Rare diseases affect fewer than 1 in 2000 people. Each one affects only a small number of patients. Yet, there are over 7000 rare diseases. And, there are no treatments for 95 percent of them. Thus, many patients suffer from these diseases. The treatments for rare diseases are often referred to as “orphan drugs.”
Orphan drug developers face distinct challenges with rare diseases including:
- Heterogeneity in disease progress and treatment outcomes
- Few patients to run new studies
- Uncertain appropriate durations of treatment
- Sparse existing data available from limited populations
Modeling and simulation methods—also known as model-based drug development—include both top-down (empirical) and bottom-up (mechanistic) models. These methods use sparse data from small populations to inform dosing and trial designs. For example, population PK/PD models can test the influence of factors such as age, weight, and disease status on drug exposure and response. Likewise, combining drug and disease models can help distinguish between treatment effects on symptoms vs changes in disease processes. Model based approaches can support accelerated approval pathways that get treatments to patients faster.
Learning from one indication to another
In some cases, information gained developing a drug for one indication can be leveraged to inform its approval for a different indication. PNH (paroxysmal nocturnal hemoglobinuria) is a rare, progressive, and life-threatening disease. It is characterized by rampant destruction of red blood cells (hemolysis) and excessive blood clotting. Likewise, aHUS (atypical hemolytic uremic syndrome) is an ultra-rare genetic disease that causes abnormal blood clots to form in small blood vessels throughout the body. The sequelae of aHUS include kidney failure, damage to other organs, and premature death. There were no FDA-approved treatments for this rare disease.
Both aHUS and PNH are caused by caused by chronic, uncontrolled activation of the complement system. During activation of the complement system, the terminal protein C5 is cleaved to C5a and C5b. C5a and C5b have been implicated in causing the terminal complement-mediated events that are characteristic of both aHUS and PNH. Eculizumab is a humanized monoclonal antibody (mAb) that binds C5, thereby inhibiting its cleavage. In 2007, Certara Strategic Consulting developed a PK/PD model that supported the approval of this mAb for treating PNH based on evidence of effectiveness from clinical studies.
Making use of all available data
Diagnosed in only a few thousand patients each year, aHUS proved extremely difficult to study in the clinic due to very low trial recruitment. Though very few patients were available for study, some additional data were available from PNH clinical studies. The drug sponsor needed to optimize dosing of eculizumab for both adult and pediatric aHUS patients, making best use of all available data.
Crafting the model-based development strategy
The sponsor again turned to our scientific consultants. As the sponsor’s resource for model-based development strategy for PNH, our scientific experts were already familiar with the drug’s pharmacokinetics and safety profile to date. Their starting point was a population PK model that had been previously constructed in adult patients with PNH. This model was customized and used to develop optimal dosing strategies for adult and pediatric aHUS patients.
Comparing the case of adults with PNH to pediatric aHUS, it became apparent that children may require lower doses. The PK/PD relationship in PNH was leveraged to measure the drug’s exposure and inform pediatric dosing for aHUS. Knowledge about eculizumab’s mechanism of action for PNH also suggested that optimal binding to the pharmacological target (C5) should translate into a clinical benefit.
Identification of the therapeutic dosing window for a mAb in pediatric patients with a rare disease involved several steps. First, to ensure patient safety, the upper exposure limit needed to be determined. As a safeguard against toxicity, the upper exposure limit was capped at what had been previously observed in adults.
To ensure efficacy, the minimum drug exposure also had to be determined. Using the predicted concentration of the soluble target and the binding characteristics of the mAb to its target, a minimum concentration threshold was set to obtain close to full inhibition of the target. Then, trial simulations using a population PK model were performed to determine which doses would optimize the probability of obtaining the mAb within the window of target engagement in neonates, children, adolescents, and adult patients.
The clinical program for aHUS involved two Phase II studies and a retrospective observational study. A total of 57 patients with aHUS participated in these studies (35 adult, 22 pediatric patients). Two different biomarkers were used to assess the efficacy of treatment. The proximal biomarker, free C5, showed complete suppression upon treatment with the mAb. Likewise, the mAb caused full inhibition of hemolytic activity (the distal biomarker). The primary endpoint indicated that the response to interventions across all age groups was very high.
Crossing the finish line
Using the model-based and observed efficacy and safety profiles, the consultants were able to recommend dosing regimens for adult and pediatric aHUS patients. Patients treated with the mAb experienced several benefits including improvement in platelet counts and other blood parameters and better kidney function, even eliminating the requirement for plasmapheresis in some patients. Soliris® (eculizumab) received FDA approval to treat aHUS adult and pediatric patients.
All information presented derive from public source materials.
Learn how Certara helped a sponsor gain approval for their drug
My colleagues wrote up another orphan drug project as a case study, “A PK Mystery Solved” for Applied Clinical Trials. I hope that you’ll read it and let me know what you think!
Are you working on an orphan drug for a rare disease? What are some of the challenges that you are facing? Let us know in the comments!