Prolonged Survival and Improved Response Rates with ARRY‐520 (Filanesib) in Relapsed/Refractory (RRMM) Patients with Low α‐1 Acid Glycoprotein (AAG) Levels: Results from a Phase 2 Study

S Lonial1, J Shah2, JA Zonder3, W Bensinger4, A Cohen5, JL Kaufman1,A Nooka1, D Weber2, B Hilder6, S Rush6, M Ptaszynski6, D Walker6, R Orlowski2

1Winship Cancer Institute, Emory University, Atlanta GA; 2MD Anderson Cancer Center, Houston TX; 3Karmanos Cancer Institute, Wayne State University, Detroit MI; 4Fred Hutchison Cancer Center, Seattle WA; 5Fox Chase Cancer Center, Philadelphia PA; 6Array BioPharma Inc., Boulder CO

1 Disclosures

• Consultant: Millenium; Novartis; Onyx; Janssen

• Research Support: Merck; Celgene; Novartis

2 Background: Targeting KSP with ARRY‐520 (Filanesib)

• Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitor – KSP is a microtubule motor protein critical to the function of proliferating cells

• KSP inhibition induces aberrant mitotic arrest and rapid cell death – Novel mechanism of action for MM – Preferentially acts on MCL‐1 dependent cells including MM – Not expected to be cross‐resistant with other drugs

3 ARRAY‐520‐212 –Phase 2 Study Design

Cohort 1: Filanesib Single-agent Filanesib 1.5 mg/m2 q 2 weeks

1 2 1 2

G‐CSF G‐CSF

Cohort 2: Filanesib + Combination Filanesib 1.5 mg/m2 q 2 weeks

1 2 1 2

G‐CSF G‐CSF Dexamethasone 40 mg PO weekly

4 Key Eligibility Criteria

• Measurable disease (serum, urine or free light chain) • ECOG performance status 0‐1 • Adequate hematology labs without transfusion support within 2 weeks • Adequate renal and hepatic function

Cohort 1: Phase 2 Filanesib Single‐agent • ≥ 2 prior treatment regimens, including BTZ and an IMiD • Disease should have progressed during or after last regimen

Cohort 2: Phase 2 FIlanesib + Dexamethasone • ≥ 2 prior treatment regimens • Refractory to last regimen (progression during or w/in 60 days) • ≥ 2 consecutive cycles of prior treatment that included Len and BTZ – Refractory to Len, BTZ, and dex (40 mg per week) • Patients intolerant to Len or BTZ not included – Adequate prior alkylator therapy 5 Demographics and Disease History

Filanesib Filanesib + Dex N = 32 N = 55 Gender Male 18 (56%) 27 (49%) Age at Enrollment (years) Median (Range) 65 (51, 82) 63 (33, 82) ECOG PS

0 5 (16%) 6 (11%) 1 26 (81%) 49 (89%) 2 1 (3%) 0 (0%)

High Risk Cytogenetics 3 (9%) 17 (31%) Years Since Diagnosis Median (Range) 3 (1, 11) 5 (1, 18)

6 Prior Therapies

Filanesib Filanesib + Dex N = 32 N = 55 Median Prior Regimens 6 8 Prior 29 (91%) 55 (100%) Prior BTZ 29 (91%) 55 (100%) BTZ‐refractory 17 (53%) 54 (98%) Prior IMiD 32 (100%) 55 (100%) Prior Len 31 (97%) 55 (100%) Len‐refractory 24 (75%) 55 (100%) Prior Corticosteroid 32 (100%) 55 (100%) Triple‐Refractory (Len, BTZ, Dex) 13 (41%) 53 (96%) Prior Alkylator 32 (100%) 55 (100%) Prior Anthracycline 16 (50%) 38 (69%) Prior Transplant 26 (81%) 49 (89%) 7 Non‐Hematologic Grade 3/4 AEs Regardless of Causality (≥ 5% Incidence)

Filanesib Single‐agent Filanesib + Dex N=32 N=55 Pneumonia

Hypokalemia

Back Pain

Fatigue

0 2550751000 255075100 Grade 3 Grade 4 % Incidence % Incidence

• Filanesib is not associated with peripheral neuropathy • No cumulative toxicity with long‐term administration 8 Hematologic Toxicity Worst Grade On‐Study

Filanesib Single‐agent Filanesib + Dex N=32 N=55 Neutrophils

Platelets

Hemoglobin

Bleeding

Febrile Neutropenia Grade 3 Grade 4 0 2550751000255075100

Hematological toxicity predicted based on mechanism of action • Managed with supportive care

• Low incidence of febrile neutropenia or bleeding events 9 SAEs and Discontinuations

SAEs Filanesib Filanesib + Dex (≥ 5% Incidence, Regardless of Causality) N = 32 N = 55 Any SAE 10 (31%) 25 (45%) Pneumonia 1 (3%) 6 (11%) Non‐neutropenic Fever 1 (3%) 4 (7%)

Discontinuations Filanesib Filanesib + Dex N = 32 N = 55 Off Treatment 30 (94%) 48 (87%) Progressive Disease 23 (72%) 41 (75%) AEs 3 (9%) 4 (7%) Death 1 (3%) 3 (5%) Withdrawal Of Consent 2 (6%) 0 (0%)

Investigator Decision 1 (3%) 0 (0%) 10 Filanesib Activity

Filanesib Filanesib + Single‐agent Dex All Pts All Pts n3255 ORR (≥ PR) 5 (16%) 8 (15%) CBR (≥ MR) 7 (22%) 11 (20%)

Duration of Response (months) 8.6 5.1

Time to Next Treatment (Months) 3.7 3.4

OS (months) 19.0 10.5

11  1‐acid glycoprotein (AAG) is a Potential Selection Marker for Filanesib

• Background –  1‐acid glycoprotein (AAG) is an acute‐phase serum protein used to diagnose and monitor inflammatory disorders – AAG binds to filanesib

– Increasing [AAG] results in increased IC50 for filanesib in vitro – No correlation between [AAG] and common MM prognostic markers

• Hypothesis: High pre‐dose [AAG] correlates with lack of ORR and shorter time on study for patients treated with filanesib

12  1‐Acid Glycoprotein (AAG) Is A Potential Selection Marker For Filanesib • AAG is an acute-phase serum protein • AAG binds to filanesib

40 3‐day cell viability assay RPMI‐8226 MM cell line

(nM) 30 50 ARRY‐520 IC

of

20 Melphalan Change ‐ 10 Fold

0 00.511.522.53 [AAG] (g/L)

Increasing [AAG] attenuates filanesib activity in vitro 13 Low AAG is Associated with Higher ORR

Filanesib Single‐agent Filanesib + Dex

All Pts1 AAG‐High AAG‐Low All Pts2 AAG‐High AAG‐Low n32621 55 15 36 ORR (≥ PR) 5 (16%) 0 (0%) 5 (24%) 8 (15%) 0 (0%) 7 (19%) CBR (≥ MR) 7 (22%) 0 (0%) 7 (33%) 11 (20%) 0 (0%) 10 (28%)

Duration of Response 8.6 ‐ 8.6 5.1 ‐ 5.1 (months)

Time to Next 3.7 2.6 5.3 3.4 2.0 5.1 Treatment (months)

OS (months) 19.0 4.5 23.3 10.5 2.9 10.8

1 5 patients did not have a baseline AAG measurement 2 4 patients did not have a baseline AAG measurement, including 1 responder 14 Pre‐Dose AAG Levels Correlate with Clinical Outcome 2.8

2.4 “High” [AAG] Partial Response Minimal Response 2 No response/PD (g/L) 1.6 [AAG] 1.2

0.8

0.4

0 5 10 15 20 25 30 35 Time on Treatment (months)

• AAG Cutoff ≥ 1.1 g/L in Array ELISA was qualitatively assigned • Absolute value of cutoff is likely to change in final assay 15 Filanesib is Active in Patients Previously Treated with New MM Drugs (Filanesib + Dex Cohort)

Prior Pomalidomide and/or Carfilzomib and/or MLN9708 AAG All High Low N195 13 ≥ PR (n) 4 0 4 ≥ PR (%) 21% 0 31%

Data suggest filanesib maintains activity in myelomas resistant to multiple PI and IMiD drugs

16 Low AAG is Associated with Longer Survival

Filanesib Single-agent Filanesib + Dex

Median 6 prior therapies Median 8 prior therapies

100 100 Low High 75 75 All

50 50

25 25 Percent survival Percent survival

0 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Overall Survival (months) Overall Survival (months)

17 Conclusions

• Filanesib is a first‐in‐class KSP inhibitor – A novel treatment approach in MM, distinct from IMiDs or PIs

• AAG may identify patients who do not benefit from filanesib – Patients with high serum AAG may not achieve therapeutic exposure

• Demonstrated single‐agent activity in heavily pretreated RRMM – Activity in patients previously treated with novel IMiD/PI – Patients with low serum AAG have improved response and survival

• Well‐tolerated safety profile with supportive care – Low incidence of non‐hematological AEs – Hematologic events are generally reversible and not cumulative

18 Future Directions

• Data in combination with carfilzomib or bortezomib also presented at this meeting – Abstracts 1938; 1982

• Broad development plan – Ongoing Phase 2 study in combination with carfilzomib in RRMM – Planned studies • Phase 3 study in combination with carfilzomib in RRMM • Phase 2 single‐agent trial in heavily pretreated RRMM

19 Acknowledgements

Thank you to all of the patients and families who contributed to this study

We would like to thank the co‐investigators, research nurses, study coordinators, and support staff

This study was sponsored by Array BioPharma, Inc. Boulder CO

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