Christopher P. Denton PhD FRCP Professor of Experimental Rheumatology

Royal Free Hospital and UCL Medical School, London, UK

Emerging therapies for systemic sclerosis

Disclosures

Consultancy: Actelion, Pfizer, GSK, Sanofi Aventis, Boehringer Ingelheim,

Roche, CSL Behring, Genzyme, Inventiva

Research grant funding: Actelion, Novartis, CSL Behring

Clinical trial investigator and steering committee :

Pfizer, Actelion, Sanofi-Aventis, MedImmune, United Therapeutics, Novartis, Celgene, Bayer

Overview:  emerging  therapies  •  Scleroderma  is  now  treatable  

–  Licensed  therapies  for  2  major  vascular  complica<ons  PAH  and  DU  

–  Recommenda<ons  and  guidelines  are  important  –  Pathways  to  access  treatments  must  be  developed  

•  Immunosuppression  is  beneficial  –  benefit  and  risk  need  to  be  balanced  

•  Targeted  approach  to  therapy  is  possible  •  Three  recent  clinical  trials  are  encouraging  

–  Posi<ve  trials  inform  about  disease  mechanism  and  underpin  further  advances  in  therapy  

dcSSc lcSSc

0 12 24 36 48 60 50

60

70

80

90

100 93%

91% P=0.534

Disease duration (months)

Sur

viva

l (%

)

Disease onset

1990 -1993 n=234

2000 -2003 n=286

0 12 24 36 48 60

50

60

70

80

90

100

84%

69% P=0.018

Nihtyanova et al, QJM 2010; 103:109-15

Improving survival in systemic sclerosis: a historical perspective

EULAR/EUSTAR  recommenda<ons  for  the  treatment  of  systemic  sclerosis  

I    SSc-­‐related  digital  vasculopathy  (RP,  digital  ulcers)  1.  Calcium  channel  blockers  and  iloprost  for  Raynaud’s    2.  Intravenous  prostanoids  (in  par<cular  iloprost)  should  be  considered  for  treatment  of  digital  ulcers  in  SSc    3.  Bosentan  should  be  considered  in  SSc  with  mul<ple  digital  ulcers    

II    SSc-­‐PAH  4.  Bosentan  should  be  strongly  considered  to  treat  SSc-­‐PAH      5.  Sildenafil  may  be  considered  to  treat  SSc-­‐PAH      6.  Sitaxentan  is  withdrawn  and  should  not  be  used  for  SSc-­‐PAH    7.  Intravenous  epoprostenol  should  be  considered  for  the  treatment  of  severe  SSc-­‐PAH        

III    SSc-­‐related  skin  involvement  8.  Methotrexate  may  be  considered  for  treatment  of  skin  manifesta<ons  of  early  diffuse  SSc        

IV    SSc-­‐ILD  9.  Cyclophosphamide  should  be  considered  for  treatment  of  SSc-­‐ILD      

V      SRC  10.  ACE  inhibitors  should  be  used  in  the  treatment  of  SRC      11.  Pa<ents  on  steroids  should  be  carefully  monitored  for  SRC  

VI    SSc-­‐related  gastrointes<nal  disease  12.  PPI  should  be  used  for  the  treatment  of  SSc-­‐related  gastro-­‐oesophageal  reflux,    13.  Prokine<c  drugs  should  be  used  for  the  management  of  SSc-­‐related  symptoma<c  mo<lity  disturbances  14.  When  malabsorp<on  is  caused  by  bacterial  overgrowth,  an<bio<cs  may  be  useful  in  SSc  

 Kowal-­‐Bielecka  et  al,  Ann  Rheum  Dis  2009;68:620-­‐628    

•  Best  prac<ce  documents  available  on  UKSSG  page  of  the  Scleroderma-­‐Royal  Free  website  

•  Stand-­‐alone  publica<ons  are  emerging    –  GI  –  published  –  excellent  North  American  feedback  –  Digital  vasculopathy  –  in  press  –  Lung  fibrosis  –  for  submission  –  Cardiac  –  in  prepara<on  –  Renal  –  in  drag  form    

UKSSG  Best  prac<ce  project  (2011-­‐14)  

h,p://www.scleroderma-­‐royalfree.org.uk/UKSSG.html  

•  Work  started  September  2012  •  February  2015  -­‐  submihed  to  BSR  and  first  stage  of  external  peer  review  –  presented  drag  April  2015  

•  Target  for  comple<on  September  2015    

•  Scope  and  structure  of  drag  guideline  A.  General  approach  to  SSc  management  B.  Key  therapies  and  treatment  of  organ  based  disease  

C.  Service  organiza<on  and  delivery  within  NHS  England  

BSR  and  BHPR  guideline  for  the  management  of  systemic  sclerosis    

Licensed targeted therapies for PAH in systemic sclerosis

Endothelin receptor antagonists

Selective phosphodiesterase inhibitors

Prostacyclin analogues

Bosentan*  (approved  2001)  Ambrisentan  Sitaxentan  (withdrawn)  Macitentan  (approved  2013)    

Sildenafil  (approved    2005)  Tadalafil  Riociguat  –  guanylate  cyclase  agonist  (approved  2013)  

Epoprostenol  Trepros<nil  Iloprost  

ET1  NO  cGMP   PGI2  Mechanism

p.o.   p.o.  

i.v.,  s.c.,  inh.  

*licensed  for  SSc  digital  ulcers  2007    

Denton CP, et al. Ann Rheum Dis 2008; 67: 1222-8. Pope J, et al. Presented at the ACR meeting, 2007.

100

80 90

70 60 50 40 30 20 10

0 Pat

ient

s su

rviv

ing

(%)

Time from treatment start (weeks) 0 16 32 48 64 80 96 112 128 144 160

Patients at risk 53 51 49 47 45 40 40 32 12 3 0

82% alive at 2 years 92% alive at 48 weeks

TRUST TRacleer Use in PAH associated with Scleroderma and other

connective Tissue diseases – 3-year survival data

SSc n=42 (80%) MCTD/overlap n=6 (11%) SLE n=5 (9%) mPAP = 40 (+13) mm Hg PVR = 559.4 (+371.5) dyn/s/cm–5

NHS  England  policy  for  DU  in  SSc*  •  Sildenafil  •  Prostenoids  (iloprost)  •  Bosentan  access  for  severe  cases  

–  Severe  refractory  disease:  persistent  or  progressive  ulcera<on  of  one  or  more  digits  causing  or  threatening  <ssue  loss  despite  op<mal  treatment  with  vasodilators  including  IV  prostanoids  and  oral  sildenafil,  or  

–  Mul<ple  DUs:  3  or  more  DUs  either  currently  or  occurring  in  the  last  12  months  despite  IV  prostanoids  and  sildenafil.  

Challenging  process  (18  months)  with  reduced  access  during  development  compared  with  previous  arrangements  (IFR)    

*First  published:  January  2015  Prepared  by  NHS  England  Specialised  Services  Clinical  Reference  Group  for  Specialised  Rheumatology  Published  by  NHS  England,  in  electronic  format  only.  

1Hoyles et al Arthritis Rheum 2006; 54:3962-70

Cyclophosphamide for lung fibrosis in SSc •  Fibrosing alveolitis in scleroderma trial (FAST)1 monthly intravenous

cyclophosphamide 600mg/m2 for 6 months followed by (po) azathioprine, or placebo in 45 patients

–  Over 12 months FVC change favoured active treatment (p=0.04, BMI corrected – uncorrected p=0.08)

FAST primary outcome: FVC

p=0.08

2.44 2.46 2.48 2.50 2.52 2.54 2.56 2.58 2.60 2.62 2.64

baseline 3 months 6 months 9 months 12 months

Months from baseline

Abs

olut

e FV

C (m

ean

at e

ach

time

poin

t)

ACTIVE PLACEBO

–  Magnitude of difference 5.5% (4.8% adjusted) •  active arm improved (+2.5 % predicted) •  placebo arm worsened (-3.0 % predicted)

Agreed  pathway  for  UK  pa<ents  to  be  evaluated  for  autologous  stem  cell  transplanta<on  

Concept of targeted therapy in systemic sclerosis

Varga, J., Denton et al. (2015) Systemic sclerosis Nat. Rev. Dis. Primers doi:10.1038/nrdp.2015.2

Pathway Process Organ

Emerging molecular therapies for SSc Candidate therapy Target pathway

•  Bosentan, macitentan ETA/ETB receptor •  Ambrisentan ETA receptor •  Selexipag IP receptor agonist •  Riociguat cGMP agonist

•  Infliximab, Adalimumab TNFα ligand •  Etanercept TNFα ligand

•  Rituximab CD20 •  Basiliximab IL-2Rα •  MLM-1202 CCR2 •  Efalizumab LFA1/ICAM-1 •  Abatacept CTLA4 •  AIMSPRO® (HCS) MSH, IL10, CCL2 •  Tocilizumab IL-6R •  ACT12339 LPA1

•  Imatinib, Dasatinib, Nilotinib c-Abl, c-Kit, PDGF •  CAT-192 TGFβ1 •  GC-1008 TGFβ1,-β2,-β3 •  FG-3019 CCN2 •  P144 TGFβ1 (topical) •  Anti-αvβ6 integrin TGFβ activation •  Pirfenidone TNFα, IL1β, TGFβ •  Nintedanib (BIBF1120) VEGF,PDGF,FGF

Vascular Inflam

matory

Fibrotic

Targeting the IL-6 axis in diffuse systemic sclerosis

1  8  0  1  2  0  6  0  0  

1  0  0  

8  0  

6  0  

4  0  

2  0  

0  

Disease  duraNon  (months)  

Number  at  risk  

High  Low  

15                                    5                                          3                                            1  24                                  15                                        5                                            1  

IL-­‐6  serum  level  at  presenta<on  predicts  survival  

Survival  %  

p=0.02,  Log  rank  analysis  

high  

Low  IL-­‐6  

Khan  et  al.  Ann  Rheum  Dis.  2012;71:1235-­‐42.    

X200  vascular  

Immunostaining  IL-­‐6  in  dcSSc  skin  

X200  fibroblast  

IL-­‐6  (p

g/ml)  

Controls  

50  

40  

30  

20  

10  

0  dcSSc  

High  plts  dcSSc  Normal  plts  

lcSSc  *

IL-­‐6  serum  level  in  SSc    

50 40 30 20 10 0

40

30

20

10

0

IL-6 (pg/ml)

MR

SS a

t 36

mon

ths

r=0.86  p<0.01    

IL-­‐6  serum  level  at  presenta<on  predicts  skin  score  at  36  months  

Conclusions  •  Treatment  of  scleroderma  is  improving  •  Established  treatments  are  being  used  in  beher  ways  e.g.  immunosuppression  

•  Licensed  drugs  are  available  for  specific  complica<ons  • Access  to  treatment  requires  co-­‐ordinated  and  persistent  efforts  of  medical  teams,  pa<ents  and  pa<ent  organisa<ons  

• Recent  clinical  suggest  more  targeted  skin  treatments  are  likely  to  emerge  over  the  next  few  years  

• New  scleroderma  lung  fibrosis  trials  are  being  planned  

Many thanks to …. •  Our patients •  The “Scleroderma team” at Royal Free •  Research Funders •  Colleagues in many institutions and organisations •  UKSSG colleagues •  International collaborators – EUSTAR, SCTC and FESCA, WSF

Arthritis Research UK, Raynaud’s and Scleroderma Association (UK), Wellcome Trust (UK), Nuffield Foundation, Scleroderma Society (UK), Rosetrees Trust, Scleroderma Research Foundation (USA), MRC, EULAR, Royal Free Charity