While clinical trials form the basis of the approval process for medical treatments, research into new therapies starts years before these trials get underway. Before a new therapy can be considered for administration to humans, it must show therapeutic promise and undergo extensive testing. Biological agents such as proteins or drugs undergo in vitro (in the laboratory) and in vivo (in a living organism) testing to determine their medicinal properties. Scientists look for treatments effective against animal diseases that resemble human afflictions (called animal models). It can take years of research on animal models before results are found that justify an application to the FDA for further testing in humans.
Having credible evidence that a treatment could benefit people, its developer applies to the FDA for investigational new drug (IND) status. With this status, the treatment can now undergo evaluation in clinical trials, i.e., experimental administration to human beings.
For the safety and protection of the people who volunteer to participate in clinical trials, the FDA has strict protocols and guidelines for conducting these medical experiments. First, the treatment enters Phase I clinical trials. In Phase I, a small number of patients, as few as 5 or up to 80, receive the proposed new treatment. The primary objective of Phase I is to determine safety. Often other aspects of treatment, such as method of administration or dosage, are also assessed in Phase I. Depending on the nature of the condition under treatment and the anticipated response time, Phase I can take months to years to complete. In the case of neurological disorders such as those for which Ceregene develops treatments, the experimental administration of the therapy begins with one surgical event. However, evaluation of the treatment involves follow-up with the patient over extended periods, from months to years, during which the investigational team conducts systematic tests of neurological function.
With safety criteria satisfied and initial treatment outcomes measured during Phase I, the study sponsors qualify to advance their therapy to Phase II clinical trials. In Phase II, the primary objective is assessing a treatment’s efficacy for the indicated condition. Usually additional data is collected to evaluate the safety and appropriate dosing of the treatment. In Phase II, larger numbers of patients receive the treatment, typically hundreds, giving researchers a large enough sample size to reach statistically valid conclusions. Similarly to Phase I, the time dedicated to generating results for neurological treatments in Phase II amounts to years of dedicated work tracking and testing for neurological improvement in patients.
Upon completion of Phase II, the treatment moves on to the final and third phase of clinical trials. In order to provide a treatment commercially in the United States, the developers of a treatment must apply for FDA approval. The study sponsors typically submit this application once they have moved to Phase III, which confirms the efficacy reported in Phase II using even larger numbers (hundreds, or even thousands) of patients to compare treated individuals with those receiving the standard therapy or none at all (control).
Clinical Programs at Ceregene
Parkinson’s disease is a movement disorder involving the progressive loss of voluntary motor function. Since the neurons involved in dopamine circuitry in the brain play a role in voluntary movement, these neurons are the targets for treatment of this disorder. Preclinical experiments indicate that neurturin (NTN), a naturally occurring neurotrophic factor, promotes survival and improves function of these neurons in animal models, showing promise as a potential therapy for Parkinson’s disease. Ceregene has created an adeno-associated viral vector (AAV, type 2), CERE-120, that carries the NTN gene. Administration of treatment involves the delivery of CERE-120 via precise injections into the target region of the brain.
In collaboration with scientists at the University of California, San Francisco (UCSF) Medical Center and Rush University Medical Center in Chicago, Phase I clinical trials assessing safety and tolerability of CERE-120 in humans have been completed with no indication of significant adverse events or side effects. Further, the results show improvement based on both subjective and objective measures (see Newsroom for press release 10-10-06).
Subjects are currently being enrolled in Ceregene’s Phase II clinical trials, where they will further quantify the effectiveness reported in Phase I. Ceregene has supplementary support from the Michael J. Fox Foundation. Information on participating in Phase II Parkinson’s disease clinical trials is now available at www.pdtrials.org and www.clinicaltrials.gov.
Alzheimer’s disease (AD) causes a decline in memory and cognition corresponding to a loss of function of specific neurons deep in the brain. Nerve growth factor (NGF) has profound protective and restorative effects on the affected neurons in animal models of Alzheimer’s disease. Ceregene has developing a product called CERE-110, that will use a modified version of adeno-associated virus, type 2, to deliver the gene for NGF to the impaired part of the brain.
Following completion of an extensive nonclinical safety and efficacy program, Ceregene initiated and is completing a Phase I clinical trial. A larger, multi-center, controlled Phase 2 clinical trial is in planning stages.