Safety Treatment -emergent AEs (TEAEs) occurred in 25 (96.2%) patients.

First-in-human trial to evaluate safety, PK/PD and initial clinical activity of NM21-1480, an affinity-balanced PD-L1x4-1BBxHSA trispecific antibody: Results of Phase 1 dose escalation David S. Hong 1 , Jason J. Luke 2 , Melissa Johnson 3 , Shirish Gadgeel 4 , Alexander Spira 5 , James CH Yang 6 , Jennifer M. Johnson 7 , Taryn Losch-Beridon 8 , Daniel Snell 8 , Stefan Warmuth 8 , Maureen Cleaver 8 , Elmar vom Baur 8 , David Urech 8 , Peter Lichtlen 8 1 Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 2 Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, USA; 3 Department of Medicine, Sarah Cannon Research Institute, Nashville, USA; 4 Department of Internal Medicine, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, USA; 5 Virginia Cancer Specialists, Fairfax, USA; 6 National Taiwan University and Department of Oncology, National Taiwan University Hospital, Taipei City, Republic of China; 7 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia; 8
Numab Therapeutics AG, Einsiedlerstrasse 34, CH-8820 Wädenswil, Switzerland SITC 2022 Poster # 732
Dose escalation trial design
All patients (N=26)
Patients with
Dose level
Patients, n
DLT
DLTs, n
Treatment:
All grades, n Grade 3, n (%)
Grade 4, n %
- Dose escalation started with an accelerated phase consisting of single-patient cohorts followed by cohorts (%)
0.15 mg
1
0
None of n 3 patients upon occurrence of a first treatment-related AE (TRAE) of CTCAEv5.0 Grade 2, Any TRAE
19 (73.1)
1 (3.8)
1 (3.8)
1.5 mg
1
0
None as guided by a Bayesian Optimal Interval (BOIN) design. TRAE in 10% of patients by preferred term 8 mg
3
0
None
- Efficacy was assessed by on-treatment CT or MRI at Week 8 and every 8 weeks thereafter until disease progression or another discontinuation criterion was met (unless the Infusion-related reaction
8 (30.8)
0 (0.0)
0 (0.0)
24 mg
3
0
None
AST/ALT elevation
3 (11.5)
0 (0.0)
1 (3.8)* investigator elected to treat beyond progression as per protocol-defined criteria). Fatigue
3 (11.5)
0 (0.0)
0 (0.0)
80 mg
5 a
1
Grade 2 Infusion-Related Reaction b Inclusion criteria
240 mg
3
0
None
Table 3. TRAEs occurring in 10% of patients. Data cut-off: 19 September 2022; AEs graded 18 years of age or above
Patients with metastatic/ unresectable solid according to NCI CTCAEv.5.0; *One patient presented with clinically silent Grade 3 AST/ALT elevation 800 mg
9
0
None tumors confirmed by pathology/fresh biopsy, with after 2 months on treatment and 15 days after receiving final dose (patient was stable with -3% Table 4. Summary of DLTs. Data cut-off: 19 Sept 2022. a progressing disease since last therapy and for decrease from baseline sum of diameters [SoD] at Week 8 scans). Liver biopsy confirmed likely non- One patient died due to rapid disease whom there is no available standard of care viral hepatitis. Patient was discontinued and rapidly improved to Grade 1 with budenoside treatment. progression on study Day 20 and was therefore not evaluable for the DLT rate calculation for this Measurable disease according to RECIST 1.1 dose level; b Patient developed a rebound to clinically silent Grade 4 transaminase elevation 57 days after Patient developed a Grade 2 IRR during second infusion. Infusion was stopped and ECOG PS 0-1 receiving final dose of NM21-1480. Event again rapidly improved to Grade 1 with treatment; patient completion of dosing following pre-medication attempted the next day. However, the patient again Adequate renal, liver, and hematologic function is doing well as per September 2022 and has since entered another clinical trial. Concomitant reported subjective symptoms and infusion was not completed. As the patient could not tolerate two Figure 3. TEAEs occurring in 10% of patients. Data cutoff: 19 September 2022; Adverse events alcohol consumption and lack of compliance with steroid treatment was reported during the entire full doses of the assigned dose level, the event was considered a DLT as per protocol. Except for Figure 2. Dose escalation trial design. NM21-1480 administered as intravenous flat dose every 2 weeks until disease graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events period. Due to liver biopsy result, the Grade 4 event was assessed as possibly related to study drug patients described under a. and b., all patients received at least two full doses of their assigned dose progression or unacceptable toxicity during dose escalation. Data cut-off date: 19 September 2022. ECOG PS, Eastern (CTCAE)v.5.0; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase. and thus represents a delayed DLT. and completed the full 28-day DLT evaluation period including all safety examinations. Cooperative Oncology Group Performance Status; RECIST, Response Evaluation Criteria in Solid Tumors. Pharmacokinetics
Pharmacodynamics (PD)
Results:
- Peak concentrations observed shortly after infusion (Figure 4). - Significant increase in various PD Patient characteristics and disposition - Mean terminal half-life after first dose ranged from 6 to 16 days markers vs. baseline observed starting (across doses of 24mg to 800mg). with 24mg dose. - 26 patients were enrolled in the dose escalation part of the trial (Table 1). - PK for doses below 24mg affected by target-mediated drug - Full PD activity maintained over broad - Patients were heavily pretreated, with median (range) of 3.5 (1-10) prior lines of treatment; disposition (TMDD). dose range between 24mg and 800mg 61.5% of patients received prior PD-(L)1 immunotherapy. - Occurrence of IRRs were typically associated with development flat doses. - As of data cut-off date (19SEP2022), treatment ongoing in 1 (3.8%) patient (Table 2). of treatment-emergent anti-drug antibodies (ADAs), generally - PD data strongly suggestive that affinity

• MTD was not reached. observed after 2-6 months on treatment. balancing built into NM21-1480 by design
• Patients discontinued treatment due to the following AEs: Infusion related reaction (n=3; all

- In some patients treated at 24mg to 240mg that developed permits for a broad optimal dose range at Figure 6. Peripheral pharmacodynamic effects induced by NM21-1480. * p<0.05, ADAs, exposure was negatively impacted. Figure 4. NM21-1480 pharmacokinetics for the first two dosing events, which strong 4-1BB agonism is maintained ** p<0.01, *** p<0.001, **** p<0.0001, Student t-test. events Grade 2) and ALT increased (n=1; Grade 4). occurring every 2 weeks. Mean PK values per dose level are shown. Data - Exposure was generally maintained at 800mg despite cutoff:24Aug 2022. at full PD-L1 blockade. - There was a single on-treatment death which was due to rapid disease progression and development of ADAs in some patients. - Soluble 4-1BB (s4-1BB) may be the most predictive and unrelated to treatment. quantitative peripheral PD biomarker dynamically reflecting Receptor Occupancy
4-1BB agonistic activity of therapeutic intervention. 12 Median (range) age, years
63 (27-76)
- Receptor occupancy was measured on circulating CD3-positive - With NM21-1480 treatment, peripheral s4-1BB continues to Median (range) on treatment,
Age groups, n (%)
23.4 (2.7-86.4) including FU, in weeks T cells and is reflective of drug binding to 4-1BB and/or PD-L1 increase over time, i.e., from visit to visit. <65 years
16 (61.5)
(Figure 5).
- Pronounced increase of s4-1BB observed starting with the 65 years
10 (38.5)
- 100% receptor occupancy is maintained for the full dosing 24mg dose of NM21-1480 and is fully maintained up to Female
11 (42.3)
Treatment ongoing, n (%)
1 (3.8) interval at doses of 24mg and greater. 800mg, the highest dose assessed in the study. Cancer type, n (%)
Reason for treatment
- Data suggests that, at 800mg dose, NM21-1480 is highly NSCLC
4 (15.4) discontinuation, n (%) active as a 4-1BB agonist. Figure 7. Peripheral s4-1BB levels increase with treatment duration and Colorectal
4 (15.4)
Progressive disease
21 (80.8)
- 800mg of NM21-1480 is suggested to provide complete correlate with signs of clinical activity. uPR: unconfirmed partial response; HNSCC
3 (11.5)
AE
4 (15.4) blockade of PD-L1. 13 SD: stable disease; SoD: Sum of Diameters (Target Lesions); W: Week Pancreatic
3 (11.5)
Appendiceal
3 (11.5)
Figure 5. NNM21-1480 receptor occupancy on CD3-positive cells for the Other*
9 (34.6)
Median (range) number of NM21first two dosing events, occurringevery 2 weeks. Data cutoff: 24 Aug 2022. 4 (1-21)
ECOG performance status, n (%) 1480 dose infusions
0
7 (26.9)
Efficacy Of 26 patients enrolled, 23 were evaluable for efficacy. Disease control occurred in 12/21 (57%) of Conclusions:
1
19 (73.1)
- NM21-1480 is a next generation immune stimulator that blocks the immune-suppressive PD-L1 axis and simultaneously signals through the immune-stimulatory receptor 4patients treated in the clinically relevant dose range of 24-800mg flat dose. Unconfirmed partial response 1BB, locally restricted to the TME. Median (range) number of prior (uPR) was achieved in one patient with colorectal cancer at study Week 16. 3.5 (1-10)
Median (range) duration of exposure, - In the dose escalation phase of this phase 1/2a study, NM21-1480 demonstrated a well-manageable safety profile and preliminary clinical activity in a heavily pretreated therapies 9.1 (2.1-42.3) in weeks population with advanced solid tumors, the vast majority of which were resistant to earlier checkpoint inhibition therapy, and/or suffered from tumors typically not Prior PD-(L)1 inhibitor treatment, n(%) 16 (61.5) responding to ICIs. - Most TRAEs were mild-to-moderate with only two Grade 3-4 TRAEs occurring in the study. Table 1. Baseline demographics and clinical characteristics Table 2. Patient disposition and exposure NCT04442126, - The most frequent TRAEs were IRRs which were typically associated with development of treatment-emergent ADAs that negatively impacted drug exposure at dose levels NCT04442126, Part A (Dose Escalation). All patients Part A (Dose Escalation). All patients N=26. Data cut-off: between 24mg-240mg, typically after patients were on treatment for 2-6 months. N=26. Data cut-off: 19 September 2022; *Cancer types 19 September 2022; AE: Adverse events; FU: follow-up

• In patients dosed at 800mg, exposure to study drug was maintained despite occurrence of treatment-emergent ADAs in some patients. occurring in less than 10% of enrolled patients were
• MTD was not reached. categorized as "Other"; NSCLC: Non-Small

Cell Lung
- Clinical benefit was observed in the majority of patients dosed at 24-800mg flat dose; one patient demonstrated uPR, overall DCR at Week 8 was 57% for patients dosed at Cancer; HNSCC: Head and Neck Squamous Cell Carcinoma 24-800mg.
- PD data strongly suggests that full 4-1BB agonism is observed at doses providing complete inhibition of PD-L1, i.e., up to 800mg of NM21-1480, thus, clinically validating the concept of affinity-balancing built into the design of the molecule. Safety
- In order to explore exposure to NM21-1480 for prolonged treatment periods and to ensure full blockade of PD-L1, the 800mg dose of NM21-1480 is currently further Treatment-emergent AEs (TEAEs) occurred in 25 (96.2%) patients. Most AEs were Grade 1-2 studied in the phase 2a (Part B) part of the trial, for which enrollment is ongoing (NCT04442126). (Figure 3).
Acknowledgements:Wethankthepatientsandallinvolvedsitepersonnel Disclosures: DH receives research grants from AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Daiichifor their participation in this trial. Special thanks to Dr. Mario Sznol (Yale Sankyo,Deciphera,Endeavor,Erasca,F.Hoffmann-LaRoche,FateTherapeutics,Genentech,Genmab,Immunogen,Infinity,Merck,Mirati,Navier,NCI- - The most common ( 10%) TEAEs were back pain, infusion-related reaction, and fatigue. Cancer Center, New Haven, USA), Dr. Ignacio Melero and Dr. Miguel F. CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Revolution Medicine, SeaGen, ST-Cube, Takeda, TCR2, Turning Point Therapeutics, VM Oncology and Sanmamed (Clinica Universidad de Navarra, Pamplona, Spain), Dr. Robert servesasconsultant/advisoryboardmemberforAdaptimmune,AlphaInsights,Acuta,Alkermes,Amgen,Aumbiosciences,Axiom,Baxter,Bayer,Boxer - Grade 3-4 TEAEs were reported for 8 (30.8%) patients. Ferris (UPMC Hillman Cancer Center, Pittsburgh, USA), and Dr. Matthew Capital,BridgeBio,COR2ed,COG,Cowen,Ecor1,F.Hoffmann-LaRoche,GennaoBio,Genentech,Gilead,GLG,GroupH,Guidepoint,HCWPrecision, - Treatment-emergent transaminase elevations (AST and/or ALT increased) occurred in Galsky(IcahnSchoolofMedicineatMountSinai,New York,USA) fortheir Immunogen, Janssen, Liberium, MedaCorp, Medscape, Numab, Oncologia Brasil, Orbi Captial,Pfizer, Pharma Intelligence, POET Congress, Prime valuable contributions, and to Numab's development partner CStone Oncology,RAIN,SeattleGenetics,STCube,Takeda,Tavistock,TriezaTherapeutics,TurningPoint,WebMD,YingLingPharma,Ziopharm. 19.2% of patients (Grade 3-4: 7.7%). Pharmaceuticals.ThistrialwasfundedbyNumabTherapeuticsAG. Treatment-related AEs (TRAEs) occurred in 19 (73.1%) patients (Table 3). References:
5. Williams, JB, et al. J Exp Med 2017;214(2):381-400. 10. Warmuth, S, et al. Oncoimmunology Figure 8. Best relative change in target lesion sum of diameters from baseline (%). Data cutoff: 19 Sept 2022. CPI:
1. Darvin, P, et al. Exp Mol Med 2018;50(12):1-17. 6. Segal, NH, et al. Clin Cancer Res 2018;24(8):1929-36. 2021;10(1):e2004661.
- Grade 3-4 TRAEs reported for 2 (7.7%) patients. No Grade 5 TRAE occurred. 2. Jenkins, R, et al. Br J Cancer 2018;118:9-16. 7. Chen, S, et al. Cancer Immunol Res 2015:3(2):149-60. 11. Glez-Vaz, J, et al. J Immunother Cancer 2022;10:e003532. Checkpoint inhibitor; NE: Not evaluable; PD: Progressive disease; SD: Stable disease; uPR: Unconfirmed partial response; - Treatment-related AST and/or ALT increases occurred in 3 (11.5%) patients (Grade 3, 3. Wilcox, RA, et al. Blood 2004;103(1):177-84. 8. Dai, M, et al. Clin Cancer Res 2015;21(5):1127-38. 12. Heery, CR, et al. Lancet Oncol 2017;18(5)587-98. NSCLC: Non-small-cell lung cancer; CRC:Colorectal; HNSCC: Headandneck squamous cell carcinoma; For 3 patients no on- 4. Weigelin, B, et al. Proc Natl Acad Sci USA 9. Wei, H, et al. Oncoimmunology 2014;3(4):e28248. 3.8%); No patient had treatment-related bilirubin elevation. treatment scans are available. 2015;112(24):7551-6.
10. Muik, A, et al. Cancer Discov 2022;12:1248-65. www.numab.com
SITC Annual Meeting 2022 - Poster # 732 SITC 2022 Poster # 732
Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, inducing durable responses in cancer patients diagnosed with various tumor types. 1 Despite the clinical success of Programmed Death (Ligand) 1 (PD-L1/PD-1) inhibitors, the majority of malignancies-even those expressing high levels of PD-L1-exhibit inadequate responses to these agents, i.e., are primary or secondary resistant to PD-L1/PD-1 blockade. 2
The co-stimulatory receptor 4-1BB expressed on tumor-infiltrating T cells is a compelling target for overcoming resistance to ICIs, but initial clinical studies of 4-1BB agonistic mAbs have been hampered due to severe liver toxicity. 3-6
Combination of PD-1/PD-L1 blockade and potent 4-1BB agonism has demonstrated pronounced activity in preclinical models and promising signals in early clinical studies. 7-10
Mechanism of action and preclinical data: NM21-1480 is a next generation ICI. The molecule is a tri-specific Fc-lacking antibody engineered to block PD-L1/PD-1 signaling and selectively co-stimulate 4-1BB in the tumor microenvironment only. The molecule lacks an Fc part (to avoid Fc receptor-mediated cross-link) but contains an anti-human serum albumin domain resulting in clinically favorable pharmacokinetics. NM21-1480 contains an ultra-potent PD-L1 blocking moiety and an affinity-balanced 4-1BB binding moiety to assure maximal tumor-targeted activity on both pathways over a broad dose range (Figure 1). NM21-1480 exhibited high efficacy for co-activation of pre-stimulated T cells in vitro. In xenograft models in humanized mice, NM21- 1480 induced tumor regression and tumor infiltration of T cells without causing systemic T-cell activation. A GLP toxicology study revealed no evidence of liver toxicity at doses up to 140 mg/kg, the maximum assessed dose in animals. 11 Here we report the results of the Phase 1 doseescalation part (PartA) of the ongoing First-in-Human Phase 1/2a clinical trial with NM21-1480. NM21-1480: PD-L1× 4-1BBxHSA antibody mechanism of action C.
D.
A.
B.
Figure 1. Affinity balancing unlocks full potential of a PD-L1x4-1BB bispecific molecule: Maximal 4-1BB activity maintained at concentrations that completely block PD-L1 11 A. Systemic stimulation of T cells through 4-1BB dimerization and interaction with Fc?R.
B. Restriction of T cell stimulation to TME due to: (1) required anchoring to PD-L1 for cross-linking 4-1BB signals; (2) lack of Fc domain; and (3) monovalent design. C. Affinity to PD-L1 = 4-1BB. Unbalanced target affinities lead to loss of 4-1BB activation at full PD-L1 blockade and vice versa. D. Affinity to PD-L1 >>> 4-1BB. Affinity-Balance results in overlapping activity and active complex formation. Objectives:
- The primary objectives of this dose escalation part of the trial were the characterization of the safety and tolerability profile of NM21-1480, the determination of its maximum tolerated dose (MTD) and the determination of dose level(s) for further evaluation of pharmacodynamics and clinical activity in expansion cohorts.

• The secondary objectives were the establishment of a pharmacokinetic profile and the evaluation of immunogenicity.
• Exploratory objectives comprised the assessment of anti-tumoral activity of NM21-1480, based on RECIST 1.1., the characterization of the pharmacodynamic profile of the compound, and the exploration of potential biomarkers of clinical response.

Methods:

• This is a first-in-human, multicenter, open-label, phase 1/2a trial of NM21-1480 in advanced solid tumors (NCT04442126) (Figure 2).
• The trial consists of two consecutive parts: dose escalation (phase 1 - Part A) and expansion

(phase 2 - Part B).
- The dose-limiting toxicity (DLT) monitoring period was 28 days, comprising two full dosing intervals. SITC Annual Meeting 2022 - Poster # 732