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As many who keep a close eye on drug development know, there are three, sometimes four, phases of clinical trials. Each clinical trial phase serves a particular purpose, although there is some variability and overlap in goals. While all trials look at safety, phase 1 trials focus on it in particular, usually in a small cohort. Phase 2 trials test investigate proper dosage and begin to look for signs of efficacy in a larger group. Phase 3 trials look to establish enough concrete evidence of efficacy in a very large cohort, with the goal of making the final case for approval from the FDA in the US. For some treatments, a phase trial 4 may also be conducted after approval to continue to collect additional data.

While these guidelines are generally descriptive of most clinical trials at each phase, there is still variation in how different trials are designed and carried out at each level. For phase 2 trials, there are two categories into which many of these studies can be broadly grouped.

  • The first are trials primarily focused on finding evidence of whether the treatment is effective.
  • The second includes trials that are more focused on establishing the right dosage needed to have a therapeutic effect while minimizing any harmful side effects. This is usually accomplished by assessing differences in biomarkers from person to person and analyzing how these biomarkers respond to drug treatment. These differences can indicate whether there are patient subgroups that are more likely to respond to drug treatment and what dosing levels safely demonstrate drug activity in the patient’s body.
Two Kinds of Phase 2 Trials

Despite both being within the definition of a phase 2 trial, these two study types tend to have quite different structures and goals. Trials primarily focused on efficacy tend to focus on a larger population and last longer. Participants are randomized into a cohort that will receive the treatment and a control group that will be on placebo. The trial sponsor may use any evidence of efficacy to pursue a phase 3 trial in an even larger population. In some rare circumstances, they may even submit the treatment for approval without moving on to a phase 3 trial.

A phase 2 trial that is more focused on dose-finding and biomarker validation tends to be shorter, and features fewer participants. In many of these trials, several different cohorts of participants will be given varying doses of a treatment. Alternatively, in what is known as a dose escalation trial, all participants who are on drug might begin with the same, smaller dose, which is gradually increased. Unlike efficacy trials, dose-finding studies may not feature a group of participants on placebo. Researchers will look at the data from a trial like this to determine what the optimal dose of a treatment is, what the maximum tolerable dose might be, and at what dose participants might begin to experience adverse side-effects that outweigh any benefits.

They may also look closely for signs that the drug is having more effect in certain groups of participants than in others or whether the drug is having an effect on the intended drug target. To this end, they will look for predictive biomarkers – or biological features that indicate that an individual is more likely to respond to a particular treatment. Examples in ALS might be the presence of specific proteins related to an ALS-related genetic mutation or the presence of inflammatory markers that would drive inclusion into a specific trial.

Pharmacodynamic biomarkers, in contrast, could show whether a drug has an effect on its intended target. For example, if a treatment is designed to control neuroinflammation, a change in levels of specific markers of inflammation could show that the drug is reaching its target. Thus, by evaluating predictive biomarkers in a phase 2 trial, researchers can then design a phase 3 study with a population that is more likely to respond to the treatment. Similarly, by evaluating pharmacodynamic markers in a phase 2 trial, researchers can design a phase 3 study that might use these markers to help determine efficacy.

Examples in ALS

An example of a primarily efficacy-focused study in ALS is the CENTAUR phase 2 trial for Amylyx Pharmaceuticals AMX0035, which was completed in 2021. This trial enrolled 135 participants for a duration of 24 weeks. These participants were randomized into one drug and one placebo group at a 2:1 ratio. The study’s primary endpoint was a slower decline in ALSFRS-r score versus placebo, although other factors such as limb strength, breathing ability, and hospitalization were considered. The drug showed signs of efficacy at the conclusion of this trial and, while the sponsor is currently conducting a phase 3 study per the FDA’s request, they also submitted the treatment for approval based on the phase 2 data in the interim.

The phase 2 trial of AT-1501 (tegoprubart), a drug that was invented by the ALS Therapy Development Institute (ALS TDI), is an example of a dose-finding and biomarker validation study. This open-label study enrolled 54 participants for a duration of 19 weeks, with no placebo group. The entire cohort was given 4 different, increasing doses of the treatment throughout the study. The primary outcome measure was safety and tolerability.

Additionally, the investigators sought to evaluate a number of biomarkers among the trial participants. These included several different blood-based biomarkers that are thought to be indicative of neuroinflammation as well as neurofilament light chain (NFL), a potential biomarker of ALS progression. They also looked CXL13, a protein that the researchers believe could indicate whether the drug was affecting its intended target, the ALS-associated immune system protein CD40L. While changes in these biomarkers would not be considered sufficient evidence to, for example, pursue FDA approval in a phase 3 trial, they may present the researchers with additional data to help determine which participants responded best to the treatment and which markers should be evaluated to help determine efficacy.

The study was fully enrolled in January, 2022, and the sponsor, Eledon Pharmaceuticals, expects topline results later this year. These results will focus on both what doses seemed to balance efficacy and safety to the best degree, and what members of the study group seemed to benefit most, if at all. This data will be crucial to planning the next step in this treatment’s development.

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