BI409306's Failure in Alzheimer Disease, Learning from Negative Results

August 23, 2018

Lutz Frölich, MD, PhD, provides a look at BI409306, a novel selective PDE9A inhibitor, and how the negative results of its phase II trial can inform the community.

Lutz Frölich, MD, PhD

The graveyard of Alzheimer disease therapies is a constantly growing one, with failures occurring frequently over the years. As researchers and developers learn more and more about the pathology of the condition, though, it is difficult to not hope for positive results.

For Lutz Frölich, MD, PhD, this is an essential part of the process. Frölich has been involved with clinical research for more than 3 decades and knows firsthand that even when there are failures, there is plenty to learn from them.

The head of the Department for Geriatric Psychiatry at the Central Institute of Mental Health, spoke with NeurologyLive to provide a more in-depth look at BI 409306, an orally administered, novel selective phosphodiesterase-9A inhibitor, and how the negative results of a phase II trial of the therapy can inform the community.

NeurologyLive: Could you provide some background on the compound you were investigating?

The compound which was studied was an inhibitor of phosphodiesterase type 9, which is a key enzyme in the second messenger systems related to the functioning of glutamate receptors. The NMDA glutamate receptor is using this pathway for their signal transduction. The inhibition of that enzyme, phosphodiesterase, leads to an increase in the levels of cyclic GMP, which is a second messenger system initiating a lot of other, different pathways intracellularly. It has been shown in animal experiments and basic science experiments that this inhibition of phosphodiesterase type 9 leads to an increase in what is called long-term potentiation—a model for learning and memory on a cellular level—and it also shows, in rat experiments, improvements in their learning and memory behavior can be achieved by that mechanism.

What were the trial results?

We had these two clinical trials with 456 subjects in total who were randomized to 4 treatment groups and 1 placebo group, and the outcome was that it shows that after 12 weeks of this randomized study there were no differences with respect to either placebo or drug treatment or within the different dosage groups of the compound, unfortunately.

However, you can you can learn lots of things from the from the results anyway because you can show that there is a certain learning effect. That shows that this is known from the anti-ß, the sensitivity test, that we if you do it over and over, the outcome will improve. That shows that the trial was executed well enough to detect this learning effect. Secondary outcomes, like the Clinical Dementia Rating Scale sum of the boxes (CDR-SB), the AD Assessment Scale-cognitive subscale (ADAS-Cog11)—they are as the usual clinical readout for phase III trials—they also did not detect any positive results.

Was there anything positive to come out of the findings?

The other side of phase II is always that you look to tolerability and safety throughout the study. Spontaneous reporting of any incident which occurs during this study is being detected and recorded. It is fortunate to say that, although 1 subject in the study group with the lowest dosage of the drug died during that course—this is possible in that type of population of patients—approximately 45% of the patients developed any kind of [suicidal] idea during the course of the study, which is very typical for a geriatric population of, let's say, 73 years of age with Alzheimer's disease of various degrees. So, this was the usual adverse event background. Severe adverse events were in a frequency of less than 3% and there was no indication that there were any differences between the groups or between placebo and drug-treated groups anyway. This was quite fortunate, and this is not so common.

In the other compounds that usually get the name of disease modifiers, you frequently have effects which are detected by MRI, like brain edema—localized brain edema—which did not show up with this component at all. In general, the safety and the tolerability were very good. After the short treatment period of 12 weeks with another 4 weeks for safety recordings there were no signs of efficacy, however, the compound was well tolerated so this is in the end, the results of the trial. So, one could say it was a well performed, well designed, and well-executed trial with a sensitive readout, but with negative results.

What are the implications of this trial for the space?

The compound did not show what it was intended to show, but this is the way it is. This trial is among hundreds of other trials in the recent years which have shown similar readouts, and still the academia—I understand myself as an academic researcher—is very, very much looking forward to continuing this path of drug development. Here, a very close interaction with the industry is desperately needed. We know that some of the big pharma industries have withdrawn from drug development in this field, unfortunately. The company which developed this type of compound is still pursuing this path, in other areas and other disease areas with other compounds, and Alzheimer disease. We only can learn from those negative clinical trials.

Transcript edited for clarity.

REFERENCE:

Frölich L, Wunderlich G, Thamer C, et al. Evaluation of the Efficacy, Safety, and Tolerability of Orally Administered BI 409306, a Novel Phosphodiesterase 9 Inhibitor, in Two Randomized Controlled Phase II Studies in Patients with Prodromal and Mild Alzheimer’s Disease. Presented at: 2018 Alzheimer's Association International Conference. July 22-26, 2018; Chicago, IL. Oral presentation #O1-12-02.