350 million patients worldwide suffer from 7,000 rare diseases, yet only 300 of these diseases have approved treatments. This gap, impacting 95% of rare disease patients, represents a huge unmet medical need. Developing drugs for rare diseases poses a range of clinical, regulatory and commercial challenges. The small number of patients are difficult to identify and recruit for clinical trials. Many orphan diseases are genetically based, and oftentimes, these patients have complex phenotypes that react very differently to proposed treatment protocols. The diseases may be poorly understood, making it difficult to set clinical endpoints, biomarkers or outcome measures. Patients may also fall into an ethically sensitive population, ranging from neonates and pediatrics to people with co-morbidities. Modeling and simulation uses disparate information to create a cohesive picture of the dose-concentration-effect relationship that informs development decisions. In this blog post, I’ll discuss a recent example of how pharmacokinetic modeling helped support the approval of a new drug for a rare disease.
Developing a new treatment for a chronic rare liver disease
Primary biliary cholangitis (PBC) is a chronic, rare disease characterized by cholestasis—the impaired flow of bile from the liver.1 The resulting increased bile acid concentrations cause cellular injury. Untreated PBC can lead to liver failure and death. The only currently approved treatment for PBC was ursodeoxycholic acid (UDCA). However, not all patients respond to UDCA.
Intercept Pharmaceuticals—an emerging global biopharmaceutical company—sought to develop obeticholic acid (OCA) as an alternative treatment for PBC. OCA is a semi-synthetic analogue of the primary bile acid chenodeoxycholic acid with similar pharmacokinetic (PK) properties.2 Like other bile salts, OCA is metabolized via conjugation to glycine acid and taurine.
OCA is a selective and potent farnesoid X receptor (FXR) agonist. 2 FXR activation decreases the concentration of bile acids in the liver to reduce cellular injury. FGF-19 was used as a biomarker for OCA pharmacological activity.
Understanding the relationship between systemic and hepatic exposure of OCA in PBC patients
Because liver damage is a consequence of disease progression in PBC patients, the Intercept team needed to develop a dosing strategy for OCA in PBC patients with and without hepatic impairment. They conducted a small clinical study wherein a single dose of OCA was given to healthy volunteers and patients with mild, moderate, and severe hepatic impairment and intensive PK sampling was performed for 24 hours.2
Study results revealed that systemic OCA concentrations increased with worsening hepatic impairment.2 Yet, plasma FGF-19 levels were increased with the administration of OCA for subjects with and without hepatic impairment suggesting similar activation of FXR. Clearly, systemic exposure of OCA failed to correspond to its pharmacological effects in the liver. Developing a robust dosing strategy required understanding the relationship between systemic and hepatic exposure of OCA in patients with and without hepatic impairment.
My colleagues and I used our population PK/PD modeling software, Phoenix NLME, to perform physiologically-based pharmacokinetic (PBPK) modeling and simulations.1,2 The PBPK model was based on a previously reported model for chenodeoxycholic acid.3 The model for OCA was calibrated using the plasma concentration-time profiles of OCA, glyco-OCA and tauro-OCA in healthy volunteers who received a single dose of OCA. Then, the model was recalibrated for patients with hepatic impairment taking a single dose of OCA. Hepatic impairment involves the following mechanisms which were incorporated into the model: decreased hepatic update of OCA and its metabolites, portal systemic shunting, decreased functional liver volume, and increased taurine conjugation.
The physiologic PK model was validated when its predicted OCA-plasma exposures were found to be comparable to observed exposures in healthy volunteers and patients with hepatic impairment.2 Both the model and clinical data showed a significant increase in systemic exposure of OCA in patients with hepatic impairment. Yet, liver exposure of OCA was predicted to only increase modestly in patients with mild, moderate, and severe hepatic impairment compared to healthy volunteers. The modeling results and clinical trial data supported the safety and efficacy of the OCA dosing strategy. Dosing reductions were only required for PBC patients with moderate and severe hepatic impairment.1, 4
Gaining FDA approval
In May 2016, the FDA approved Ocaliva (obeticholic acid) for the treatment of PBC in combination with UDCA in adults who show inadequate response to UDCA alone or as a single therapy in adults who cannot tolerate UDCA.5 It is the first new drug for PBC in almost 20 years.
Because of Ocaliva’s potential to address an unmet medical need, the FDA granted it fast track designation.5 Ocaliva also received orphan drug designation which entitles its sponsor to tax credits, user fee waivers, and market exclusivity rights. The case of Ocaliva demonstrates how sponsors can accelerate their drug approvals through leveraging pharmacometric modeling.
 US Food and Drug Administration. Clinical Pharmacology Review—Ocaliva http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207999Orig1s000ClinPharmR.pdf
 Edwards J, LaCerte C, Peyret T, Gosselin NH, Marier JF, Hofmann AF, and Shapiro D. Understanding the Relationship between Systemic and Hepatic Exposure of Obeticholic Acid for the Treatment of Liver Disease in Patients with Cirrhosis. Presented at the American Association for the Study of Liver Diseases Liver Meeting. November 13-17, 2015, San Francisco, CA.
 Molino G, Hofmann AF, Cravetto C, Belforte G, Bona B. Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic model. Eur J Clin Invest. 1986;16(5):397-414
 US Food and Drug Administration. Full Prescribing Information—Ocaliva http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207999s000lbl.pd
 US Food and Drug Administration. FDA News Release: FDA approves Ocaliva for rare, chronic liver disease. 31 May 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503964.htm
All information presented derive from public source materials.
Learn more about orphan drug development
For another example of how modeling and simulation can inform orphan drug development, please read this case study on a promising new drug formulation for a very rare disease that presented a mystery in clinical development.