Following the Yellow Brick Road: The Path through Clinical Trials

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Barb Bailus, PhD

Hello Everyone!

Today we are going to spend some time reviewing the various phases of drug discovery and clinical trials, which can allow for advancement of promising therapeutics into the clinic for patients. There are many variations on this scheme but this is the traditional approach.

The very first phase of treatment development is considered pre-clinical studies; these are the initial discovery studies. Often, these initial studies will take place at a university laboratory and will serve as a proof of concept either in cells or a dish (in vitro) or in a live animal (in vivo). Several of the most promising therapeutic programs for Angelman syndrome that FAST has funded began in this way, including: artificial transcription factors (ATFs), antisense oligonucleotides (ASOs), gene replacement therapy and drug discovery. These studies will utilize a variety of models, including: cells, invertebrate species (flies, worms, yeast) and rodents (mice or rats). In rodents, different dosages can be tested for drug tolerance, and behavioral studies can be done to test for drug effect in changing any of the behaviors characteristic of this disorder. The purpose of these studies is to establish preliminary data on efficacy, toxicity, and information regarding how much of the drug is able to reach the desired location, how large of a dose must be given, how long does the drug last and what side effects occur from treatment (pharmacokinetics). Usually, before entering human trials, a treatment must be tested in a higher vertebrate species; this can include: dogs, rabbits, pigs, sheep or non-human primates. Phase I human clinical trials rely on the details from these preclinical studies. They help to determine the doses and frequencies that will be needed in first-in-human trials (or Phase 1 safety studies). These pre-clinical studies assess the safety and efficacy in non-human models in order to determine the range of minimal effective to maximal tolerated doses. This is required to guide Phase 1 studies. Phase 1 studies are usually first in human for a certain drug or indication and the primary endpoints of assessment are safety and tolerability, with exploration of patient focused outcome assessments to see what changes in patients after treatments. These studies are usually small numbers (~20-30), and serve as a guidance to Phase 2 and 3 studies which focus more on efficacy endpoints.

A few select universities have the facilities to move from preclinical to Phase I human clinical trials. One of the reasons for this is that the treatment will need to be produced under the Current Good Manufacturing Practices (CGMP), as the treatment will be going into human patients, and the testing needs to be performed under GLP (Good Laboratory Practice) for FDA Investigational New Drug (IND) and European Medicine Agency (EMA) guidelines. In order for a human Phase 1 trials to begin, there must be approval by the EMA or FDA with something like an Investigational New Drug (IND) application (USA). This application consists of all preclinical data, pharmacokinetics and clinical trial strategies outlining the plan to minimize patient risk. The FDA then reviews the IND and determines if human clinical trials can proceed. Since the primary objective is to establish safety, a relatively small group (~20-30 in rare diseases) of individuals are enrolled.

Patient recruitment is an essential component, and all patients (or their guardians) must consent to the treatment. Phase I is the stage where initial collection of relevant outcome assessments and biomarkers (behavioral or molecular measurements) would be tested, helping establish which potential outcome measure(s) or biomarker(s) will be carried forward into future clinical trials (Phase 2, Phase 3 or Phase 2/3). If the treatment passes the safety profile and minimal adverse effects are observed, then the treatment will advance.

If a new treatment successfully completes a Phase 1 clinical trial then the treatment enters Phase 2, where the efficacy of the treatment is established with a larger patient population (50-100+). This is typically a blinded, placebo-controlled, randomized, clinical study. Placebo studies are necessary in order to have a baseline of patients to compare to those getting treatment in order to ensure that any assessed improvements in symptoms are truly from the drug and not the biases that are commonly seen when individuals “think” they are receiving a drug. These studies are also blinded so that the patient and the doctors do not know which treatment group an individual is in. It is at this time that the previously established clinical outcome assessments and biomarkers are essential as these measurements will determine if the treatment is “effective.” If these measures used do not reflect a significant change then it is unlikely the treatment will advance to Phase III clinical trials, or to the patient population. In Angelman syndrome, where several behavioral modifications could be used as potential outcome assessments, it is essential that an accurate measurement scale be used to detect improvements. In order to obtain an accurate scale for Angelman syndrome, many investigators are working diligently to create different measures so that the incremental improvements in patients can be measured after treatments. The Angelman Syndrome Biomarker and Outcome Measure Consortium (ABOM) was created through a collaboration between FAST and the ASF in order to create a precompetitive environment where all investigators and pharmaceutical/biotherapeutic companies work together to determine the priority areas of focus. Some of the areas of focus include communication/cognition, motor function, seizures, and sleep disturbances. Molecular biomarkers that can also be assessed include evaluation of various body fluids (saliva, blood, urine, spinal fluid) are these can be used to monitor for changes of a desired protein or metabolite before and after treatment. This can help assess target engagement of a drug, showing biochemically that it is functioning as anticipated.

The passage through human clinical trials can appear a very long and daunting journey, especially to patient families, but this route ensures safety and efficacy. For rare diseases like Angelman syndrome, the FDA understands that the patient population is limited and that current treatment options are minimal, allowing these diseases to be termed “orphan diseases”. With respect to these limitations, the FDA allows for smaller treatment groups and more flexibility for clinical endpoints. In addition, there are financial incentives for companies to develop “orphan disease treatments.” Due to the relatively small patient population size, a patient registry becomes an invaluable resource for helping follow patient populations longitudinally, and to connect with patients when enrollment begins. The partnership of FAST with both basic scientists, clinicians, and pharmaceutical companies allows for the co-development of outcome measures and biomarkers, and support the future of potential therapies. These partnerships drastically increase the speed of this process.