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Investigational Pruritus Agents
Looking Toward the Future: Investigational PBC Pruritus Agents

Released: May 24, 2024

Expiration: May 23, 2025

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Key Takeaways
  • PBC-related pruritus is common, does not respond well to historical treatments, and can negatively affect patients’ quality of life.
  • Investigational IBAT inhibitors, PPAR agonists, and KOR agonists represent promising new treatments for PBC-related pruritus.

Pruritus due to cholestasis is a common and vexing symptom of primary biliary cholangitis (PBC) that can be difficult to eradicate. PBC-related pruritus can occur during any stage of PBC, independent of time since diagnosis, degree of liver disease, and medical treatment.

Some medications that were historically used to ameliorate cholestatic itch include antihistamines, bile acid binding resins, opioid antagonists (eg, naltrexone), rifampin, sertraline, and gabapentin. However, their efficacy and tolerability are limited, leaving an unmet need for highly effective and well-tolerated pruritus treatments.

Fortunately, there are several new classes of agents being studied for PBC-related pruritus, including ileal bile acid transport (IBAT) inhibitors, which are furthest along in the development pipeline, peroxisome proliferator-activated receptor (PPAR) agonists, and kappa opioid receptor (KOR) agonists.

IBAT Inhibitors
IBAT inhibitors are a relatively new class of drug that reduce bile acid levels by blocking their reabsorption in the gut. Within the last few years, 2 drugs in this class, maralixibat and odevixibat, have been FDA approved for itch in patients with pediatric cholestatic diseases. Meanwhile, phase II and III clinical trials of 2 other IBAT inhibitors— volixibat and linerixibat, respectively—for use in PBC pruritus in adults are ongoing.

PPAR Agonists
Broadly, PPARs are a family of 3 nuclear hormone receptor isotypes, including PPAR-α, PPAR-γ, and PPAR-β/δ. PPARs play a key role in regulating transcription of genes involved in energy homeostasis and metabolic function, making them crucial targets for treatment of PBC. Each PPAR isotype performs a different function in metabolic regulation, so the different types of PPAR agonists have different therapeutic effects.

Fibrates
Bezafibrate is a fibrate that acts as a weak pan-PPAR agonist. It demonstrated positive effects in reducing PBC-related pruritus in clinical trials. In a phase III study of bezafibrate in people with primary or secondary sclerosing cholangitis or PBC, bezafibrate was superior to placebo in reducing moderate to severe itching in people with PBC as measured by a visual analog scale. It is thought that during cholestasis, increased serum autotaxin activity increases lysophosphatidic acid, which activates sensory nerve endings that create the itching sensation. Due to its anti-inflammatory, anticholestatic, and antifibrotic properties, it is hypothesized that bezafibrate alleviates PBC-related itch by mitigating hepatobiliary injury. Although bezafibrate has been used in Japan and Europe for many years, it is currently available in the United States only under an orphan drug designation as a fixed-dose combination product with obeticholic acid.

Nonfibrates
Seladelpar (PPARδ agonist) and elafibrinor (dual PPARα/δ agonist) are 2 investigational nonfibrate PPAR agonists being studied for their use in PBC-related pruritus.  

In a double-blind, placebo-controlled, randomized phase III study of seladelpar vs placebo in patients with PBC, notable improvements in pruritus (measured with a numerical rating score) were observed early in the cohort receiving seladelpar. After 6 months of treatment, itch scores decreased dramatically from baseline in patients receiving seladelpar, compared to patients receiving placebo. It is thought that seladelpar relieves PBC-related itch by selectively activating PPARδ, which releases fibroblast growth factor 21 from hepatocytes, thereby reducing accumulation of bile acids by inhibiting expression of cholesterol 7α-hydroxylase, the primary enzyme involved in bile acid synthesis.

Similarly, in a double-blind, placebo-controlled, randomized phase III study of elafibranor vs placebo in patients with PBC, patients who received elafibranor demonstrated a numerical improvement in their Worst Itch Numeric Rating Scale, although this improvement was not statistically significantly different from placebo. However, elafibranor was associated with statistically significant improvement in biochemical indicators of cholestasis, vs placebo. Like seladelpar, elafibrinor is thought to reduce PBC-related itch by modulating bile acid metabolism and reducing inflammation.

As of the writing of this commentary, seladelpar and elafibranor are awaiting FDA approval for use in PBC and PBC-related pruritus.

KOR Agonists
Lastly, KOR agonists are hypothesized to improve pruritus by binding to KOR on keratinocytes and cutaneous and/or central itch neurons to inhibit itch signals. Difelikefalin and nalbuphine are KOR agonists that have been studied and used in chronic kidney disease–related pruritus. Both are being studied for their use in PBC-related pruritus. Nalfurafine hydrochloride is a KOR approved for chronic pruritus in Japan.

Conclusions
PBC-related pruritus is an important facet of PBC that deserves attention and pharmacotherapy to ameliorate its effects. Although there is currently an unmet need for effective treatments, there are several new, promising classes of agents to treat itch that will likely see FDA approval for use in the near future, improving our armamentarium for PBC-related itch.

Your Thoughts?
Which new PBC-related pruritus therapies are you most excited about? Leave a comment to join the discussion!