Investigación Clínica

¿Cómo se construye la evidencia?

El ejemplo de Denosumab

Miquel Balcells AMGEN Iberia

Premisas a cumplir cuando queremos

generar evidencia en salud

Identificar y cuantificar la relevancia del problema

Comprender las causas del problema (fisiopatología)

Seleccionar el candidato adecuado

Diseño adecuado

– Brazo control

– Enmascaramiento

– Objetivos y variables

– Seguridad

Plan de desarrollo clínico post-autorización

XGEVA® (denosumab)2

Dose 120 mg SC

Regimen Every 4 weeks

Indication(s)

Prevention of skeletal related events (pathological fracture,

radiation to bone, spinal cord compression or surgery to bone) in

adults with bone metastases from solid tumours

Denosumab (XGEVA®) – Therapeutic

indication approved by EMA

EMA: European Medicines Agency; SC, subcutaneous.

1. McClung MR et al. New Engl J Med 2006;354:821–31.

2. XGEVA® (Denosumab) Summary of product characteristics, Amgen. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002173/human_med_001463.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124 Accessed 14 May 2012.

Denosumab is a fully human monoclonal antibody that binds human RANK Ligand with high affinity and specificity1

Metástasis óseas y eventos relacionados con

el esqueleto (EREs/SREs):

la magnitud del problema

Bone metastases may result in clinically significant and serious consequences of skeletal-related events (SREs)

SREs are defined as1,2:

1. Saad F, et al. J Natl Cancer Inst 2004;96:87982;

2. Ibrahim A, et al. Clin Cancer Res 2003;9:23949.

Pathological

fracture

Radiation to

bone

Surgery to

bone

Spinal cord

compression

SREs are both common and frequent in patients with advanced cancer untreated for bone metastases

Perc

enta

ge o

f patients

Breast1

(24 months)

Lung and

other solid

tumours3

(21 months)

Prostate2

(24 months)

Percentage of patients

developing SREs Mean number of SREs

per patient per year

Mean n

um

be

r of

SR

Es/p

atient/year

SRE: skeletal related event; IV: intravenous.

1. Lipton A, et al. Cancer 2000;88:108290;

2. Saad F, et al. J Natl Cancer Inst 2004;96:87982;

3. Rosen LS, et al. Cancer 2004;100:261321.

Breast1

Lung and

other solid

tumours3

Prostate2

Data are from the placebo arms of 3 major trials of

placebo vs. IV bisphosphonate in different tumour types

Patients have increased chances of developing SREs as survival times improve

Prostate3,4

Breast1,2

Lung5,6

12.3

21.7

25.2

5.2

10.7

7.0

0 5 10 15 20 25 30

Months

SRE: skeletal related event.

1. Lipton A, et al. Cancer 2000;88:108290; 2. Miller K, et al. N Engl J Med 2007;357:266676;

3. Saad F, et al. J Natl Cancer Inst 2002;94:145868; 4. Kantoff PW, et al. N Engl J Med 2010;363;41122;

5. Rosen LS, et al. Cancer 2004;100:261321; 6. Sandler A, et al. N Engl J Med 2006;355:254250.

Median time to first SRE

Median overall survival

Median time to first SRE vs median overall survival

Los EREs llevan asociadas una serie de implicaciones que agravan

significativamente la carga económica de esta enfermedad sobre el

Sistema Sanitario español.1

Se ha estimado que en España el coste medio de cada ERE oscila entre

los 2.378€ y los 7.903€ (€2010).1

1. Hechmati G, et al. J Med Econ 2013;16(5):691-700.

COSTES DEL TRATAMIENTO DE LOS EREs

Fisiopatología de las metástasis óseas

Normal bone remodelling is tightly regulated

RANK Ligand binds to

RANK on osteoclast

precursor cells, which

then develop into

osteoclasts and become

active

Osteoblasts

RANK Ligand

Osteoblasts release

RANK Ligand

Osteoclast

Active osteoclasts

remove bone tissue

(resorption)

RANK Ligand is an important mediator of bone resorption

The resultant bone lost needs to

be replaced – by osteoblasts

(formation)

Boyle WJ et al. Nature 2003;423:337–42.

RANK, receptor activator of nuclear factor κ B

A vicious cycle of bone destruction may

develop in the presence of tumour cells

Overexpression of RANK

Ligand drives increased

formation, function and

survival of osteoclasts,

leading to excessive

bone resorption

Osteoblasts

Tumour cells produce

factors that stimulate

osteoblasts to secrete

RANK Ligand

RANK Ligand

Tumour

Osteoblasts and

other bone cells

increase expression

of RANK Ligand

Osteoclast

Bone resorption releases growth

factors from the bone matrix that

may perpetuate tumour activity

Roodman GD. N Engl J Med 2004;350:1655–64;

Mundy GR. Nat Rev Cancer 2002;2:58493.

RANK, receptor activator of nuclear factor κ B

Denosumab targets RANK Ligand to break the

vicious cycle

By binding to RANK

Ligand denosumab

inhibits osteoclast

formation, function, and

survival

Osteoblasts

Osteoclast

Denosumab precisely

binds to RANK Ligand,

preventing activation of

the RANK receptor on

osteoclasts

Denosumab prevents the

maturation of osteoclasts,

decreasing bone resorption and

breaking the vicious cycle of

bone destruction

Tumour

RANK

Ligand

Denosumab

Roodman GD. N Engl J Med 2004;350:1655–64;

Mundy GR. Nat Rev Cancer 2002;2:58493.

RANK, receptor activator of nuclear factor κ B

Selección del diseño adecuado :

estudios fase III en prevención de SREs

• Primary endpoint: time to first on-study SRE (non-inferiority)

• Secondary endpoints: time to first on-study SRE (superiority);

time to first and subsequent on-study SRE; safety and tolerability 1. Stopeck AT, et al. J Clin Oncol 2010;28:5132–9; 2. Fizazi K, et al. Lancet 2011;377:813–22;

3. Henry DH, et al. J Clin Oncol 2011;29:112532; 4. Lipton A, et al. Eur J Cancer 2012;48:3082–92. *Excluding breast and prostate.

Three pivotal Phase III trials of denosumab

vs zoledronic acid in patients with bone metastases

from advanced cancer

Supplemental calcium and vitamin D

†Per protocol and Zometa® label, IV product dose

adjusted for baseline creatinine clearance and subsequent

dose intervals determined by serum creatinine.

Denosumab 120 mg SC Q4W

+

Placebo IV Q4W†

Zoledronic acid 4 mg IV Q4W†

+

Placebo SC Q4W

Breast cancer1

Prostate cancer2

Other solid

tumours*/MM3

R

A

N

D

O

M

I

S

A

T

I

O

N

Pre

-pla

nn

ed

in

teg

rate

d a

naly

sis

4

(N =

5723)

Inclusion Criteria: Overview

Unspecific Inclusion Criteria 136 244 103

Current or prior radiographic (ie x-ray, CT, MR) evidence of 1 bone met X X X

ECOG PS 0-2 X X X

Adequate organ function X X X

Written informed consent X X X

15

IV: intravenous, BP: bisphosphonate, ONJ: osteonecrosis of the jaw, BC: breast cancer, Cis: carcinoma in situ, BCC: basal cell carcinoma, HIV: human

immunodeficiency virus, HBV: hepatitis B virus, HCV:hepatitis C virus, ZA: zoledronic acid, Dmab: denosumab, Ca2+ : calcium, Vit D: vitamin D

Specific Inclusion Criteria

136 244 103

Adult (incl men) with

histologically or cytologically

confirmed breast

adenocarcinoma

Adult with histologically or

cytologically confirmed

advanced cancers including

solid tumors, multiple myeloma

and lymphoma

Men with histologically confirmed prostate

cancer

+

Documented failure of at least one hormonal

therapy as evidenced by a rising PSA

+

Serum testosteron level of <50 ng/dl due

either chemical or surgical castration

Protocol denosumab study 20050136, 20050244, 2005103

SRE definition

Pathologic fracture (vertebral or non-vertebral)

– Fracture that occurs spontaneously or results from trivial trauma

Radiation therapy to bone (including radioisotopes)

– Pain control

– Treat or prevent pathologic fractures or spinal cord compression

Surgery to bone

– Prodedures to set or stabilize a fracture or to prevent an

imminent fracture or spinal cord compression

Spinal cord compression 16 Protocol denosumab study 20050136, 20050244, 2005103

Risk reduction in time to first SRE consistently

favoured denosumab across tumour types

1. Stopeck AT et al. J Clin Oncol 2010;28:5132–9;

2. Fizazi K et al. Lancet 2011;377:813–22;

3. Henry DH et al. J Clin Oncol 2011;29:112532. †Excluding breast and prostate. All data from primary analyses

Pa

tie

nts

with

ou

t S

RE

(%

)

Denosumab

Study month

0 0 3 6 9 12 15 18 21 24 27

Breast

cancer

study1

(n = 2046)

HR = 0.82 (95% CI: 0.71–0.95)

P = 0.01 (superiority)

Prostate

cancer

study2

(n = 1901)

HR = 0.82 (95% CI: 0.71–0.95)

P = 0.008 (superiority)

0 3 6 9 12 15 18 21 24 27

Other solid

tumour/multiple

myeloma study3†

(n = 1776)

HR = 0.84 (95% CI: 0.71–0.98)

P = 0.0007 (non-inferiority)

P = 0.06 (NS for superiority)

0 3 6 9 12 15 18 21 24

100

90

80

70

60

50

40 26.4 months

Not yet reached

20.6 months

17.1 months 16.3 months

Zoledronic acid

18% Risk

Reduction

20.7 months

18% Risk

Reduction

16% Risk

Reduction

30

20

10

Time to first SRE

SRE, skeletal related event.

Significantly fewer SREs with denosumab across

different tumour types

Cu

mu

lati

ve

me

an

nu

mb

er

of

SR

Es

per

pati

en

t

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0 0 3 6 9 12 15 18 21 24 27

RR = 0.77 (95% CI, 0.66–0.89)

P = 0.001 (superiority)

Total SREs:

Zoledronic acid: 608

Denosumab: 474

0 3 6 9 12 15 18 21 24 27 30 33

RR = 0.82 (95% CI, 0.71–0.94)

P = 0.008 (superiority)

Total SREs:

Zoledronic acid: 584

Denosumab: 494

0 3 6 9 12 15 18 21 24 27

RR= 0.90 (95% CI, 0.77–1.04)

P = 0.14 (NS for superiority)

Total SREs:

Zoledronic acid: 436

Denosumab: 392

Breast

cancer1

(n = 2046)

Prostate

cancer2

(n = 1901)

Other solid tumour/

multiple myeloma3

(n = 1776)

23% Risk

Reduction

18% Risk

Reduction

10% Risk

Reduction

1. Stopeck AT et al. J Clin Oncol 2010;28:5132–9; 2. Fizazi K et al. Lancet

2011;377:813–22; 3. Henry DH et al. J Clin Oncol 2011;29:112532.

All data from primary analyses;

RR, rate ratio

Time to first and subsequent SREs

Study month SREs, skeletal related events.

Integrated analysis: power from identical study

designs

Zoledronic acid 4 mg IV Q4W*

+

Placebo

SC Q4W

(n = 2862)

Denosumab 120 mg SC Q4W

+

Placebo

IV Q4W*

(n = 2861)

Breast Cancer

N = 2046

R

A

N

D

O

M

I

S

A

T

I

O

N

Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012;48:3082-3092.

IV, intravenous; Q4W, every 4 weeks; SC, subcutaneous

Daily supplementation with calcium (≥ 500 mg) and vitamin D (≥ 400 IU)

*Per protocol and Zometa® label, IV product dose adjusted for baseline

creatinine clearance and subsequent dose intervals determined by serum creatinine

N = 5723

Prostate Cancer

N = 1901

Solid Tumors + Multiple Myeloma

N = 1776

Key inclusion criteria: Patients with ≥ 1 bone metastasis/lesion

Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012;48:3082-3092.

Significantly longer time (8.2 months) without

an SRE with denosumab vs zoledronic acid

17% Risk

Reduction

HR = 0.83

(95% CI: 0.76–0.90)

P 0.0001 (superiority)

Zoledronic acid 2861 1596 991 522 178 26

Denosumab 2862 1666 1077 570 197 22

Study month

Patients

without

SR

E (

%)

0

40

60

80

100

0 6 12 18 24 30

27.6 months

19.4 months

90

70

50

30

No. at risk

Time to first SRE

(n = 5723)

Denosumab Zoledronic acid

20

10

HR, hazard ratio SRE, skeletal related event.

Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012;48:3082-3092.

Significantly fewer SREs with denosumab

vs zoledronic acid

18% Risk

Reduction

Time to first and subsequent SREs

(n = 5723) RR = 0.82

(95% CI, 0.75–0.89) P < 0.001 (superiority)

0 3 6 9 12 15 18 21 24 27 30 33 36

Cum

ula

tive m

ean n

um

be

r of

SR

Es p

er

patient

Study month

0.0

1.0

1.6

1.4

1.2

0.8

0.6

0.4

0.2

Total SREs:

Zoledronic acid: 1628

Denosumab: 1360

Events occurring at least 21 days apart (multiple event analysis)

RR, rate ratio SREs, skeletal related events.

von Moos R, et al. Support Care Cancer 2013;21:3497507. †BPISF worst pain score. Patients with MM were not included in this analysis.

Denosumab delayed pain worsening

by almost 2 months vs zoledronic acid M

edia

n tim

e f

rom

no o

r m

ild p

ain

to

modera

te o

r severe

pain

(m

onth

s)

+ 1.8

mths

HR = 0.83

(95% CI, 0.760.92)

P < 0.001

Time to moderate or severe pain (> 4 points)

among patients with no or mild pain (0–4 points) at baseline (n = 2683)†

• Depending on the tumour type:

− Treatment of 7.8−16 patients for 1 year with denosumab would be

needed to prevent 1 additional first SRE

− Treatment of 5−7 patients for 1 year with denosumab would be needed

to prevent 1 additional recurrent SRE

1. Martin M, et al. Clin Cancer Res 2012;18:4841−9;

2. Miller K, et al. AUA 2011:abstract 648 (and oral presentation);

3. Richardson G, et al. J Clin Oncol 2011;29(Suppl):abstract 9115 (and poster) NNT, number needed to treat.

Denosumab had a favourable NNT vs zoledronic

acid for prevention of first and recurrent SREs

First on-study SRE, n Recurrent SREs, n

Tumour

type

Zoledronic

acid Denosumab NNT

Zoledronic

acid Denosumab NNT

Breast

cancer1 372 315 16 853 660 7

Prostate

cancer2 386 341 10 943 780 5

Other solid

tumours3 277 234 7.8 535 461 6.5

Análisis de seguridad

ONJ, osteonecrosis of the jaw.

Safety results of interest

Patient incidence, n (%) Zoledronic acid

(n = 2836) Denosumab (n = 2841)

Infectious AEs 1218 (42.9) 1233 (43.4)

Infectious serious AEs 309 (10.9) 329 (11.6)

Acute phase reactions (first 3 days) 572 (20.2) 246 (8.7)

Cumulative rate of ONJ 37 (1.3) 52 (1.8)

Year 1 15 (0.5) 22 (0.8)

Year 2 28 (1.0) 51 (1.8)

Hypocalcaemia 141 (5.0) 273 (9.6)

New primary malignancy 18 (0.6) 28 (1.0)

AEs leading to study discontinuation 280 (9.9) 270 (9.5)

572 (20.2) 246 (8.7)

141 (5.0) 273 (9.6)

37 (1.3) 52 (1.8)

Lipton A, et al. Eur J Cancer 2012;48:308292.

Cumulative incidence of ONJ

0.5

1.0 0.8

1.8

1.3

1.8

0

2

4

012 024 036*

Pro

port

ion o

f patients

(%

)

Denosumab (n = 2814)

Zoledronic acid (n = 2836)

Saad F, et al. Ann Oncol 2012;23:1341–7.

Proportions are % of all patients treated with zoledronic acid or denosumab.

No significant difference in ONJ rate between

treatment arms

*P = 0.13

Denosumab

(n = 52)

1.8%

Zoledronic acid

(n = 37)

1.3%

Positively adjudicated

for ONJ

(n = 89)

Potential ONJ

(n = 276)

All patients

(N = 5723)

Study month

*Treatment and outcomes as per 1 October 2010. †Resolved = complete mucosal coverage of exposed bone.

‡Among patients with ONJ resolution.

Resolution of ONJ occurred in 40% of patients

who experienced ONJ on denosumab

Outcomes* Zoledronic acid

(n = 37)

Denosumab

(n = 52)

All

(n = 89)

Resolved,† n (%) 11 (30) 21 (40) 32 (36)

Median time to resolution,‡

months (range) 8.7 (3.718.3) 8.0 (0.225.6) 8.2 (0.225.6)

Ongoing, present at time of death

or unknown, n (%) 26 (70) 31 (60) 57 (64)

Saad F, et al. Ann Oncol 2012;23:1341–7.

Desarrollo clínico post-autorización

Estudios orientados a responder las preguntas que han

quedado abiertas en la fase de previa a la autorización

1.- Cummings SR, et al. N Engl J Med. 2009;361:756-765. 2.- Bone HG, et al. J Clin Endocrinol Metab. 2008;93:2149-2157. 3.- Brown JP, et al. J Bone Miner Res. 2009;24:153-161. 4.- Kendler DL, et al. J Bone Miner Res.

2010;25:72–81. 5.- Smith MR, et al. N Engl J Med. 2009;361:745-755. 6.- Ellis GK, et al. J Clin Oncol. 2008;25:4875-4882. 7.- www.clinicaltrials.gov Accessed 14 Feb 2014. 8.- Smith MR, et al. Lancet 2012;379:39-46. 9.-

Fizazi K et al. The Lancet 2011;377;813-822. 10.- Stopeck AT et al. J Clin Oncol 2010;28:5132-5139 11.- Henry DH et al. J Clin Oncol 2011;29(9):1125-32.

PMO Treatment (FREEDOM)1 (n = 7.868)

Prostate cancer5 (n = 1.468)

Prostate cancer8 (n = 1.432)

Prostate cancer9 (n = 1.904)

PMO Prevention (DEFEND)2 (n = 332)

Breast cancer6 (n = 252)

Breast cancer - D-CARE7 (n ~ 4500)

*Active, not enrolling

Breast cancer10 (n = 2046)

Denosumab vs. alendronate (DECIDE)3 (n = 1.189)

ABCSG-18 breast7 (n ~ 2.800)

*Active, not enrolling

Solid tumor and MM11** (n = 1.776)

Alendronate to denosumab Transition (STAND)4

(n = 504)

MM7** (n ~1.520)

*Enrolling

Postmenopausal osteoporosis

~ 10.000 patients

Cancer Treatment-Induced Bone Loss

~ 4.500 patients

Prevention or Delay of Bone Metastasis*

~ 6.000 patients

SREs = Skeletal Related Events; PMO = postmenopausal osteoporosis; FREEDOM = Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months; DEFEND = DEnosumab Evaluation For PrEserving BoNe

Density; DECIDE = Determining Efficacy: Comparison of Initiating Denosumab vs. AlEndronate; STAND = Study of Transitioning from AleNdronate to Denosumab; ABCSG = Austrian Breast and Colorectal Cancer Study Group;

D-CARE= Denosumab as adjuvant Treatment for Women with early-stage breast CAncer at high risk of Recurrence; MM = multiple myeloma .

*Denosumab is currently not approved in EU for the prevention or delay of the development of bone metastases. Denosumab is investigational in that setting.

**Denosumab is not indicated for use in patients with multiple myeloma (MM). Denosumab is investigational in that setting.

Prevention or Delay of SREs

~ 7.000 patients

60 mg Q6M 120 mg Q4W

Discovery and development of denosumab and the RANK/RANK Ligand/OPG pathway

2008 2007 2006 2004 2001 1998 1997 1995 2009

OPG is

disclosed in

patent filings as

an important

regulator of

bone density

Identification and cloning of

RANK/RANK Ligand and OPG

published in Nature and Cell1,2

A molecule that binds to OPG

was identified and referred to

as OPGL; found to be identical

to RANK Ligand; OPG

recognised as a decoy

receptor3,4

Mid-2001

first-in-human dose

study for denosumab

First single-dose study

of denosumab in

PM women published in

J Bone Miner Res5

Phase 3 trials with denosumab in

oncology pts and

PM women initiated6

Phase 2 trial in PMO with low

BMD published in

N Engl J Med7

Phase 1 trial of denosumab in

breast cancer or MM patients

with bone metastases

published in Clin Can Res8

Phase 2 trial in breast cancer

patients with bone metastases

published in

J Clin Oncol9

Phase 3 CTIBL-BC

published in JCO10

Phase 3 PMO fracture (216) study

published in

N Engl J Med11

Phase 3 CTIBL-PC published in N

Engl J Med12

Denosumab

120 mg Q4W (XGEVA®) approved in

USA for prevention of SREs

in pts with bone metastases from

solid tumors

Denosumab 60 mg Q6M (Prolia®)

approved in USA and EU in PMO

and EU PMO and CTIBL13,14

Phase 3 oncology study(breast

cancer) in SREs published in JCO15

2010 2011-12

Denosumab 120 mg Q4W (XGEVA®)

approved in EU for prevention of

SREs in adults with bone metastases

from solid tumours14

Denosumab 60 mg Q6M (Prolia®)

approved in USA in CTIBL13

Denosumab 60 mg Q6M (Prolia®)

available in Spain

Phase 3 (ST-MM

and prostate

cancer) in SREs

published in

JCO16 and The

Lancet17

Phase 3 and bone

metastasis free

survival study

published in The

Lancet18

2013

Denosumab

120 mg Q4W

(XGEVA®)

available in

Spain.

1. Anderson DM, et al. Nature 1997;390:175–9; 2. Simonet WS, et al. Cell 1997;89:309–19;

3. Lacey DL, et al. Cell 1998;93:165–76; 4. Yasuda H, et al. Proc Natl Acad Sci USA

1998;95:3597–602; 5. Bekker PJ, et al. J Bone Miner Res 2004;19:1059–66;

6. www.amgen.com; 7. McClung MR, et al. New Engl J Med 2006;354:821–31;

8. Body JJ et al. Clin Cancer Res 2006;12:1221–8; 9. Lipton A et al. J Clin Oncol 2007;25:4431–7; 10. Ellis GK, et al.

J Clin Oncol 2008;26:4875–82; 11. Cummings SR, et al. N Engl J Med 2009;361:756–65; 12. Smith MR, et al. N

Engl J Med 2009;361:745–55; 13. www.fda.gov; 14. www.ema.europa.eu; 15. Stopeck AT, et al. J Clin Oncol

2010;28:5132–9; 16. Henry DH, et al. J Clin Oncol 2011; 29:1125-1132; 17. Fizazi K, et al. Lancet. 2011;377:813–

822; 18. Smith MR, et al. Lancet 2012;379:3946.

Denosumab is not indicated for use in patients with multiple myeloma (MM). Denosumab is investigational in that setting.

Denosumab is currently not approved in EU for the prevention or delay of the development of bone metastases. Denosumab is investigational in that setting.

BC, breast cancer; BMD, bone mineral density; CTIBL, cancer treatment

induced bone loss; SREs, skeletal related events; OPG, Osteoprotegerin; PM,

postmenopausal; MM, multiple myeloma; PMO, postmenopausal osteoporosis;

Q4W, every four weeks; Q6M, every six months; RANK, receptor activator of

nuclear factor κ B; ST; solid tumors; PC, prostate cancer.

Overview of guideline recommendations

for denosumab

ASCO NCCN ESMO EAU AUA

Breast cancer N/A N/A

CRPC N/A

NSCLC N/A N/A N/A

Renal cell carcinoma N/A N/A N/A

Bladder cancer N/A N/A N/A N/A

Cancer pain N/A N/A

Bone health N/A N/A N/A A/A

Denosumab use recommended

N/A No relevant guidelines exist

†Guideline published in 2012 states that denosumab use is still investigational in renal cell carcinoma.

ASCO, American Society of Clinical Oncology; AUA, American Urological Association;

CRPC, castration-resistant prostate cancer; EAU, European Association of Urology;

ESMO, European Society for Medical Oncology; NCCN, National Comprehensive Cancer Network;

NSCLC, non-small cell lung cancer.

†

Denosumab use not currently recommended

¡Muchas gracias!