The Earlier The Better for BPH Patients with Moderate Symptoms Who at Risk of Progression? New Evidence CONDUCT Study Basuki B. Purnomo

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only Optimal initial treatment for BPH patients with moderate symptoms who at risk of progression; What do you think, who they are? What are the evidence and guideline said? What will you do? TreatmentTreatment Diagnosis Ongoing management BPH Patient’s Journey BPH Patient’s Journey

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only Evidence-Based Medicine approach 3 Clinical Expertise Patient ValuesBest Evidence Evidence-based practice (EBP): when healthcare decisions are guided by conscientious and judicious use of current best evidence in conjunction with clinical expertise and patient values Optimal Decisions Titler MG. Chapter 7: The Evidence for Evidence-Based Practice Implementation. Patient Safety and Quality: An Evidence-Based Handbook for Nurses. Hughes RG, editor. Rockville (MD): 2008 Apr.

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only Who is at risk of BPH disease progression? 1.Older age (> 60 years) 2.Moderate-to-severe symptoms (IPSS > 8) 3.Low urinary flow rate (Qmax <10.6mL ⁄ s) 4.Enlarged prostate (PV > 30mL) 5.Increased PSA level (≥ 1.5 ng/mL) 1. McConnell J et al. N Engl J Med. 2003;349:2387–2398; 2. Emberton M et al. IJCP. 2008;62:1076 ‒ 1086; 3. Emberton M et al. BJU Int. 2011;107:876 ‒ 880.

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only HOW TO TREAT BPH PATIENT WHO AT RISK OF DISEASE PROGRESSION? 5 For Healthcare Professional Use only [5ARI + α-blocker] combination therapy is the only medical treatment with LONG-TERM evidence of benefit in men with BPH at risk of disease progression.

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only WHAT IS THE EVIDENCE? 1. Füllhase C et al. Eur Urol. (2013), doi: /j.eururo ; 2. Roehrborn C et al. Eur Urol. 2010;57:123– Roehrborn CG et al. BJU Int 2015 doi: /bju The only [5ARI + α 1 -blocker] combinations assessed for efficacy and safety in long-term RCTs ALFIN year 1051 patients Alfuzosin 2x5 mg/ Finasteride 5 mg ALFIN year 1051 patients Alfuzosin 2x5 mg/ Finasteride 5 mg MTOPS 1 6 year 3047 patients Doxazosin 4-8 mg/ Finasteride 5 mg MTOPS 1 6 year 3047 patients Doxazosin 4-8 mg/ Finasteride 5 mg VA-COOP 1 1 year 1229 patients Terazosin 10 mg/ Finasteride 5 mg VA-COOP 1 1 year 1229 patients Terazosin 10 mg/ Finasteride 5 mg PREDICT 1 1 year 1095 patients Doxazosin 4–8 mg/ Finasteride 5 mg PREDICT 1 1 year 1095 patients Doxazosin 4–8 mg/ Finasteride 5 mg CombAT 2 2–4 year 4844 patients Tamsulosin 0.4 mg/ Dutasteride 0.5 mg CombAT 2 2–4 year 4844 patients Tamsulosin 0.4 mg/ Dutasteride 0.5 mg yrs CONDUCT 3 2 year 742 patients *Fixed-dose DUT+TAM combination vs. WW with initiation of tamsulosin if symptoms did not improve CONDUCT 3 2 year 742 patients *Fixed-dose DUT+TAM combination vs. WW with initiation of tamsulosin if symptoms did not improve 2015 Primary endpoint AUA-SS/IPSS and Qmax 2yrs Clinical progression Evidence from CombAT resulted in changes to the guidelines [DUT + TAM] CombAT, CONDUCT [FIN + DOX] MTOPS study Is dutasteride now the most studied drug in BPH patients at risk of progression? *Fixed-dose combination therapy (dutasteride + tamsulosin) vs.Watchful Waiting with initiation of tamsulosin if symptoms did not improve Both treatment arms included lifestyle advice administered

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only 7 For Healthcare Professional Use only Can we do more right from the start for our BPH patients with moderate symptoms at risk of progression? 1.Roehrborn CG et al. Eur Urol. 2010;57:123–131

Comparative efficacy of dutasteride/tamsulosin combination plus lifestyle advice versus watchful waiting plus lifestyle advice with step- up therapy to tamsulosin in the management of treatment-naïve men with moderately symptomatic benign prostatic hyperplasia and prostate enlargement Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only

Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only Rationale for the CONDUCT study Adds to existing evidence CONDUCT 1,2 adds to existing evidence, investigated: Less symptomatic (moderate) patients All Treatment-naive patients Earlier (4 weeks) fixed-dose combination of dutasteride and tamsulosin efficacy measurement Comparison to a recognised clinical approach for some patients at risk of progression – Watchful Waiting with initiation of tamsulosin if symptoms did not improve 1.Protocol Summary : (Accessed 5 April 2015) 2.Roehrborn CG et al. BJU Int 2015 doi: /bju.13033

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only Randomisation 1:1 V1 (screening) V2 (baseline) V3 (W4) V4 (W13) V9 (W78) V10 (W91) V11 (W104) IPSS, BII score, Patient Perception of Study Treatment measured at each visit If initiated, escalation to tamsulosin 0.4 mg once daily at any visit after Visit 2 would be continued for the remainder of the study unless the subject elected to withdraw prematurely Fixed-dose combination of dutasteride and tamsulosin + lifestyle advice Watchful Waiting with initiation of tamsulosin if symptoms did not improve from baseline (V2) + lifestyle advice CONDUCT: study design 1.Protocol Summary : (Accessed 5 April 2015) 2.Roehrborn CG et al. BJU Int 2015 doi: /bju.13033

Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only Combination therapy was superior in symptom reduction vs watchful waiting + tamsulosin if symptoms did not improve 1.Study Results Summary at (Accessed on 5 April 2015) 2.Adapted from Roehrborn CG et al. BJU Int 2015 doi: /bju Adapted from Barry et al : J Urol Nov;154(5): Fixed dose combination of dutasteride and tamsulosin (n=369)** Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=373)** p<0.001 Patient assessment of improvement thresholds *3 Adjusted mean change from baseline in IPSS Slight -1.9 Moderate -4.0 Marked *Improvement thresholds were selected for the lower IPSS baseline score (8-19) **Both treatment arms included lifestyle advice administered -5.4

Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only 1.Study Results Summary at (Accessed on 5 April 2015) 2.Roehrborn CG et al. BJU Int 2015 doi: /bju Barry et al : J Urol Nov;154(5): Fixed dose combination of dutasteride and tamsulosin (n=369)** Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=373)** p<0.001 Patient assessment of improvement thresholds *,3 Adjusted mean change from baseline in IPSS Slight -1.9 Moderate -4.0 Marked *Improvement thresholds were selected for the lower IPSS baseline score (8-19) **Both treatment arms included lifestyle advice administered -5.4 Rapid symptom improvement with combination therapy (measured at month 1) Superior symptom improvement with combination therapy at each post-baseline visit (p<0.001) vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve Sustained superiority of fixed dose combination in symptom improvement over 2 years of treatment vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve Combination therapy was superior in symptom reduction vs watchful waiting + tamsulosin if symptoms did not improve

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only Mean IPSS at visit (LOCF) demonstrates the effect of study treatment arms on the symptom category (moderate vs mild) throughout the study course 1, Fixed dose combination of dutasteride and tamsulosin (n=359)** Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=368)** Combination therapy resulted in shifting of BPH symptom score from moderate to mild category from month 9 onwards *Last observation carried forward; **Both treatment arms included lifestyle advice administered Moderate Mild Combination therapy was associated with a change in symptom category from moderate to mild 1.Study Results Summary at (Accessed on April 2015) 2.Roehrborn CG et al. BJU Int 2015 doi: /bju.13033

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only Combination therapy reduced the risk of clinical progression* over 2 years compared vs watchful waiting + tamsulosin if symptoms did not improve Adapted from Roehrborn CG et al. BJU Int 2015 doi: /bju *Overall clinical progression events defined by a rise in IPSS of ≥3 points at any visit when compared to Visit 2 (baseline), AUR related to BPH, UTI related to BPH, Incontinence related to BPH, Renal insufficiency related to BPH. **Both treatment arms included lifestyle advice administered Fixed dose combination of dutasteride and tamsulosin** Watchful Waiting with initiation of tamsulosin if symptoms did not improve** 29% 18% Cumulative number of events/Subjects at riskYear 1Year 2 Fixed dose combination of dutasteride and tamsulosin48/36917/276 Watchful Waiting with initiation of tamsulosin if symptoms did not improve94/37314/ % relative risk reduction at year 2; (p<0.001) 11.3% absolute risk reduction (risk difference) Number needed to treat: 9

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only Safety was monitored in all subjects Fixed dose combination of dutasteride and tamsulosin (n=369)** Watchful Waiting with initiation of tamsulosin (n=229)** Subjects, n (%) Years of subject exposure* Any AE190 (51)95 (41) Drug-related AE87 (24)23 (10) Any serious AE (SAE)38 (10)19 (8) AE leading to discontinuation of study drug 27 (7)11 (5) AE leading to withdrawal from study 27 (7)11 (5) Any fatal AE02 (<1) # * Years of patient exposure is the sum of study drug exposure (days) across patients for each treatment group, divided by 365 days. # Fatal SAEs were not related to treatment; **Both treatment arms included lifestyle advice administered CONDUCT: extent of exposure and summary of adverse events Study Results Summary at (Accessed on 5 April 2015) Roehrborn CG et al. BJU Int 2015 doi: /bju.13033

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only 16 For Healthcare Professional Use only WHAT ARE THE GUIDELINES SAID?

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only For Healthcare Professional Use only eGFR=estimated glomerular filtration rate Guideline recommendations for initial assessment of men with LUTS/BPH EAU 1,2 AUA 3 Medical historyRecommended (initial)Recommended Symptom score questionnairesRecommended (initial)Recommended Frequency volume charts and bladder diaries In men with predominant storage symptoms/nocturia In select patients (significant nocturia predominant symptom) Physical examination (incl. DRE)Recommended (initial)Recommended Prostate specific antigen (PSA)Recommended (initial if it assists in decision making for patients at risk of progression of BPE) Recommended (in select patients) UrinalysisRecommended Renal function (creatinine/eGFR)In selected patientsNot recommended Post-void residual volumeRecommended (initial)Optional UroflowmetryRecommended (prior to treatment) Optional Pressure flow studiesIn selected patientsNot recommended routinely Imaging of the upper urinary tractIn selected patientsIn select patients Imaging of the prostatePrior to treatmentOptional UrethrocystoscopyIn selected patientsNo guidance 1.Adapted from Gratzke C et al. Eur Urol (2015), 2.Adapted from Gravas S et al. European Association of Urology Adapted from McVary KT et al. J Urol 2011;185(5):1793–803

Zinc Code CEM/Pharma/0004/15 Date of Preparation: 04/15 For Healthcare Professionals Use Only EAU 2014 guidelines: LUTS assessment algorithm Male LUTS (men aged ≥40 yrs) History (+ sexual function) Symptom score questionnaire Urinalysis Physical examination PSA* PVR measurement History (+ sexual function) Symptom score questionnaire Urinalysis Physical examination PSA* PVR measurement *If diagnosis of prostate cancer will change management **If test would alter the choice of surgical modality US= Ultrasound Significant PVR US of kidneys +/- renal function assessment MEDICAL TREATMENT according to algorithm Endoscopy** Pressure flow studies Endoscopy** Pressure flow studies Abnormal DRE Suspicion of neurological disease High PSA Abnormal urinalysis Abnormal DRE Suspicion of neurological disease High PSA Abnormal urinalysis Evaluate according to guidelines/clinical standard Treat any underlying conditions Bothersome symptoms Yes FVC (in cases of predominant storage LUTS/nocturia) Prostate ultrasound Uroflowmetry FVC (in cases of predominant storage LUTS/nocturia) Prostate ultrasound Uroflowmetry Benign conditions of bladder and/or prostate with baseline values PLAN TREATMENT Benign conditions of bladder and/or prostate with baseline values PLAN TREATMENT Surgical treatment according to algorithm No Manage according to EAU male LUTS treatment algorithm Adapted from Gratzke C et al. Eur Urol (2015),

Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only Guidelines recommend first-line [5ARI + α-blocker] combination therapy for men with BPH at risk of progression NICE, 2 UK 2010 Bothersome m–s LUTS and prostate >30 mL or PSA >1.4 ng/mL NICE, 2 UK 2010 Bothersome m–s LUTS and prostate >30 mL or PSA >1.4 ng/mL AUA, 3 USA 2010 LUTS with prostatic enlargement (vol. measurement, PSA as a proxy for vol. and/or DRE) CUA, 1 Canada 2010 LUTS with prostatic enlargement CUA, 1 Canada 2010 LUTS with prostatic enlargement AEU, 4 Spain 2011 Moderate IPSS (8–20), large PV on DRE or >30 mL and PSA >1.5 ng/mL AEU, 4 Spain 2011 Moderate IPSS (8–20), large PV on DRE or >30 mL and PSA >1.5 ng/mL JUA, 9 Japan 2011 m ‒ s LUTS/BPH prostate >30 mL prostate >30 mL JUA, 9 Japan 2011 m ‒ s LUTS/BPH prostate >30 mL prostate >30 mL EAU, 5 Europe 2014 m–s LUTS, enlarged prostate and reduced Q max AURO.it, 6 Italy 2012 LUTS/BPH, IPSS Q8 ≥4 and risk of progression (PV ≥30 mL and PSA ≥1.45 ng/mL), AURO.it, 6 Italy 2012 LUTS/BPH, IPSS Q8 ≥4 and risk of progression (PV ≥30 mL and PSA ≥1.45 ng/mL), SMU, 8 Mexico 2012 m–s LUTS, prostates >30 mL for treatments ≥6 months SAU, 7 Argentina 2012 m–s LUTS, prostates >30 mL or PSA >1,5 ng/mL, for treatments ≥1 year Indonesia, IAUI m ‒ s LUTS/BPH, enlarged prostate, PSA >1.3ng/mL, elderly (when long-term therapy is planned, > 1 year). Finasteride – PV >40mL Dutasteride – PV >30mL Indonesia, IAUI m ‒ s LUTS/BPH, enlarged prostate, PSA >1.3ng/mL, elderly (when long-term therapy is planned, > 1 year). Finasteride – PV >40mL Dutasteride – PV >30mL UAA, Asia m ‒ s LUTS and prostate ≥ 30 mL or PSA >1.4 – 1.6 ng/L UAA, Asia m ‒ s LUTS and prostate ≥ 30 mL or PSA >1.4 – 1.6 ng/L Adapted from 1. Nickel J et al. Can Urol Assoc J 2010;4:310–316; 2. NICE clinical guideline 97 (2010) 3. AUA. Management of BPH (2010) 4. Molero García JM et al. Aten Primaria doi: /j.aprim ; 5. Gravas et al. Guidelines on management of male LUTS, incl. BPO (2014) 6. Spatafora S et al. Ther Adv Urol 2012;4:279–301; Homma Y et al. IJU 2011;18:e1–e33; 11. IAUI, February 2015; 12. UAA

Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only SUMMARY 20 For Healthcare Professional Use only Combination therapy with dutasteride and tamsulosin is the only medical treatment with prospective Level 1b evidence specifically demonstrating benefit for BPH patients at risk of progression CONDUCT complements CombAT data in BPH patients at risk of progression with only moderate symptoms and who are naïve to treatment CONDUCT provides evidence of rapid symptom improvement with dutasteride/tamsulosin combination (measured at month 1) in BPH patients with moderate symptoms and at risk of progression Combination with dutasteride and tamsulosin is recommended as first-line treatment in men with moderate LUTS/BPH at risk of progression

Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only TERIMA KASIH 21 Presentation title

Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only Understanding the study patient populations MTOPS vs. CombAT vs. CONDUCT MTOPS IPSS range (8 ‒ 30) MTOPS 1 (4.5 years mean follow up) Combination therapy vs. Placebo and Doxazocin 4–8 mg and Finasteride 5 mg 3047 pts Entry criteria: Age ≥ 50, PSA ≤10 ng/mL Baseline: Mean PSA: 2.4 ng/mL, Median PV: 31.0 mL International Prostate Symptom Score (IPSS) Mean IPSS Mean IPSS 16.6 ModerateSevere CONDUCT* IPSS range (8 ‒ 19) CONDUCT 4,5 (2y) Fixed-dose combination therapy (dutasteride + tamsulosin) vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve 742 pts 100% treatment naive, PSA ng/mL PV ≥30 mL Baseline, : Mean PSA: 3.9 ng/mL Mean PV: 51.0 mL Mean IPSS % patients with moderate symptoms 2 CombAT IPSS range (12 ‒ 35) CombAT 2,3 (4y LOCF) Combination therapy (dutasteride + tamsulosin) vs. dutasteride 0.5 mg and tamsulosin 0.4 monotherapy 4844 pts Entry criteria: Age ≥50, PSA 1.5 ‒ 10 ng/mL, PV ≥30 mL Baseline: Mean PSA: 4.0 ng/mL Median PV: 48.9 mL, 38% treatment naïve *Both treatment arms included lifestyle advice administered 1.McConnell J et al. N Engl J Med 2003;349:2387–98; 2. Roehrborn CG et al. Eur Urol 2010;57:123–31; 3. Roehrborn CG et al., Eur Urol 2009;55:461–71; 4. Protocol Summary : (Accessed 5 April 2015) 5. Roehrborn CG et al. BJU Int 2015 doi: /bju.13033

Zinc Code ID/DUTT/0005/15 AD: DD/MM/YY ED: DDMM/YY For Healthcare Professionals Use Only DUODART TM Product Information Composition: Each capsule for oral use contains 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride. Indication: DUODART is indicated for the treatment of moderate to severe symptomatic benign prostatic hyperplasia (BPH) in men with enlarged prostate. Dosage and Administration: The recommended dose of DUODART is one capsule (0.5 mg/ 0.4 mg) taken orally approximately 30 minutes after the same meal each day. Capsules should be swallowed whole and not chewed or opened. Contraindication: DUODART is contraindicated in patients with known hypersensitivity to dutasteride, other 5 –alpha ‑ reductase inhibitors, or any of the excipients, women and children and adolescent, patients with severe hepatic impairment and patient with a history of orthostatic hypotension. Warnings and Precautions: Concomitant administration of tamsulosin hydrochloride with strong inhibitors of CYP3A4 (e.g. ketoconazole), or to a lesser extent, with strong inhibitors of CYP2D6 (e.g. paroxetine) can increase tamsulosin exposure. Tamsulosin hydrochloride is therefore not recommended in patients taking a strong CYP3A4 inhibitor and should be used with caution in patients taking a strong (e.g. paroxetine) CYP2D6 inhibitor. Patients receiving DUODART should have a new PSA baseline established after 6 months of treatment with DUODART. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on DUODART may signal the presence of prostate cancer (particularly high grade cancer) or non-compliance to therapy with DUODART and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5alpha-reductase inhibitor. Caution is advised when alpha adrenergic blocking agents including tamsulosin are co-administered with PDE5 inhibitors. Alpha adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension.Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients treated with alpha-1 adrenergic blockers, including tamsulosin. IFIS may lead to increased procedural complications during the operation. Adverse reactions: Postmarketing Data: Immune system disorders: Very rare: Allergic reactions, including rash, pruritus, urticaria, localised oedema, and angioedema. Skin and subcutaneous tissue disorders. Rare: Alopecia (primarily body hair loss), Hypertrichosis. Nervous system disorders: Common: Dizziness. Reproductive system and breast disorders. Common: Abnormal ejaculation. Abbreviated PI based on GDS11/IPI09 (13-Mar-2013) Before prescribing, please consult to PI which is available upon request. Adverse Events yang terjadi, harus dilaporkan kepada GSK Indonesia di nomer telpon atau ke Kami menghimbau Dr/Prof yang berstatus pegawai negeri bahwa setiap penerimaan apapun yang bernilai dianggap sebagai gratifikasi dan perlu dilaporkan ke UPG di Kementerian Kesehatan (5 hari sejak menerima) atau ke KPK (30 hari sejak menerima) sesuai dengan peraturan yang berlaku. Menara Standard Chartered 35 th Floor | Jl. Prof. Dr. Satrio No. 164 Jakarta Telp. (62-21) Fax. (62-21)