NEWER IMMUNOSUPPRESSIVE

DRUGS IN RENAL TRANPLANTATION

SANJEEV V NAIRDEPT OF NEPHROLOGY

Journey so far…Surgery techniqueIrradiationChemical

immunosuppressionSteroidsAzathioprine; ComboCyclosporineTacrolimusMMFBiologic agents: Depleting Non-

depleting

BELATACEPT: New kid on the block FDA approved on

15/6/2011 Fusion protein: Fc

fragment of human IgG1 linked to extracellular domain of CTLA-4.

Costimulatory signal blockade

Nulojix (Bristol-Myers Squibb)

Belatacept

Belatacept BENEFIT (Belatacept Evaluation of

Nephroprotection and Efficacy as First-line Immunosuppression Trial) & BENEFIT-EXT Trials

3 arms ( low dose, high dose, and CsA arm)

Basiliximab, MMF, Prednisone

Belatacept Results: • Both belatacept regimens had similar

patient/graft survival versus cyclosporine (94/95/91)

• Associated with superior renal function as measured by the composite renal impairment endpoint and by mGFR (55/54/78)

• Belatacept patients experienced a higher incidence & grade of acute rejection episodes. (22/17/7)

• PTLD was more common in the belatacept groups (3/2/1)

Belatacept FDA caveat: Patients should be tested for EBV

and should only receive Belatacept if the test shows they have already been exposed to EBV

Other side effects: anemia, constipation, UTI and pedal edema

Pros Cons

Better pt/graft outcome Route/?Compliance

Better CV risk profile PTLD/EBV status

Compliance/? monitoring Study vs CsA; C0 vs C2

Belatacept Clinicaltrials.gov17 trials overall1 for s/c regimen2 Steroid free regimens3 for DM & Islet Tx1 for long term safety in Renal transplant

Voclosporine Isomeric cyclosporine A analog mixture;

ISA247; Oral ? More potent than CsA Isotechnika Inc Completed phase2b trials in

May 08. PROMISE trial vs Tac 334 pts Similar graft preservation with better CV risk

profile esp NODM & TGs Ongoing phase 3 trial

http://www.clinicaltrials.gov/ct/show/NCT00270634?order=1 - JV

Sautrastaurin AEB07: Oral; Protein Kinase C inhibitor Blocks T-cell activation and IL-2

production with min action on NFAT 3 Phase II clinical trials:• Attempted CNI withdrawal (Tac+AEB

x3m; f/b AEB+MPS)• CNI free (AEB+MPS)• AEB+RAD+ Steroids vs

Tac+MPS+Steroids

Janus Kinase Inhibitors CP690550; Tofacitinib JAKs: cytoplasmic tyrosine kinases; 4 types

in mammals JAK3 vs JAK2 Proven efficacy in murine & NHP studies PhaseII trial 15mg/30mg antiJAK3 vs Tac

(anti IL-2R, MMF, Steroids) Comparable BPAR & graft function in all

groups at 6m More infns, CMV ds & BKAN in study grp

Alefacept Humanized LFA-3-IgG1 Efficacy proven in

primates Ongoing phase 2

clinical trials in humans

Dec07-Jan 11. University of Michigan http://clinicaltrials.gov/ct2/show/NCT00543569

2 more trials in enrollment stage in Maryland & Utah

Reperfusion Injury Aim to prevent initial inflammatory

response evoked by ischemia & reperfusion rPSGL-Ig: Fusion protein. rPSGL-Ig inhibits

all selectin molecule interactions. Disrupts proinflammatory events related to thrombosis and pathologic cell adhesion. rPSGL-Ig is currently in a phase I-II clinical trial to prevent ischemic reperfusion injury for delayed graft function.

Reperfusion Injury Reparixin is a LMW allosteric inhibitor of

CXCR1 & CXCR2 receptors for IL-8. IL-8 implicated in ischemic reperfusion injury and antibody mediated rejection. Undergoing Phase I/II trials for DGF in renal Tx

Diannexin: dimerized form of Annexin V. In Phase II trials for DGF in ECD

Small interfering RNA strands (siRNA): AKI-5 is a siRNA that inhibits p53 and has been shown experimentally to prevent ischemia reperfusion injury.

Targeting B-Cell

Eculizumab Monoclonoal Ab directed against the

complement protein C5. FDA approved for paroxymal nocturnal hemoglobinuria.

Mayo Clinic study: 10 positive crossmatch kidney transplant patients. None of the treated patients developed AMR compared to historical controls(~60%)

Phase I/II trials at Mayo currently recruiting.

Cytokine Pathways Genz29155: inhibits TNF-α induced

apoptosis Unknown intracellular target, but has been shown to have salutary effects

Preliminary NHP studies have been initiated showing prolonged renal allograft survival in rhesus monkeys treated with Genz29155 and sirolimus compared to sirolimus alone.

Stalled molecules Humanized OKT3: OKT3 non human murine Ab Side effects: 1st dose reaction, infections, PTLD,

HAMATo counter these s/e humanized variant

developed and underwent multiple phase I trials but further development appears to be stalled.

T10B9.1A Ab: monoclonal murine Ab against epitope of T Cell receptor. Developed as a replacement for OKT3.

Lesser 1st dose reactions but HAMA+

Stalled molecules Enlimommab (Anti ICAM-1 Ab): stalled bcos ?

No e/o efficacy vs placebo in reducing BPAR/DGF

Efalizumab: LFA-1 member of β-2 integrin family; αchain(CD11a) βchain (CD18)

Humanized CD11a-specific IgG1 FDA approved for psoriasis

S/c maintenance I/S agent: Phase II trial showed promising results but higher incidence of PTLD

No trials in Renal Tx on clinicaltrials.gov

Stalled molecules Fingolimod: Sphingosine analogue, alters

normal T-cell lymphocyte homing patterns. Trial vs CsA showed lesser efficacy and Macular edema in treatment arm

FK778: Metabolite of Leflunomide. s/e anemia, hypoK, symptomatic IHD & esophagitis.

Conclusion Several challenges impede both industry

and clinical investigators BPAR: reduced; ?yardstick in clinical trials Toxicities of current regimens as endpoint? No validated biomarkers to evaluate

impact of novel drugs. Tx drug development: • unaddressed immune targets• Long term toxicities of current regimens