Pathophysiological treatments

Having seen the symptomatic treatments, let’s move on to the pathophysiological ones. With the tooth example, we contrasted what we call pain treatment (symptomatic treatment), where we merely aim to treat the symptom (pain), not the tooth itself, with causal treatments, as in treating a cavity, extracting a tooth, which are radical treatments. 

Those are causal treatments. Now, let’s look at these causal treatments, known as disease modifiers. First up, and it’s very important, they are not yet available. None of them are on the European market. It’s worth mentioning. It’s worth talking about because there are many of them. 

Take the upper quadrant in green (phases 1 to 3). You can see that many are already in phase 3, that is, medicines in the final development phase. Quite a few medicines are being developed to stem the pathological process underlying the symptoms. Indeed, the results are truly spectacular in terms of the effects these medicines have on brain amyloid lesions. They are anti-amyloids, and I’ll talk about three of them: Aducanumab, Lecanemab and Donanemab. You can see the effect these medicines have on brain lesions, as seen on an amyloid-PET scan. 

When you look at the concentration of lesions in the beginning (t0) and their concentration 18 months after treatment during therapeutic trials for each of these three medicines, you can see up to 80% fewer brain lesions in patients after 18 months of treatment. In other words, these medicines, these anti-amyloids, clear out brain amyloid lesions. It is an amazing feat, an extraordinary result, and an incredibly exciting one. Except that they have no effect on symptoms, at least not in late-stage patients. 

That is problematic. We are not here to treat lesions. We are here to treat symptoms. As such, having an effect on lesions but not the symptoms is a real concern. One of the reasons given is that perhaps they were tested on patients whose disease was too advanced. That is why we are now conducting research into these medicines in the prodromal phase I mentioned previously – the early stages of the disease. For the first time, we are starting to get positive results, not just for lesions but also symptoms. As you can see, the black disease aggravation slope is less severe for patients who received treatment (shown in dark green above and light green below). 

That means these medicines slow disease progression. Therefore, they influence the pathological process which products symptoms in the patient. As such, it continues to be a moderate condition. However, note that this effect tends to last. We can infer from that if we already observe this effect after 18 months, we can double it after 36, and so on. That means the more time passes, the greater effect we can expect to see. 

So, we have medicines with a moderate effect but one that may increase over time. For the first time, in my view, we have medicines that validate the amyloid cascade underlying this therapeutic approach. On the bottom left you see this illustrates the idea that amyloid lesions are somewhat at the origin of it all. And if we treat the amyloid lesions, we can expect fewer neuronal deaths and cognitive disorders, which was the model underlying this therapeutic approach. 

For the first time, we have a relationship between an effect on amyloid lesions using these medicines, a reduced concentration of tau lesions in the cerebrospinal fluid – I didn’t show the result but take my word for it – and an effect on cognitive disorders. 

Firstly, it confirms the amyloid cascade. However, they are not without consequences. You have seen that the effect is not huge, far from it. Unfortunately, they also carry serious side effects for around 1% of cases – a significant proportion. Especially given that seven cases across all trials resulted in death, which raises questions. 

These are medicines that are somewhat effective. It’s good news, but their effectiveness is not astounding, and they have potentially serious side effects. As such, when prescribing it to a patient, who is still in the early stages of the disease and often relatively young (given it won’t be prescribed to the very elderly), it’s no small thing to say that they are running a potentially serious risk. 

The third key notion is that the medicines aren’t ready yet. They are still in development. Two of them – Aducanumab and Lecanemab – have FDA approval in the United States, and we await the results from the EMA in Europe. It is not clear whether the EMA will approve them, and even if it does, there will still be institutional procedures, meaning that these medicines will not be available in France before 2025 at the earliest in my opinion.