281 evaluation of glucosylsphingosine as a biomarker of...

Evaluation of Glucosylsphingosine as a Biomarker of the Eliglustat Treatment Response in Patients with Gaucher Disease Type 1

M. Judith Peterschmitt,1 Meredith Foster,1 Kate Zhang,2 Allena Ji,1 Gerald Cox3

1Sanofi Genzyme, Cambridge, MA, USA; 2Editas Medicine, Cambridge, MA, USA; 3Boston Children’s Hospital, Boston, MA, USA

Background Introduction and Methods

Conclusions Acknowledgments References

Baseline Demographics and Disease Characteristics: Phase 2 and Phase 3 ENGAGE

Biomarker Response to Treatment Over Time Correlations of Lyso-GL-1 and Clinical Parameters

Gaucher Disease

Gaucher disease type 1 (GD1) is caused by deficient activity of acid β-glucosidase, the enzyme that breaks down the major substrate glucosylceramide (GL-1) and the minor substrate glucosylsphingosine (lyso-GL-1), the deacylated form of GL-1, leading to the accumulation of these lipid substrates throughout the body, especially in cells of macrophage monocyte origin.1 Lipid-engorged macrophages, known as Gaucher cells, accumulate primarily in the spleen, liver, and bone marrow, causing progressive hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease.1

Biomarkers linked to GD1 have enhanced our understanding of disease pathogenesis, clinical status, and treatment response.2 Clinical trials of eliglustat in treatment-naïve GD1 adults have demonstrated long-term clinical gains and >80% reductions in lyso-GL-1, as well as chitotriosidase, the most established and widely used GD1 biomarker.3-7 Lyso-GL-1 is increasingly recognized as a prognostic biomarker of GD, as elevations are highly specific to the disease and in the causal pathway.2,8,9

Eliglustat (Sanofi Genzyme, Cambridge, MA, USA) is a first-line oral substrate reduction therapy approved for adults with GD1 with extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (>90% of patients10).

Phase 25

98% of adverse events were mild or moderate

94% of adverse events were considered unrelated to eliglustat

7 patients withdrew from the trial:

3 due to pregnancy

2 due to asymptomatic nonsustained ventricular tachycardia detected during protocol-mandated cardiac telemetry (both after a single 50-mg dose on Day 1)

1 due to a bone lesion that was retrospectively found to have been present at baseline

1 for administrative reasons (protocol at study site not approved beyond 2 years)

Biomarkers for Monitoring Gaucher Disease

Safety Summary

Results

Statistical Analyses

All analyses were performed separately in the Phase 2 and ENGAGE study samples.

Baseline associations of plasma lyso-GL-1 with disease characteristics are described using Pearson correlation coefficients (r) and graphically using scatter plots.

The upper limit of normal (ULN) for plasma lyso-GL-1 was determined by evaluating 100 healthy volunteers (50 female and 50 male).

Change from baseline in disease characteristics and plasma levels of lyso-GL-1 over time were calculated for all patients with available data at each timepoint up to 8 years (Phase 2) or 4.5 years (ENGAGE) of eliglustat treatment.

Associations of change in plasma lyso-GL-1 with change in clinical outcomes and change in chitotriosidase at each time point were estimated based on Pearson correlation coefficients. Associations of overall change from baseline for plasma lyso-GL-1 with overall change in clinical parameters were estimated using correlation coefficients derived from repeated measures mixed models.

These data show marked elevations in lyso-GL-1 in all patients before

treatment with no overlap with normal values. Lyso-GL-1 levels correlated

with disease parameters both at baseline and after treatment. These findings

underscore the utility of lyso-GL-1 as a clinically useful biomarker for

Gaucher disease type 1.

1. Grabowski G, Petsko G, Kolodny E. Gaucher Disease, In: Valle D, Beaudet A, Vogelstein B et al., eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw Hill; 2012.

2. Aerts JM et al. Acta Paediatr Suppl. 2005; 94:43-46. 3. Lukina E et al. Blood. 2010; 116:893-899. 4. Lukina E et al. Blood Cells Mol Dis. 2014;53:274-276. 5. Lukina E et al. Am J Hematol. 2019;94:29-38.

6. Mistry PK et al. JAMA. 2015: 313:695-706. 7. Mistry PK et al. Mol Genet Metab. 2016;129: S97. 8. Orvisky E et al. Mol Genet Metab. 2002;76:262-270. 9. Murugesan V et al. Am J Hematol. 2016;91:1082-1089. 10. Peterschmitt MJ et al. Blood Cells Mol Dis. 2018;68:185-

191.

The authors would like to acknowledge the patients and their families; the study site coordinators, nurses, and investigators who participated in the Phase 2 trial and the Phase 3 ENGAGE trial.

Editorial support was provided by Lisa Underhill, Marianne B. Zajdel, and Grace Lewis, Sanofi Genzyme. Poster layout and design was provided by Laurie LaRusso, Chestnut Medical Communications, and funded by Sanofi Genzyme.

The Phase 2 and Phase 3 ENGAGE trials are sponsored by Sanofi Genzyme.

Disclosures: MJP, MF, and AJ are employees of Sanofi Genzyme; KZ and GC are former employees of Sanofi Genzyme.

The text and figures in this presentation cannot be reproduced without the explicit permission of the authors and Sanofi Genzyme.

Desirable Characteristics

Chitotriosidase CCL18 GL-1 Lyso-GL-1

Markedly elevated in GD

Yes Yes No Yes

No overlap with normal values

Yes Yes No Yes

Decreases with treatment

Yes Yes Yes Yes

Highly specific to GD No No Yes Yes

Measurable in all GD patients

No Yes Yes Yes

Measurable in plasma or DBS

Yes Yes Yes Yes

No genotype information required

No Yes Yes Yes

In the causal pathway of GD

No No Yes Yes

CCL18: chemokine ligand 18; DBS: dried blood spot; GD: Gaucher disease.

Objectives

We report correlations between plasma lyso-GL-1 and baseline disease burden and treatment response to oral eliglustat in these two Sanofi Genzyme-sponsored trials (with long-term extensions) of treatment-naïve adults with GD1.

In both the Phase 2 and Phase 3 ENGAGE studies of previously untreated adults with GD1, eliglustat therapy resulted in clinically meaningful improvements in platelet and hemoglobin levels, spleen and liver volumes and corresponding decreases in GD biomarkers such as chitotriosidase, CCL18, and GL-1.3-7

Phase 23-5

(NCT00358150)

ENGAGE6,7

(NCT00891202)

Study design

• Open-label • Single-arm • 1-year primary analysis

period followed by long-term treatment/follow-up phase

• Randomized • Placebo-controlled • 9-month primary analysis

period followed by extension in which all patients received eliglustat

Patient population

26 untreated adults with GD1

40 untreated adults with GD1

Primary efficacy endpoint

Improvement (baseline to 1 year) in at least 2 of 3 efficacy parameters (spleen volume, hemoglobin level, and platelet count)

Change in spleen volume (baseline to 9 months) in the eliglustat group versus the placebo group

GD severity at start of trial

Moderate to severe Mild to moderate

Mean time on eliglustat

6.5 years 3.9 years

Data reported Changes in lyso-GL-1 over 8 years

Changes in lyso-GL-1 over 4.5 years

Eliglustat Phase 2 and Phase 3 ENGAGE Trials in Treatment-Naïve Patients

Lyso-GL-1 Measurements All plasma samples from Phase 2 and ENGAGE trials were

analyzed at a Sanofi Genzyme laboratory using the same assay method.

Lyso-GL-1 was extracted from plasma and analyzed by ultra performance liquid chromatography coupled with tandem mass spectrometry.

Phase 3 ENGAGE samples were analyzed prospectively; Phase 2 samples were analyzed post hoc after a protocol amendment.

Parameter Phase 3-5

N=19* ENGAGE6,7

N=40

Sex, n (%) Male Female

9 (47%) 10 (53%)

20 (50%) 20 (50%)

Ethnicity, n (%)

Caucasian, Ashkenazi Jewish Caucasian, Non-Jewish Hispanic Asian

3 (16%) 14 (74%) 2 (11%)

0

11 (28%) 26 (65%)

2 (5%) 1 (3%)

Age at treatment, years Mean ± SD 33.6 ± 12.5 31.8 ± 11.3

Age at diagnosis, years Mean ± SD 24.4 ± 13.9 21 ± 11.5

Hemoglobin, g/dL Mean ± SD 11.3 ± 1.5 12.1 ± 1.9

Platelet count, x 109/L Mean ± SD 68.7 ± 21.2 73.3 ± 20.2

Spleen Volume, MN Mean ± SD 16.84 ± 9.5 13.4 ± 6.11

Liver Volume, MN Mean ± SD 1.7 ± 0.46 1.4 ± 0.33

Plasma Lyso-GL-1, ng/mL Median (Min, Max) 587

(146, 1570) 304

(61.8, 1040) SD=standard deviation, MN=multiples of normal *19 of 26 patients completed 8 years of treatment

Phase 2: Improvements in Clinical Outcomes at 8 Years5

Phase 3 ENGAGE: Improvements in Clinical Outcomes at 4.5 Years7

Correlation Between Lyso-GL-1 and Baseline Disease Severity

Correlation Between Lyso-GL-1 and Change in Clinical Parameters after Treatment

Spleen Liver Hemoglobin Platelets Chitotriosidase*

Phase 2 (N=24)

r = 0.491 P = 0.0147

r = 0.434 P = 0.0341

r = -0.532 P = 0.0075

r = -0.180 P = 0.3997

r = 0.523 P = 0.0105

ENGAGE (N=38)

r = 0.760 P < 0.0001

r = 0.723 P < 0.0001

r = -0.488 P = 0.0019

r = -0.286 P = 0.0823

r = 0.399 P = 0.0130

*Different chitotriosidase assays were used in the two trials.

Spleen Liver Hemoglobin Platelets Chitotriosidase*

Phase 2†

r = 0.72 P < 0.0001

(n=21)

r = 0.28 P < 0.0001

(n=21)

r = -0.649 P < 0.0001

(n=22)

r = -0.2638 P = 0.0021

(n=22)

r = 0.5049 P < 0.0001

(n=21)

ENGAGE (N=38)

r = 0.629 P < 0.0001

r = 0.5689 P < 0.0001

r = -0.3391 P = 0.0113

r = -0.1772 P < 0.0001

r = 0.399 P = 0.0130

*Different chitotriosidase assays were used in the two trials. †The n values for Phase 2 indicate the number of patients with data at both baseline and after treatment for each parameter.

Reduction in Lyso-GL-1 Correlated with Reduction in Spleen Volume ENGAGE7

99% of adverse events were mild or moderate

84% of adverse events were considered unrelated to eliglustat

12 patients withdrew from the trial:

7 when eliglustat became commercially available in the United States

2 due to pregnancy

3 for reasons unrelated to an adverse event -100

-50

0

50

100

150

-3.5-3

-2.5-2

-1.5-1

-0.50

0.51

1.52

2.53

3.54

4.55

0 1 2 3 4 5 6 7 8 9

Pe

rcen

t Ch

ange

from

Base

line

Ch

ange

in

He

mo

glo

bin

(g/

dL)

fro

m B

ase

line

Years on Eliglustat N=38-40 n=38-39 n=38-39 n=31-35 n=21-28 n=10-13

Platelets +87%

Spleen Volume -66%

Liver Volume -23%

Hemoglobin +1.4 g/dL

-100

-50

0

50

100

150

-3.5-3

-2.5-2

-1.5-1

-0.50

0.51

1.52

2.53

3.54

4.55

0 1 2 3 4 5 6 7 8 9

Pe

rcen

t Ch

ange

from

Base

line

Ch

ange

in

He

mo

glo

bin

(g/

dL)

fro

m B

ase

line

Years on Eliglustat

Platelets +113%

Spleen Volume -69%

Hemoglobin +2.2 g/dL

Liver Volume -34%

N=24-26 n=20-22 n=18-20 n=17-19 n=17-19 n=16-19 n=17-19 n=15-19 n=14-16

Mean Percent Change Over Time

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5

Me

dia

n P

erc

en

t R

ed

uct

ion

fro

m B

ase

line

Time on Eliglustat in Years

Lyso-GL-1 Phase 2

Lyso-GL-1 ENGAGE

Chitotriosidase Phase 2

Chitotriosidase ENGAGE

Biomarker Median Values

Normal Range Baseline After

Treatment* Percent

Reduction

Lyso-GL-1 (ng/mL)

Phase 2 <5 624 (n=16) 47.6 (n=16) -92%

ENGAGE <5 304 (n=38) 72.1 (n=10) -84%

Normalized Chitotriosidase† (nmol/hr/mL)

Phase 2 <15 to 181‡ 8084 (n=17) 902 (n=17) -91%

ENGAGE 4-120‡ 11356 (n=39) 2312 (n=11) -82% *After 8 years of treatment with eliglustat in Phase 2 and after 4.5 years in ENGAGE. †Excludes 2 patients in Phase 2 and 1 patient in ENGAGE with absent chitotriosidase (CHIT) activity due to a homozygous null mutation in the CHIT1 gene. In addition, values were doubled in 10 patients in ENGAGE who were heterozygous for this mutation. ‡Normal ranges are different due to different assays used in each trial.

In both trials:

Baseline levels of lyso-GL-1 were substantially elevated in all patients.

Moderate to strong correlations were seen between baseline lyso-GL-1 levels and baseline disease severity with respect to spleen volume, liver volume (positive correlations), and hemoglobin (negative correlation); P<0.05 for all.

Moderate to strong correlations were seen between change in lyso-GL-1 levels and improvements in spleen volume, liver volume, and hemoglobin concentration after eliglustat treatment; P<0.05 for all.

Correlations between lyso-GL-1 and platelet count at baseline and after treatment were weak.

Plasma Lyso-GL-1 vs. Spleen Volume at Baseline

Mean Percent Change Over Time

Spleen Volume in Multiples of Normal

5 10 15 20 25 30 35 40 45 50 55 60 65

Spleen volume (MN)

0

200

400

600

800

1000

1200

1400

1600

Pla

sma L

yso

GL

-1 (

ng/m

L)

Phase 2Engage

Phase 2Engage

Scatter plot of Plasma Lyso GL-1 vs. spleen volume at baseline - Safety population

Baseline refers to last assessment prior to day 1 Eliglustat dose.

MN: Multiples of Normal.

Names of input datasets: APHASE2.ADBIO, APHASE2.ADSL, APHASE2.ADEFF, AENGAGE.LYSOGL102507,

AENGAGE.ADEFF and AENGAGE.ADSL

PGM=Z:\Genzyme-RDGMA\Eliglustat\Phase2_Engage\08pgm_tlf\Figures\f_lyso_bl_1.sas

OUT=Z:\Genzyme-RDGMA\Eliglustat\Phase2_Engage\12out_graphics\f_lyso_bl_spl_1.rtf

(11SEP18 - 17:53:03)

+ ENGAGE ⃝ Phase 2

1600

1400

1200

1000

800

600

400

200

0

5 10 15 20 25 30 35 40 45 50 55 60 65

Pla

sma

Lyso

-GL-

1

(ng/

nL)

Sple

en V

olu

me

(M

N)

(Ch

ange

fro

m B

ase

line)

-1500 -1250 -1000 -750 -500 -250 0

Lyso-GL-1 (change from baseline)

-40

-30

-20

-10

0

Sple

en V

olu

me

(MN

) (c

hg. fr

. bas

elin

e)

Genzyme

Protocol No: Eliglustat Phase 2 study

Scatterplot

Change from Baseline

Spleen Volume (MN) versus Lyso-GL-1

______________________________________________________________________________________________________________________________________________________________________________________________________________________

Note: p-value = <.0001 for association of change in Lyso-GL-1 with change in Spleen Volume (MN) based on a Repeated Measures Mixed Model (N=21

patients).

Program: Y8_f_scatter_chg_fr_baseline.sas 20APR2018 11:35

-1500 -1250 -1000 -750 -500 -250 0


-40

-30

-20

-10

0

Sple

en V

olu

me

(MN

) (c

hg. fr

. bas

elin

e)

Year 8

Year 7

Year 6

Year 5

Year 4

Year 3

Year 2

Year 1

Month 6

Genzyme

Protocol No: Eliglustat Phase 2 study

Scatterplot



______________________________________________________________________________________________________________________________________________________________________________________________________________________


patients).

Program: Y8_f_scatter_chg_fr_baseline.sas 20APR2018 11:35

0

-10

-20

-30

-40

-1500 -1250 -1000 -750 -500 -250 0

Lyso-GL-1 (ng/mL) (Change from Baseline)

Month 6 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8

Phase 2

-800 -700 -600 -500 -400 -300 -200 -100 0


-20

-15

-10

-5

0

Sp

leen

Vo

lum

e (M

N)

(chg

. fr

. b

asel

ine)

Genzyme

Protocol No: GZGD02507

Scatterplot



______________________________________________________________________________________________________________________________________________________________________________________________________________________


patients).

Program: CSR2016_f_scatter_chg_fr_baseline.sas 10SEP2018 16:36

-800 -700 -600 -500 -400 -300 -200 -100 0


-20

-15

-10

-5

0

Sp

leen

Vo

lum

e (M

N)

(chg

. fr

. b

asel

ine)

Year 5

Year 4

Year 3

Year 2

Month 6

Genzyme

Protocol No: GZGD02507

Scatterplot



______________________________________________________________________________________________________________________________________________________________________________________________________________________


patients).

Program: CSR2016_f_scatter_chg_fr_baseline.sas 10SEP2018 16:36

0

-5

-10

-15

-20

-800 -700 -600 -500 -400 -300 -200 -100 0

Lyso-GL-1 (ng/mL) (Change from Baseline)

Month 6 Year 2 Year 3 Year 4 Year 5

ENGAGE

The median percent reduction in lyso-GL-1 levels was 92% in the Phase 2 trial after 8 years of eliglustat and 84% in ENGAGE after 4.5 years of eliglustat, but levels did not fully normalize in either trial.

281

Scan for All Sanofi Genzyme Posters

Scan for this Poster

281 evaluation of glucosylsphingosine as a biomarker of...

Documents