Results of an ongoing Phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC)Johann S. De Bono1, Lawrence Fong2, Tomasz M. Beer3, Xin Gao4, Daniel M. Geynisman5, Howard A. Burris III6, James Fredric Strauss7, Kevin Dale Courtney8, David I. Quinn9, David James VanderWeele10, Yifah Yaron11, Che-Leung Law11, Mark N. Stein12

1Royal Marsden Hospital and The Institute of Cancer Research, Sutton, UK, 2University of California, San Francisco, CA, USA, 3Oregon Health and Science University, Portland, OR, USA, 4Massachusetts General Hospital, Boston, MA, USA, 5Fox Chase Cancer Center, Philadelphia, PA, USA, 6Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA, 7Mary Crowley Cancer Research Center/Texas Oncology, Dallas, TX, USA, 8UT Southwestern Harold C. Simmons Comprehensive Cancer Center, Dallas, Tx, USA, 9USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 10Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA, 11Harpoon Therapeutics, South San Francisco, CA, USA, 12Columbia University, New York, NY, USA

• HPN424 is a prostate-specificmembrane antigen (PSMA)-targeting T cell engager, engineeredwith three binding domains:• PSMA (for tumor binding)• Albumin (for half-life extension)• CD3 (for T cell engagement)

• HPN424 is constructed as a small,globular protein (~50kDa) to enableefficient solid tumor penetrationwith prolonged half-life andexcellent stability

• HPN424 binds monovalently to CD3and PSMA, minimizing non-specificT-cell activation

• These features are designed to increase the therapeutic index compared to earliergenerations of T cell engagers by minimizing off-target toxicities

Figure 1. HPN424 Mechanism of Action

Table 2. Baseline Characteristics and Demographics

BACKGROUND BASELINE CHARACTERISTICS

TRIAL DESIGN

Target Population• Disease progression on the prior

systemic regimen• At least two prior systemic therapies

approved for mCRPC• Prior chemotherapy allowed, but

not required

Trial Design• Objectives include characterization

of safety, PK, pharmacodynamicsand identification of expansion dose• Tumor assessments performed q9w

and include conventional CT andbone scans and PSA

Dosing, Administration & Exposure• HPN424 administered qw, 1 hour IV

infusion (one cycle = 3 weeks)• Starting dose of 1.3ng/kg

established by minimally anticipatedbiological effect level

Dose Escalation / Expansion, Safety & PK Study in mCRPC

a Includes AEs that were reported as concurrent symptoms of the CRS eventsb CRS Grading according to ASTCT 2019 criteria

PHARMACOKINETICS

• Median of 5 prior systemic therapies, median of 2 prior novel hormonal agents• 73% of patients had prior chemotherapy in metastatic castrate-resistant setting

Age (Years)

Median 70

Range 43 - 91

Race

White 69 (78%)

Black 8 (9%)

Asian 2 (2%)

Other / Not reported

10 (12%)

ECOG Performance Status

0 39 (44%)

1 50 (56%)

PSA (ng/mL) Mean 464Median 129Range 0.1 - 5000

Time Since Diagnosis (Years)

Mean 8.5

Median 6.9

Range 0.9 – 27.1

Stage at Diagnosis (n=75)a

M0 37 (49%)

M1 38 (51%)

Location of Metastases

Bone 78 (88%)

Lymph Node 43 (48%)

Lung 12 (14%)

Liver 10 (11%)

Other Visceral 10 (11%)

Other Non-visceral 4 (5%)

Prior Therapies n (%)Median (Range)

All Prior Therapy 89 (100%) 5 (1 – 12)

Novel Hormonal Therapy

87 (98%) 2 (0 – 4)

Chemotherapy (mCRPC)

65 (73%) 1 (0 – 3)

Immunotherapy 30 (33%) 0 (0 – 3)

Reason for Entering Study (n=64)a

PSA Progression 27 (42%)

PSA & Clinical Progression 3 (5%)

PSA & Radiographic Progression

10 (16%)

Radiographic Progression 24 (38%)

Dose Escalation:

Single Patient

Fixed Dose Escalation:

3 + 3(3 – 6 pts per dose

level)

20 pts treated at RP2D determined in Part 1

Maximum Tolerated Dose (MTD) orRecommended Phase 2 Dose

(RP2D)

Step DosingDose Escalation:

3 + 3(3 – 6 pts per dose

level)

Gr 2 study drug related toxicity

Part 2 – Dose Expansion

• As of April 23, 2021, 89 patients were treated in either fixed dose or step dose arms• Highest target dose evaluated to-date:• Fixed Dose: 160ng/kg• Step Dose: 300ng/kg

CIRCULATING TUMOR CELLS

1.3

Fixed Dose Arm Step Dose Arm

70 patients 19 patients

Target DoseAdministered on Cycle 1 Day 1 and

thereafter

Target DoseAdministered subsequent to Prime

Dose(s)

1.3 – 160ng/kg 225 – 300ng/kg

Table 3. Common Treatment Emergent Adverse Events (TEAEs)by Grade per CTCAE, V5.0

• Maximum-tolerated dose (MTD) has not yet been reached• Dose Limiting Toxicities (DLTs):• Observed at doses ranging from 96 to 300ng/kg• Did not limit escalation• Most Common: Transaminitis G4 (n=6); Cytokine Release Syndrome G3 (n=4)• Majority of events occur with first dose

• No Grade 4 or 5 CRS, no Grade 5 treatment-related AEs• Two of 89 (2%) pts discontinued treatment due to treatment-related AEs

• Fifteen of 74 (20%) patients with at least 6 months of follow-up have remained ontreatment beyond 24 weeks

• One patient experienced confirmed PR per RECIST at 160ng/kg

TIME ON TREATMENT

Figure 3. Time on Treatment Target Dose <120ng/kg Cohorts

Figure 4. Time on Treatment Target Dose >150ng/kg Cohorts

* Intended Target Dose after initiation of Prime Dose(s)

• Dose proportional increase in Cmax• Mean T1/2 with dose group of N>2 is 24 hrs (range of 9 – 70 hrs)• PK parameters: T1/2, CL, and volume of distribution are dose independent suggesting

linear PK kinetics

• Reduction in CTCs was seen in 36 of 64 (56%) patients with available baseline and on-treatment CTC counts; 14 patients had CTC0 response

• At Week 13, 15 of 28 (54%) patients had >30% CTC reduction from baseline, including 5CTC0 responses; 4 of 5 CTC0 responses observed at Target Doses >150ng/kg

Figure 8. Change in CTCs From Baseline

CHEMO-NAÏVE PATIENTS• Median of 5 prior regimens, including median of 2 prior novel AR therapies; median

baseline PSA of 84ng/mL

• Eight of 17 (47%) chemo-naïve patients in castrate-resistant with at least 6 months offollow-up have remained on treatment beyond 24 weeks

• 6 of 20 (30%) patients with >1 post-baseline PSA value showed PSA declines, including 3PSA50 and 1 PSA30 response

SUMMARY

Figure 2. HPN424-1001 Trial Schema

Table 1. Dose Escalation Study Design

ADVERSE EVENTS

Event, n (%) All Grades Grade 3+Cytokine-Related AEsa

Cytokine Release Syndrome (CRS)b 61 (69%) 4 (4%)

Chills 60 (67%) 0 (0%)

Pyrexia 58 (65%) 2 (2%)

Hypotension 35 (39%) 6 (7%)

Infusion Related Reaction (IRR) 20 (22%) 0 (0%)

Flushing 13 (15%) 0 (0%)

Hypoxia 11 (12%) 4 (4%)

Liver Function Tests

AST Increase 28 (31%) 19 (21%)

ALT Increase 26 (29%) 14 (16%)Other Adverse Events

Fatigue 45 (51%) 3 (3%)

Nausea 40 (45%) 1 (1%)

Vomiting 34 (38%) 1 (1%)

Anemia 28 (31%) 10 (11%)

Headache 24 (27%) 0 (0%)

Back Pain 21 (24%) 4 (4%)

Tachycardia 20 (22%) 1 (1%)

Constipation 20 (22%) 0 (0%)

Decreased Appetite 20 (22%) 0 (0%)

a Actual n is indicated where full dataset not available

a CRS Grading according to ASTCT 2019 criteriab 1 patient experienced Grade 3 CRS at first exposure of Target Dose, which occurred in Cycle 2

• HPN424, a novel half-life extended PSMA-targeting T cell engager, is active and generallywell tolerated

• HPN424 has antitumor activity including a confirmed PR per RECIST, PSA declines and CTCreductions

• Treatment duration > 24 weeks observed in 15 of 74 (20%) pts, including 8 of 17 (47%)chemo-naïve patients

• CRS has been transient and manageable with 4% of patients experiencing Grade 3 CRS,no Grade 4 or 5

• CRS and transaminitis events observed most often in Cycle 1, with diminished frequencyand severity in subsequent cycles

• Introduction of step dose regimens has allowed for the administration of higher targetdoses, currently at 300ng/kg

• Assessment of optimal target dose and patient population for expansion ongoing

Figure 5. Chemo-Naïve Patients Time on Treatment

(A) Best CTC Response (B) CTC Response at Week 13

Reference for CTC evaluation at Week 13: Heller G et al. J Clin Oncol. 2017;36:572-580.

• Higher frequency and severity of CRS and transaminitis observed in Cycle 1(Days 1 – 21) compared to Cycle 2 or later• All Grade 3 CRS events occurred with administration of 1st target dose

Table 4. Frequency and Duration of Relevant Adverse Events

Figure 6. Mean (SD) Cycle 1 Day 1 HPN424 Maximum Concentrations Over Priming or Target Dose of 1.3 to 300ng/kg

PSA CHANGES ON TREATMENT

MEASURABLE DISEASE

Figure 7. Patient PSA Values on Treatment

• Fifteen of 74 (20%) pts with >1 post-baseline value had PSA decreases from baselineranging from -2% to -76%, including 4 pts with PSA50 response and 2 pts with PSA30response

• 41 patients of 89 (46%) had measurable disease at baseline, including 34 patients with >1post-treatment protocol scheduled disease assessment• In those 34 evaluable patients, sum of target lesions in 19 of 34 (56%) pts remained

stable or showed reduction, including 1 confirmed partial response per RECIST

PATIENT PROFILESPatient 057, a 75-year old male, diagnosed January 2002

• Initiated HPN424 at 160ng/kg

• Demonstrated RECIST partial response (-32%) at 1st post-baseline scan (Week 9),confirmed PR (-43%) at Week 18, response maintained at Week 36

• Remains on study after 41 weeks of treatment

Baseline Characteristics

ECOG 1 Reason for Study Entry Radiographic Progression

PSA (ng/mL) 39Location of Metastases

Lymph Node

Stage at Diagnosis M0 Prior Therapies ADT, Bicalutamide, Apalutamide

Patient 054, a 66-year old male, diagnosed August 2014

• Initiated HPN424 at 96ng/kg and escalated to 120ng/kg in Cycle 4

• Demonstrated a steady PSA decline over course of treatment, currently -60% PSAdecline from baseline

• Stable disease per RECIST with 18% reduction in target lesion at Week 45

• Remains on study after 45 weeks of treatment

Baseline CharacteristicsECOG 1 Reason for Study Entry Radiographic Progression

PSA (ng/mL) 8.9Location of Metastases

Lymph Node

Stage at Diagnosis M1 Prior TherapiesADT, Docetaxel, Abiraterone,

Enzalutamide, Talazoparib, ATR Inhibitor

CRS TransaminitisCycle 1 Cycle 2+ Cycle 1 Cycle 2+

% of Pts Experiencing Grade 3 - 4 Events

3% 1% 20% 11%

Median Duration of AEs 1 Day 4 Days

b

a

Presented at the American Society of Clinical Oncology Annual Meeting; June 4 – 8, 2021 Abstract #333381 Contact the author at johann.debono@icr.ac.uk for questions or comments

Results of an ongoing Phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC)

Figure 9. Patient 057 Target Lesion Scan

Figure 10. Patient 054 Target Lesion Scan

* Data cut-off at 700% increase