Biomarkers, Pruritus Management, and Real-World Evidence​ in PBC

For CME Information & Credit Visit: https://www.iridiumce.com/leveling-up-pbc-podcast-2

Summary:
This conversation delves into the management of Primary Biliary Cholangitis (PBC), focusing on the role of biomarkers in treatment, the impact of pruritus on patients' quality of life, and the latest strategies for managing this condition. The discussion highlights the importance of effective monitoring and treatment options, as well as the need for new therapies to address the challenges faced by patients with PBC.

Takeaways:

• Biomarkers are crucial for monitoring PBC progression.
• Alkaline phosphatase and bilirubin are key indicators.
• UDCA is the first-line treatment for PBC.
• Pruritus affects up to 75% of PBC patients.
• Antihistamines are ineffective for PBC-related pruritus.
• Colestyramine is the first-line therapy for pruritus.
• New therapies for pruritus are in development.
• Patient quality of life is significantly impacted by pruritus.
• Real-world evidence shows under-treatment of pruritus.
• Effective management strategies are essential for patient adherence.

Sound Bites:

• "Biomarkers play a key role in the management of PBC."
• "Pruritus significantly impacts the lives of patients with PBC."
• "Antihistamines are not effective for PBC-related pruritus."

Clinical Resource Tool: https://www.iridiumce.com/leveling-up-pbc-management-resource 

Episode Transcript

Dr.Atoosa Rabbie (00:00):
Welcome to Lavelinga Primary Biliary
Cholangitis, optimizingbiomarker surveillance
addressing PBC related pruritusand application of real world
evidence. My name is Doctor.Atoosa Rabbie. I'm joined today
by 2 of my colleagues, Doctor.Hannah Blaney, MDMPH, Transplant

(00:22):
Hepatology Fellow from MathStarHealth Georgetown University, as
well as, Doctor.
Anahita Rabbie, MD MHS, who is aTransplant Hepatology, from
Digestive Disease Section, YaleSchool of Medicine. For full,
relevant financial disclosureinformation, please see the,
iridium .com landing page forthis activity. This is supported

(00:44):
by an independent educationalgrant from Intercept
Pharmaceutical. We would like tothank them for their support for
this initiative. The learningobjective for today's program
are assess the role of biomarkermonitoring in PBC, recognize the
role of pharmacologic and nonpharmacologic management
strategy for PBC relatedpruritus.

(01:05):
Hannah, can you give us a briefsummary of the role of
biomarkers in the management of,PBC? What are the most common
biomarkers that are used?

Dr. Hannah Blaney (01:15):
Biomarkers play a key role in the
management of PBC. So we look atour liver associated enzymes
primarily. We know that alkalinephosphatase and bilirubin levels
are associated with deep diseaseprogression with the ultimate
goal of being a significantreduction, if not normalization,
of these two indices withtreatment. We specifically use
these markers to assess theresponse to UDCA and determine

(01:39):
eligibility for second linetherapies. Transaminases should
also be followed.
While these can be mildlyelevated in adequately treated
PBC, if they are elevated above5 times the upper limit of
normal, this should prompt theclinician to consider a
diagnosis of PBC autoimmunehepatitis overlap syndrome.

(02:01):
Albumin should also be assessedalong with platelet count as
these may be signs, indicatingthe development of cirrhosis and
portal hypertension. Sometimes,we will have a patient with a
negative AMA, however, anincreased alkaline phosphatase
level. These patients shouldhave their biomarkers monitored

(02:21):
at least yearly. In patientswhere we have a high suspicion
clinically of PBC, we canconsider ordering PBC specific
AMA serology including anti GP210 and anti SP 100.
We should order these ifavailable, or we could consider
a liver biopsy to house help usassist with a diagnosis of AMA

(02:44):
positive AMA negative PBC. And,AMA negative PBC, really has a
similar disease course as wellas a response to treatment as,
what we see with, AMA positivePBC. In patients with AMA
positivity, however, with normalliver associated enzymes, these

(03:05):
patients may have an increasedrisk of developing PBC. There's
one study that showed that about16% of these patients progress
to PBC within 5 years. As such,these patients are at high risk
of developing PBC, and theyshould be followed more closely
with assessment of liverassociated enzymes every 6 to 12
months.
Anahita, how does biomarkermonitoring fit into the new

(03:28):
treatment algorithms for PBC?

Dr. Anahita Rabbie (03:32):
That's a great question. So I'm gonna go
over the new treatment algorithmand, we'll kind of put where
biomarkers come in. Once thediagnosis of PBC is confirmed,
you first wanna, stage thedegree of fibrosis in these
patients. And it is best done bytransient elastography or, an MR

(03:54):
elastography. Basically, youstart them on treatment with
UDCA.
It's the first line treatment.And it's usually it's weight
based, 13 to 15 milligram perkilogram per day. And around at
the same time, you wanna stageyour fibrosis. So you either get
transient elastography or MRelastography. If, the transient

(04:17):
elastography is less than 10 orthe MRE is less than 4
kilopascal, that means that thepatient does not have advanced
fibrosis.
So you have a little bit of moretime to monitor the patient and
see if they're responding toUDCA. However, if the patient
has evidence of advancedfibrosis and, you know, with the

(04:39):
transient osteography being 10or above, you wanna, go back and
make sure that they'reresponding sooner. So basically
at 6 months, you wanna evaluatetreatment response. And, the
treatment response would be at 6months. The alkaline phosphodies
being less than 1.9 upper limitof normal, plus the, the

(05:02):
bilirubin being less than upperlimit of normal.
And at 12 months, it would bealkaline phosphodies being less
than 1.5 upper limit of normal,plus bilirubin being less than,
upper limit of normal. So ifthey are responding based on
these criteria, you continue thesame treatment and you monitor

(05:23):
bilirubin and alkalinephosphatase every 3 to 6 months.
However, if the patient is notresponding to this treatment, or
for whatever reason the patientis intolerant of UDCA, you wanna
think about second agents. Onepart of the algorithm that comes
into play here is if the patienthas evidence of clinically

(05:45):
significant portal hypertensionor has decompensations, you
wanna consider a referral forliver transplant early on. So
going into, basically, secondline treatments, you can start
the patient on obeticholic acid.
Usually, it started at 5milligram once a day, and you

(06:05):
can increase it to 10 milligramafter 3 months if the patient is
able to tolerate the dose. Oryou can consider off label use
of Fenofibrate. Usually, itstarted at a low dose of, 45
milligram per day, and it can betitrated up again based on
tolerance. And, you wanna assessalkaline phosphatase and

(06:29):
bilirubin at, 3 to 6 months tosee if they are responding. And
response criteria would bealkaline phosphatase being less
than 1.5 upper limit of normaland bilirubin being less than
upper limit of normal.
However, if they are notresponding to this treatment or
specifically in the case ofobeticholic acid, patient is

(06:50):
intolerant because it can causea lot of pruritus, you wanna
consider another second linetherapy. Or, so basically, you
can switch or you can considerdoing a triple therapy,
basically, having the patienton, UDCA, obeticholic acid, and
phenofibrate. The you mightrecognize that, elafibrinole is

(07:15):
not included in this algorithm.This was very recently approved
about a month ago. And I'm surein, in the future, it will make
its way to the algorithm.
But, currently, it's kind of hotoff the press, so it's still not
included in this algorithm as asecond line therapy.

Dr.Atoosa Rabbie (07:35):
So now let's talk, about PBC related
pruritus. This obviously,significantly impacts, the lives
of patients with PBC. To managethe symptom effectively not only
means improved patient comfort,but also, it enhances patients'
overall treatment adherence andquality of life. Can you give us

(07:57):
an overview of what kind ofimpact can pruritus have on
patients' quality of life andwhat it would mean, for
treatment adherence? Pruritus isone of

Dr. Hannah Blaney (08:08):
the most common symptoms of PBC. Up to 75
per se percent of patients withPBC will experience pruritus. So
pruritus has been shown tonegatively impact quality of
life, including contributing tofatigue, depression, sleep
disturbance, as well as sociallife interference. It can be
really frustrating for patientsand then providers alike, for

(08:29):
for treating these patients. So,unfortunately, ursa deoxycholic
acid or UDCA does not improve,pruritus and in rare incidences
can actually worsen pruritus.
Our second line agent of,obeticholic acid, while it's a
great medication for thetreatment of PBC, it can
actually induce or intensifypruritus in about 40% of

(08:53):
patients. There are some of thePPAR agonists, the newer
medications that are beingstudied, including elafarbanor
as well as the fibrates. Andthen there's some other agents
that are currently under studythat do seem to significantly
reduce cholestatic pruritus.Hopefully, we'll have some new
options, for these patients inthe the near future.

Dr.Atoosa Rabbie (09:14):
Thank you, Hannah. Anahita, can you provide
us with, some strategy formanaging pruritus, both
pharmacological andnonpharmacological approaches,
specifically to manage dosedependence, pruritus in
patients, who are treated withalcholic acid, and, how you

(09:36):
recommend, that the physiciansadjust the dose, based on the,
the patient's pruritus symptoms?Good question. So in terms of
the pruritus, you know, one ofthe first line, medications that
we use is colostiramine, and, itcan be helpful in many

Dr. Anahita Rabbie (09:56):
patients. Other medications that we use
that are generally off labelinclude rifampin, naltrexone,
sertraline, and bisofibrate.There are also a
nonpharmacological treatmentsuch as skin care, phototherapy,
and severe cases we can eventhink about albumin dialysis,

(10:17):
plasmapheresis, and biliarydrainage. In terms of the
medication management,specifically, obeticholic acid
is important because this is amedication that can result in,
severe pruritus in, manypatients treated with this and
one of the main reasons fordiscontinuation of treatment. So

(10:39):
basically, if the patient hasmoderate, pruritus and, you are
at 5 milligram dose, youbasically, wanna, you know,
either still you could consideroptite rating or stating staying

(11:00):
at 5 milligram.
If you're already at 10milligram, you stay at 10
milligram. And once the patienthas severe pruritus, if you're
at 5 milligram, you can decreaseit down to 5 milligram every
other day or pause treatmenttemporarily for 2 weeks. And
after that, again, start withthe lower dose of 5 milligram.

(11:22):
If you have severe pruritus,you're at 10 milligram. You can
decrease it to 5 milligram.
So, basically, by adjusting ortrying to reduce the dose, you
see if you can, have the patientbe able to continue the
treatment rather than completelystopping it.

Dr.Atoosa Rabbie (11:40):
Thank you. So now let's, talk about the real
world evidence about managementof, pruritus in PBC. Can you
highlight some of the keystudies that have been done?
And, what are some highlights ofthe promising treatments, for,
pruritus, specifically

Dr. Hannah Blaney (11:58):
in PBC patients? The target PBC trial
is a large real world US cohort,that highlights the pervasive
impact of pruritus in patientswith PBC as well as, some of the
shortcomings of the medicalcommunity's current response.
So, it's a 2023 study thatincluded 211 patients with PBC,

(12:20):
with the overall prevalence ofarthritis, pretty high in this
population with 81% ofrespondents reporting itch of
any degree and 37% reporting anitch that was at least severe
enough to be deemed clinicallysignificant using the PBC 40
scoring, which is a patientderived validated questionnaire.

(12:41):
So patients with clinicallysignificant pruritus were more
likely to receive treatmentversus patients with just a mild
itch with 51% of patients withclinically significant itch
receiving treatment versus 28%of those with mild itch. This
shows us that only half ofpatients with PBC, that with

(13:02):
clinically significant prurituswere treated.
And it really suggests theundertreatment of patients with
PBC related pruritus. Of thosereceiving treatment for for
pruritus, antihistamines werecommonly prescribed for both
mild, which was 73% of allpatients as well as clinically
significant, including 66% ofthese patients, followed by

(13:26):
acid, bile acid binding resins,such as cholestyramine. So as
the pruritus of PBC is notmediated by histamine,
antihistamine therapy is reallynot, it is not effective in
these patients. Furthermore,antihistamines may exacerbate
symptoms like fatigue as well assicker symptoms such as dry

(13:48):
mouth. So these data from thestudy revealed that clinicians
were not complying to guidelinerecommendations for the
management of pruritus.
Cholestyramine is our first linetherapy for pruritus, as
recommended by both ASLD, andEASL. And really it was not used
at a high, percentage in thesepatients. The undertreatment of

(14:08):
pruritus and PBC, could be dueto several reasons, including a
lack of effective currenttreatment options, tolerate
tolerability issues, as well asdifficulty in dosing as well as
the appropriate use of bile acidresins. It can be challenging
for patients to time the dosewith their other medications and
with eating as well as a lack ofFDA approved treatments. In

(14:30):
another study involving 225patients, Pruritus in PBC was
under recorded in patientmedical records.
Pruritus of any severity wasself reported by up to 90% of
patients with PBC. However, it,only in 31% of these patients,
had a recent documented pruritusin their medical record. As

(14:55):
such, there's a big mismatch inpatient reported measures and
medical records suggesting thatpruritus is really under
recorded in medical records. Thehigh percentage of patients
reporting pruritus despiteavailable antipyretic treatment
suggests that pruritus continuesto be undertreated and
undermanaged. This should remindus to always ask, document, and

(15:19):
treat symptoms associated withPBC like pruritus at every
patient visit.
There is still a need for newertherapies to address the
debilitating impact of pruritusin patients with PBC with some
exciting possible therapies inthe pipeline. First, we have
linarixibat, which is a ilealbile acid transporter,

(15:43):
inhibitor, which is under studyfor cholestatic pruritus, in a
GLIMR study. And the GLIMRstudy, which was a phase 2b
trial for itching, there was asignificant decrease in itch in
the per protocol population.This drug is currently in the
phase 3 trial. Besafibrate,which is not available in the

(16:03):
United States, is a pan PPARagonist.
This medication was shown tosignificantly decrease pruritus
in the phase 3 trial. Anothermedication, seladelpar with,
which is a PPAR delta agonistdemonstrated a significant
reduction in pruritus frombaseline in a recent phase 3

(16:24):
clinical trial. Elafrivenor,which was recently approved in
June of 2024 by the FDA fortreatment of PBC, is an alpha
and delta PPAR agonist.Ellafibrinor also had a
reduction in moderate to severepruritus at 52 weeks, from
baseline according to scoresfrom the p PBC 40 questionnaire

(16:47):
as well as the, 5 d itch scale.

Dr.Atoosa Rabbie (16:50):
Thank you. That was great. If I may
summarize, this session, we relyheavily on biomarkers to monitor
progression of primary biliarycholangitis and to assess the
effectiveness of treatment.Unfortunately, pruritus is
common, very, troublesome, andcan significantly impact
patients' quality of life, butoften doesn't receive adequate

(17:14):
attention in treatment plan.This really underscores that we
need newer, more effectivetreatments and, including dose
dependent management strategies.
We have reached the end of theprogram. I wanna thank all, my
colleagues and faculty for this,engaging discussion. We would
also like to thank Intercept fortheir support of the program. Be

(17:38):
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