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FIRMAGON® (Degarelix)– a new-generation GnRH antagonist for advanced hormone-dependent prostate cancer

20/04/2016

Jeffrey Hsiao 蕭哲文

START STRO NG.STAY IN CO NTRO L.

ADT, androgen deprivation therapy

1. Walsh PC. Urol Clin North Am 1975;2(1):125-140.2. Ockrim J, et al. Nat Clin Pract Oncol. 2006;3(10):552-563.3. Lepor H, et al. Rev Urol. 2012;14(1/2):1-12 doi:10.3909/riu0547.4. Huggins C, et al. Arch Surg 1941; 43: 209-223.5. Hellerstedt BA, et al. CA Cancer J Clin 2002; 52; 154-179.

Background to Androgen Deprivation Therapy (ADT) in Prostate CancerBackground to Androgen Deprivation Therapy (ADT) in Prostate Cancer

2

� Testosterone is essential for growth and viability of prostate tumour cells1

� ADT results in the death (apoptosis) of androgen-sensitive cells1

� Hormonal treatment of prostate cancer ‘started’ in 19412-4

� In the 1980s, luteinizing hormone-releasing hormone (LHRH) agonists were introduced5


Degarelix belongs to a class of synthetic drugs: GnRH antagonistsDegarelix belongs to a class of synthetic drugs: GnRH antagonists

GnRH, gonadotropin-releasing hormone

Millar RP, et al. Endocr Rev 2004;25:235–75

GnRH

D-Leu NEt

pGlu His Trp Ser Tyr Gly Leu Arg Pro Gly NH2

NH2

D-Ser NEt

D-Trp NH2

D-NaI D-Cpa D-PaI Aph D-Aph D-Ala NH2

D-NaI D-Cpa D-PaI D-Cit D-Ala NH2

D-NaI D-Cpa D-PaIN-MeTyr

D-Asn Lys D-Ala NH2

D-NaI D-CPa D-PaI D-hArg D-hArg D-Ala NH2

Leuprolide

Goserelin

Triptorelin

Buserelin

DegarelixDegarelix

Abarelix

Cetrorelix

Ganirelix

GnRHagonists

GnRHantagonists

D-Ser

Lys


Degarelix is a Synthetic Peptide Modelled on the Body’s Own GnRH Degarelix is a Synthetic Peptide Modelled on the Body’s Own GnRH

4

AcAcAcAc----DDDD----NalNalNalNal----DDDD----CpaCpaCpaCpa----DDDD----PalPalPalPal---- SerSerSerSer----Aph(Hor)Aph(Hor)Aph(Hor)Aph(Hor)----DDDD----Aph(Cbm)Aph(Cbm)Aph(Cbm)Aph(Cbm)----LeuLeuLeuLeu----Lys(iPr)Lys(iPr)Lys(iPr)Lys(iPr)----ProProProPro----DDDD----AlaAlaAlaAla----NHNHNHNH2222

� Acetate salt, amorphous, soluble in water

� A fully synthetic, linear decapeptide amide

� 7 synthetic amino acids, 5 of which are D-amino acids

Biochemical Structure of DegarelixBiochemical Structure of DegarelixBiochemical Structure of DegarelixBiochemical Structure of Degarelix

HHHH3333CCCC

OOOO

DDDD AlaAlaAlaAla DDDD DDDD AlaAlaAlaAlaPhePhePhePhe SerSerSerSer PhePhePhePhe DDDD PhePhePhePhe LeuLeuLeuLeu LysLysLysLys ProProProPro DDDD AlaAlaAlaAla NHNHNHNH2222

CICICICI OOOO NHNHNHNH

NNNN

NHNHNHNH

NNNN

HHHH

OOOO OOOO

NHNHNHNH OOOO

NHNHNHNH2222

HHHH3333CCCC CHCHCHCH3333

NNNN6666

3333 4444 3333 4444 4444



Mechanism of action of GnRH agonistsMechanism of action of GnRH agonists

• Acute pituitary effects

– Surge in FSH, LH and testosterone

• Chronic pituitary effects

– LH and testosterone suppression, but microsurges on repeat injection (‘acute-on-chronic’)

– FSH suppression not maintained

FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinising hormone

GnRH agonists


Mechanism of action of GnRH antagonistsMechanism of action of GnRH antagonists

• Acute pituitary effects

– Immediate suppression of FSH, LH and testosterone

• Chronic pituitary effects

– Prolonged suppression of FSH, LH and testosterone

– No microsurges

GnRH antagonists

FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinising hormone


健保資訊與適應症健保資訊與適應症

PAGE 7

藥品代碼藥品代碼藥品代碼藥品代碼藥品名稱藥品名稱藥品名稱藥品名稱(中文中文中文中文) 成分成分成分成分成分含量成分含量成分含量成分含量價格價格價格價格

BC25882253 輔美康注射劑 80毫克 Degarelix 80 MG 4,791

BC25883257 輔美康注射劑120毫克 Degarelix 120 MG 4,791

• 健保給付規範健保給付規範健保給付規範健保給付規範5.5.1.1.Degarelix（如Firmagon）：（103/9/1）

限用於成年男性晚期荷爾蒙依賴型前列腺癌患者。

• 適應症適應症適應症適應症成年男性晚期荷爾蒙依賴型前列腺癌


用法用量用法用量

• 因為 degarelix不會導致睪固酮濃度激增，所以初始治療時不不不不需要併用抗雄性激素藥物以抑制睪固酮激增。

• FIRMAGON®僅用於腹部皮下注射腹部皮下注射腹部皮下注射腹部皮下注射，不可靜脈注射。不推薦肌肉注射，因為無相關研究。與其他皮下注射的藥物一樣，注射區域應該作週期性更改，應選擇無外在壓力的區域，不適合靠近腰帶和束帶，也不應靠近肋骨

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初始劑量初始劑量初始劑量初始劑量維持劑量維持劑量維持劑量維持劑量 (每月每月每月每月1次次次次)240mg，，，，皮下注射皮下注射皮下注射皮下注射2次次次次，，，，每次每次每次每次120mg 80mg，每月1次

第一次維持劑量應在初始1個月。


FIRMAGON® (Degarelix): Dosage and AdministrationFIRMAGON® (Degarelix): Dosage and Administration

9

� Initiation dose: 240 mg (two 120 mg injections)

� Monthly maintenance dose: 80 mg (single injection)


Degarelix Forms a Gel-like Depot upon InjectionDegarelix Forms a Gel-like Depot upon Injection

10

� After subcutaneous injection, degarelix forms a gel-like sustained-release depot when contact is made with subcutaneous tissue

� This sustained-release depot facilitates a steady release of the drug into the circulation and ensures that effect is maintained


禁忌症與注意事項禁忌症與注意事項

• 對FIRMAGON ® 的活性成份或賦型劑過敏者禁用。

• 懷孕分類等級 X。

• 肝功能不全：可見輕度和短暫的ALT和AST升高，但都不伴有膽紅素升高和臨床症狀。對於已知或懷疑肝功能不全患者，建議在治療過程中檢測肝功能。

• 腎功能不全：尚無degarelix應用於嚴重腎功能不全的病人的相關研究，因此應慎用於嚴重腎功能不全患者。

• 葡萄糖耐受性：在曾接受去勢手術或促性腺激素釋放激素促效劑(GnRH agonist)治療的男性患者中可觀察到葡萄糖耐受性減低，可能發生糖尿病的發展或惡化，因此糖尿病的病人在接受雄激素阻斷治療時可能需要更頻繁檢測血糖濃度。尚無相關degarelix對於胰島素和血糖濃度影響的研究

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常見不良反應常見不良反應

• 在III期臨床研究中，使用FIRMAGON®治療最常見的不良反應是由於睪固酮抑制導致的生理學變化，包括潮熱和體重增加(在接受治療1年時間內，報告分別有25%和7%)，及注射部位的副作用。注射後數小時偶爾有短暫的寒顫、發熱或類流感疾病的報導(分別佔3%、2%和1%)。注射部位的不良反應主要是疼痛和紅斑，分別佔病例數的28%和17%。較少出現的不良反應有腫脹(6%)、硬結(4%)和結節(3%)。這些通常發生在初始劑量治療時。而以維持劑量治療時，這些反應的發生率為：每100次注射中，有3次疼痛，少於1次的紅斑、腫脹、結節和硬結。這些不良反應大多數是短暫及屬輕度至中度強度，並且很少導致治療中斷(<1%)

PAGE 12


藥物交互作用藥物交互作用

• 尚未進行正式藥物交互作用的相關研究。

• 因雄性激素阻斷治療可能使心電圖QTc interval 延長，使用degarelix時如伴隨其他已知導致QTc interval 延長或誘導Torsades de Pointes的藥物應謹慎評估。例如抗心律不整藥物IA類（如：quinidine, disopyramide）和III類（如amiodarone, sotalol, dofetilide, ibutilide）抗心律不整藥品、methadone、cisapride、moxifloxacin、抗精神病藥等應該小心評估。

– 在一項FIRMAGON® 與leuprorelin的對照確認研究中，進行了週期性心電圖檢查（每月一次）。結果顯示，兩種治療方法都使20%病人的QT/QTc interval延長450毫秒，而分別有1%使用FIRMAGON® 的病人和2%使用leuprorelin的病人QT/QTc interval 延長500毫秒。

• Degarelix 不是人類CYP450系統的受質，並沒有證據顯示在體外會大量誘導或抑制CYP1A2、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP2E1或CYP3A4/5的變化。因此在臨床上未必與同功酶發生與代謝相關的顯著藥物間的藥物動力學交互作用。

PAGE 13


藥物動力學藥物動力學

• 吸收：前列腺癌的病人接受皮下注射濃度為40mg/ml的degarelix 240mg後，(血漿濃度時間)曲線下面積AUC0-28為635天*ng/ml，最高藥物血中濃度Cmax為66.0（61.0-71.0）ng/ml，，，，到達最高血中濃度時間到達最高血中濃度時間到達最高血中濃度時間到達最高血中濃度時間Tmax發生在發生在發生在發生在40（（（（37-42））））小時小時小時小時。平均波谷濃度在初始劑量後大約為11-12 ng/ml，在維持劑量為80mg（濃度20 mg/ml）後為11-16 ng/ml。Degarelix以二相性形式被清除。根據群體的藥物動力學模型，估計初始劑量的半衰期初始劑量的半衰期初始劑量的半衰期初始劑量的半衰期（（（（t1/2））））中位數大約為中位數大約為中位數大約為中位數大約為43天天天天，維維維維持劑量的半衰期中位數大約為持劑量的半衰期中位數大約為持劑量的半衰期中位數大約為持劑量的半衰期中位數大約為28天天天天。。

• 分佈：在健康老年男性體內的分佈體積大約為1 L/Kg，血清蛋白結合率大約為90%。

• 代謝：Degarelix通過肝膽系統時經一般胜肽類降解，主要降解為肽類殘餘物由糞便排泄。皮下注射後在血漿樣本中沒有觀察到明顯的代謝物。

• 排泄：單次靜脈注射後，在健康男性中大約20-30%的藥物劑量會從尿液中排尿液中排尿液中排尿液中排泄泄泄泄，顯示70-80%經過肝膽系統排泄。單次靜脈注射degarelix後（0.864-49.4µg/kg），健康年老男性的清除率為35-50ml/h/kg。

PAGE 14


PHASE III TRIAL

A multiA multiA multiA multi----centre randomised trialcentre randomised trialcentre randomised trialcentre randomised trialcomparing the efficacy and safety of Firmagoncomparing the efficacy and safety of Firmagoncomparing the efficacy and safety of Firmagoncomparing the efficacy and safety of Firmagon®®®® (degarelix) with (degarelix) with (degarelix) with (degarelix) with

leuprolide 7.5 mg in patients with prostate cancer requiring leuprolide 7.5 mg in patients with prostate cancer requiring leuprolide 7.5 mg in patients with prostate cancer requiring leuprolide 7.5 mg in patients with prostate cancer requiring androgen deprivation therapyandrogen deprivation therapyandrogen deprivation therapyandrogen deprivation therapy (CS21)(CS21)(CS21)(CS21)

15


Dosing Schedule: CS21Dosing Schedule: CS21

16

Klotz L, et al. BJU Int. 2008;102(11):1531-1538.

Day 0Day 0Day 0Day 0Starter doseStarter doseStarter doseStarter dose

Day 28Day 28Day 28Day 28----364364364364Maintenance doseMaintenance doseMaintenance doseMaintenance dose

Degarelix160 mg (1 x 4 mL s.c.)

(n = 202)Degarelix

240 mg (2 x 3 mL s.c.)Degarelix

80 mg (1 x 4 mL s.c.)(n = 207)

Leuprolide7.5 mg (i.m.)*

(n = 201)

Monthly; in total, 13 doses are given to each patientDosing

Patients N = 610 (ITT)

Leuprolide7.5 mg (i.m.)

*Antiandrogen was allowed at the discretion of the investigatori.m., intra-muscular; ITT, intent to treat; s.c., subcutaneous


CS21- Study Endpoints CS21- Study Endpoints

17


� Probability of testosterone ≤0.5 ng/mL at all monthly measurements from day 28 to day 364

Primary endpoint

� Proportion of patients with testosterone surge � Proportion of patients with testosterone ≤0.5

ng/mL at day 3 (testosterone microsurges) � Percentage change in PSA from baseline to day

28 and time to PSA failure � Frequency and severity of adverse events

Secondary endpoints

PSA, prostate-specific antigen


Patient Demographics and Disease CharacteristicsPatient Demographics and Disease Characteristics

18


ITT, intent to treat; PCa, prostate cancer; PSA, prostate-specific antigen

Baseline CharacteristicsDegarelix

240 �� 160 mgDegarelix

240 �� 80 mg*Leuprolide

7.5 mg

Number of patients (ITT) 202 207 201

Age, years 72.1 71.6 72.5

Median testosterone, ng/mL 3.78 4.11 3.84

Median PSA, ng/mL 19.9 19.8 17.4

PCa stage, %

Localised 29 33 31

Locally advanced 31 31 26

Metastatic 20 18 23

Gleason score, %

2-4 11 10 12

5-6 34 33 32

7 28 30 31

8-10 28 27 26

*240/80 mg is the approved and marketed dose regimen


Degarelix is Non-inferior to Leuprolide in Suppressing Testosterone to <0.5 ng/mL for 1 Year

Degarelix is Non-inferior to Leuprolide in Suppressing Testosterone to <0.5 ng/mL for 1 Year

19

1. Klotz L, et al. BJU Int. 2008;102(11):1531-1538;2. Boccon-Gibod L et al. Poster presentation. 23rd EAU Congress, Milan, Italy, 2008.


Probability of testosterone Probability of testosterone Probability of testosterone Probability of testosterone ≤≤≤≤0.5 ng/mL from day 280.5 ng/mL from day 280.5 ng/mL from day 280.5 ng/mL from day 28----364 364 364 364

SuccessSuccessSuccessSuccesscriterioncriterioncriterioncriterion

DegarelixDegarelixDegarelixDegarelix240 240 240 240 �� 160 mg160 mg160 mg160 mg

(n = 202)

DegarelixDegarelixDegarelixDegarelix240 240 240 240 �� 80 mg80 mg80 mg80 mg****

(n = 207)

LeuprolideLeuprolideLeuprolideLeuprolide7.5 mg7.5 mg7.5 mg7.5 mg

(n = 201)

Patients with treatment response

199 202 194

Response rateFDA:

CI ≥90%

98.3%

(94.8-99.4%)

97.2%

(93.5-98.8%)

96.4%

(92.5-98.2%)

Difference to leuprolide

EMEA:

CI ≥-10% points

1.9 %

(-1.8 to 5.7%)

0.9%

(-3.2 to 5.0%)


Degarelix – Rapid Testosterone Reduction, No Risk of Clinical FlareDegarelix – Rapid Testosterone Reduction, No Risk of Clinical Flare

20



-100

20

60

100

3 7 14 28

Leuprolide 7.5 mg (n = 201)

10 21

-80

-60

-40

-20

0

40

80

****

Time (days)

Med

ian

perc

enta

ge

chan

ge in

test

oste

rone

(%

)

Degarelix 240/80 mg* (n = 207)

P < 0.001


Degarelix – Very Low TestosteroneLevels Maintained Over 1 YearDegarelix – Very Low TestosteroneLevels Maintained Over 1 Year

21



Time (days)

4

5

7

0

1

9

28 84 3640 56 112 140 168 196 224 252 280 308 336

2

3

6

8

Med

ian

test

oste

rone

(ng

/mL)

Castration level



± interquartile range


Degarelix - No TestosteroneMicrosurges Degarelix - No TestosteroneMicrosurges

22


**240/80 mg is the approved and marketed dose regimen* Increase in testosterone >0.25 ng/mL at any two measurements 3 and 7 days post-dose

Testosterone microsurges*Testosterone microsurges*Testosterone microsurges*Testosterone microsurges*

Change: Day 3 andChange: Day 3 andChange: Day 3 andChange: Day 3 and

7 after 9th injection7 after 9th injection7 after 9th injection7 after 9th injection

DegarelixDegarelixDegarelixDegarelix

240 240 240 240 � 80 mg** 80 mg** 80 mg** 80 mg**

(n = 207)(n = 207)(n = 207)(n = 207)

LeuprolideLeuprolideLeuprolideLeuprolide

7.5 mg7.5 mg7.5 mg7.5 mg

(n = 201)(n = 201)(n = 201)(n = 201)

>0.25 ng/mL 0 8 (4%)*


Degarelix – Significantly Faster Reduction in PSADegarelix – Significantly Faster Reduction in PSA

23


**240/80 mg is the approved and marketed dose regimen

* * * * The differences in the PSA reduction from baseline between degarelix and leuprolide patients at days 14 and 28 were statistically significant (P < 0.001); ; ; ; 11% of leuprolide patients received bicalutamide as flare protection

Change in PSA From Baseline in all PatientsChange in PSA From Baseline in all PatientsChange in PSA From Baseline in all PatientsChange in PSA From Baseline in all Patients

-100

-80

-60

-40

-20

0

20

0 7 14 21 28 35 42 49 56

Time (days)Time (days)Time (days)Time (days)

Change f

rom

C

hange f

rom

C

hange f

rom

C

hange f

rom

b

aseline,

%b

aseline,

%b

aseline,

%b

aseline,

%

Treatment


Degarelix 240/80 mg** (n = 207)

****

****


Degarelix – Faster PSA Suppression; Sustained Over 1 YearDegarelix – Faster PSA Suppression; Sustained Over 1 Year

24



Time (days)

10

12

16

0

2

20

28 84 3640 56 112 140 168 196 224 252 280 308 336

4

6

14

18

Med

ian

PS

A (

ng/m

L)

8




Higher Probability of PSA PFS with Degarelix in Patients with Baseline Metastatic DiseaseHigher Probability of PSA PFS with Degarelix in Patients with Baseline Metastatic Disease

25

PSA, prostate-specific antigen; PSA PFS, PSA progression-free survival

Tombal B, et al. Eur Urol. 2010;57(5):836-842.

Number at risk37 37 36 36 35 34 33 31 30 28 26 25 24 2147 45 43 43 42 40 38 36 34 33 31 29 27 25

Time (days)

100

80

40

20

0

0 28 56 84 112 140 168 196 224 252 280 308 336 364

60

Pro

babilit

y (

%)

Pro

babilit

y (

%)

Pro

babilit

y (

%)

Pro

babilit

y (

%)

Degarelix 240/80 mg*

Leuprolide 7.5 mg

P = 0.149



Incidence and Probability of PSA Progression or Death Incidence and Probability of PSA Progression or Death

26


Degarelix

240 � 80 mg*

(n = 207)

Leuprolide

7.5 mg

(n = 201)

Incidence of PSA progression, n (%) 16 (7.7) 26 (12.9)

Probability of PSA progressiona, % (95% CI) 8.9 (5.5-14.1) 14.1 (9.8-20.1)

Incidence of death, n (%) 5 (2.0) 9 (4.0)

Probability of deatha, % (95% CI) 2.6 (1.1-6.2) 4.9 (2.6-9.3)

a Probability of experiencing PSA progression or death by day 364 (estimated using Kaplan-Meier method)

CI, confidence interval; PSA, prostate-specific antigen

Patients receiving degarelix had a statistically lower risk of PSA progression or death compared with leuprolide (P = 0.05, log rank)



Higher Probability of PSA PFS with Degarelix in Patients with Baseline PSA >20 ng/mLHigher Probability of PSA PFS with Degarelix in Patients with Baseline PSA >20 ng/mL

27


Time (days)

0 28 56 84 112 140 168 196 224 252 280 308 336 364

0

20

40

60

80

100

Pro

bab

ility

(%

)

Degarelix 240/80 mg*

Leuprolide 7.5 mg

Number at risk100 100 96 97 96 93 92 90 88 84 81 79 77 7393 92 91 93 88 86 82 83 78 75 71 67 63 58

P = 0.04

*240/80 mg is the approved and marketed dose regimenPSA, prostate-specific antigen; PSA PFS, PSA progression-free survival


PSA progression by Baseline Disease Stage and PSA LevelsPSA progression by Baseline Disease Stage and PSA Levels

28



PSA progression occurred more frequently in both treatment groups in patients with higher baseline PSA and in patients

with more advanced disease

Pat

ien

ts w

ith

PS

A p

rog

ress

ion

(%

)

Prostate cancer stage PSA (ng/mL)

Pat

ien

ts w

ith

PS

A p

rog

ress

ion

(%

)In patients with baseline PSA >20 ng/mL, risk of PSA progression was significantly

lower with degarelix (P = 0.04)


Faster and More Profound S-ALP Control With Degarelix in Metastatic DiseaseFaster and More Profound S-ALP Control With Degarelix in Metastatic Disease

29

Schröder F, et al. BJU Int. Jul 2010;106(2):182-187.

S-ALP, serum alkaline phosphatase

Degarelix has a faster and more profound effect on the suppression of S-ALP levels in the subgroup of patients with metastatic disease (day 364; 96 vs. 179 IU/L; P = 0.014)

150

100

50

0

-50

-100

-150

0 28 56 84 112 140 168 196 224 252 280 308 336 364Time, days

Ab

solu

te c

han

ge

in S

-AL

Pn

orm

aliz

ed t

o b

asel

ine,

IU/L

Degarelix 240/80 mg (n = 207) Leuprolide 7.5 mg (n = 201)

Number of patients (metastatic disease)Degarelix 37 37 36 36 35 34 34 34 31 31 29 28 27 26Leuprolide 47 45 44 43 43 43 42 42 41 40 40 40 40 39



Disease stage at baseline Treatment

Metastatic

Locally advanced

Localized

Data are means ± standard error; P = 0.014 for overall S-ALP suppression vs. leuprolide


CS21 (Phase III) Efficacy Conclusions CS21 (Phase III) Efficacy Conclusions

30

FSH, follicle-stimulating hormone; PSA, prostate-specific antigen; S-ALP, serum alkaline phosphatase

1. Klotz L, et al. BJU Int. 2008;102(11):1531-1538.2. Tombal B, et al. Eur Urol. 2010;57(5):836-842.3. Schröder F, et al. BJU Int. Jul 2010;106(2):182-187.

� Firmagon® (degarelix) achieves immediate testosterone reduction and maintains the hormone at low and constant concentrations1

� No need for flare protection with Firmagon® (degarelix); a simplified treatment approach1

� Firmagon® (degarelix) causes a rapid and sustained PSA suppression, indicating a beneficial tumour response in patients with prostate cancer1

� Patients receiving degarelix had a statistically lower risk of PSA progression or death compared with leuprolide2

� Patients with metastatic disease or elevated PSA levels (≥50 ng/mL) at baseline had greater reductions in S-ALP levels with Firmagon® (degarelix) than with leuprolide3

� Firmagon® (degarelix) achieves a rapid and sustained decrease in FSH level1


AE (%)AE (%)AE (%)AE (%)DegarelixDegarelixDegarelixDegarelix

240 240 240 240 �� 160 mg160 mg160 mg160 mg(n = 202)

DegarelixDegarelixDegarelixDegarelix240 240 240 240 �� 80 mg80 mg80 mg80 mg# # # #

(n = 207)

Degarelix Degarelix Degarelix Degarelix pooled pooled pooled pooled

(n = 409)

LeuprolideLeuprolideLeuprolideLeuprolide7.5 mg7.5 mg7.5 mg7.5 mg

(n = 201)

Any AEAny AEAny AEAny AE 83838383 79797979 81818181 78787878

Injection site AEs 44 35 40 <1***

Hot flush 26 26 26 21

Weight increased 11 9 10 12

Back pain 6 6 6 8

Arthralgia 3 5 4 9*

Hypertension 7 6 6 4

Fatigue 6 3 5 6

Urinary tract infection 1 5 3 9**

Nausea 5 4 5 4

Constipation 5 3 4 5

Hypercholesterolaemia 6 3 5 2

Chills 5 3 4 0**

CS21 Adverse Events CS21 Adverse Events

31

*P < 0.05, **P < 0.01, and ***P < 0.001 vs. degarelix pooled


#240/80 mg is the approved and marketed dose regimen


Injection Site Reactions –Predominantly with Starter DoseInjection Site Reactions –Predominantly with Starter Dose

32




240 240 240 240 � 160 mg160 mg160 mg160 mg


240 240 240 240 � 80 mg*80 mg*80 mg*80 mg*

Total Total Total Total number number number number of dosesof dosesof dosesof doses

Number of Number of Number of Number of doses doses doses doses

associated associated associated associated with ISRwith ISRwith ISRwith ISR

%%%%Total Total Total Total

number number number number of dosesof dosesof dosesof doses

Number of Number of Number of Number of doses doses doses doses

associated associated associated associated with ISRwith ISRwith ISRwith ISR

%%%%

Starter dose 202 68 34 207 66 32

Maintenance dose(s) 2208 95 4 2244 82 4

ISR, injection site reaction


CS21 (Phase III) Safety ConclusionsCS21 (Phase III) Safety Conclusions

33

�The most frequent events tended to be related to androgen suppression i.e. hot flushes, weight increase, and the majority were of mild or moderate intensity

�Degarelix had a higher incidence of injection site reactions and chills but a lower incidence of side-effects like urinary tract infection and musculoskeletal events (arthralgia)

�Most injection site reactions with degarelix occurred with first dose

Incidence of adverse events similar with Firmagon®(degarelix) and leuprolide1

1. Klotz L, et al. BJU Int. 2008;102(11):1531-1538. 2. Ferring Internal Data: Injection site reactions document (for internal use) 2013.

NSAIDS, non-steroidal anti-inflammatory drugs

� No serious adverse events considered related to degarelix

� Majority of the injection site reactions were managed with analgesics (53.2 %), typically paracetamol (23.4%) and NSAIDs (19.4%, mostly ibuprofen)2


Overall ConclusionsOverall Conclusions

34

AA, antiandrogen; AE, adverse event; FSH, follice-stimulating hormone; LH, luteinizing hormone; PSA, prostate-specific antigenPSA PFS, PSA progression-free survival; S-ALP, serum alkaline phosphatase

� Firmagon® (degarelix) has a direct mechanism of action which provides

o Rapid and profound PSA and testosterone reductions1,2

o Low PSA and testosterone levels, maintained over time

o Better PSA PFS in patients with baseline PSA >20 ng/mL3

o Specific reduction of both LH and FSH levels1,2

� No need for antiandrogen flare protection with Firmagon® (degarelix), providing a simple treatment

� Degarelix provides faster and more profound control of S-ALP levels compared to leuprolide over time4

� Lower probability of experiencing a urinary tract AE5

1. Van poppel H, et al. Int J Urol. 2012;19(7):594-601.

2. Drudge-Coates L. Int J Urol. Nursing. 2009;3:85-92.3. Tombal B, et al. Eur Urol. 2010;57(5):836-842.4.Schröder F, et al. BJU Int. Jul 2010;106(2):182-187.5.Klotz L, et al. BJU Int. 2008;102(11):1531-1538.


35

Faster and more sustained FSH control with degarelix vs leuprolide

1. Klotz et al. BJU Int 2008;102:1531-8; 2. Crawford et al. J Urol 2011; 186:889–97; 3. Ben-Josef et al. J Urol 1999;161:970–6; 4. Heracek et al. Neuro Endocrinol Lett 2007;28:45-51

Data are median (quartiles)

CS21: degarelix or leuprolideCS21: degarelix or leuprolideCS21: degarelix or leuprolideCS21: degarelix or leuprolide CS21A: All degarelixCS21A: All degarelixCS21A: All degarelixCS21A: All degarelix

• FSH stimulates PCa

cell growth in

hormone-refractory

cell lines3

• In man, FSH levels

are higher in those

with more advanced

disease4


36

PSA PFS significantly improved after crossover from leuprolide to degarelix (all patients)

CS21: degarelix CS21: degarelix CS21: degarelix CS21: degarelix or leuprolideor leuprolideor leuprolideor leuprolide

CS21A: all patients received degarelix*

*Month 13 to 60 Extension study. Crossover at 12 months was pre-planned and not due to failure of leuprolide treatment.

PFS, progression-free survival; PSA, prostate-specific antigen

Crawford ED, et al. Urology 2014;83:1122-8


37

PSA PFS significantly improved after crossover from leuprolide to degarelix (all patients)



Significant hazard rate change following crossover (p=0.002)





38

Data from randomized phase III/IIIb trials of degarelix vs GnRH agonists were pooled

‣ Efficacy data was collected from the degarelix clinical trials database

‣ Safety data was patient reported and categorised by MedDRA criteria

Study Duration (months) Comparator Publication

CS21Pivotal phase III, monthly dose

12 Leuprolide Klotz et al. BJU Int 2008

CS353-month depot formulation

12 Goserelin Shore et al. SUO 2012

CS28LUTS relief

3 Goserelinb Anderson et al. Urol Int 2012

CS30Neoadjuvant to radical RT

3 Goserelinb Mason et al. Clin Oncol 2013

CS31TPV reduction

3 Goserelinb Axcona et al. BJU Int 2012

CS37a

Intermittent dosing7-12 Leuprolide Trial completed Q4 2012

GnRH, gonadotropin-releasing hormone; LUTS, lower urinary tract symptoms; RT, radiotherapy; TPV, totalprostate volume


39

Pooled analysis: Background

‣ Key differences between degarelix and LHRH agonists have been reported from a phase III randomized trial1

‣ Pooled data from multiple trials allows robust analysis of outcomes from a large patient population

‣ Individual patient data were pooled from 6 prospective phase III or IIIb trials comparing degarelix with an LHRH agonist. Patients received 1 year or 3 months of degarelix or LHRH agonist treatment.

‣ The initial degarelix dose was 240mg in all trials. Maintenance doses were 80mg except in CS21, which compared maintenance doses of 80mg and 160mg, and CS35, which used a maintenance regimen of 480mg every 3 months.

LHRH, luteinising hormone-releasing hormone1Klotz et al. BJU Int 2008;102:1531-8


40

Pooled analysis: Improved PSA PFS with degarelix vs GnRH agonists

HR=0.71 (95% CI 0.54–0.94)p=0.017

Numberat risk

GnRH, gonadotropin-releasing hormone; LHRH, luteinising hormone-releasing hormone; PFS, progression-free survival; PSA, prostate-specific antigen

Klotz L, et al. Eur Urol 2014;66:1101–8


41

Pooled analysis: Improved overall survival with degarelix vs LHRH agonists (1st year)

• Data in the graph is risk of death from any cause

• Very few patients died of prostate cancer over the year of the study

• Most men with prostate cancer die of other causes such as CVD

HR=0.47 (95% CI 0.25–0.90)p=0.023

Numberat risk

CVD, cardiovascular disease; LHRH, luteinising hormone-releasing hormone



42

Pooled analysis: Treatment emergent adverse events (>5% in either group)

Event, n (%) Degarelixn=1266

GnRH agonistn=659

Any adverse event 942 (74) 445 (68)

Hot flush 386 (30)* 171 (26)

Injection-site reactions

Pain

Erythema

Swelling

Nodule

380 (30)*

257 (20)*

76 (6)*

73 (6)*

6 (<1)

0 (0)

0 (0)

0 (0)

Fatigue 59 (5) 35 (5)

Arthralgia 45 (4) 41 (6)

Back pain 50 (4) 41 (6)*

Urinary tract infection 43 (3) 37 (6)*

*p<0.05




43

Pooled analysis: Lower probability of musculoskeletal events with degarelix vs GnRH agonists

Numberat risk

p=0.007 (log-rank)

GnRH, gonadotropin-releasing hormone; LHRH, luteinising hormone-releasing hormone



44

Pooled analysis: Lower probability of joint-related signs and symptoms with degarelix vs GnRH agonists

HR=0.64 (95% CI 0.42–0.98)p=0.041

Numberat risk

Adapted from original reference




45

Degarelix and high risk patients


46

Baseline PSA >20 ng/mL: Longer time to PSA failure with degarelix vs leuprolide

p=0.0436 (log-rank)

Probability of freedom from PSA failureProbability of freedom from PSA failureProbability of freedom from PSA failureProbability of freedom from PSA failure

Patients with more advanced disease are likely to have faster progression – differences between treatments may therefore be easier to detect


Tombal B et al. Eur Urol 2010;57:836-42


47

Baseline PSA >20ng/mL: Reduced risk of PSA progression with degarelix

The risk of PSA progression after 1 year was significantly lower in patients with baseline PSA >20 ng/mL treated with degarelix (p= 0.04) vs leuprolide

PSA

pro

gre

ssio

n (%

)

Degarelix 240/80 mg

Leuprolide 7.5 mg

0

10

20

30

40

PSA level at baseline (ng/mL)(n=215) (n=90) (n=103)

≤20 >20–50 >50


Tombal B et al. Eur Urol 2010;57:836-42


48

Baseline PSA ≥20 ng/mL: Longer time to PSA failure or death with degarelix vs leuprolide

TTPTTPTTPTTP25% 25% 25% 25% was was was was significantly greater significantly greater significantly greater significantly greater for degarelix 240/80 for degarelix 240/80 for degarelix 240/80 for degarelix 240/80 mg vs leuprolide in mg vs leuprolide in mg vs leuprolide in mg vs leuprolide in analyses using analyses using analyses using analyses using degarelix data degarelix data degarelix data degarelix data beyond 1 year: beyond 1 year: beyond 1 year: beyond 1 year: 514 vs 303 days 514 vs 303 days 514 vs 303 days 514 vs 303 days (P=0.01)(P=0.01)(P=0.01)(P=0.01)

7 months longer time to PSA failure/death vs leuprolide7 months longer time to PSA failure/death vs leuprolide7 months longer time to PSA failure/death vs leuprolide7 months longer time to PSA failure/death vs leuprolide

The magnified area of the graph shows the time for 25% of patients with baseline PSA≥20 ng/mL to experience PSA failure or death.

KM, Kaplan Meier; PSA, prostate-specific antigen; TTP25%, time to progression in 25% of patients

Boccon-Gibod L et al. Therap Adv Urol 2011;3:127-40


49

PSA PFS significantly improved after crossover from leuprolide to degarelix (baseline PSA ≥20 ng/mL)







50

PSA PFS significantly improved after crossover from leuprolide to degarelix (baseline PSA ≥20 ng/mL)






Significant hazard rate change following crossover (p=0.019)


51

Lower probability of a urinary tract event in men with baseline PSA >20 ng/mL

DegarelixGnRH agonist


HR=0.44 (95% CI 0.31–0.63)p<0.0001

Numberat risk

GnRH, gonadotropin-releasing hormone; PSA, prostate-specific antigen

Data on file


52

Pooled analysis: Lower probability of musculoskeletal events with degarelix vs GnRH agonists

Numberat risk

p=0.007 (log-rank)




53

Improved control of S-ALP in metastatic patients with degarelix vs LHRH agonists

p=0.037

p=0.038

LHRH, luteinising hormone-releasing hormone; S-ALP, serum alkaline phosphatase

Miller K et al. EAU Congress 2013, Klotz L, et al. Eur Urol 2014;66:1101–8

Data are mean ± 95% CI

Elevated S-ALP levels have been associated with progression of skeletal metastases and reduced survival times


54

Patients with cardiovascular disease


55

Pooled data from randomized phase III/IIIb trials of degarelix vs GnRH agonists

‣ Efficacy data was collected from the degarelix clinical trials database

‣ Safety data was patient reported and categorised by MedDRA criteria

Study Duration (months) Comparator Publication

CS21Pivotal phase III, monthly dose

12 Leuprolide Klotz et al. BJU Int 2008

CS353-month depot formulation

12 Goserelin Shore et al. SIU 2012

CS37Intermittent dosing

7-12 Leuprolide Crawford et al. SUO 2013

CS28LUTS relief

3 Goserelin* Anderson et al. Urol Int 2012

CS30Neoadjuvant to radical RT

3 Goserelin* Mason et al. Clin Oncol 2013

CS31TPV reduction

3 Goserelin* Axcrona et al. BJU Int 2012

*All patients on goserelin also received antiandrogen flare protection

GnRH, gonadotropin-releasing hormone; LUTS, lower urinary tract symptoms; RT, radiotherapy; TPV, totalprostate volume


56

Pooled analysis: Lower incidence of CV events (all patients)

Degarelix, n (%) n=1491

GnRH agonist, n (%) n=837

Any CV event 42 (2.8) 37 (4.4)

Death 20 (1.3) 22 (2.6)


HR=0.60 (95% CI 0.41–0.87) p=0.008

CV, cardiovascular; CVD, cardiovascular disease

Albertsen PC, et al. Eur Urol 2014;65:565–73


57

Pooled analysis: Lower incidence of CV events (baseline CV disease)

Degarelix, n (%) n=463

GnRH agonist, n (%) n=245

Any CV event 21 (4.5) 23 (9.4)

Death 9 (1.9) 13 (5.3)


HR=0.44 (95% CI 0.26–0.74) p=0.002




58

Pooled analysis: A different impact on CVD morbidity with degarelix vs agonists

The absolute risk reduction after the first year was 8.2%,

which yielded a number needed to treat to avoid 1 CV event or death of 12

Adapted from original reference

56%56%56%56%relative relative relative relative

risk risk risk risk reductionreductionreductionreduction

(HR: 0.44; 95% CI, 0.26 – 0.74; p=0.002)

Risk reduction of CV events or death after the first year of treatment in

men with pre-existing CVD (n=708)



Several study limitations confine findings to hypothesis generating: the nature of a post hoc analysis, the studies were open-label and CV events may have been underreported, CV events were reported as adverse events and were not independent study endpoints, and finally, reported CV events were not systematically validated.

Cardiac events were defined as: arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease.


59

ADT and possible pathogenesis of CV risk

• Indirect mechanisms‣ Androgen (testosterone) deficiency causing increased weight and

metabolic complications � may destabilize/ accelerate the atherosclerotic process, or exacerbate preexisting cardiac risk factors

‣ Primarily depression of LH by LHRH agonists vs LH and FSH supression by GnRH antagonists. FSH receptors play a role in endothelial cell function, lipid metabolism, and fat accumulation

• Direct mechanisms‣ Role of potentially functional GnRH receptors on lymphocytes

and cardiomyocytes/secondary messengers (protein kinase A) and CV events?

CV, cardiovascular; FSH, follicle stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinising hormone; LHRH, luteinising hormone-releasing hormone


60

Plaque instability is at the heart of cardiovascular disease

Lumen

Fibrous cap

Lipid core

Vulnerable plaque

Lipid coreFibrous cap

Lumen

Stable plaque

T cell

Thick Cap Thin

Rich in SMC and matrix CompositionRich in inflammatory cells:

proteolytic activity

Poor Lipid Rich

Inflammatory Inflammatory state Highly inflammatory

Macrophage

SMC, smooth muscle cells

Libby P J. Lipid Res. 2009;50:S352–7


61

Further FSH suppression after crossover from leuprolide to degarelix

CS21: degarelix or leuprolide CS21A: all degarelix

FSH, follicle stimulating hormone

Crawford ED et al. J Urol 2011;186:889-97


62

FSH and adipogenesis

‣ Stimulation of FSH receptors possibly alters endothelial cell function, lipid metabolism and fat accumulation

‣ Pre-clinical studies have shown:‣ Mice treated with degarelix have lower FSH levels than those

treated with LHRH agonist or orchiectomy

‣ Degarelix-treated mice gain less weight and visceral fat than mice treated with LHRH agonists

FSH, follicle stimulating hormone; LHRH, luteinising hormone-releasing hormone

Hopmans SN, et al. Urol Oncol 2014;32:1126-34


63

FSH and total and necrotic plaques

Pre-clinical mouse model with four treatment arms:no treatment, orchiectomy, leuprolide, degarelix

Significantly less plaque area changes were observed with degarelix

Aortic atherosclerotic plaque area in mice receiving different modes of ADT at 4 months calculated as percentage of plaque and necrotic plaque area of aortic tissue. ap<0.05 vs control; bp<0.05 vs orchiectomy; cp<0.05 vs leuprolide

ADT, androgen deprivation therapy; FSH, follicle-stimulating hormone


12

10

8

6

4

2

0

Tota

l pla

que a

rea (

% o

f to

tal)

Necro

tic p

laque a

rea (%

of to

tal)

2

1

0

Control Orchiectomy Leuprolide Degarelix

a

a

bc

aa


64

FSH and plaques

ADT, androgen deprivation therapy; FSH, follicle-stimulating hormone


Aortic atherosclerotic plaque area in mice receiving different modes of ADT at 4 months calculated as percentage of plaque and necrotic plaque area of aortic tissue. This animal data is not directly applicable to humans.


65

A role for the GnRH receptor: Agonists and antagonists act differently on T lymphocytes


Chen HF, et al. J Clin Endocrinol Metab 1999;84:743-50; Tanriverdi F, et al. Clin Exp Immunol 2005;142:103-10; Grasso G, et al. Life Sci 1998;62:2005-14; Jacobson JD, et al. Endocrinol 1994;134:2516-23

T-cells

GnRH-R

LHRH agonist

Increased interleukin-2γreceptor expression

Increased proliferation

Fibrotic cap disruption andplaque instability

T-cells

GnRH-R

GnRH antagonist

Complete blockade of receptorswith no signal transduction

Inhibition of stimulatedresponses


66

Neo-adjuvant therapy and LUTS


67

Degarelix studies vs. LHRH agonists -Prostate size and symptom control

Study Study Study Study ComparatorComparatorComparatorComparator Patient populationPatient populationPatient populationPatient population DurationDurationDurationDurationPrimary Primary Primary Primary endpointendpointendpointendpoint

CS281 Goserelin + bicalutamide

PCa – all stages (80% T3/4)PSA >10 ng/mL, IPSS ≥12N=40

12 weeks IPSS

CS302

(Neoadjuvant)Goserelin + bicalutamide

Intermediate- to high-risk PCa (T2b/c–4/N0/M0 or Gleason ≥7 or PSA ≥10 ng/mL)TPV >30cm3

N=246

12 weeks TPV

CS313 Goserelin + bicalutamide

PCa – all stagesPSA >2 ng/mL, TPV >30 mLN=182

12 weeks TPV

IPSS, International Prostate Symptom Score; PCa, prostate cancer; PSA, prostate-specific antigen; TPV, total prostate volume

1. Anderson et al. Urol Int 2013;90:321-8; 2. Mason M, et al. Clin Oncol 2013;25:190-6; 3. Axcrona K, et al. BJU Int 2012;110:1721–8


68

Non-inferior reduction in TPV after 3m with degarelix vs goserelin + bicalutamide before RT

-36.0 -35.3-40.0

-30.0

-20.0

-10.0

0.0

% c

hange in t

ota

l pro

sta

te v

olu

me

(SEM

)

Degarelix (n=176)

Goserelin + bicalutamide

(n=62)

Full analysis set

ADT, androgen deprivation therapy; PSA, prostate-specific antigen; RT, radiotherapy; SEM, standard error of the mean; TPV, total prostate volume

Mason M, et al. Clin Oncol 2013;25:190-6

Rapid reduction in testosterone and PSA levels consistent with goserelin plus bicalutamide in patients eligible for ADT neoadjuvant to radiotherapy


69

Testosterone and PSA reduction similar



Median (± interquartile range)


70

CS30: Significant reduction in IPSS with degarelix

‣ After 12 weeks: -1.71 ± 0.42 with degarelix vs + 0.11 ± 0.65 with goserelin plus bicalutamide

‣ Adjusted (for baseline IPSS) difference: -1.42 (-2.81, -0.035); p=0.044

‣ IPSS reduction before RT is important as RT can cause LUTS

IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; RT, radiotherapy



71

Pooled analysis:Significant reduction in IPSS (all patients)

IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms

Mason M, et al. LUTS 2015: DOI: 10.1111/luts.12114

‣ Adjusted mean treatment difference was -1.24 (p=0.03)


72

Pooled analysis: Significant IPSS reduction based on LUTS data (≥13 points)

‣ Adjusted mean treatment difference was -2.56 (p<0.01) in the group of patients with moderate to severe LUTS

IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms

Mason M, et al. LUTS 2015: DOI: 10.1111/luts.12114


73

Pooled analysis: Total Prostate Volume based on LUTS data (all patients)

‣ Median percentage decrease was 37.0% for degarelix and 38.4% forgoserelin

IPSS, International Prostate Symptom Score; LUTS, lower urinary tract symptoms; TPV, total prostate volume

Mason M, et al. EAU congress 2014


74

Pooled analysis: Significantly lower probability of urinary tract events with degarelix vs GnRH agonists

Numberat risk

(all patients)

Overall: p=0.001




75

Summary

• Degarelix achieves immediate and sustained low testosterone levels and fast PSA reduction compared to leuprolide

• PSA PFS and overall survival is improved with degarelix comparedto GnRH agonists at 1 year

• A pooled analysis showed an absolute risk reduction of 8.2% oncardiovascular event/death after the first year with degarelix compared to GnRH agonists in men with pre-existing CV disease

• A pooled analysis showed a significant decrease in IPSS with degarelix compared to GnRH agonist within the first 3 months. This was even more pronounced in patients with a baseline IPSS score≥13

• Degarelix is suitable for intermittent treatment

CV, cardiovascular; GnRH, gonadotropin-releasing hormone; IAD, intermittent androgen deprivation; IPSS,International Prostate Symptom Score; PFS, progression-free survival; PSA, prostate-specific antigen

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