Eli Lilly And Baricitinib In PBC: What's The Story?

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About: Eli Lilly and Company (LLY), Includes: CBAY, ICPT
by: First Genesis Consulting
Summary

Liver Therapy Forum weekly digest provides an overview of what's happening in liver diseases in 2019. This week focuses on Eli Lilly.

Baricitinib is a specific inhibitor of the Janus-associated kinases signalling molecules.

Baricitinib is currently approved for therapeutic use in patients with rheumatoid arthritis and in clinical development for autoimmune diseases, psoriasis, lupus, and dermatitis.

In PBC, baricitinib could potentially limit immune system activation that is believed to trigger PBC. I elaborate in text.

Market Assessment

Eli Lilly (LLY) is a large-cap ($102.6B) biopharma known for innovative and diverse therapeutics for diseases affecting the endocrine system, immune system, and the brain. Its oncology products are broad with therapeutics for cancers affecting non-small cell lung, colon, head and neck, pancreas, breast, ovary, bladder, and gut.

Developing liver therapeutics does not appear to be of significant clinical interest to Eli Lilly. As a matter of fact, Eli Lilly does not have a clinical program for liver diseases. For this reason, the initiation of a Phase 2 study of baricitinib (formerly LY3009104) in cholestatic liver disease, PBC was a surprise. The 12 weeks Phase 2 study will evaluate the safety and efficacy of baricitinib in PBC patients who are unresponsive or unable to take UDCA, the current standard of care. In Q1/2019, Eli Lilly launched:

A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study Evaluating the Efficacy and Safety of Baricitinib (LY3009104) in Patients With Primary Biliary Cholangitis Who Have an Inadequate Response or Are Intolerant to UDCA.

In my opinion, when discussing investigative drug candidates for cholestatic liver diseases, baricitinib is not a classical drug candidate based on the current clinical trend. Most may anticipate FXR, PPAR agonists, and NOX-1/4 inhibitors as likely investigative drug candidates for PBC. This begs the question of why would Eli Lilly clinically assess the therapeutic potential of baricitinib in PBC. The answer lies in the presumed mechanism of baricitinib in autoimmune diseases.

Why Baricitinib In PBC?

Baricitinib is an orally available, specific inhibitor Janus-associated kinases (mainly JAK1 and JAK2) that is used to treat moderate-to-severe rheumatoid arthritis. The Janus kinases signalling pathways have key roles in immune activation and hematopoiesis. The immunomodulatory effects of baricitinib may be the clinical rationale for its evaluation in several autoimmune diseases including systemic lupus erythematosus, dermatitis, and alopecia. Baricitinib, marketed as Olumiant, was approved for rheumatoid arthritis in the United States in 2018.

PBC is a rare, autoimmune, cholestatic, progressive chronic liver disease characterized by both immune-mediated destruction of intrahepatic bile ducts by T cells that leads to bile leakage and local toxic liver injury due to bile salt toxicity. The trigger for immune system activation is unknown. PBC may advance to biliary fibrosis and ultimately biliary cirrhosis.

I have written several articles on PBC and PSC. I can say confidently that the focus of most investigative drug candidates is not on the role of immune system in PBC. Meaning that the trigger for immune system activation in PBC is unknown or undetermined.

The clinical interest for LLY in PBC may be evaluating the effect of baricitinib on the immune component of PBC. This is important for several reasons: (i) we could get a clinical answer on the clinical impact of immune system in the pathophysiology of PBC (ii) is dampening the activation of the immune system important in halting or reversing PBC progression? (iii) is immune activation in PBC an ongoing immunological event or a trigger event?

Baricitinib therapy has been associated with mild serum liver enzyme elevations. For this reason, patients on baricitinib are monitored for serum aminotransferase levels. Top-line Phase 2 data readout of baricitinib is expected in late Q4/2020.

Financials

At the end of Q1/2019, LLY reported revenue of $5B and net income of $4.2B. CEO David A. Ricks elaborates:

We delivered volume-based revenue growth despite the loss of patent exclusivity for several products, increased our investments in new brands, and further funded our pipeline of potential new medicines. We also completed two transformative transactions in the first quarter, the disposition of our remaining ownership in Elanco Animal Health and the acquisition of Loxo Oncology, which adds a potential 2020 launch and strengthens our oncology pipeline of precision medicines for patients with difficult to treat cancers.

Josh Smiley, CFO, on the financials for Q1/2019:

While income declined this quarter versus Q1/2018 we made important progress on several fronts that will drive future growth, as demonstrated by growing revenue despite significant headwinds from the loss of exclusivity of Cialis in the U.S., investing behind key growth brands, such as Emgality, Verzenio, Taltz, Jardiance and Trulicity, and advancing several pipeline assets to the next phase of development, including multiple regulatory submissions.

Market Outlook

PBC as most diseases with an immune trigger is incompletely defined pathophysiologically. However, clinical progress has been made recently with the approval of Obeticholic acid by Intercept (ICPT). Equally important, several drug candidates are in clinical trials with seladelpar by CymaBay (CBAY) considered the frontrunner and, potentially, an improved second-line therapeutics based on the 52-week Phase 2b PBC clinical data.

LLY via baricitinib clinical development provides a unique clinical approach to assessing and understanding the role of immune system in PBC pathophysiology. No one has succinctly ascertained if suppressing the dysregulated immune system in PBC could be important in maintaining the therapeutics benefits afforded by other pharmacological targets, approved and in development.

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