Will difficult-to-treat patients remain difficultto-treat. generation of treatments?

Transcription

1 Will difficult-to-treat patients remain difficultto-treat with the new generation of treatments? Jordan J Feld MD MPH Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health University of Toronto

2 Disclosures Dr. J. Feld Consulting or speaker fees: AbbVie, Achillion, BI, BMS, Gilead, Idenix, Janssen, Merck, Roche, Vertex

3 What does Difficult-to-Treat mean? Difficult-to-Treat Difficult-to-Cure Some overlap but not always the same With HCV both groups exist Factors: Host Virus Treatment

4 Difficult-to-Treat vs Difficult-to-Treat Host Cirrhosis Age Co-morbidities Difficult-to-Cure Renal failure, autoimmunity, Hemoglobinopathy, Psych, transplant Social factors Virus None Treatment Injections, Pill burden Side effects Difficult-to-Cure Host Cirrhosis Age Co-morbidities Renal failure, Transplant HIV/HCV Past non-responder Genetics ethnicity, IL28B Virus Genotype (1a, 3) Viral load Treatment None

5 Difficult defined by IFN-use Sustained Virological Response % 80% 60% 40% 20% Standard Interferon % % Ribavirin Peginterferon % % 34% 42% 39% DAA+PR % IFN IFN IFN/R IFN/R PegIFN PegIFN/R 6 mo 12 mo 6 mo 12 mo 12 mo 12 mo PegIFN/R/S-C 6-12 mo Courtesy of Jay Hoofnagle

6 Therapy got a lot harder Additional side effects

7 Other issues with PI-based therapy Pill Burden Food Requirement Resistance BOC = 18/d TVR = 12/d Drug-Drug Interactions PI CYP3A4 Metabolites

8 First generation PIs? Actually made it more Difficult-to-Treat Increased side effects Pill burden Drug-interactions and add good ol Peg/RBV to all that What about Difficult-to-Cure Greatest improvement actually in Easy-to-Cure PIs augment a good IFN-response PIs minimal ability to overcome a poor IFN response

9 What about first generation PIs? Prior relapsers Prior partial responders Prior null responders Pooled T12/PR48 Pbo/PR48 SVR (%) n/n= 144/167 12/38 53/62 2/15 48/57 2/15 34/47 3/17 10/18 0/5 11/32 1/5 24/59 1/18 15/38 0/9 7/50 1/10 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Zeuzem EASL 2011

10 Room for improvement But we all know what s coming No AEs ~% SVR IFN-free RBV-free No DDIs Short Duration 1 pill OD Minimal/No Resistance

11 Priorities for Difficult-to-Cure Non-responders Cirrhosis Decompensated cirrhosis Co-morbidities Renal disease HIV co-infection Post-transplant Genotypes 1a 3

12 Second Wave DAAs for G1 80 PR + SMV PR 80 Treatment Naïve Simeprevir + PR x 24 weeks Prior Relapsers 79 Sofosbuvir + PR X 12 weeks SVR12 (%) SVR12 (%) SVR12 (%) / / / / 134 QUEST 1 QUEST / / 133 PROMISE / 292 NEUTRINO Jacobson I, et al. EASL Abst Manns M, et al. EASL Abst Lawitz E, et al. NEJM 2013

13 What about in the Harderto-Cure? Treatment Experienced Sofosbuvir + PR X 12 weeks 85 SMV + PR x 12 + PR x SVR24 (%) FDA Analysis 45/ / 27 Relapsers 32/ /23 Partials 45 15/ / 16 Nulls SVR12 (%) Poor or no results in null responders ? Modeled Numbers

14 What about cirrhosis? Sofosbuvir + PR x 12 wks 249/ / / / / / / / 54 Week 2 Week 4 Week 12 SVR 12 On treatment Improved results for Child s A cirrhotics, particularly with sofosbuvir/pr Post-treatment Jacobson I, et al. EASL Abst Lawitz E, et al. NEJM 2013

15 Options without interferon Nuc High barrier to resistance Modest barrier to resistance PI Curability NS5A RBV NNI Low barrier to resistance (esp to G1a) Easy: G2, G3? Nuc RBV Medium: G1b, G3? Hard: G1a, G3? Nuc Nuc Nuc NS5A PI NS5A NNI PI PI NNI NS5A PI NNI NS5A RBV?

16 PI + NS5A in prior null responders Daclatasvir (NS5A) + asunaprevir (PI) x 24 wks (IFN-Free) Daclatasvir (NS5A) + asunaprevir (PI) + BMS (NNI) x 12 wks US [1] Japan [2] SVR24 (%) /11 9/10 G1a 121/ 133 G1b 27/ 28 US Study 9/11 G1a Japanese Study 10/10 G1b 2 drugs for 1b, 3 for 1a Excellent results in NULL responders! 1. Lok et al NEJM 2012;366:216-24, 2. Chayama AASLD 2011 LB-4 3. Everson AASLD 2013 LB-1

17 AVIATOR: PI/r + NS5A + NNI + RBV x 12 wks Treatment Naive Prior Nulls SVR12 (%) a 1b 1a 1b 1a 1b 1a 1b RBV RBV RBV a 1b 1a 1b RBV RBV Kowdley AASLD drugs (3 pills) BUT 12 wks, 1 size fits all

18 Post-AASLD: IFN-Free Phase 3 study ABT-450/r + ABT ABT RBV x 12 wks Naive Treatment Failures (49% nulls) SVR12 (%) SVR12 (%) / 473 All 307/ 322 G1a 148/ 151 G1b / 297 All 166/ 173 G1a 119/ 123 G1b Clear prior null response can be overcome Abbvie press release Nov and Dec to be presented at EASL 2014

19 If nucs are good and PIs are good How about nucs + PIs?

20 If only we could all get along FDA SMV SOF

21 Nuc (SOF) + PI (SMV) Naïve & Prior Null Responders Sofosbuvir (Nuc) + Simeprevir (PI) +/- RBV x 12 wks F0-2 Sofosbuvir (Nuc) + Simeprevir (PI) +/- RBV x 12 wks F3-4 78% G1a 50% Q80K 94% non-cc SVR4 or 8 (%) [1] 93 [1] 26/27 13/14 S/S/R F0-2 S/S 96 [2] [2] 26/27 14/14 S/S/R F3-4 S/S 78% G1a 40% Q80K 79% non-cc 47% F4 54% Null Major caveats: small n, no plan for Phase 3 trial Jacobson AASLD 2013

22 Another option: Nuc + NS5A Sofosbuvir (Nuc) + Daclatasvir (NS5A) +/- RBV x 24 wks Sofosbuvir (Nuc) + Daclatasvir (NS5A) +/- RBV x 12 wks SVR4 or 12 (%) /14 15/15 D/S/R D/S 24 wks 40/41 39/41 D/S/R D/S 12 wks Major caveats: small n, no plan for Phase 3 trial Sulkowski M, et al. NEJM 2014

23 2 drugs, 1 pill LONESTAR: SOF (nuc) + LDV (NS5A) FDC +/- RBV Naïve PI Failures SVR4 or 12 (%) /20 21/21 S/L 8 wks S/L/R 19/19 S/L/R 12 wks 18/19 20/21 S/L 12 wks S/L/R No breakthrough, relapses all without RBV 1 case of resistance retreated w/ RBV x 24 wks SVR Lawitz AASLD 2013

24 Just in ION 1, 2 & 3: SOF (nuc) + LDV (NS5A) FDC +/- RBV Naïve Prior Trt (incl PI) Failures SVR4 or 12 (%) / 214 S/L 211/ 217 S/L/R 12 wks 102/ 109 S/L 107/ 111 S/L/R 12 wks 108/ 109 S/L 110/ 111 S/L/R 24 wks 202/ / / 216 S/L S/L/R S/L 8 wks 12 wks Includes 15-20% cirrhosis, only 1 BT non-compliant Gilead Press Release Dec to be presented at EASL 2014

25 Priorities for Difficult-to-Cure Non-responders Cirrhosis Decompensated cirrhosis Co-morbidities Renal disease HIV co-infection Post-transplant Genotypes 1a 3

26 FUSION: (Treatment Failures) SVR12 by HCV Genotype/Cirrhosis SOF + RBV 12 weeks SOF + RBV 16 weeks SVR12 (Percentage) 25/26 23/23 6/10 7/9 14/38 25/40 5/26 14/23 No cirrhosis Cirrhosis No cirrhosis Cirrhosis GT 2 GT 3 Cirrhosis clearly matters limited data G2 Convincing data for G3 Jacobson NEJM 2013

27 VALENCE SOF + RBV x 24 wks No Cirrhosis Cirrhosis SVR12 (%) wks / 92 12/ 13 Naive 85/ 27/ 45 Treatment Failures 14/ weeks better for naives Not ideal for cirrhotic treatment failures Zeuzem AASLD 2013

28 Do we still need IFN for G3? LONESTAR 2: Peg + RBV + SOF x 12 wks No Cirrhosis Cirrhosis SVR12 (%) % treatment failures / 9 G2 13/ 14 10/ 12 G3 10/ 12 Small single centre study but looks promising IFN is not dead yet! Lawitz AASLD 2013

29 Treatment pre-transplant for HCC (low MELD) > 30 days TND No Recurrence (n = 28) Recurrence (n = 10) SOF + RBV x up to 48 wks Median days undetectable No recurrence: 95 Recurrence: 5.5 (P <.001) Days With HCV RNA Continuously TND Prior to Liver Transplant Only 1 of 24 with HCV RNA neg > 30 days with recurrence 330 Curry MP, et al. AASLD Abstract 213.

30 Cirrhosis Cirrhosis is still an issue with current regimens Simple IFN-free regimens sub-optimal in cirrhosis (esp G3) Increased duration only partially overcomes this More potent IFN free regimens seem to work equally well in compensated cirrhotics in G1 VERY limited data to date Possibly higher relapse rate No data in decompensated cirrhosis Studies ongoing

31 Priorities for Difficult-to-Cure Non-responders Cirrhosis Decompensated cirrhosis Co-morbidities Renal disease HIV co-infection Post-transplant Genotypes 1a 3 (?)

32 HCV RNA < LLOQ (%) n/n = / 114 PHOTON-1: HCV/HIV coinfected ARVs: PI/NNRTIs/Integrase Inhibitors 103/ / 114 Genotype 1 Genotype 2 Genotype 3 SOF + RBV 24 Wks / 26 22/ / / 41 SOF + RBV 12 Wks 39/ / 42 Wk 4 EOT SVR12 Looking fairly similar to HCV mono-infected pop n Sulkowski M, et al. AASLD Abstract 212.

33 Priorities for Difficult-to-Cure Non-responders Cirrhosis Decompensated cirrhosis Co-morbidities Post-transplant Genotypes 1a 3 (?) Renal disease No data no RBV will help HIV co-infection

34 Sofosbuvir + RBV ± PegIFN in Post-LT HCV with Severe Recurrence 69% of pts had SVR4; 56% had SVR12 Deaths and posttreatment relapse accounted for nearly all cases of virologic failure 64% demonstrated improvement of decompensation events 11% showed stabilization of events Forns X, et al. AASLD Abstract SVR4 (%) n/n = 0 69 FCH 45% Mean MELD 15 SVR4 Outcomes /36 20/27 5/9 Overall SOF + RBV SOF + PegIFN/RBV

35 Not quite so sick post-oltx SOF + RBV x 24 wks wks post OLTx (n=40) G1 n=30 MELD<=17 CPT<=7 Cirrhosis n=16 Relapse 23% DC due to AEs n= 2 Looking fairly similar to HCV non-oltx pop n Charlton AASLD 2013 LB-2

36 Priorities for Difficult-to-Cure Non-responders Cirrhosis Decompensated cirrhosis Co-morbidities Post-transplant Genotypes 1a 3 (?) Renal disease No data no RBV will help HIV co-infection (?)

37 Priorities for Difficult-to-Treat Cirrhosis Decompensated cirrhosis Co-morbidities Renal disease Psychiatric disease Hemoglobinopathy Social Factors People who inject drugs Incarcerated Access to specialists?

38 More drugs shorter therapy SOF/LDV FDC SVR4 20/20 SVR12 20/20 SOF/LDV FDC + NNI (GS-9669) SOF/LDV FDC + PI (GS-9451) 18/20 20/20 NA NA Weeks IFN and RBV-free therapy for 6 wks or less possible Will increase options for treating difficult-to-treat Kohli AASLD 2013

39 Priorities for Difficult-to-Treat Cirrhosis Decompensated cirrhosis Co-morbidities Renal disease Psychiatric disease Hemoglobinopathy Social Factors People who inject drugs Incarcerated Access to specialists? Few DDIs, Few AEs, No RBV Few DDIs, No IFN No IFN, No RBV No IFN, Few AEs, PCP treat No IFN, Short Duration PCPs can treat

40 $$$$$$$$$$$ May become our biggest barrier to treatment

41 Bottom Line Difficult-to-Cure populations disappearing Non-responders, compensated cirrhosis, HIV, posttransplant, co-morbidities likely to be non-issues Decompensated cirrhosis likely to remain a challenge Difficult-to-Treat populations decreasing Minimal toxicity will allow more to be treated Simple regimens will increase treaters increase access Difficult-to-Reach populations Our new challenge Paying for it all Everyone s challenge!!

42 Evaluation and Certificate of Attendance Please visit the CAG website at to complete the session evaluation and to print your certificate of attendance. Thank you!

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44 Accreditation This event has been approved as an accredited (Section1) group learning activity as defined by the Maintenance of Certification program of the RCPSC. It has been produced under RCPSC guidelines for the development of co-developed educational activities between CAG and Vertex Pharmaceuticals.

45 2013 CDDW/CASL Winter Meeting CanMEDS Roles Covered: Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical knowledge, clinical skills, and professional attitudes in their provision of patient-centered care. Medical Expert is the central physician Role in the CanMEDS framework.) Communicator (as Communicators, physicians effectively facilitate the doctor-patient relationship and the dynamic exchanges that occur before, during, and after the medical encounter.) Collaborator (as Collaborators, physicians effectively work within a healthcare team to achieve optimal patient care.) Manager (as Managers, physicians are integral participants in healthcare organizations, organizing sustainable practices, making decisions about allocating resources, and contributing to the effectiveness of the healthcare system.) Health Advocate (as Health Advocates, physicians responsibly use their expertise and influence to advance the health and well-being of individual patients, communities, and populations.) Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning, as well as the creation, dissemination, application and translation of medical knowledge.) Professional (as Professionals, physicians are committed to the health and well-being of individuals and society through ethical practice, profession-led regulation, and high personal standards of behaviour.)

46 Learning Objectives At the end of this session, participants will be able to: 1. Describe the baseline laboratory and clinical profile in the cirrhotic patient that contraindicates interferon-based treatment. 2. Describe clinical current experience and future protocols for treatment of patients with HCV after liver transplantation. 3. Discuss the newer therapies for HCV for relapsers and non-responders.