Improvement in Global Longitudinal Strain (GLS) correlates with NT-proBNP response

in Patients with Cardiac Amyloidosis Treated on a Phase 1b Study of Anti-

Amyloid mAb CAEL-101

Divaya Bhutani MD, Sofia Shames, MD, Jeff Goldsmith, PhD, Siyang Leng MD, Mathew S. Maurer, MD, Andrew Eisenberger MD, Suzanne

Lentzsch, MD, PhD

Columbia University Medical Center

New York, NY

Disclosures

• Divaya Bhutani: No conflict of Interest

• Sofia Shames: No conflict of Interest

• Jeff Goldsmith: No conflict of Interest

• Siyang Leng: No conflict of Interest

• Mathew S. Maurer: Pfizer: Personal fees and Research Funding. Eidos: Personal fees and Research Funding. Alnylam: Research Funding. Glaxo Smith Kline: Personal Fees. Prothena: Research Funding. Akcea: Personal fees. Ionis: Personal fees and Research Funding

• Andrew Eisenberger: No conflict of Interest

• Suzanne Lentzsch: Janssen: consultancy. Caelum Biosciences: consultancy, Shareholder for Caelum Biosiences, recused herself as an investigator from the Phase 1a/b trial testing CAEL-101 in 11/2017. Bayer: consultancy. BMS: Consultancy

AL Amyloidosis

• Primary AL Amyloidosis is a disorder characterized by presence of a Monoclonal Plasma cell population in the Bone Marrow leading to production and extracellular deposition of abnormal monoclonal Immunoglobulin Light chains in one or more organs

• Overall Incidence 8 per million per year

• Heart and Kidney are the most commonly affected organs (70%)

• The deposition of the Monoclonal immunoglobulin can lead to organ dysfunction manifested diastolic dysfunction and Heart failure with cardiac involvement and Proteinuria and renal failure with renal involvement

Cardiac AL Amyloidosis-Prognosis

• Degree of Cardiac dysfunction remains the main prognostic factor for survival in patients with systemic Amyloidosis

• Revised Mayo clinic staging system consists of the following factors:

1. NT-Pro-BNP ≥1800pg/ml

2. Troponin T ≥ 0.025 ng/ml

3. Free light chain difference ≥ 18mg/dl

Kumar S et al. Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements. J Clin Oncol 30:989-995.

Fibril directed therapy for AL Amyloidosismu11-1F4

Untreated Treated

• mu 11-1F4 mAb is a monoclonal IgG1 antibody that binds to a conformational epitope present on both human kappa and lambda light-chain amyloid fibrils

• The 11-1F4 mAb leads to dissolution of human ALλ and κamyloidomas in mice

Wall, JS et al, Tijdschr Nucl Geneeskd. 2011 Dec;33(4):807-814

mu 11-1F4: localization to the amyloid tissue

Jonathan Wall et al. Blood. 2010;116(13): 2241-2244Wells K. J Nucl Med 2011 vol 52 supplement: 1;1090

Global Longitudinal Strain

• Longitudinal strain is an Echocardiographic measurement of base to apical shortening of the left Ventricle during each cardiac cycle

• It can be reported by each cardiac region or as a global average called Global Longitudinal Strain (GLS)

• Sensitive and specific marker for diagnosis as well as prognosis of Cardiac Amyloidosis

• As a diagnostic tool apical sparing has been shown to be a specific marker of Cardiac Amyloidosis

Agha Ali et al. Role of cardiovascular imaging for the diagnosis and prognosis of cardiac amyloidosis. Open Heart 2018: 26;5(2):e000881.

GLS: A prognostic marker for Cardiac AL-Amyloidosis

Salinaro F et al. European Heart Journal - Cardiovascular Imaging (2017) 18, 1057–1064.Pun Shawn et al. J Am Soc Echocardiogr 2018;31:64-70.

Salinaro F et al. European Heart Journal - Cardiovascular Imaging (2017) 18, 1057–1064

Phase 1a/b Study of ch 11-1F4 (CAEL-101) in Patients with AL Amyloidosis

• GMP-grade amyloid fibril-reactive chimerized IgG1 11-1F4 mAbwas produced by NCI’s Biological Resource Branch

• Secondary outcome of GLS in patients enrolled in Open-label, dose-escalation phase 1b study of Ch IgG1 11-1F4 mAb (CAEL-101)

• Patients who received anti-plasma cell directed therapy in the past but with persistent organ dysfunction.

https://clinicaltrials.gov/ct2/show/NCT02245867

Eligibility

• Confirmed diagnosis of AL amyloidosis

• Age > 21 years

• ECOG performance status ≤ 3

• Received prior systemic therapy

• Does not require plasma cell targeted therapy

KEY INCLUSION CRITERIA

• EF < 40%

• Intraventricular Septum > 25mm

• Creatinine clearance < 30 cc/min

• Alkaline phosphatase > 3 times institutional upper limit of normal

• Bilirubin > 3.0 mg/dL

KEY EXCLUSION CRITERIA

https://clinicaltrials.gov/ct2/show/NCT02245867

Phase 1b Dose Escalation

LevelDose

(mg/m2)

-2 0.125

-1 0.25

1 0.5*

2 5

3 10

4 50

5 100

6 250

7 500

Ch 11-1F4 mAb (CAEL-101) infusion

Clinical Evaluation

0 1 2 3 4 8

weeks

Ch mAb 11-1F4 infusion (10, 50, 100, 250, 500 mg/m2)

Clinical evaluation

125

Weeks

• 11-1F4 mAb (CAEL-101) infusion once per week for 4 weeks

• Starting again at Dose Level 1

• Once tolerated, successive patients each received progressively higher doses of 11-1F4 mAb (CAEL-101)

• 6 additional patients enrolled at Dose level 6

• 6 additional patients enrolled at Dose level 7

https://clinicaltrials.gov/ct2/show/NCT02245867

Study Design

• Phase 1b study of patients with systemic AL amyloidosis (N=19)

• All patients underwent transthoracic echocardiograms at screening and 12 weeks post therapy

• GLS was measured using speckle-tracking (TomTec-Arena 1.2, Germany) and calculated as an average of 4-, 2-, and 3- chamber based measurements

• Paired student’s t-test was used to compare echocardiographic variables at screening and 12 weeks after therapy start with CAEL-101. GLS was correlated with NT-proBNP using Pearson correlation coefficient

Patient Characteristics (Phase 1b)characteristic MedianAge (N=19) 63 (Range Gender Male N=13 (68%)

Female N=6 (32%) Light chain type Lambda N= 9 (47%)

Kappa N=10 (53%)Revised Mayo Stage II (I-IV)Organ Involvement Median=2 (range 1-4) Cardiac N=10

Renal N=7

GI N=3

Liver N=2

Soft tissue N=4

MSK N=2

Neurological N=4Prior Anti-Plasma cell chemotherapy 2 (range 1-4) Proteasome Inhibitor N=15(78%)

Immunomodulator: N=6 (30%)

Auto-SCT N=8 (42%) Hematologic disease status at enrollment CR N=10 (52%)

Active disease N=9 (48%)Baseline NT-proBNP (cardiac involvement

only)

1186 (699-3964)

Baseline Proteinuria (renal involvement

only)

3272 mg/24h (1078-7260mg/24h)

Results-Organ Response (phase 1b)

• 10 patients had cardiac involvement but 8 were considered evaluable for NT-proBNP response

• 6/8 (75%) evaluable patients with Cardiac involvement met cardiac response criteria with ≥ 30% decrease in NT-proBNP

• 4/7 (57%) patients with Renal involvement met Renal response criteria with ≥ 50% decrease in 24 hour urine proteinuria

• Median time to organ response was 3 weeks• Overall 17/19 patients were alive at a median follow up of 19

months• No difference in organ response rates in patients with and without

active hematologic disease

Edwards, V. et al, Blood Abstract, 2017 130:509

Global Longitudinal Strain (GLS)

• Mean GLS at screening was -15.58 -4.14% in patients with cardiac Amyloidosis vs -22.77 -3.12% in patients without cardiac Amyloidosis

• Mean GLS improved significantly in 9/10 patients with cardiac involvement from -15.58 -4.14% at screening to -17.37 -3.53% at week 12, p = 0.004

• Pearson correlation coefficient between NT-proBNP response and GLS response (in 8 cardiac evaluable patients) was 0.345

• No changes in GLS in patients without cardiac involvement (Mean GLS -22.77 -3.12% at screening and -22.36 -3.02% at end of treatment)

D= 1.79

Change in GLS

GLS response by Light chain type

Patient (N) Baseline Follow-up P-value

GLS Mean 6 (Kappa) -16.6 (4.10) -18.16 (3.48) 0.074

4(Lambda) -14.3 (4.38) -16.17 (3.74) 0.022

Conclusion

1. Monoclonal antibody CAEL-101 is able to induce rapid organ responses in patients with AL Amyloidosis

2. Improvement in Global Longitudinal Strain correlates with improvement in NT-proBNP in in patients with cardiac AL Amyloidosis treated with CAEL-101

3. Global Longitudinal Strain should be further evaluated as a marker of early Cardiac Response in patients with Cardiac AL Amyloidosis

Acknowledgements

• Columbia Amyloidosis Multidisciplinary Program (CAMP), Columbia University, New York

➢ Multiple Myeloma and Amyloidosis Program : Suzanne Lentzsch

➢ Advanced Heart Failure Group: Matthew Maurer

➢ Nephrology: Jai Radhakrishnan

➢ Bone Marrow Transplant: Markus Mapara

➢ Renal Pathology: Glen Markowitz

➢ Cardiac Pathology: Chuck Marboe

• Funding

➢ NCI Experimental Therapeutics (NExT) Grant

➢ R01 FD005110-01 PI

➢ Columbia Technology Ventures

➢ Caelum Biosciences