The elixir of youth instead of a pill for old age
"Our task is to fight aging"
Mikhail Kirov, MednovostiWhy is a drug being developed as an anti-aging therapy registered as eye drops?
How safe is this drug? For what other indications do the developers plan to use it? When will the "old age pill" appear? Maxim Skulachev, Deputy Scientific director of the Ion Skulachev project, director of the Mitotech company established at Lomonosov Moscow State University, answered these and other questions in an interview with Mednovosti.
The continuation of the interview, read the first part here.
– While developing an anti-aging drug, you registered a drug for the treatment of dry eye syndrome. How did it happen that you started with the ophthalmological direction?
– The eye, along with the lungs, is the most oxygenated organ, and reactive oxygen species, it has been repeatedly proven, play a huge role there. On the other hand, it has practically no natural protection from oxygen, because it is located outside. Thirdly, the eye, its most important parts, belongs to the nervous tissue, which is very vulnerable to oxidative stress. Well, a practical consideration: the eye can be treated locally, and this greatly simplifies the conduct of research.
If we could take all this into account in advance, we would definitely start with the eyes, but in fact everything happened quite accidentally. In 2006, Natalia Gorislavovna Kolosova from the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences approached us and offered to test our drug on OXYS rats – this is a unique line of animals subject to accelerated aging. Then we had the opportunity to investigate the effect of SkQ1 on all the tissues and organs that we could think of. And Natalia Gorislavovna attracted familiar Novosibirsk ophthalmologists to the observations – especially since these rats are prone to early development of cataracts and retinal dystrophy. And the difference between the control group and the rats receiving the drug was obvious after 3 months – some went blind, while others did not. And then we managed to partially reverse the development of cataracts in already blinded rats. Later, new and very good results appeared on dogs and other animals. And then we realized how convenient the eye is for our purpose – that this is a real opportunity to dramatically accelerate the development of drugs. And indeed, despite the fact that the story with SKQ is quite long, we started the real development of the drug in 2008, and registered it already in 2012. Of course, you need to make a reservation that this is a local application and a fairly simple disease. But it was already our conscious choice.
– Then another question. Dry eye syndrome is treated with tear substitutes – their components are also in your preparation....
– Indeed, dry eye syndrome is a rather slippery indication. There are a huge number of drugs that do about the same thing – make up for the lack of tears, and that's it. Although this disease can be caused by various reasons – increased, or, conversely, insufficient viscosity of the tear fluid, lack or excess of water in it, lack of fat-soluble components, etc. But at the same time, there is still a lot of room for the so–called metoodrugs - you add some component, and then you declare that it is he who has the therapeutic effect, although it's all about excipients. Therefore, in order to get reliable results, a new drug must be compared with a really good drug. In the CI conducted for the registration of "Visomitin", it was a natural Tear of the company Alcon. And the results were quite convincing: after a three-week course, 60% of patients from the SkQ1 group and 20% from the comparison group stopped complaining about the manifestations of SSG.
But it is more important to show what we were guided by when choosing this particular disease. Firstly, SSG is one of the main signs of aging, Vladimir Petrovich likes it very much. Secondly, the main consequence of dry eye syndrome is corneal microtrauma, in the West they are considered the only adequate parameter for evaluating the effectiveness of treatment. At the initial stage, the damage is reversible, but then the inflammatory process begins, which, in turn, affects the production of tears, that is, a vicious circle is triggered. The drugs currently used cannot do anything with these microtraumas, and we knew about SkQ1 that it promotes wound healing. But what to do with this, it is unclear – do not compete with zelenka? And now in the field of ophthalmology, this property has found an application.
But it didn't seem enough to us, because we expect that SkQ1 should not only relieve symptoms, but also treat dry eye (which, by the way, none of the existing drugs does). That is, that after the course of the drug, it will be possible to refuse a permanent substitute for natural tears. Therefore, after completing the registration tests, which were quite small, we launched a new double-blind study for 240 people in 8 Russian and 2 Ukrainian hospitals. There we proceed as follows: we drip for a month and a half, then stop and after another month and a half we see if there is a therapeutic effect. Unfortunately, it is too early to announce the results, because the Ukrainian branch has lagged far behind – due to problems with customs, we simply could not import the drug to Ukraine for almost a year. So the tests have just begun there, and in Russia they have been finished for a long time, but we still cannot "blind" the received data.
– Will you also study dry eye syndrome in the USA?
– Yes, since we have succeeded with a dry eye here, this will be our first testimony in the USA. Because it is impossible to register a drug based on data from Russia to the USA. That is, the Food and Drug Administration (FDA) was pleased to accept our dossier, primarily human research data, we were praised for the high-quality collection of information. But they definitely need a repeat of clinical trials. By the way, the effectiveness of Visomitin in dry eye syndrome has already been proven in an American laboratory. However, so far only on laboratory mice.
– In the spring, as far as I remember, it was about testing for patients with uveitis?
– Yes, but later we were offered a very interesting design of the dry eye study, which allows us to immediately conduct phases II and II (safety and effectiveness) for the same money and for the same time. According to this proposal, SkQ1 will be tested on healthy volunteers in whom corneal damage characteristic of dry eye syndrome will be caused by directed exposure to a stream of dry air. Of course, this is a reversible condition if the person is healthy. But this approach allows you to drastically reduce the sample, because, given that dry eye syndrome is a whole group of diseases of various origins, you will have to recruit a huge number of patients. And here only a few dozen volunteers will be enough for us. Of course, we could not refuse such an offer. But we are investigating the dry eye only because it will help us achieve significant results faster and register the drug. Our main task is the fight against aging, and we are primarily interested in the treatment of senile diseases: cataracts, glaucoma, retinal dystrophy.
– Have there been studies of SkQ1 for these indications?
– When we first proposed this to ophthalmologists, they met the idea with hostility. Find a cure for at least one of these diseases – and it's a ready-made Nobel Prize… And now they are incurable. But we have already completed phase two trials on volunteers for cataract and glaucoma. The cataract results are quite positive, they are being considered by the Ministry of Health right now. The data on glaucoma has just been received, they are being decrypted. I think we will get concrete figures within 1-2 months. But we have not launched studies on retinal dystrophy…
– Because it will take too much time?
– Firstly, because it's been a long time. And then, in our American laboratory studies, the increased concentration of SkQ1 in drops suddenly began to work better. It is 10 times higher than in Visomitin (250 nmol/L), but its safety has also been confirmed. Therefore, we were a little late with retinal dystrophy – after all, this is a very deep part of the eye, we need to be sure that a sufficient amount of substance will get there. And we have one shot: the test will take about three years, and if it doesn't work with one dose, I'm not sure if we will be able to repeat it?
– And what is the situation with the introduction of other forms of SkQ1 to the market?
– Now we have, as they say, two new forms. Firstly, it is a cosmetic product with SkQ1, the need for the release of which we have recently been finally convinced. This is not a very revolutionary step – there are quite a lot of cosmetics with antioxidants, but since we soon find out that people are trying to smear Visomitin on their skin, although the concentration of the active substance in it is insufficient for such an application, since the skin, unlike the eye, is protected by a stratum corneum, then why not satisfy this request? So already at the end of February, a fundamentally new antiage serum Mitovitan containing 10 mmol / l SkQ1 will appear in pharmacies in Russia and (if we manage to pass certification).
The oral form is much more interesting. It is designed for systemic use, but our problem is that there are a lot of diseases associated with mitochondrial oxidative stress. Almost all inflammatory autoimmune diseases, everything related to ischemia – heart attacks, strokes, kidney damage, the consequences of diabetes – mitochondria and reactive oxygen species are involved everywhere, respectively, we can theoretically treat them. And this is what we promised from the very beginning and what we do not intend to give up. An application has been submitted to the Ministry of Health for the start of oral clinical trials. This will be a SkQ1 solution – after all, we had to take into account that the substance feels better in liquid form, and not in solid form. So pills for old age, alas, will not work. But you can get an elixir or medicine.
– What diseases will research be conducted on?
– It's not an easy question, we have such a wide choice that our eyes run away. And the Ministry of Health requires specifics and does not want to hear about any fight against aging. So the first indication that we intend to investigate is neuroprotection. We have good data on the use of mitochondrial antioxidants in disorders of cerebral circulation or Alzheimer's disease. But since the first tests are devoted to safety assessment and will be conducted on healthy volunteers, we still have some time to determine specific diseases.
– Who conducts clinical trials? Do you cooperate with some CRO (contract research organizations)?
– In Russia, clinical trials of medicines are a relatively new field of activity, so the difficulties that arise with their implementation are quite understandable. The legislative framework is constantly changing, regulatory mechanisms for conducting clinical trials have not yet been worked out, there are very few doctors who have experience in organizing them, therefore, during the first studies of our drugs, we could not avoid some flaws that did not allow us to evaluate the effect of SkQ1 in all the parameters that we expected. In such a situation, we decided that it was too risky to outsource the most important part of drug development – clinical research – to full outsourcing. It was necessary, within the framework of the project "Ion Skulachev", to create a separate organization – the Mitoengineering Research Institute of Moscow State University. This institute is engaged in pure science, attracts a very large number of world-renowned scientists to work, publishes articles in reputable journals. He owns the GLP vivarium, the production of fine organic synthesis, which allows us to synthesize our molecules in sufficient quantities, according to GMP standards, the staff includes about 200 people - biochemists, chemists, physiologists (mostly part–timers from Moscow State University). There is also a special department that includes specialists involved in clinical research protocols, monitoring, biostatistics – that is, we now do all this ourselves. And such a structure allows us not only to fully satisfy our own requests, but even to fulfill third-party research orders.
– Well, what's in the West? Won't you be working there too?
– Of course, moreover, we are already actively working. We have confirmed our most important results in Western laboratories. But it is important to understand that we do not plan to independently establish the production and marketing of our drugs in the USA and the EU. Small companies (and by the standards of the Western pharmaceutical market, we are just such a company) usually conduct the first stages of clinical trials of their drugs, and after that they conclude an agreement with the so–called "big pharma" - multinational pharmaceutical companies such as Pfizer, Novartis, Bayer. They finance the last stages of testing, establish the production and sale of drugs in developed countries. Ultimately, we would like to follow this scenario. But on certain conditions. Most likely, in the form of a partnership. We have studied the market well enough and have a good idea of what exactly large pharmaceutical companies are interested in. They will never acquire a Russian enterprise or institute. They are interested in intellectual property: drug rights, patents and test results. For this kind of interaction, we have created another division – the company MitotechS.A., registered in Luxembourg, where there are a number of benefits for transactions with intellectual property. But there is one limitation that we have set for ourselves, based, as it seems to me, on healthy patriotism: whatever deals are concluded, the rights to the Russian market and the CIS will remain with us – that is, we will always be able to launch our medicines in Russia.
– Are you negotiating?
– So far only preliminary, but the interest of "big pharma" is clearly there. We are not in a hurry – the later we start discussing the actual transaction, the more data we will have (first of all, clinical studies). And, consequently, the stronger our position will be in negotiations with these pharmaceutical giants. So far, we link their beginning with the completion of the I-II phase of the SkQ1 study in the USA. After that, maybe we'll start a conversation, if everything works out, of course. On the other hand, there are quite strong investors behind us now. 50-50 we are funded by Rusnano and a private entrepreneur engaged in IT – so far he asks not to be named. Our investments are still not enough for a full test cycle in the USA, but if the first results are good, investors who perfectly understand all the prospects of the project will agree to increase funding.
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