Nehal Lakhani¹, Patricia LoRusso², Navid Hafez², Anuradha Krishnamurthy³, Timothy O’Rourke¹, Manali Kamdar³, Chan-Young Ock⁴, Yung-Jue Bang⁴, Philip Fanning⁵, Yonggang Zhao⁵, Feng Jin⁵, Hong Wan⁵, Jaume Pons⁵, Sophia Randolph⁵, Wells Messersmith³
1START Midwest, Grand Rapids, MI, USA; 2 Yale Cancer Center, New Haven, CT, USA; 3 University of Colorado Cancer Center, Aurora, CO, USA; 4Seoul National University Hospital, Seoul, South Korea; 5Alexo Therapeutics, Burlingame, CA, USA, and Dublin, Ireland.

ALX148 Potential for Best in Class: Potency and Safety
High Affinity CD47
Binding Domains of SIRPαInactive
Fc Domain

TNFαCD47

CD47

iNOS

TCR

CD47

MHC I

CD163

CD47

M1 TAM

Arginase 1

M2 TAM

M1M2

SIRPα

ALX148Fc Receptor

TNFα

CD86

Tumor Antigen

CCR7

Anticancer Antibody

MHC II

Dendritic
Cell

Cancer Cell

53.5 (48-73)

64.5 (48-70)

67 (58-73)

F

1652–

M

12

1

4

3

Once a week

White

27

552

2

1

Once a week

Black

1–

1–

33

Once a week

Native American–1––

4

10*

Once a week

Asian–––

1

530

Once every 2 weeks

as a single agent (Part 1) and in combination with pembrolizumab, trastuzumab, andrituximab (Part 2).
• Additional assessments include:• Adverse events, characterized by type, frequency, severity (using NCI CTCAE v. 4.03),
timing, seriousness, and relationship to study therapy;• Pharmacokinetic parameters of ALX148, and CD47 target occupancy;• Investigator-assessed tumor response (using RECIST v 1.1 ; 2014 Lugano Criteria forNHL patients) at screening, every 8 weeks thereafter, and at the end of treatment or
upon withdrawal.

• The primary study objective is to characterize the safety profile of ALX148 as a single

Patient Baseline Characteristics• A total of 43 patients have been enrolled and treated across both Parts of the study.

Part 1 enrollment is complete. Part 2 enrollment is ongoing. A summary of patient
baseline characteristics is presented in Table 2.
• The majority of patients were female (53%) and most of the trial population (74%) had
an ECOG PS score of 1.

Adverse Event

1/2

Thrombocytopenia
Diarrhoea• Death unknown etiology in patients with NSCLC (30 mg/kg, ALX148 single agent).
• Disease progression in patients with GEJ ca (10 mg/kg, ALX148 + Trastuzumab).

reported in Table 5.
• Three Dose Limiting Toxicities (DLTs) were reported across the study (Tables 4b and 5):• Neutropenia+infection (3 mg/kg, ALX148 single agent);• Thrombocytopenia with significant bleed (30 mg/kg, ALX148 single agent);• Autoimmune hemolytic anemia (10 mg/kg ALX148 + Pembrolizumab).

Part 1: ALX148 Single Agent

62

3–

1

224

33

Breast1–

1–

Colorectal

8–––

Gastric/GEJ

1–

3–

Leiomyosarcoma1–––

Lung

72–

–

Adverse EventOvarian52––

Pancreatic2–

1–

Peritoneal

11––

Appendiceal

1–––

Thymic1

1––

Urothelial––

1–

DLBCL

–––

2

Marginal Zone Lymphoma–––

1• No patient required a dose reduction due to an adverse event, and the most commonTotal

–

1–

11–

–

1

Nausea1––

1

Pyrexia1––

1

Fatigue

1––

1

Infusion Related Reaction

1––

1

Neutrophil Count Decreased–1–

1

Leukocyte Count Decreased

1––

1Pain

1––

1GradeTotal
1Fatigue

4Anaemia

1––

1

Thrombocytopenia

3Diarrhea

1––10120 0AST Increased

2Nausea2––

2100ALT Increased

2Fatigue

1––

180Dizziness Postural

2Pyrexia

1––1Pruritus

2

Rash

2

3

4

3

Thrombocytopenia

1

–

1*

Pancreatitis––

1

45Total

––

2––

1

Death––––

1^

1

Infection

1*

–––

–

1

Neutropenia

–

1*–––

1

Table 3. Patient Drug Exposure and Disposition

Part 2 ALX148 Combination Cohorts: Treatment Related Adverse EventsAll Grades by Combination Partner and Dose level in any Patient
Part 2
ALX148 10mg/kg + Combination

0.3
N=31

1
N=4–

3
N=61

10
N=3–

30
N=123

Pembrolizumab
N=61Trastuzumab
N=61

Rituximab
N=31

DoseReductions, n (%)–

Discontinuation
Due to TRAE, n––

1–

2

1––

Discontinuation
Due to PD, n3

4

5

3

7

1

1

1––––––––

3–

4–

5–

2

GradeAdverse Event

1/2

34TotalALT Increased

1––

1

AST Increased

1––

1Alk Phos Increased1––1

Hyponatremia–

1–1Autoimmune Hemolytic Anemia

–

–

1*

1

Vaginal Spotting

1–

–

1

Myalgia1––1

Hypoaesthesia

1––

1

Rash

1–

–

1

*Dose Limiting Toxicity.

Cohort 2(1 mg/kg)

Cohort 3(3 mg/kg)

Cohort 4(10 mg/kg)

Cohort 5(30 mg/kgQoW)

10
10.1
48

96

144

192

240

288

336

40
20

80
60
40
20

14

28

42

56

70

Days

0.3 mg/kg
1 mg/kg84

3 mg/kg
10 mg/kg

98

112

0120 01428

100
30 mg/kg
80
10 mg/kg + pembrolizumab

4256

70Days

84

98

112

10 mg/kg + trastuzumab
10 mg/kg + rituximab• Nearcomplete CD47 target occupancy (TO) by ALX148 is maintained at ≥3 mg/kg
40406060

QW and in combinations.
20
20 and target occupancy data from• PKPD
modeling using systemic vs tumor exposure
tumor
bearing mice suggests ALX148 dose above
3 mg/kg QW provides complete
00targetcancer
0 occupancy
14 28 42at tumor
56 70sites
84 in98
112 patients.0
14 28 42 56 70 84 98 112• ALX148 exposure at Days
10 mg/kg QW exceeds the exposure needed Days
to achievepreclinical antitumor
activity.
0.3 mg/kg
3 mg/kg
30 mg/kg
1 mg/kgConclusions

10 mg/kg

10 mg/kg + pembrolizumab

10 mg/kg + trastuzumab
10 mg/kg + rituximab

Designed to safely enhance the activity of established anti-cancer antibodies
ALX148 demonstrates a tolerable safety profile in combination to date.

• No ALX148 MTD was reached in combination or as a single agent in patients with

Table 6. ALX148 PK Parameters Following IV Infusion at Cycle 1 Day 1
Cohort 1(0.3 mg/kg)

Table 5a. ALX148 10 mg/kg + Pembrolizumab (N=6)

Part 1

Pharmacokinetics and Pharmacodynamics

1 mg/kg3 mg/kg
10 mg/kg
30 mg/kg
10 mg/kg + pembrolizumab (N=3)
10 mg/kg + trastuzumab (N=2)
10 mg/kg + rituximab (N=1)

80

4Grade336

10060–

3.0 mg/kg, colorectal ca.; 10 mg/kg, ovarian; 30 mg/kg [2] NSCLC, [1] appendicealca) achieved a best response of stable disease as of data cutoff. One patient withNSCLC demonstrated a 15% reduction in tumor size.
• In Part 2, with ALX148 administered as 10 mg/kg QW, 3 out of the first 5 responseevaluable patients ( [1]NSCLC, [1] appendiceal ca - pembrolizumab; [1] Breast ca-trastuzumab) achieved a best response of stable disease and are ongoing as ofdata cutoff.

288

120

330mg/kg (N=12)240

100–3mg/kg (N=6)

192

Hour

120

1Adverse Event#144

1001/2• In Part 1, six out of 24 response evaluable patients (0.3 mg/kg, leiomyosarcoma;

96

Hour
Figure 4. CD47 Target Occupancy by ALX148

GI Tract Infection

Response

48

0Adverse Event#There were no ≥G3 TRAE reported in patients administered single agent ALX148 at 0.3, 1, and 10 mg/kg QW.
* Dose Limiting Toxicity reported in one patient.
^ Unknown etiology.

ALX148 Single Agent (mg/kg)

0.1
1,000 05reason for discontinuation was disease progression across both Parts (Table 3).
• At the time of data cutoff, 14 patients remained on study, and 4 patients had
discontinued due to a treatment related AE (Table 3).

OngoingTreatment, n4

Table 5c. ALX148 10 mg/kg + Rituximab (N=3)

Table 4b. Treatment Related Adverse Events ≥Grade 3 in any Patient (N=28)

Patient Drug Exposure and Disposition

1TotalHeadachePrimary Disease, nDose InterruptionsDue to AEs, n (%)

Grade3

Table 4a. Treatment Related Adverse Events in ≥2 Patients (N=28)0toxicity had occurred.
• The data cutoff date for this analysis is 23May2018.

Primary Objective

were Headache and Fatigue (Table 4a). Treatment related adverse events that wereof at least Grade 3 severity are shown in Table 4b.
• There were 2G5 events across the trial.

• The most common Part 1 (ALX148 single agent) treatment related adverse events• Part 2 combination treatment related adverse events were of low frequency and are

ECOG PS, n• Treatment continued until disease progression, patient refusal, or unacceptable

Results

agent (Part 1) and in combination with established anti-cancer antibodies (Part 2).
• Here we report preliminary results from the fully enrolled Part 1 and Part 2 dose
escalation cohorts of the study as of 23May2018.

67 (37-88)

Age, Median Year (range)

0.3• The primary endpoint is first cycle ALX148 dose limiting toxicity (DLT) administered

CD28

CD8

N=31

Endpoints and Assessments

CytotoxicGranules

N=6Race, n• Patients with known symptomatic CNS metastases or leptomeningeal disease.
• Prior treatment with any anti-CD47 or anti-SIRPα agent.

IFNγ

CD8+ T Cell

CD68

N=6Frequency of Dosing

Hodgkin lymphoma (NHL) that are resistant to standard therapy or for which nostandard therapy is available.
• Adequate organ function and hemoglobin ≥9 g/dL (≥8 g/dL, NHL).
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.

ALX148 Activates
Dendritic Cells (DCs) andEnhances Cross-Primingof T Cells

N=28

Dose ALX148 (mg/kg)

Key Exclusion Criteria

ALX148 Increases the Ratioof Inflammatory M1 Tumor
Associated Macrophages (TAMs)
to Suppressive M2 TAMs

ALX148 +RituximabCohort• Patients age ≥18 years with advanced/metastatic solid tumor malignancy or nonFigure 2. ALX148 Bridges Innate and Adaptive Immunity Against Cancer1, 2, 3Macrophage

Table 1. ALX148 Dose Escalation Cohorts

Key Inclusion Criteria

Mechanism of Action
ALX148 Blocks CD47
“Don’t Eat Me” Signal andEnhances Macrophage
Phagocytosis

Study DesignStudy Population

The molecular weight of ALX148 is half thatof a typical antibody allowing higher molarconcentrations to be delivered.

ALX148

ALX148 +Trastuzumab

Sex, n* ALX148 10 mg/kg was administered as single agent (Part 1) and in combination (Part 2) with standard regimens ofpembrolizumab, trastuzumab, or rituximab.

Figure 1. ALX148 is an intravenously
administered fusion protein containing
an engineered high affinity N-terminal D1
domain of SIRPα, which binds and blocks
CD47, and is genetically linked to an inactive
human Fc domain.

s-ss-sTable 1, once weekly (QW) in a 3 week cycle; or once every other week (QoW) in a4 week cycle as a single agent (Part 1 ) or in combination with standard regimens ofpembrolizumab, trastuzumab, or rituximab (Part 2).

Part 2
ALX148 +Pembrolizumab

1 mg/kg
3 mg/kg
10 mg/kg
30 mg/kg
10 mg/kg + pembrolizumab (N=3)
10 mg/kg + trastuzumab (N=2)
10 mg/kg + rituximab (N=1)

10TO (CD4+)

By blocking CD47 interaction with its myeloid cell receptor SIRPα, it may be possible
to enhance innate and adaptive immunity against cancer.¹• ALX148 is a fusion protein comprised of an engineered high affinity CD47 binding
domain of SIRPα genetically linked to an inactive Fc region of human immunoglobulin(Figure 1).2, 3• In non clinical models, ALX148 blocks CD47 and safely enhances the activity ofseveral anti-cancer targeted antibodies and checkpoint inhibitors through Fc
dependent and independent mechanisms, bridging innate and adaptive anti-cancer
immune response.2,3• Based upon these observations, AT148001, a first-in-human phase 1 study of ALX148
administered as a single agent (Part 1) and in combination with established anticancer antibodies (Part 2) was initiated.

Part 1

100TO (CD4+)• Patient cohorts were administered escalating doses of ALX148, intravenously, as in

1,000

Figure 3. Observed Mean ALX148 PK at Cycle 1 Day 1

ALX148 Serum
Concentration (µg/mL)• Tumors attempt to evade the immune system by upregulating CD47, a marker of self.

Table 5b. ALX148 10 mg/kg + Trastuzumab (N=6)

TO (RBC)

Methods

SafetyTO (RBC)

Background

Table 2. Baseline Characteristics

ALX148 Serum
Concentration (µg/mL)

A Phase 1 Study of ALX148, a CD47 Blocker, Alone and in Combination with Established Anti-Cancer Antibodies
in Patients with Advanced Malignancy and Non Hodgkin Lymphoma

advanced solid tumors and NHL.

Part 2Combo(10 mg/kg)

Parameters

N=2

N=4

N=6

N=3

N=9

N=6Cmax(µg/mL)0.379 ±
0.192*

7.03 ±
2.17

54.5 ±
18.3

247 ±
32.5

727 ±
180

285 ±
77.3

AUCinf(µg*h/mL)

N/A

48.5 ±
32.4

1830 ±745

19700 ±
4940

105000 ±35700

22000 ±
9690

CL(mL/h/kg)

N/A

34.3 ±
31.1

1.92 ±
0.853

0.527 ±0.122

0.32 ±0. 123

0.54 ±0.234

Vss(mL/kg)

N/A

154 ±
73.3

61.3 ±
18.7

59.8 ±
7.62

79.8 ±
22.0

56.4 ±
13.2* Reported for Cycle 2 day 1, Cmax at Cycle 1 day 1 were all BQL.

• ALX148 PK profiles showed trend of non-linear PK with faster clearance at lower

doses and slower clearance at higher doses of 10 mg/kg QW and 30 mg/kg QoW,indicating saturation of target mediated clearance.
• Steady-state half-life of ALX148 at 10 mg/kg QW is predicted to be ~16 days.
• ALX148 PK profile(10 mg/kg QW) in combination with pembrolizumab, trastuzumab, orrituximab was not changed from that of a single agent.

• The MAD of ALX148 is 10 mg/kg QW in combination, and is 30 mg/kg QoW as asingle agent.

• The molecular weight of ALX148 is half that of an anti-CD47 antibody, thus delivering
twice the molar concentration at the same dose level.

• ALX148 PK approached linear range and maintained complete TO over the dosinginterval at and above 3 mg/kg QW. Initial data suggests ALX148 PK and PD profiles
are not impacted by combination drugs.
• 3 of the first 5 response-evaluable patients in Part 2 have ongoing SD as a best
response as of data cutoff.

• Enrollment into combination expansion cohorts is now ongoing (NCT03013218).
References
1. Weiskopf, K. Eur J Cancer. 2017 May;76:100-109.
2. Kauder, S. et al. 59th Annual Meeting, American Society of Hematology 2017.
3. Kauder, S. et al. Manuscript submitted.

Acknowledgments• We would like to thank all of the participating patients and their families as well as siteresearch staff.
• Contact email: info@alexotherapeutics.com• Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago,IL, USA, June 1-5, 2018.