"[...] This would be a unique selling point: demonstrating efficacy [...] without expecting major side effects. [...]": Dr. Guido Koopmans on neuropathy and the currently ongoing Algiax study on the agent AP-325 (Part 1)

Neuropathic pain is not "normal" pain – its treatment is considered complex and challenging. A promising phase II study is currently being conducted on behalf of Algiax Pharmaceuticals GmbH: Hopes are pinned on a new compound called AP-325. We at emovis are pleased to be one of the many study sites who have been invited to participate in this trial.

Read the first part of our interview with Dr. Guido Koopmans, developer of AP-325 and sponsor of the associated study: You will learn what makes his compound so special and what research results are already available on it.

What exactly is neuropathic pain? How does it manifest itself? How does it differ from "normal" pain?

“Normal" or nociceptive pain is a protective warning system. For example, if we come close to a candle flame and feel its heat, the pain will tell us to pull our hand away so that we do not burn ourselves. Nerve pain, on the other hand, is not a protective mechanism, but ultimately a disease in itself. Basically, it is a false adaptation by the body to nerve damage. This is based on plastic processes: The injured nerve fibers try to grow back out, to make new connections. This can lead to a false cross-linking or false reproduction of what is actually felt. This can explain why what would be felt as pressure in a healthy person is suddenly felt as pain instead. Neuropathic pain can be so bad that, for example, even wearing a T-shirt or being in normal water temperature in the shower hurts immensely at the corresponding part of the body.

What determines the severity of neuropathic pain? Does the duration play a role?

This is quite difficult to say. There is no clear indication in the literature that the severity has anything to do with duration. It is known that the pain is very often very severe in the case of a really serious injury – such as a complete severing of a nerve or several nerves or an amputation. But in some people, there is hardly any indication that a nerve has been injured, and yet they have high levels of pain. This shows that pain in general is a very subjective experience. Let me illustrate this further: Algiax has done three phase I studies. In the third one, we injected capsaicin under the skin of the forearm of 16 young, healthy volunteers. Capsaicin is one of the world's hottest substances and is found, for example, in peppers, chili peppers and red pepper. The capsaicin led to hyperalgesia, i.e. hypersensitivity to pain. We then asked the subjects to rate the intensity of the pain using a visual analog scale from 0 to 100. In fact, one person rated the pain as a mere 8, i.e. hardly painful. But there was also one person who indicated 100, meaning they could not imagine a worse pain. Each person has their own pain threshold, which is a difficulty in treatment.

As part of your work at Algiax Pharmaceuticals GmbH, you have developed the compound AP-325 for the treatment of (postoperative) neuropathic pain. The compound has already been investigated preclinically and in a phase I study. What have been the results of these studies?

We have investigated AP-325 in detail in so-called preclinical pain models. In these, a peripheral nerve, for example a leg nerve, is usually injured in rats. After one week of treatment with AP-325, the pain of these animals was relieved and, interestingly, this relief lasted for a relatively long time. Now we are trying to reproduce these results in humans. This would, after all, be a unique selling point: demonstrating efficacy, possibly over a longer period of time, without any expected major side effects.

In our phase I study with healthy volunteers, we started with a single dose of AP-325. We then progressed to multiple doses over 7 days. We also saw that the drug was well tolerated: Subjects reported no negative side effects such as fatigue, drowsiness, or dizziness – side effects that are caused by painkillers, such as pregabalin, which have already been approved. Only once we received a report of slightly elevated blood pressure. All in all, the phase I study was successful.

Currently, AP-325 is being further investigated in a multicenter Phase IIa study. Could you describe the target population of this study?

Neuropathies are caused by damage to the nervous system. This can occur during an operation, for example. Some people react to this damage and develop nerve pain, but some do not react at all – it varies greatly. Our study is aimed at patients who have suffered from peripheral neuropathic pain since surgery. For this purpose, we have selected three major groups of surgical procedures that relatively often result in neuropathic pain. These are; breast and axillary surgery for treatment of breast cancer, surgery on the torso – such as for lung cancer or as part of open-heart surgery, and surgery for inguinal hernia. Our study is being conducted in Germany, Spain, and the Czech Republic – currently 17 study sites and other institutions are participating – and we would like to include a total of 94 patients.

How does participation in your study work?

Potential patients are first examined in a screening phase regarding the inclusion and exclusion criteria of the study. We also ask them if they are willing to give up their current painkillers for the duration of the study and only use paracetamol as an emergency medication in case of an insufficient response to AP-325. After one week, we record the patients’ baseline pain. For this purpose, they were asked to record the intensity of their pain in a diary using an 11-point scale. Patients whose average score is within the predefined range are randomized to receive either AP-325 or a placebo for 10 days. They also must keep a diary during this phase. At the end of the 10 days, they then receive 26 more days without treatment.

What specific results do you hope to achieve from your study?

The primary objective of our study is to compare days 6 to 10 of the treatment phase with the baseline phase. On the one hand, we hope to see an effect within this one week of treatment and, on the other hand, that this effect is long-lasting, i.e., that it can be detected during the subsequent 26 days without treatment at least. We expect to see a good difference compared to the placebo – the placebo effect should disappear relatively quickly.

What is so special about AP-325? How is the active ingredient supposed to work against neuropathic pain, and in what way is it supposed to be better than previously used drugs?

One of the reasons for the development of neuropathies is that the balance between inhibition and excitation is destroyed: due to the lack of inhibition, even the lightest touch can be felt as painful. This is where AP-325 comes in: Its main effect is probably due to the alteration of the GABAA receptor. GABA is a messenger substance in the nervous system that mainly has an inhibitory effect on the brain. AP-325 is a so-called positive-allosteric modulator of the GABAA receptor: it increases the effect of GABA so that less of it is needed for a very strong effect. Many other agents also based on GABA act on the central nervous system, often causing side effects such as sedation, fatigue, drowsiness, or dizziness. AP-325, on the other hand, barely crosses the blood-brain barrier – which protects the brain from toxic substances. This allows us to build up quite high levels of GABA in the peripheral nervous system, i.e. outside of the brain and spinal cord. This is not possible with other drugs, because the patient would simply fall asleep or would no longer be able to function.

Why is AP-325 being researched in patients with postoperative neuropathic pain? In principle, is it also suitable for the treatment of neuropathic pain that has a different origin?

We started with postoperative neuropathic pain because these patients form a relatively manageable population. In addition, the pathophysiology, i.e., the cause of pain development, is relatively well understood in this population: The site which was operated on and the site where pain is felt correspond, pretty much, one-to-one and dermatomes – areas of skin each supplied by a spinal cord nerve – can be traced relatively well. For other types of nerve pain, such as back pain or complex regional pain syndrome (CRPS), the cause is much more complex. If we are indeed able to demonstrate the efficacy of AP-325 in postoperative neuropathic pain, it is natural to explore other neuropathic pain indications as well. This is especially true for nerve pain as a consequence of diabetes: we have also done preclinical research on this at Algiax and the results so far look good.

When are the results of your study expected to be available?

Recruitment has been ongoing for about a year. So far, about 25 patients have completed their participation in the study, and two are still in the midst of it. Of course, we had hoped that things would progress a little faster. The corona pandemic definitely didn't help – some potential patients had reservations about participating in a study during this time for example. But we have the first indications that the situation is now easing a bit and that then recruitment will move a bit faster. We will need at least one more recruitment year. In March to April 2022, there will be an interim analysis, provided that we have found 15 more patients by then. This is a very important milestone for us: If we don't see any difference between the two groups of patients, we may decide to discontinue the study. But of course, we assume that we will be able to demonstrate the effectiveness of AP-325 and achieve our objectives.

In part 2 of our interview, you can read about the experiences that led Dr. Koopmans to pursue a career in science, what a "typical" working day is like for him - and much more.