How "Himrar" became one of the main conductors of pharmaceutical innovations for Russia

Alexey Kamensky, Vademecum 

It is known that the invention of drugs is a dangerous business in terms of finances. But the Himrar company has learned to participate in this process without risking anything. Its creator realized in time the prospects of combinatorial chemistry – the rapid synthesis of many similar molecules, among which there is a chance to find a candidate for a new drug. As a result, representatives of Big Pharma invented drugs, and Himrar earned money by combining them on their order. But all good things come to an end, and the demand for combinatorial chemistry has declined. Then Himrar decided to take a risk and took up the development of drugs itself. A relatively small company does not have blockbusters blowing up the market yet, but the way its owners manage to find billions for their development, including in the public purse, is almost a blockbuster in itself.

Successful scientist-inventor Alexander Ivashchenko was one of the first to see a new direction in pharmaceuticals – combinatorial chemistry. On orders from large foreign companies – Merck, Fluka, Acros – he synthesized rows of similar molecules and tested their effectiveness. The son, Andrey Ivashchenko, was engaged in more mundane things – he collected and sold computers. He was a co-owner of the well-known companies Inel and Excimer at the time. But the margin on computers was falling, and the demand for contract research was growing. Soon Andrey, together with his partner Nikolai Savchuk, joined his father's firm. It was in the mid-90s.

Ivashchenko's business started in Russia, but the partners quickly realized that it was time to move. "In order to sell complex research in America at that time, it was necessary to be across the street from the client," explains Andrey Ivashchenko. They registered ChemDiv in Milwaukee, on Lake Michigan, next door to the headquarters of their main client Aldrich. Here the chemists miscalculated – the centers of growth of "biotechs" were Boston and California. "We were rushing around for a long time, but then we decided that it would be warmer in California, we opened the first laboratory and sales office there," Ivashchenko grins. It was also about the convenience of fulfilling orders. "There you call, and the next day all the reagents come, you can do an experiment. And in Russia, it takes several months and a lot of effort to do this," explains the chairman of the Board of Directors of Himrar. The company conducted routine research in Russia, and complex, exclusive research in the USA, where Alexander Ivashchenko lives almost constantly. Employees were also sent there to study, and those, returning, tried to take with them the "beush" equipment. After all, in Russia, Ivashchenko says, the creation of a laboratory costs about three times cheaper than in the United States - $ 1 million for a laboratory for 10 jobs versus $3 million in America.

Alexander Ivashchenko was one of the first in this field, but not the only one, evaluates a colleague, professor of the Chemical Faculty of Moscow State University Evgeny Babaev, who himself did a lot for the development of combinatorial chemistry. There was, for example, the Chembridge company. It exists even now, but it is hardly noticeable on the market. The Institute of Organic Chemistry could also be considered a competitor of Himrar. "Chembridge was also engaged in combinatorial chemistry by order of Big Pharma, and they had an office in San Diego across the street from Ivashchenko," says the CEO and founder of the consulting company DrugDevelopment.En Dmitry Kulish. Ivashchenko's company, in his opinion, acted smarter and quicker than competitors. For example, Big Pharma was the first to offer integrated solutions, to cooperate with regional Russian laboratories – that is, to increase the capacity of the enterprise without attracting large investments.

Although there were difficulties here. With the growing number of orders, "Himrar", "sprayed" across the scientific centers of the former USSR, looked increasingly strange. He had laboratories everywhere – in Moscow, Yaroslavl, St. Petersburg, and Ukraine. "Foreigners came to see how we work here, and did not understand the structure of all this. I take them, for example, to our laboratory at the Institute of Plant Protection. The laboratory itself is nothing, but while you walk through the institute corridors, you experience unpleasant emotions," says Ivashchenko.

They searched for a long time, found not exactly what they wanted, but, as it turned out later, for the better. Instead of 5 thousand well–equipped square meters for laboratories, there is an eight-storey box in Khimki with a fourfold larger area, which has stood for several years without heating and a roof. But for the same money. "We got such a "Stalker zone". But most importantly – with all the papers: it was an old laboratory building with permits for all kinds of activities that we needed," says Ivashchenko. – The territory, however, did not belong to the building, then they fought for it separately."

For the purchase and repair of the company for the first time had to attract investors. Contract chemistry was then a high–margin business, but the money earned was still not enough: $50 million was needed - a huge amount for a company with a turnover of $30 million. A bank loan was not even considered because of the high cost. Ivashchenko Jr. had to fuss. Funds were collected among friends, colleagues, and not only. "He also offered us to become investors in the Khimki project," recalls Galina Baryshnikova, Development director of Kanonfarma, which competes with the Himrar Group in some market segments.

Ivashchenko does not name the creditors, but claims that after four years the shareholders of Himrar paid off all. The shareholders are himself with about a 25% stake, Nikolay Savchuk with exactly the same package, Ivashchenko Sr., who has "a little more", and several other Russian owners. In some companies that are now part of the Himrar group, shareholders are their own directors who have received small incentive packages. Formally, part of the companies of the Himrar group, through the Himinvest company, belongs to Torrey Pines Investment, registered in California. Moreover, among the investments of Torrey Pines Investment there are also international startups that are not related to Russia. Torrey Pines works as an investment fund, explains Ivashchenko, "Himrar" is one of the projects in her portfolio.

"We took out 500 KAMAZ trucks of construction debris alone," Ivashchenko returns to the construction topic. – The room was repaired in parts, there was no physical opportunity to do everything at once." The arrangement of the areas at that time cost less than $ 1 thousand per meter, most of the funds were spent on laboratory equipment and the fulfillment of special construction requirements for laboratory facilities. So "Himrar" turned into a landlord – mainly for firms associated with the pharmaceutical business. In its structure there is a separate company that manages real estate, it receives about 120 million rubles a year from rent. To this must be added the income from the cooperation of "Himrara" with tenants. Among others, the Rusnano portfolio company Selecta has settled here. "As landlords, they are comfortable," says Dmitry Ovchinnikov, General Director of Selecta. "Skolkovo has been under construction for many years and will not be completed in any way, but everything is ready here."

But in the contract research of the Himrar group, after rapid growth, stagnation set in: turnover did not grow. Synthesis and testing of thousands of compounds per day did not bring the previous profits – Chinese companies entered the market, which lowered prices by almost half. Some complex synthesis options have not yet been obtained by the Chinese, there is still a place on the market, says Ivashchenko. But the decline in prices affected all types of research. The old days will not return, a new "Chemrar" cannot be built on combinatorial chemistry, Ivashchenko is sure. "They have stagnated in recent years and have been thinking all the time about what else to do," says a market participant familiar with the work of Himrar. The company decided to switch from contract research to its own. But there was not enough money again, and it is more difficult to lure an investor into a pharmaceutical venture than into the construction of a laboratory complex. But there was a way out again.

The reputation of an innovator helped Himrar, Andrey Ivashchenko is sure. The appearance of its own research center in Khimki prompted the company to become more open, start sharing information about its work, and interact with the authorities. Just at this time, with the filing of Viktor Khristenko, work began on a multibillion–dollar investment program in pharmaceuticals - Pharma 2020. "We were called as innovation experts to the group that created the draft of this strategy, and about a year later Viktor Borisovich [Khristenko. – VADEMECUM] tells us: the feeling that you are the only ones who are not fighting with anyone here in the market. Of course, I say, we don't swear, because we don't sell anything in Russia. And then he invited us to become an integrator of the expert community for the development of a draft strategy." The scientific merits of Academician Alexander Ivashchenko also played a role, Dmitry Kulish believes. Himrar also had one more feature, market participants remind: it's no secret in the industry that Ivashchenko Sr. and academician Anatoly Tsyb were close friends, and their children, Andrei Ivashchenko and the current Deputy Minister of Industry and Trade Sergey Tsyb, retained this friendship. "We really knew Sergey Anatolyevich even before he headed the relevant department. He knew that we had international–level expertise in the field of innovative pharmaceuticals, as we gave relevant conclusions on iodine-containing drugs produced in Obninsk," Ivashchenko comments. The first state contractor company was the "Technology of Medicines" created by Himrar in 2007. In 2011, she received a grant of 18 million rubles for the development of technology and organization of the production of generic sotalol – a drug against tachycardia, angina and other cardiac problems. Himrar registered its sotalol at the end of 2014 – two years after the registration certificate for a similar drug was received by Kanonfarma, which dispensed with grants. During the sotalol competition, Kanonfarma's application for registration was already submitted. "Such cases are not uncommon," says Galina Baryshnikova from Kanonfarma. – We have several drugs in production from the list of 57 import-substituting ones. We tried to participate in grant competitions, but we were refused three times – for formal reasons, in my opinion." Kanonfarma did not notice another sotalol entering the market – it did not affect its sales.

In total, the "Technology of Medicines" won state contracts in the amount of about 500 million rubles. For the entire time of its existence, it has registered a dozen and a half generics and only in three cases was ahead of its Russian competitors in this. The idea of Pharma 2020 is that in a few years the "generic potential" of the industry will be exhausted, and then innovative drugs will be needed to develop further. But the cycle of their creation is longer, so funds for development are already being allocated now, in parallel with grants for generics. Himrar is an important actor in the innovative part of the state program.

Over the past four years, the Ministry of Industry and Trade has issued several hundred grants for innovative medicines. VADEMECUM has compiled a rating of their recipients. Since the names of the winners sometimes mean nothing even to a specialist – these may be newly created venture projects – we have summarized the grants of companies with the same major shareholder. These are the companies "Selecta", "Bind" and "Panacela Labs", where the investor is Rusnano, or the companies "Infectex", "Neuromax", "Osteros Biomedica" and a number of others, in which RVC owns shares through one of the funds created with its participation. The same is true with startups supervised by Himrar. For example, the company "Intellectual Dialogue", specializing in the development of innovative drugs for the treatment of infectious diseases, is wholly owned by "Himrar" and "Himrar Ventures". Biointegrator, a developer of drugs based on recombinant proteins, was 91% owned by Himrar Ventures at the beginning of 2012. In the capital of Saterex, which is engaged in "a wide range of pharmaceutical developments of new promising compounds," 98.5% belongs to Himrar Pharma and so on. According to VADEMECUM's calculations, in total, startups to which Himrar was directly related received almost 1.8 billion rubles from the Ministry of Industry and Trade for a dozen venture projects over four years. The next "Pharmstandard" earned half as much on the innovative part of "Pharma 2020" (for more details, see the table "Nowhere except in the Ministry of Industry").

One of the options for such a transfer is the refinement of the molecule, which some representative of Big Pharma refused for one reason or another. There are three of them in the Himrara portfolio – one from Pfizer and two from Roche. The Americans provided the company with a molecule for a diabetes drug for free – in exchange for royalties from possible future income, expressed, according to Ivashchenko, in the single digits of percent. "A company of the caliber of Big Pharma needs to get a billion," explains Ivashchenko, "and it makes no sense to work with a molecule that promises an income of, say, $50 million." Big Pharma can transfer such molecules to a small but well-known innovative company like Himrar.

By transferring the Pfizer molecule in 2011, she decided to contribute to the development of the Russian healthcare system, Olga Krylova, the company's senior research director in Eastern Europe, told VADEMECUM. There were few companies that could bring new molecules to the market, Himrar, of course, was among the candidates, for its part also showed interest, and the contract was signed. Prior to that, Krylova clarified, Pfizer had not cooperated with Himrar. Roche gave Himrar the molecules for an innovative antithrombotic and anti-AIDS medication. Both are currently at the stage of clinical trials. The drug against AIDS is still called VM-1500, the Register of Issued Permits for Clinical Trials of Medicines (RCTs) reports that an international multicenter study of its efficacy and safety began on April 21, 2014 and should end in December 2016. Clinical trials of the drug TRX (the so-called antithrombotic), according to the RCT, have been going on since August 2013 and are completed in December this year. Roche did not answer the question of how this cooperation arose.: "In June, all the speakers who have this information are on business trips." A rumor is popular on the market that Viktor Khristenko personally lobbied for the transfer of three molecules to Himrar. They say, having the status of a partner of Big Pharma, it will be easier for an unknown person in broad power circles of the Central Bank to fight for participation in the distribution of state subsidies.

At least, it is still difficult to determine a different value of the gift and its prospects. "Large companies usually have portfolios for outsourcing, this is a fairly common story," says Dmitry Ovchinnikov. – Some molecules may not suit them because of the narrowness of the market. Or their action is not what the company needs." As a rule, the seller earns not on the transfer of development, the fate of which is unclear, but on participation in possible future income. The Chairman of the Board of Directors of Himrara believes that the products will "shoot" to everyone's satisfaction. According to Ivashchenko, his research experience allows his companies to choose promising molecules: "For example, we chose two out of a dozen projects from Roche, one from Pfizer, and nothing was chosen from Novartis."

The company, even after winning a grant for a transfer, is seriously at risk. Grant recipients are required to finance a startup in half with the state, and allocate half of the amount provided by the Ministry of Industry and Trade to the pre-clinic and CI. In the case of Himrar, this is more than 700 million rubles for technology transfer contracts and about 100 million for clinic and preclinical contracts. "The ratio of amounts strongly depends on the specifics of accounting," says a market participant who asked not to be named. Another innovator confirms that the "under-contribution" of the required amount is a common practice in the execution of such contracts. Ivashchenko also assures that all innovative companies of the Himrar group spend several times more funds than the grants attracted under state contracts. If we recall the figure of annual turnover of $ 30 million that he named, then an amount close to the turnover of the entire group should be spent on innovations.

In the spring of 2010, he signed an agreement with the leader of the market of public procurement of medicines – Alexey Repik's R-Pharm – on the joint production of pharmaceutical substances in Yaroslavl. The project was named "Pharmoslavl". Half of it belonged to Himrar, half to R–Pharm, Vasily Ignatiev, CEO of R-Pharm, told VADEMECUM. Himrar was supposed to provide R&D – develop production technologies. And R-Pharm was responsible for investments, production and sales. "There is no longer the same format of cooperation," Ignatiev says. – And we have retained Pharmoslavl, having bought out the share of Himrar in it.

Why did the cooperation break down? The scheme of this very closed transaction was more complicated, explains a market participant familiar with the situation. Among other things, the responsibilities of the "Himrar", who has serious experience in this field, most likely could include receiving state support for the project. It is possible that Ivashchenko's company did not have time to receive the promised registration certificates for drugs and substances on time, and maybe it did not fully implement its other promises. Which, apparently, gave R-Pharm a reason to break the agreement, while becoming the absolute owner of the project. At the same time, Himrar also lost the "Technology of Medicines": according to SPARK Interfax, now 10% of this company belongs to Alexey Repik, the owners of the remaining 90% are not specified.

Pharmoslavl will start working next year, Ignatiev says, but R-Pharma does not have a permanent R&D partner right now: "We are free to take what we need from the market." Pharmoslavl is now "scaling up the development of "Drug Technology" at its factories independently, we have nothing to do with this," confirms Ivashchenko. But, according to him, "Drug Technology" is an example of a successful exit of "Himrar" from the project. The details of the transaction with R-Pharm are not subject to disclosure, but, Ivashchenko claims, it certainly brought a certain profit to Himrar.

In any case, the "production theme" did not end there. This spring, it became known about a new project: this time Himrar has agreed on a partnership with another ambitious wholesaler – the Lancet company. For the industry audience, the project is declared as a "joint activity using complementary competencies" for the development, production and marketing of innovative medicines. But the essence is still the same: the partner is again the fast-growing Lancet company, which broke into the top ten of the rating of state drug order operators by the end of 2014. It is noteworthy that the co–owner of Lancet, he is also the commercial director of the company Anton Zybin, also left R-Pharma. Andrey Ivashchenko and Lancet's top managers did not want to tell VADEMECUM the details of the agreement. However, it is known that the joint venture will try to copy the business model of R-Pharma, locking in the functions of a developer, manufacturer and distributor of drugs, the main market for which remains public procurement. First, Lancet will try to establish cooperation with the already mentioned "Chemrar" company "Biointegrator", which aims to produce analogues of best-selling state drug programs, including the "Seven Nosologies" program. Next, the partners want to build a factory from scratch, where they will be able to produce both their own drugs and products for third-party customers interested in contract manufacturing services and promotion of drugs on the state order market. Dmitry Kulish believes that in this partnership, the success of Himrar is more likely – he has more developments close to the registration stage and already on the market now than a few years ago. And it will be easier to implement them (through government orders or in commerce) together with the Lancet.

In a word, it is possible that as a result of all the tricks and hundreds of millions spent by the Ministry of Industry and Trade, "Himrar" will finally get off the "combinatorial needle". Andrey Ivashchenko sees the future of pharmacology not in combinatorics and in general not in traditional blockbuster medicines, but in the development of personalized medicine. In his group of companies, the project of developing a personal vaccine "NewVak" is dedicated to this. "They take a weak immune response of the body to a specific type of cancer, strengthen it in the laboratory and inject it back to the person," explains Ivashchenko. But in order for such a medicine worth $ 10-15 thousand per course to start being used regularly, a lot of changes must occur in the entire healthcare system. In the meantime, the project, which received a 120-million grant, had to be frozen. Now "NewVak" is engaged together with Johnson & Johnson in research of innovative drugs, but not so much ahead of their time.

Portal "Eternal youth" http://vechnayamolodost.ru

23.06.2015