Joseph Gligorov : Lipegfilgrastim : A new long-ac,ng recombinant human G-CSF

Lipegfilgras+m A new long-‐ac,ng recombinant human G-‐CSF

Joseph Gligorov MD, PhD ESO Advanced Breast Cancer Task Force

APHP-‐HUEP-‐Tenon, Paris Ins+tut Universitaire de Cancérologie

Université Pierre & Marie Curie, Sorbonne Universités

Conflict of interest

•  Amgen® •  Genomic Health®

•  Eisai® •  Roche-‐Genentech® •  Nanostring ® •  Novar,s ®

Clinical trials support, advisory boards, speaker

•  Molecular structure : « glycoPEGyla+on technology »

•  Long-‐ac+ng human recombinant G-‐CSF (r-‐metHuG-‐CSF)

Lipegfilgrastim

GlycoPEGyla+on

Explanation §  Two enzymes - one-pot reaction §  Two substrates

•  Activated sugar •  Activated sugar linked to PEG

§  The PEGylation site is threonine 134 (THR134)

Filgrastim (E. coli derived)

Lipegfilgrastim (glycoPEGylated XM21)

ENZYME 1 ENZYME 2

XM21

S 1

THR134

XM21

THR134

XM21

S 1

S 2

THR134 S 1 A1

A1 S 2 A2

A2

S 1 A1 S 2 A2 PEG

Clinical development Phase I studies

XM22-01-CH PK/PD single dose, bodyweight adjusted dosing N=53 25/50/100 µg/kg lipegfilgrastim vs pegfilgrastim

XM22-05-CH PK/PD single dose, fixed dose N=36 6 mg lipegfilgrastim vs pegfilgrastim

XM22-06 PK at three different injection sites (upper arm, abdomen, thigh)

N=20 6 mg lipegfilgrastim vs pegfilgrastim

Phase II studie

XM22-02 Dose finding with three different doses of Lonquex® compared to 6mg pegfilgrastim in breast cancer patients

N=208 3/4.5/6 mg lipegfilgrastim vs 6mg pegfilgrastim

phase III studies

XM22-03 Efficacy and safety of 6mg Lonquex® compared to 6 mg pegfilgrastim in breast cancer patients

N=202 6 mg lipegfilgrastim vs 6mg pegfilgrastim

XM22-04 Efficacy and safety of 6 mg Lonquex® compared to placebo in non small cell lung cancer patients

N=373 6 mg lipegfilgrastim vs placebo

Phase I studies Healthy volunteers

1.  lipegfilgras,m 25, 50, 100 µg/kg vs pegfilgras,m 100 µg/kg: XM22-‐01

2.  lipegfilgras,m, 6 mg vs pegfilgras,m 6 mg: XM22-‐05

3.  lipegfilgras,m, 6 mg, 3 sites d’injec,on: XM22-‐06

1 ANC : absolute neutrophil count

XM22-‐01

XM22-‐05

Objec+ves PK/PD single dose 25, 50, 100 μg/kg of lipegfilgras+m or 100 μg/kg pegfilgras+m bodyweight adjusted dosing (n = 53)

PK/PD single 6 mg fixed dose lipegfilgras+m or pegfilgras+m (n = 36)

Methods Phase I randomised, single-‐blind study in healthy volunteers

Phase I randomised, single-‐blind study in healthy volunteers

Primary endpoint

ANC1 AOBEC (area over baseline effect curve)

ANC AOBEC

Secondary endpoints

§  PD: CD34+ AOBEC, CD 34+ max , ANC max,

§  PK: AUC, Cmax, Tmax, T ½ terminal §  Safety

§  PD: CD34+ AOBEC, CD 34+ max , ANC max,

§  PK: AUC, Cmax, Tmax, T ½ terminal §  Safety

Phase I studies

0 24 48 72 96 120 144 168 192 216 240 0

XM22-01-CH body weight depending dosing

Bioavailability AUC of lipegfilgrastim 56-57% > AUC of pegfilgrastim

(Median ± SD)

XM22-05-CH fixed dose

100000

200000

300000

400000

500000

600000

Time* [h]

Con

cent

ratio

n [p

g/m

l]

0 0 24 48 72 96 120 144 168 192

100000

200000

300000

400000

500000

600000

Time* [h] C

once

ntra

tion

[pg/

ml]

216 240

50 µg/kg lipegfilgrastim (n=15) 100 µg/kg pegfilgrastim (n=15)

25 µg/kg lipegfilgrastim (n=8) 100 µg/kg lipegfilgrastim (n=15)

6 mg pegfilgrastim, n = 15

6 mg lipegfilgrastim, n = 18

Bioavailability AUC of lipegfilgrastim 63-64% > AUC of pegfilgrastim

(Median ± SD)

Seiberling M, et al. Research report. XM22-01-CH. Mannheim, Germany: BioGenerix, 2009. Seiberling M, et al. Research report. XM22-05-CH. Mannheim, Germany: BioGenerix, 2009

0

10

20

30

40

50

60

0

10

20

30

40

50

60



96 168 192 216 264 288 360 384 408

Time*[h]

AN

C [n

eut /

nl]

336 312 240 144 120 72 48 24 0 96 168 192 216 264 288 360 384 408

Time*[h] A

NC

[neu

t /nl

] 336 312 240 144 120 72 48 24 0

50 µg/kg lipegfilgrastim (n=15) 100 µg/kg pegfilgrastim (n=15)

25 µg/kg lipegfilgrastim (n=8) 100 µg/kg lipegfilgrastim (n=15)

6 mg pegfilgrastim, n = 15

6 mg lipegfilgrastim, n = 18

With equivalent doses, ANC AUC with lipegfilgrastim > 32% ANC AUC with pegfilgrastim

(Median ± SD)

ANC AUC with lipegfilgrastim > 30% ANC AUC with pegfilgrastim

(Median ± SD)


0 48 96 168 192 216 240 264 288 432 456 480 504

20

0

60

80

100

120 140

Time (h)

CD

34 +

[cel

l cou

nt/u

l)

40

24 72 120 144 312 336 360 384 408

100 µg/kg lipegfilgrastim (n=15)

100 µg/kg pegfilgrastim (n=15)



0 48 96 168 192 216 240 264 288 432 456 480 504

20

0

60

80

100

120 140

Time (h)

40

24 72 120 144 312 336 360 384 408

CD

34 +

[cel

l cou

nt/u

l) With equivalent doses: CD34+ 83% and CD34+ max

98% higher with lipegfilgrastim vs pegfilgrastim (Median)

6 mg pegfilgrastim, (n=18)

6 mg lipegfilgrastim, (n=18)


CD34+ 9% and CD34+ max 16% higher with lipegfilgrastim vs pegfilgrastim (ns)

(Median)



11

XM22-‐01 n=53

XM-‐05 n= 36

Lipegfilgras+m n=38

Pegfilgras+m n=15

lipegfilgras+m n=18

Pegfilgras+m n=18

Any AE 35 (92,5%) 14 (93,3%) 15 (83,3%) 17 (94,4%)

Gastrointes+nal 7 (18,4%) 1 (6,7%) 3 (16,7%) 3 (16,7%)

Arthralgia 30 (79%) 13 (86,7%) 1 (5,6%) 0 (0%)

Back pain 4 (10,5%) 0 (0%) -‐ -‐

Headaches 21 (55,2%) 7 (46,7%) 10 (55,6%) 9 (50%)

Bone pain 1 (2,6%) 2 (13,3%) 12 (66,7%) 15 (83,3%)

•  AEs were mostly mild to moderate in severity •  No serious AEs •  No clinicaly significant change in biologic and vital signs, ECG and sonographic examina,on of the spleen •  No injec,on site was observed


Safety in studies XM22-‐01, XM22-‐05

*AE = adverse events

Phase II study

Breast cancer lipegfilgras,m 3mg, 4.5 mg , 6 mg vs pegfilgras,m 6mg

§  Primary objective:

§  To identify the optimal fixed dose of lipegfilgrastim in breast cancer patients treated with chemotherapy compared to 6mg pegfilgrastim

§  Methods:

§  Multinational, multicentre, randomised, double-blind, controlled study with 4 treatment arms (6 european countries; 37 centres)

§  Patients were stratified according to geographical localisation, indication of chemotherapy (adjuvant/metastatic) and body weight

Kaufmann M, et al. Research report XM22-02. Mannheim, Germany: BioGenerix, 2011.

Phase II study

§  Main inclusion criteria: §  Stage II,III,IV Breast Cancer Cancer treated with 4 cycles of AT (doxorubicine 60 mg/m2- docetaxel 75 mg/m2) every 3 weeks §  No previous chemo §  ANC ≥ 1,5 x 109/L, thrombocytes ≥ 100 x 109/L §  ECOG* ≤ 2 §  Normal heart, kidney and liver function

§  Main exclusion criteria: §  Previous G-CSF exposure §  Anti infectious treatment (antibiotics) ≤ 72 hours before chemo initiation §  Radiotherapy ≤ 4 weeks before study inclusion §  Previous bone marrow transplantation

*ECOG= Eastern Cooperative Oncology Group

Phase II study

Doxorubicin 60 mg/m2 + Docetaxel 75 mg/m2

( n=208)

lipegfilgrastim 3.0 mg (n=53)



pegfilgrastim 6.0 mg (n=54)

Primary breast cancer patients (N=229)

Randomization Next chemo cycle if ANC ≥1.5 x 109/L and platelet

count ≥100 x 109/L

One chemotherapy cycle

= 21 days

rGCS-‐F therapy

Chemotherapy

Run-‐in Cycle 1 Cycle 2 Cycle 3 Cycle 4 Follow-‐up D1 D22 D43 D64

D85 End of study D180

Ab test D360

Ab test D2 D23 D44 D65

Ab=antibody test; D=day; chemo=chemotherapy.

Haematological and biochemical parameters measured on Day 15 of each cycle

Multinational, multicenter, randomized, double blind

Data on file Buchner, A. et all JCO, 29:2011 (Suppl; abstr 9080)

Phase II study

§  Primary Endpoint: Dura,on of Severe Neutropenia (DSN) in the first cycle of chemotherapy in the respec,ve arms

§  Secondary Endpoint

§  Incidence of Febrile Neutropenia in cycles 1, 2, 3, and 4 and across all cycles. Febrile

§  DSN in cycles 2, 3, and 4. §  The following secondary efficacy endpoints were evaluated in cycles

1, 2, 3, and 4: §  Depth of ANC nadir. §  Time to ANC recovery ( ANC ≥2.0 x 109/L). §  Incidence of grade 4 neutropenia (ANC < 0.5 x 109/L). §  Safety

Data on file Buchner, A. et all JCO, 29:2011 (Suppl; abstr 9080)

Severe Neutropenia =grade 4 neutropenia (ANC < 0.5 x 109/L). Very Severe Neutropenia (ANC < 0.1 x 109/L)

Febrile Neutropenia was defined as axillary body temperature of > 38.5°C for more than 1 h and ANC <0.5 x 109/L, both measured on the same day L)

Phase II study

No significant difference between groups

4 groupes aux caractéristiques démographiques et médicales comparables (en ITT et en PP)

Pegfilgrastim N=54

lipegfilgrastim 3 mg, N=53

lipegfilgrastim 4,5 mg, N=51

lipegfilgrastim 6 mg, N=50

Total N=208

Age (years) Median ± SD ≤ 64 years, %

49,5 ±11,1

92,6%

53,1 ±9,2

86,8%

52,8 ± 10,1

88,2%

51,4 ± 9,8

90%

51,7 ±10,1

89,4%

Weight ≤ 60 kg

60 à 75 kg > 75 kg

25,9% 33,3% 40,7%

22,6% 45,3% 32,1%

25,5% 39,2% 35,3%

26,0% 38,0% 36,0%

25,0% 38,9% 36,1%

CT indication Adjuvant

Métastatic

79,6% 20,4%

81,1% 18,9%

86,3% 13,7%

82,0% 18,0%

82,2% 17,8%

Disease stage High-risk stage II

Stage III Stage IV

40,7% 42,6% 16,7%

39,6% 43,4% 17,0%

37,3% 51,0% 11,8%

36,0% 48,0% 16,0%

38,5% 46,2% 15,4%

ECOG status 0 1 2

61,1% 38,9%

0%

64,1% 34,0% 1,9%

51,0% 43,1% 5,9%

56,0% 42,0% 2,0%

58,2% 39,4% 2,4%

Patients caracteristics

Duration of Severe Neutropenia in cycle 1 (ITT population)

pegfilgrastim 6mg

Lonquex® 3mg

Lonquex® 4.5mg

Lonquex® 6mg

N valid, Mean ± standard deviation (median) Minimum to maximum

54

0.9±1.0 (1.0)

0.0 to 3.0

53

1.1±1.1 (1.0)

0.0 to 4.0

51

0.8±1.0 (1.0)

0.0 to 4.0

50

0.8±1.1 (0.0)

0.0 to 3.0

No statistically significant difference between treatment arms Same results in PP population and within sub-groups analysis..

Phase II study

§  Conclusion :

§  Non-inferiority of lipegfilgrastim 6 mg vs pegfilgrastim 6 mg was demonstrated on DSN in cycle 1

§  Significantly more patients without severe neutropenia in the lipegfilgrastim group vs pegfilgrastim group, in cycles 2, 3 and 4

§  Time to ANC recovery (ANC ≥ 2 x 10 9/L) significantly shorter with lipegfilgrastim than pegfilgrastim 6 mg, in each cycle

§  Safety profile similar to pegfilgrastim 6 mg

Phase II study

Phase III study XM22-‐03

Lipegfilgras,m 6mg vs pegfilgras,m 6 mg

Breast cancer

Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.

§  Primary Objective : §  Demonstration of non-inferiority of Lonquex® versus

pegfilgrastim in patients treated for breast cancer (doxorubicine-docétaxel)

Non inferiority hypothesis demonstrated if : Δ DSN (lipegfilgrastim –pegfilgrastim) < 1 day

§  Design: §  Multinational, multicenter, randomized, double-blind, phase III

study

Phase III study, XM22-‐03

Doxorubicin 60 mg/m2 + Docetaxel 75 mg/m2

(Pooled n=202)

Lipegfilgrastim 6 mg (n=101)

pegfilgrastim 6.0 mg (n=101)

Ab=antibody test; D=day; CTX=chemotherapy; ANC=absolute neutrophil count.

Primary breast cancer

patients (n=218)

Randomization Next CTX

cycle if ANC ≥1.5 x 109/L and platelet

count ≥100 x 109/L

One chemotherapy cycle = 21 days

Multinational, multicenter, randomized, double-blind, phase III study

rGCS-‐F therapy

Chemotherapy

Run-‐in Cycle 1 Cycle 2 Cycle 3 Cycle 4 Follow-‐up D1 D22 D43 D64

D85 End of study

D180 Ab test

D360 Ab test D2 D23 D44 D65

Bondarenko, I. et all JCO, 30, 2012 (Suppl; abstr 19587) Bondarenko et al,Jcancer Research and Clin Oncology , 2012, Submitted


§ Primary Endpoint: Duration of Severe Neutropenia (DSN) in the first cycle of chemotherapy.

§ Secondary Endpoints: §  Efficacy parameters

§  Incidence of Febrile Neutropenia in cycles 1-4 §  Duration of Severe Neutropenia in cycle 2-4 §  Depth of ANC nadir in each cycle §  Time to ANC recovery (ANC ≥ 2.0 109/L) §  Incidence of severe neutropenia

§  Safety parameters

Bondarenko, I. et all JCO, 30, 2012 (Suppl; abstr 19587)

• Severe Neutropenia/Grade 4 (NCI) :ANC < 0.5X109/L • Febrile neutropenia (FN): Severe Neutropenia + Axyllary temperature > 38.5° C for at least one hour +/-(documented neutropenic sepsis and /or documented of serious or life threatening infection)


Patients caracteristics : similar in both groups

Pegfilgras+m 6 mg

N=101 Lipegfilgras+m 6 mg

N=101

Age Median ± SD (years)

≤ 64, n (%) 65 à 74, n (%)

51.1 ± 9.4 94 (93.1) 7 (6.9)

49.9 ± 10.1 94 (93.1) 7 (6.9)

Body weight Median ± SD (kg)

≤ 60, n (%) >60 à ≤75, n (%)

>75, n (%)

73.2 ± 14.6 16 (15.8) 49 (48.5) 36 (35.6)

73.9 ± 17.1 22 (21.8) 40 (39.6) 39 (38.6)

Indica+on for CT, n (%) Adjuvant

Métasta,c

74 (73.3) 27 (26.7)

75 (74.3) 26 (25.7)

ECOG status 0 1 2

47 (46.5) 54 (53.5) 0 (-‐)

45 (44.6) 56 (55.4) 0 (-‐)

Stage High-‐risk stage II

III IV

36 (35,6) 45 (44,6) 20 (19,8)

39 (38,6) 48 (47,5) 14 (13,9)



Tumor and treatment caracteristics similar in both arms

Variable Pegfilgras+m 6 mg N=101 (%)

Lipegfilgras+m 6 mg N=101 (%)

Months since diagnosis Mean ± SD

Median Varia,ons

6,1 ± 26,6

1 0 à 185

5,3 ±16,7

2 0 à 130

Surgery 59 (59,4) 50 (49,5)

Time since surgery (months) Mean ± SD

9,1 ± 34,1

6,7 ± 15,5

Type of surgery Conserva,ve Mastectomy

Axillary dissec,on

7 (6,9) 55 (54,5) 46 (45,5)

4 (4)

46 (45,5) 44 (43,6)



Primary endpoint : DSN in cycle 1

Non-inferiority of Lipegfilgrastim 6 mg vs Pegfilgrastim 6 mg demonstrated (Δ DSN < 1 jour)

Results confirmed in sub-groups analysis by country, indication for CT and body weight

Lipegfilgrastim 6mg

Pegfilgrastim 6 mg

Δ Lipegfilgrastim- pegfilgrastim (IC95) p

PP population

DSN median ± SD LS Mean (95% CI)

0,7 ± 0,9 jours 0

0,8 ±0,9 jours 1

-  0,218 jours (-0,498 à 0,062) 0,1260



Secondary endpoints (PP population)

Pegfilgras+m 6mg

Lipegfilgras+m 6mg p

DSN Cycle 2 Cycle 3 Cycle 4

0,3 ± 0,6 0,2 ± 0,4 0,2 ± 0,5

0,1 ± 0,5 0,1 ± 0,3 0,2 ± 0,6

0,1287 0,6227 0,922

Incidence of FN Cycle 1

Cycles 1 to 4

3,2% 3,2%

0,0% 0,0%

NS

Incidence of SN Cycle 1 Cycle 2

Cycles 1 à 4

51,1% 21,5% 58,5%

43,6% 8,5% 50,0%

0,341 0,013* 0,269



Neutropenia in cycles 1-4 (PP population)

Nadir comparable in cycle 1 in both treatment groups ANC values to nadir significantly higher in cycles 2 and 3 in the lipegfilgrastim group

Pegfilgrastim 6 mg (N=94) [NCx109/L]

Lipegfilgrastim 6 mg (N=94) [NCx109/L]

p

Nadir (109/L) Cycle 1 Cycle 2 Cycle 3 Cycle 4

1,0 ± 1,3 2,0 ± 1,6 2,0 1,5 2,3 1,8

1,2 ± 1,3 2,6 ± 2,1 2,5 ± 1,6 2,7 ± 1,7

0,254 0,019 0,035 0,112

ANC recovery* Cycle 1 Cycle 2 Cycle 3 Cycle 4

1,6 ± 1,2 0,8 ± 1,0 0,8 ± 1,0 0,7 ± 0,9

1,3 ± 1,0 0,5 ± 0,7 0,4 ± 0,7 0,4 ± 0,7

0,062 0,076 0,021 0,076

*Time to ANC recovery ≥1,5x109 /L after nadir (days)



Time to ANC recovery (≥ 2x 109/L after ANC < 2x 109/L ) in cycles 1-4 (PP

population)

Cycle pegfilgras+m 6mg N=94

Lipegfilgras+m 6mg

N=94

p

1 7.4±3.6 5.9±3.4 0.003* 2 5.3±4.6 3.6±4.1 0.008* 3 5.1±4.3 3.9±4.8 0.033* 4 4.3±4.7 3.3±4.1 0.223

Course of ANC in cycle 1



30

Quality of life •  Global decreasing of the score during the treatment phase •  No sta,s,cal difference among the 2 arms according to QLQ-‐C30 nor

QLQ-‐BR23 scales

Mean variations of EORTC QLQ-BR23 scoring scales between inclusion and end of the study


Safety

Safety profile similar in both treatment groups

a : 1 neutropenia and 1 paroxysmal tachycardia b : epistaxis c : FN stage 3 and enterocolitis


pegfilgras+m 6mg N=101

lipegfilgras+m 6mg N01=1

Category of TEAE N (%) N (%) Any TEAE 99 (98.0) 100 (99.0)

Drug related TEAE=TEADR 26 (25.7) 28 (27.7)

Serious TEAE 7 (6.9) 3 (3.0)

Serious TEADR 1 (1.0) 1 (1.0)

Severe TEAE 35 (34.7) 26 (25.7)

Severe TEADR 2 (2.0) a 1 (1.0) b

Discon,nued due to TEAE 2 (2.0) 3 (3.0)

Discon,nued due to TEADR 1 (1.0) 0 (0)

Death 0 (0) 1 (1.0) c

Comparable safety profile


Most frequent side effects occurring in ≥ 3 % pa+ents (ITT popula+on)

Side effects Pegfilgras+m 6 mg (N=101)

Lonquex® 6 mg (N=101)

N (%) N (%)

Bone pain 10 (9.9) 13 (12.9)

Myalgia 5(5.0) 7 (6.9)

Erythema 3(3.0) 6 (5.9)

Arthralgia 0 (-‐) 3 (3.0)

Nausea 3 (3.0) 2 (2.0)

Conclusions :

§  Non inferiority of lipegfilgrastim 6 mg vs pegfilgrastim 6 mg demonstrated on

DSN in cycle 1

§  Secondary endpoints : significant differences in favor of lipegfilgrastim on following

endpoints :

§  Lower incidence of severe neutropenia in cycle 2

§  Lower depth of neutropenia in cycles 2 and 3

§  Time to ANC recovery ≥ 2 x109/L shorter in cycles 1, 2 and 3

§  Comparable safety profiles


Conclusion

Lipegfilgras+m:

• Molecular structure : « glycoPEGyla,on technology »

• Long-‐ac,ng human recombinant G-‐CSF (r-‐metHuG-‐

CSF)

• Efficacy and safety profile comparable to pegfilgras,m

THANKS

Joseph Gligorov : Lipegfilgrastim : A new long-ac,ng recombinant human G-CSF

Health & Medicine

cd 34 max

phase iii

therapy chemotherapy

breast cancer

platelet count

blind study

secondary

anc max