Proof-of-Concept Studies in Humans
In early clinical development, translational medicine strategies emphasize designing clinical trials aimed at obtaining rapid POC in humans. The goal is to enable companies to rapidly and cost-effectively advance drugs that achieve POC into Phase II trials, and to eliminate drugs that do not achieve POC. Biomarkers are key to the design of POC clinical trials.
For example, Novartis has adopted a drug discovery and development model based on biochemical pathways. In many cases, rare Mendelianly inherited familial diseases are caused by mutated genes that disrupt pathways that are also involved in more common, sporadic diseases. Novartis researchers design small POC clinical trials in patients with the genetic disease. Upon achieving POC, the drug may also be tested in patients with complex, sporadic diseases that involve the same pathway.
The first drug that Novartis has been developing using this strategy is the mAb drug Ilaris (canakinumab), which specifically targets the proinflammatory cytokine interleukin-1b (IL-1β). The company conducted its initial POC trial in three patients with Muckle-Wells syndrome. This is a rare autosomal dominant disease caused by a mutation in a gene involved in processing IL-1β.
Macrophages from Muckle-Wells patients constitutively secrete this cytokine, resulting in chronic inflammatory symptoms including skin rash, periodic arthritis, deafness, and chronic fatigue. When the patients were treated with Ilaris, their rashes, as well as biochemical markers of inflammation, resolved in several days, according to the company.
Novartis went on to test the drug further in patients with cryopyrin-associated periodic syndromes (CAPS), a group of rare inherited auto-inflammatory conditions that includes Muckle-Wells syndrome as well as several other conditions, all of which result in overproduction of IL-1b. In June 2009, the FDA approved Ilaris for treatment of CAPS, which affects approximately 7,000 patients worldwide.
Novartis is currently testing Ilaris in more common diseases in which the IL-1b pathway is thought to play a major role, including chronic obstructive pulmonary disorder, rheumatoid arthritis, type 2 diabetes, and gout. The company reports that it is using biomarkers to predict response to treatment, with the goal of providing patients with a personalized approach to treatment of their disease.
In June, Novartis presented a Phase I/II study of treatment of children with systematic juvenile idiopathic rheumatoid arthritis at the “Congress of the European League Against Rheumatism.” In this open-label study of 19 patients with acute disease, a single dose of Ilaris enabled the 59% of patients who were responders to reportedly achieve 50% control of their disease (as measured by standard American College of Rheumatology criteria) within 15 days.
More generally, Novartis’ early clinical trial strategy involves testing drugs in POC clinical trials in small homogeneous populations, either with a rare genetic disease or defined by biomarkers. Upon achieving POC, Novartis then goes on to conduct conventional Phase II–Phase III trials aimed at registration of the drug.
Other companies are also using biomarkers to define patient populations for POC clinical trials and to help determine the results of these trials.
Biomarkers constitute a young discipline, and there is a need to identify more biomarkers and to qualify and validate them for use in POC trials and other types of early clinical studies. The FDA’s Critical Path Initiative emphasizes biomarker development and use in drug development. Such research consortia as the Biomarkers Consortium, the Alzheimer’s Disease Neuroimaging Initiative, and the High-Risk Plaque Initiative are attempting to improve the state of biomarker science and technology via collaborative, precompetitive studies. The vast majority of biomarker development, however, takes place in individual academic laboratories and companies.
“Biomarkers and translational medicine are something the whole industry is struggling with, to be honest,” said Evan Loh, M.D., vp of clinical R&D at Wyeth. “With the biomarker concept, we are struggling to determine the true value that any biomarker gives us relative to increased confidence in decision-making.”
According to Peter Lassota, Ph.D., divisional vp, imaging biology and oncology at Caliper Life Sciences, “Biomarkers have many flavors. We need better markers for early detection of disease, particularly cancers, in order to improve therapeutic outcomes. We are in need of surrogate markers of efficacy. Pharmacodynamic markers used in preclinical drug discovery and development will accelerate moving the compounds through the pipeline.”
Two other strategies for early clinical design are Phase 0 human clinical studies using microdosing (i.e., administering doses of a drug that are too low to induce pharmacologic effects), and adaptive clinical trials. Phase 0 trials are first-in-human studies that may be used to evaluate pharmacokinetics, pharmacodyamics, and/or mechanism of action, or to evaluate imaging of specific targets.
Adaptive clinical trials constitute a flexible trial design that allows, for example, for continuous dose selection and refinement of hypotheses. In early clinical development, a company may use adaptive design to look at dose-response relationships. The goal is to reduce failed late-stage trials due, for example, to using the wrong dose of a drug or treating the wrong group of patients.