in Patients with Cardiac Amyloidosis Treated on a Phase 1b Study of - - PowerPoint PPT Presentation

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in Patients with Cardiac Amyloidosis Treated on a Phase 1b Study of - - PowerPoint PPT Presentation

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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

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SLIDE 1

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

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SLIDE 2

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

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SLIDE 3

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
  • rgan dysfunction manifested diastolic dysfunction and Heart failure

with cardiac involvement and Proteinuria and renal failure with renal involvement

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SLIDE 4

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.

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SLIDE 5

Fibril directed therapy for AL Amyloidosis mu11-1F4

Untreated Treated

  • mu 11-1F4 mAb is a monoclonal

IgG1 antibody that binds to a conformational epitope present

  • n both human kappa and

lambda light-chain amyloid fibrils

  • The 11-1F4 mAb leads to

dissolution of human ALλ and κ amyloidomas in mice

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

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SLIDE 6

mu 11-1F4: localization to the amyloid tissue

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

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SLIDE 7

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.

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SLIDE 8

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.

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SLIDE 9

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

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SLIDE 10

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

  • GMP-grade amyloid fibril-reactive chimerized IgG1 11-1F4 mAb

was 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

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SLIDE 11

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

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SLIDE 12

Phase 1b Dose Escalation

Level Dose (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

1 2 3 4 8 weeks 12 5

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

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SLIDE 13

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

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SLIDE 14

Patient Characteristics (Phase 1b)

characteristic Median Age (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=4 Prior 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

  • nly)

1186 (699-3964) Baseline Proteinuria (renal involvement

  • nly)

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

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SLIDE 15

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

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SLIDE 16

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)

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SLIDE 17

D= 1.79

Change in GLS

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SLIDE 18

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

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SLIDE 19

Conclusion

  • 1. Monoclonal antibody CAEL-101 is able to induce rapid
  • rgan 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

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SLIDE 20

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