TARGETING CYTOKINES, YOU'VE
HEARD ABOUT IL-1 AND IL-6.
I WANT TO SAY YOU ACTUALLY DO
NOT ELIMINATE COMPLETELY THE
RISK IN PATIENTS WHEN INHIBITED,
THIS IS THE RATE OF PROBABLY OR
DEFINITE EVENTS IN THE TWO
DEVELOPMENT PROGRAM ANAKINRA,
YOU SEE THE INCIDENCE RATE IS
STILL PRETTY EVIDENT THERE.
WHAT ABOUT IL-1 INHIBITION?
THERE IS EVIDENCE OF EFFICACY OF
ANAKINRA IN SOME CASES OF
PATIENTS WITH MAS, YOU HAVE TO
USE HIGH DOSE, THERE IS SOME
EVIDENCE OF RESOLUTION ON HIGH
DOSE, I THINK THIS IS SIMPLY A
PATIENT TREATED WITH ANAKINRA
THAT DEVELOPED MAS BECAUSE THE
DISEASE WAS NOT SUFFICIENTLY
CONTROLLED, I DON'T THINK
ANAKINRA TRIGGERED MAS.
THE SAME WITH IL-6, THERE ARE
SOME RESPONSES OF GOOD RESPONSE,
CERTAINLY THE CYTOKINE STORM
THAT FOLLOWS, KNOWN TO RESPOND
SATISFACTORILY IN SEVERAL
PATIENTS.
IT'S CLEAR TWO TARGETS ARE
BECOMING TARGETABLE IN MAS AND
IN HLH.
IL-18 IS PRODUCED THROUGH
INFLAMMASOME, CASPASE 1, WHICH
CLEAVE INTO A SECRETABLE
INTERLEUKIN 18.
THERE PECULIARIATI, AN INHIBITOR
IS AN IL-18 BINDING PROTEIN,
DOES NOT BIND TO RECEPTOR.
IL-18 DOES VERY LITTLE BY
ITSELF, IT'S A CO-FACTOR FOR A
NUMBER OF ACTIVITIES IN THE
IMMUNE SYSTEM AND OUTSIDE OF THE
IMMUNE SYSTEM, NOT LISTED HERE,
IN THE PRESENCE OF OTHER
CYTOKINES.
THE REASON BEING THAT BETA CHAIN
OF RECEPTOR IS NOT USUALLY
EXPRESSED BUT INDUCIBLE BY THE
FOLLOWING CYTOKINES THAT YOU
ACTUALLY FIND LISTED HERE,
CO-FACTOR OF EFFECT OF
INTERLEUKIN 18.
IT'S TARGETABLE USING BINDING
PROTEIN WHICH IS BECOMING A
DRAG, IT'S BEEN USED TO TREAT
ADULT ONSET STILL'S DISEASE,
HIGH LEVELS BEING PRESENT IN
PATIENTS WITH SJIA AND STILL'S
DISEASE AND ALTHOUGH THE PRIMARY
OUTCOME OF THE PHASE 2 STUDY WAS
IMPROVEMENT BY 20%, ONLY 40% OF
THE PATIENTS ACHIEVED PRIMARY
OUTCOME.
NOT WHAT WE'RE USED TO SEEING
WITH IL-1 OR IL-6 INHIBITION IN
SJIA OR STILL'S DISEASE.
THE TARGET IS INTERFERING.
THIS IS DATA FROM A PAPER THAT I
BELIEVE WAS SHOWN BY SCOTT CANNA
SHOWING IL-18 LEVELS ARE
INCREASED IN PATIENTS WITH MAS
IN A NUMBER OF PATIENTS WITH
SECONDARY INFECTION ASSOCIATED
HLH, PARTICULARLY INCREASED WITH
PRIMARY FAMILIAL HLH.
INTERLEUKIN 18 APPEARED TO
PREDISPOSE, TRANSGENIC MICE,
HIGH LEVEL OF IL-18, FREE IL-18,
NOT BOUND, THEY ARE FINE UNLESS
TRIGGERED WITH IMMUNE, INNATE
IMMUNE STIMULI TO DEVELOP SEVERE
MAS FEATURES IN THESE MICE.
THIS IS ALSO TRUE IN THE THE
REVERSE EXPERIMENT IN THE
KNOCKOUT MICE.
THEY ARE FINE UNLESS THEY GET
TRIGGERED AGAIN, STIMULATION,
THEY DO DEVELOP SEVERE MAS
FEATURES.
SO THE DATA IN MICE ARE
CONSISTENT WITH WHAT WE HAVE
OBSERVED, WE AND OTHERS, SEVERAL
PEOPLE OBSERVED IN PATIENTS WITH
AUTO-INFLAMMATORY DISEASE
ASSOCIATED WITH HIGH LEVEL OF
INTERLEUKIN 18.
PATIENTS HAVE HIGH LEVELS
CHRONIC ELEVATED LEVELS BUT DO
NOT HAVE MAS ALL THE TIME.
THERE IS NEED FOR TRIGGER.
THIS IS VERY CONSISTENT WITH
ROLE OF IL-18 AS CO-FACTOR FOR
TRIGGERING IMMUNE CELLS,
PARTICULARLY THE PRODUCTION OF
INTERFERON GAMMA.
IL-18 BINDING PROTEIN IS USED IN
TWO CASES.
THIS IS A PATIENT WITH DISEASE
WITH RECURRENT HLH, ONCE IL-18
BINDING PROTEIN TREATMENT WAS
DECREASE IN CRP, IN FERRITIN AND
THE PATIENT DID APPARENTLY VERY
WELL.
THIS IS A PATIENT FROM ALEXI,
REPORTED I GUESS A FEW WEEKS
AGO, WITH SEVERE PERSISTENT
SYSTEMIC JIA, AND INCREASED
RECURRENT AND REFRACTORY EPISODE
OF MAS.
YOU CAN SEE FOLLOWING BEGINNING
OF IL-18 BINDING PROTEIN THERE
WERE MAS, PLATELET COUNTS,
THROMBOCYTOPENIA, IN GENERAL MAS
WAS REDUCED, IMPROVEMENT IN
ABILITY TO WEAN, CLINICAL LOW
DOSE OF GLUCOCORD CAMP --
GLUCOCORTICOID.
WE HAVE A PATIENT, PRESENTLY
ENROLLING PATIENTS, THIS STUDY
HAS BEEN CONCLUDED, NO OTHER
STUDIES TO THE BEST OF MY
KNOWLEDGE ARE BEING PLANNED.
ALEXI ALLUDED TO FAMILIAL HLH,
AND MENTIONED THE ROLE OF
EXAGGERATED PRODUCTION OF
INTERFERON GAMMA IN DRIVING THE
MACROPHAGE ACTIVATION AND
EXPANSION AND CYTOKINE STORM.
WE HAVE LEARNED FROM FAMILIAL
HLH WHERE CYTOTOXICITY LEADS TO
PERMANENT OR PERSISTENT CD8
ACTIVATION WITH LONG LASTING
CONTACT WITH ANTIGEN PRESENTING
CELL.
THERE IS NO DOUBT THAT GENETIC
DEFECT PATHWAY CAN LEAD TO
INCREASED CELL EXPANSION AND
INTERFERON GAMMA PRODUCTION,
PLAYING A ROLE IN A VICIOUS LOOP
IN WHICH MACROPHAGE ACTIVATION
AD EXPANSION LEADS TO
ACTIVATION AND THIS IS DUE IN
MONOGENIC PATIENTS, DUE TO
DEFECT IN CYTOTOXICITY.
HOWEVER, THERE ARE DISEASES,
CERTAINLY CD4 2 DISEASE AS WELL
AS SJIA, DOES INDUCE SAME
VICIOUS CYCLE WITH
OVERPRODUCTION THAT APPARENTLY
MAY BE THE COMMON, AT LEAST IN
MICE.
THERE ARE MODELS OF PRIMARY OR
SECONDARY HLH, DUE TO INFECTION,
ESSENTIALLY, OR MIMIC OF
INFECTION IN MICE WHICH HAVE
BEEN GENETICALLY MODIFIED, OR
WILD TYPE, INCREASED PRODUCTION
OF INTERFERON GAMMA.
THIS WAS TRANSLATED INTO TWO
CLINICAL TRIALS, THIS IS
CONCLUDED IN PRIMARY HLH, LED BY
FRANK AND MICHAEL, AND THIS
TRIAL TO MAKE A LONG STORY SHORT
STARTED AS A SECOND LINE TRIAL
IN PATIENTS WITH PREVIOUSLY
FAILED TRADITIONAL TREATMENT FOR
PRIMARY HLH, LISTED HERE.
THESE PATIENTS TO MAKE A LONG
STORY SHORT DID PRETTY WELL,
AROUND 70% SURVIVAL RATE, HLH
OVERALL SURVIVAL IS POSSIBLY
50%, SURVIVAL CLOSE TO 95%, LED
TO ANOTHER FINDING, YOU'VE HEARD
ABOUT CXCL9 AS A MARKER OF
INTERFERON GAMMA.
SCOTT TOLD YOU ABOUT THIS.
YOU CAN USE IT AS A MARKER OF
NEUTRALIZATION.
LEVEL DROPPED TO NORMAL IN A
MATTER OF A FEW DAYS.
BASED ON THIS DATA, IT IS
APPROVED.
THIS IS THE LABEL OF EMAPALUMAB
IN THE U.S., APPROVED BY THE
FDA.
I THINK YOU SHOULD REFER TO THIS
DOCUMENT WHICH IS THE
MULTI-DISCIPLINARY REVIEW THAT
PROVIDES THE RATIONALE FOR
APPROVAL BY THE FDA WHICH I
THINK IS A VERY GOOD DOCUMENT.
THE PAPER ON THE CLINICAL TRIAL
DATA HAS BEEN SUBMITTED.
A FEW YEARS AGO WE STARTED
LOOKING IN PATIENTS WITH MAS IN
THE COURSE WHICH IS THE
INCREASED DURING MAS BUT NOT
DURING SJIA, THE CORRELATION
WITH FERRITIN, WHICH IS EVIDENT
IN MAS BUT NOT ACTIVE SJIA,
INDEED THE CASE FOR FERRITIN AND
NUMBER OF TRADITIONAL
PARAMETERS, SHOWING CORRELATION
BETWEEN ACTIVATION OF INTERFERON
GAMMA PATHWAY AS REFLECTED BY
CXCL9.
THIS MAY BE TRUE INCREASED, YOU
KNOW, ACTIVATION OF MACROPHAGE
MAY LEAD TO SAME VICIOUS CIRCLE
THAT DOES INVOLVE INTERFERON
GAMMA AND DATA IN MICE SUPPORT
THIS HYPOTHESIS, FOR TRIAL IS
UNDERWAY, ACTUALLY TWIN STUDY
PROTOCOLS UNDERWAY WITH THE
ANTIBODY IN NORTH AMERICA AND
EUROPE, THE PREDICTED -- EACH
ONE OF THE TWO TWIN SHOULD HAVE
RECORDED FIVE PATIENTS IN
EUROPE, SIX ALREADY, I'M GOING
TO PRESENT THE DATA OF THE SIX
PATIENTS RECRUITED IN EUROPE.
SO THE DOSING REGIMEN WITH 6
MILLIGRAMS PER KILOGRAM FIRST
DOSE, 3 PER KILOGRAM EVERY THREE
DAYS, TWICE A WEEK, ADMINISTRATE
FOUR WEEKS, THEN THE PATIENT IS
FOLLOWED UP OVER TIME, TREATMENT
MAY BE SHORTENED, IF THE PATIENT
ACHIEVED COMPLETE RESPONSE.
I WILL SKIP INCLUSION CRITERIA
AND SHOW YOU BASELINE
DEMOGRAPHIC AND BASELINE FEATURE
OF THESE PATIENTS.
FOUR OF THEM HAD CONFIRMED SJIA,
ACCORDING TO CRITERIA, HIGH
DOSE, THREE WERE RECEIVING
CYCLOSPORIN, TWO ANAKINRA.
THIS IS THE MAS ACTIVITY AT
BASE, AT SCREENING, AND THESE
STANDARD LABORATORY THAT YOU CAN
READ SCREENING, AT BASELINE, A
FEW DAYS IN BETWEEN IN WHICH THE
PATIENT IS RECEIVING THIS
TREATMENT.
YOU SEE NO SIGNIFICANT
IMPROVEMENT, NO SIGNIFICANT
CHANGE IN THE VARIABLES.
AND THIS IS THE STORY OF THE
STUDY, SIX PATIENTS ENROLLED,
ALL ACHIEVED COMPLETE RESPONSE,
FIVE OF THE SIX TAPERED
GLUCOCORTICOIDS, ALL ALIVE, NO
RELAPSES.
THIS IS RAPID DECREASE BACK TO
NORMAL, DEMONSTRATING RAPID
NEUTRALIZATION OF INTERFERON
GAMMA.
PRIMARY OUTCOME OF THE STUDY WAS
COMPLETE RESPONSE, DEFINED AS
SOLUTION, NORMALIZATION OF
LABORATORY PARAMETERS RELEVANT
TO MAS AS SHOWN DOWN LEER.
AS I MENTIONED, 6 OUT OF 6
PATIENTS ACHIEVED COMPLETE
RESPONSE AT WEEK 8, 3 OF 6
COMPLETE RESPONSE AT WEEK 4.
MEDIAN VALUES OF 6 PATIENTS OF
CLASSICAL PARAMETERS, FERRITIN,
COUNTS GOING UP, D DIMER GOING
DOWN, MORE THAN THE SINGLE --
MEDIAN LEVEL, IT'S NICE TO SEE
THE TREND OF INDIVIDUAL PATIENT.
WE USE SPIDER PLOTS WHICH THE
LOG -- RATIO BETWEEN THE VALUE
AND THE NORMAL VALUE, VALET
CORDING TO PATIENT EXPRESSED AS
LOG VALUE, AND SO JUST TO MAKE
AN EXAMPLE THIS PATIENT HAS FIVE
HERE, THE LOG VALUE, EACH VALUE
IS 1920 UNITS, THIS IS ONE
PATIENT AT BASELINE, WHAT YOU
SEE AT WEEK 2 IS -- WEEK 4, IS
ESSENTIALLY VALUES IN BETWEEN
ORANGE DOTS AREA THAT SHOWS
LIMITS OF NORMAL.
ESSENTIALLY NORMAL ABNORMALITY
AT DAY 28, WEEK 4, ONE PATIENT,
LONGITUDINALLY, A NUMBER OF
ABNORMALITIES, QUICKLY GOING
INTO THE NORMAL AREA.
THIS IS PATIENT 1 TO 6, DAY
ZERO, DAY 14, DAY 28 28.
YOU SEE THE BLUE AREA
DISAPPEARING SHOWING
NORMALIZATION.
THIS IS TAPERING, THIS IS
PERCENTAGE OF GLUCOCORTICOID
TAPERING IN WEEK 1, ONE SITE OF
SERIOUS EVENTS, CMV
REACTIVATION, ONE FAILURE
UNRELATED DURING DAY 1 OF
TREATMENT, MAS WORSENING.
A FEW INFECTIONS REPORTED, MOST
AFTER A TEST POSITIVE, ONE FOR
ADENO, ONE PARA INFLUENZA, IN
CONCLUSION VERY EFFICIENT,
EFFECTIVE IN PATIENTS, ALL
PATIENTS ACHIEVED COMPLETE
RESPONSE, WE NOW RECORDED 8
PATIENTS, ALL OF THEM ACHIEVED
COMPLETE RESPONSE, THERE ARE
ALSO TWO PATIENTS WHO RECEIVED
EMAPALUMAB, COMPASSIONATE USE,
BOTH ACHIEVED COMPLETE RESPONSE,
SO I THINK THIS DATA SUGGESTS
THAT THIS TREATMENT IS VERY
EFFECTIVE.
IN SUMMARY, I THINK IL-1 AND
IL-6 TARGETING DOES NOT OFFER
COMPLETE PROTECTION FROM MAS IN
SJIA.
THERE ARE CASES WITH INHIBITION
IN SOME FORMS, RATIONALE FOR
INHIBITING, THE MAJOR MEDIATOR
IN SEVERAL DISORDERS IN THE
CONTEXT OF
THE HLH/MAS SPECTRUM
DISORDER.
WE'VE TREATED PATIENTS, THE 42
PATIENTS RESPONDED TO INTERFERON
GAMMA.
I WANT TO PEOPLE IN THE STUDY,
TOGETHER WITH THE TEAM LEADING
THE DEVELOPMENT OF EMAPALUMAB.
THANK YOU VERY MUCH.