Visceral Leishmaniasis combination therapies

Transcription

1 Best Science for the Most Neglected From patient needs to implementation of new treatments Visceral Leishmaniasis combination therapies Shyam Sundar Institute of Medical Sciences Banaras Hindu University 1

2 Treatment Seeking Behaviour of Patients with Kala-azar Qualifed 27% Quakes 73% First contact 30 Days <30 Days Duration of Treatment Irregular 42% Regular 58% Regularity of Treatment Inadeq uate 74% Adequ ate 26% Dose & Duration

3 Decreasing SSG efficacy Efficacy of SSG 20mg/kg/d in Bihar, India during Sundar & Olliaro

4 Miltefosine (licensed in 2002) Miltefosine was chosen as drug for VL Elimination programme in India, Nepal and Bangladesh Pros and Cons Big Oral Advantage Easy to implement in programe BUT 28 days treatment Teratogenic, ~2% severe adverse events (lab monitoring?) Long half life (rapid emergence of resistance) In a recent evaluation we found 20-33% patients discontinued therapy May lose this important drug in next few years 4

5 Paromomycin (licensed in 2006) Pros and Cons Cheapest Can be used as out patient therapy Suitable for women Manufactured in India 21 intramuscular injections! Has to be delivered as DOT Hepatotoxicity in a small proportion of patients Aminoglycoside (prone to develop resistance) 5

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7 Amphotericin B (Standard Treatment) Administered at doses of mg/kg daily for 30 days or alternate days for infusions Pros and Cons High Cure rates ~100% Infusion reactions, thrombophlebitis common. Occ. Hypokalemia, myocarditis, death can occur Prolonged hospitalisation of 5-6 weeks Expensive (Treatment cost ~ US$) Clinical & lab. monitoring is required 7

8 Efficacy of Single Dose liposomal amphotericin B (10 mg/kg) S Sundar- et.al. N Engl J Med 2010;362:504-12

9 Rationale for combination treatment of VL Every drug (possibly with the exception of Amphotericin B) is prone to development of resistance No new drug in pipeline The only way to protect the newly developed drugs is to develop combination chemotherapy Shorten duration Better compliance Reduce costs; improve cost-effectiveness Less chances of development of drug resistance by reducing drug pressure; mutual protection prolong therapeutic life-span of effective use Safety and Efficacy data in animals support use of combination therapy 9

10 Experimental and clinical evidence for the use of M, P and A in combination 1. Activity Enhancement Index (AEI) in vivo (Siefert & Croft) Miltefosine + Ampho B 11.3 Miltefosine + Paromomycin 7.2 Miltefosine + SAG Evidence of clinical efficacy of individual treatments: Single dose of Ambisome (5mg/kg) cured 91% patients Two weeks of miltefosine cured 89% patients Initial cure rate with 14 days of paromomycin is 91% These findings suggested that short course combination treatment is a feasibility 10

11 Results of a phase II combination trial in Indian VL (Sundar et al, CID 2008) Regimen n Initial Cure Rate (%) Final Cure Rate 95% Confidence Interval AmBisome (5mg/kg) AmBi 5 + Milt 14 days AmBi Milt 14 days AmBi 5 + Milt 10 days AmBi 5 + Milt 7 days

12 Phase 3 short-course combination treatment for VL in India A randomized, controlled, non-inferiority trial of 3 different combinations versus a standard treatment with Amphotericin B Powered for expected cure rate of 97% for standard and Δ= -7% between each combination and Ampho B Treatments: Standard treatment : 15 Amphotericin B infusions 1mg/kg alternate days for 30 days Single infusion of 5 mg/kg liposomal amphotericin B (L-AmB) on D1 followed by 7-days oral miltefosine Single infusion of 5 mg/kg L-AmB on D1 followed by 10-day paromomycin 12 Miltefosine and paromomycin for 10 days

13 Variable Baseline characteristics of all patients Randomized (ITT) Ampho B (N=157) AmB-5 + Milt- 7 (N=160) AmB-5 + Paro-10 (N=158) Age (Yr) 28 ± ± ± ± 16 Milt Paro-10 (N=159) Male sex- no. (%) 98 (62) 117 (73) 100 (63) 107 (67) Splenic aspirate score 2.2 ± ± ± ± 1.1 Weight - (kg) 40.5 ± 40.5 ± ± ± Spleen size - (cm) below left costal 5.0 ± ± ± ± 3.2 margin Hemoglobin - (g/dl) 8.1 ± ± ± ± 1.9 White-cell count (per 3084 ± 3280 ± ± ± 2008 µl) 1264 Platelet count (per µl) ± ± ± ± Creatinine - (mg/dl ) 0.81 ± 0.83 ± ± ± Alanine 39.5 ± 42.5 ± ± ± 26.3 aminotransferase- (U/L) 27.3

14 Efficacy: high definitive cure rates Definitive cure at 6 months All randomised population (N=634) No. Of patients Cured Ampho B AmB-5+ Milt-7 AmB-5+ Paro-10 Milt-10+ Paro Percent 93.0% 97.5% 97.5% 98.7% [95% CI] [87-96] [93-99] [93-99] [95-99] Per-protocol population (N=618) No. Of patients Cured Percent 98.6% 98.7% 98.7% 98.7% [95% CI] [88-97] [95-100] [95-100] [95-100]

15 Most frequent adverse events AmphoB AmB-5 +M AmB-5+P M+P Diarrhea 3 ( 1.9) 3 ( 1.9) 1 ( 0.6) 5 ( 3.1) Vomiting 30 ( 19.1) 25 ( 15.6) 5 ( 3.2) 16 ( 10) Asthenia 1 ( 0.6) 3 ( 1.9) 2 ( 1.3) 3 ( 1.9) Chills 113 ( 72.0) 20 ( 12.5) 20 ( 12.7) 0 ( 0.0) Injection site pain 0 ( 0.0) 0 ( 0.0) 10 ( 6.3) 14 ( 8.8) Pyrexia 37 ( 23.6) 31 ( 19.4) 33 ( 20.9) 32 ( 20) Increased creatinine 15 (9.6) 1 (0.6) 6 (3.8) 6 (3.8) Treatment was withdrawn in 7 patients in Ampho B group (5 Nephrotoxicity, 1 hepatotoxicity, 1 deterioration of clinical condition)

16 Serious Adverse Events 4 SAEs reported one death (cardiac infarct) during the first infusion in the amphotericin B group as probably related one generalized allergic reaction (urticaria) during L-AmB testing in the L- AmB and miltefosine group as related\ One Guillain-Barré Syndrome in Ampho group One unrelated death in car accident 16

17 Hb evolution over time in each treatment arm Ampho B AmB-5 + Milt-7 AmB-5 + Paro-10 Milt-10 + Paro-10 3a Haemoglobin (g/dl) Baseline Day 7 Day 15/31 Day 45 Days 17

18 Creatinine evolution over time in each treatment arm b Ampho B AmB-5 + Milt-7 AmB-5 + Paro-10 Milt-10 + Paro-10 Creatinine (mg/dl) Baseline Day 7 Day 15/31 Day 45 Days 18

19 Therapeutic Options Ranked by Preference (For Bangladesh, Bhutan, India and Nepal) (WHO TRS 797, 2010) 1. Liposomal amphotericin B (Single or multiple infusions) 2. Combination therapy using liposomal ampho B with miltefosine liposomal ampho B with paromomycin Paromomycin with miltefosine 3. Amphotericin B infusions (15-30 days) 4. Miltefosine alone, Or Paromomycin 5. Pentavalent antimonials (daily for 30 days) in areas where they remain effective:bangladesh, Nepal and the Indian states of Jharkhand, West Bengal and Uttar Pradesh 19

20 Conclusion: Therapeutic options for VL New options treatments were recently developed using either single dose Ambisome or a set of 3 different combination treatments with high efficacy Both represent promising alternatives from the existing monotherapy treatments in terms of efficacy, safety, and prevention of the development of resistance. 20

21 Acknowledgements DSMB: P. Smith, C.P. Thakur, N.K. Arora, R.M. Pandey Independent parasitology audit A. Moody Independent Auditor: Rita Walt Consulting GmbH, Schaffhausen, Switzerland Michel Vaillant, (Statistician) GVK-BIO (CRO) Gurgaon Gilead (Contributed AmB) Ethical Committees: Institutional, ICMR, DCGI, Basel (Switzerland) Steering Committee: DG, ICMR, Dir. RMRI (P.Das), WHO, SEARO (S. Bhattacharya), HQ (J. Alvar), TDR (P. Olliaro), Rep. MoH & Local Experts, DNDi Team: Farrokh Modabber, Bhawna Sharma Sally Ellis, Manica Balasegaram, Nathalie Strub-Wourgaft Shing Chang Bernard Pecoul 21

22 Thank you 22 Best Science for the Most Neglected

23 Best Science for the Most Neglected Evaluation o All patients were hospitalised or 15 days in combination arms & 31 days in Ampho B arm o Daily clinical and weekly lab evaluation were done o Parasitological cure (initial cure) was done on day 15 and 30 for combination arms and Ampho B, respectively o Final cure was assessed at 6 months in all patients * If there were scanty parasites at end of treatment, reassessment was done at day 45 23

24 Best Science for the Most Neglected A total of 634 patients Results were randomly assigned Amphotericin B (n=157) AmBisome and miltefosine (n=160) AmBisome and paromomycin (n=158) Miltefosine and paromomycin (n=159) DCGI: First enrol 120 adults and evaluate results; then enrol all (5-60 years old) 293 adults first, then 169 adult children 24