 (29)

17 (23)

16 (22)

3 (25)

8 (57)

TRAEs

Grade ≥3

143 (89)

42 (26)

68 (92)

16 (22)

12 (100)

3 (25)

Nuzefa-related

Nivo-related

12 (86)

4 (29)

10 (71)

3 (21)

TRSAEs

Grade ≥3

14 (9)

12 (8)

6 (8)

5 (7)

1 (7)

2 (14)

Dose modifications

TEAEs leading to dose reduction TEAEs leading to drug interruption TEAEs leading to drug withdrawn

18 (11)

68 (42)

4 (3)

2 (3)

18 (24)

2 (3)

3 (25)

5 (42)

Nuzefa

Nivo

2 (14)

10 (71)

6 (43)

2 (14)

Very few adverse events led to the withdrawal of nuzefatide across the dose range finding cohorts

Data as of 09Feb2026. Nivo: nivolumab; nuzefa: nuzefatide pevedotin; Q2W: once every 2 weeks; Q4W: once every 4 weeks; TEAE: treatment-emergent adverse event; TESAE: treatment-emergent serious adverse event; TRAE: treatment-related adverse event; TRSAE: treatment-related serious adverse event.

Nuzefatide pevedotin shows a differentiated safety profile with no bleeding to date and few Grade 3 toxicities associated with ADCs

TRAEs of clinical interesta,b, n (%)

All Patients (N=161)

Nuzefa 6.5 mg/m2 Q2W (n=74)

Nuzefa 8.0 mg/m2 Q2W (n=12)

Nuzefa 6.5 mg/m2 Q2W

+ nivo 480 mg Q4W (n=14)

All Grades

Grade ≥3

All Grades

Grade ≥3

All Grades

Grade ≥3

All Grades

Grade ≥3

Peripheral neuropathyc

31 (19)

13 (18)

2 (17)

2 (14)

Skin reactionsd

23 (14)

11 (15)

2 (17)

5 (36)

Neutropeniae

13 (8)

5 (3)

6 (8)

2 (3)

1 (8)

Eye disordersf

5 (3)

2 (3)

1 (7)

Hemorrhageg

EphA2 targeted ADCs have been plagued with severe bleeding, while MMAE bearing ADCs have been limited by Grade 3 peripheral neuropathy and skin reactions

Data as of 09Feb2026. aIncludes AEs related to nuzefa; bPatients can have multiple PT within a category; cBased on MedDRA SMQ [Broad] for peripheral neuropathy; dIncludes the MedDRA SMQ [broad] for Severe Cutaneous Adverse Reactions (SCAR) and MedDRA SOC of Skin and Subcutaneous Tissue disorders, excluding alopecia; ePreferred term; fSOC of Eye disorders; gHemorrhage (excluding laboratory terms) [narrow] SMQ. ADC: antibody drug conjugate; EphA2: ephrin type-A receptor 2; MedDRA: Medical Dictionary for Regulatory Activities; nivo: nivolumab; nuzefa: nuzefatide pevedotin; PT: Preferred Term; Q2W: once every 2 weeks; Q4W: once every 4 weeks; SCAR: Severe Cutaneous Adverse Reactions; SMQ: Standardized

Nuzefatide pevedotin monotherapy is active across a range of EphA2+ tumor types in the late line setting

Waterfall plot by EphA2 status 6.5 mg/m2 nuzefa Q2W in dose expansion Efficacy evaluable analysis set

150

140

130

120

110

100

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

150

140

130

120

110

100

-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

Urothelial (N=11) Ovarian (N=12) Gastric/ Upper GI (N=6)

H&N (N=7) NSCLC (N=7) TNBC (N=9)

EphA2 IHC

status

- (TPS ≤1)

Data as of 09Feb2026. EphA2: ephrin type-A receptor 2; GI: gastrointestinal; H&N: head and neck carcinoma; NSCLC: non-small cell lung cancer; nuzefa: nuzefatide pevedotin; Q2W: once every 2 weeks; TNBC: triple-negative breast cancer; TPS: Tumor Proportion Score

Nuzefatide has exquisite selectivity for EphA2 over other Eph family members

Nuzefatide has a differentiated profile from ADCs that often bind to additional Fc receptors and proteins

Nuzefatide pevedotin binds only to EphA2, and clinically shows rapid delivery and tumor retention with limited systemic exposure

Nuzefatide only binds EphA2

Membrane protein array: no binding of nuzefatide @1µM to 5,527 other proteins, including Fc receptors

Tumor 10x

plasma at 24h

Human PK following treatment with nuzefatide at 5 mg/kg, the estimated minimum efficacious dose (MED)

Nuzefatide human PK shows delivery & retention of payload in tumor, with rapid clearance from circulation

Ligand-binding domain

Binding affinity (SPR KD nM)

EphA2

1.2

EphA1

>5000

EphA3

>5000

EphA4

>5000

EphA5

>5000

EphA6

>5000

EphA7

>5000

EphB4

>5000

Data generated internally using commercial TMA samples and CST

mAb (clone D4A2), detecting the intracellular domain of EphA21

EphA2 is a widely expressed tumor antigen with highest expression in pancreatic cancer

All data shown uses EphA2 CST 6997 mAb (Cell Signaling Technology) to detect the intracellular domain of EphA2 using commercially available tissue microarray (TissueArray) and whole slides (Discovery Life Science). TPS ≥ 1 (membrane and/or cytoplasmic) was used to determine positivity

Indication

% TPS ≥1

Mean H-score

Pancreas

63.4% (59/93)

74.7

HNSCC

61.4% (43/70)

19.9

Bladder

50.0% (28/56)

34.8

Rectal adeno

47.3% (43/91)

44.7

Esophagus

37.1% (26/70)

38.8

Melanoma

36.7% (29/79)

88.8

GEJ

28.0% (23/82)

12.6

CRC

25.2% (35/139)

35.3

EphA2 is expressed in a range of high value tumors including pancreas, HNSCC and urothelial

Bicycle Advantage in PDAC

Bicycle approach overcomes high intra-tumoral pressure & dense stroma

SUV values showing tracer uptake in patient with lymphonodal and hepatic metastasized pancreatic ductal adenocarcinoma

EphA2 is a clinically validated target, and the Bicycle advantage can potentially apply in pancreatic cancer

EphA2 PDAC

expression

PDAC sensitivity to MMAE

Patient identification strategy

Highly expressed in PDAC TPS>1 (>60% of PDAC)

PDAC PDX models responsive to MMAE

68Ga BIA5501 >80%1 EphA2

+ve in human imaging

We are exploring nuzefatide pevedotin in a Phase 2 2L+ pancreatic cancer study

BT5528-201 Schema

Eligibility

Metastatic recurrent

PDAC*

Failed one current line of therapy

Measurable disease on RECIST v1.1

ECOG PS 0 or 1

Taxane naïve

Evaluable archival or fresh tumor biopsy

Stage 1

Stage 2

BT5528 8 mg/m2 Q2W (n=25)

If ≥ 4 responses

proceed to stage 2

BT5528 8 mg/m2

Q2W (n=9)

If 2 or 3 responses the study may also proceed if efficacy signal seen in an EphA2+ subgroup

BT5528 8 mg/m2 Q2W

(n=14 EphA2+)

Prescreening

required

Primary Endpoint

ORR by investigator using RECIST v1.1

*Metastatic recurrent PDAC 2L+ to

include any KRASi in either 1L or 2L

8 mg/m2 Q2W selected as preferred monotherapy dose based on acceptable safety profile and enhanced ability to deliver payload to tumor1

1Bicycle Therapeutics unpublished data. 2L: second-line; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EphA2: ephrin type-A receptor 2; ORR:

Pancreatic cancer could provide an important opportunity for nuzefatide pevedotin to bring a first-in-class treatment to patients

Annual Incidence (Stages 0-IV)1,2,3

510,992 Worldwide

65,176 United States

Rank among all cancers (Incidence)

12 Worldwide

11 United States

Patients diagnosed at advanced stage

80%

5-year Survival

11% / 3%

Pancreatic cancer

Stages 0-IV Stage IV

1Oracle Life Sciences CancerMPact, Treatment Architecture US Pancreatic Cancer, Sep 2025. Sources: Based on CancerMPact® Patient Metrics U.S., accessed Feb 2025. Ranking is based on relative incidence of 32 tumors in the US; 2World Health Organization, International Agency for Research on Cancer: Cancer Fact Sheet, Pancreas (gco.iarc.who.it) 3Li, Lancet,

Disclaimer

Bicycle Therapeutics plc published this content on April 20, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on April 20, 2026 at 11:23 UTC.