Biopharma 22-1
Important biopharma news of the first half of 2022
Ilya Yasny, XX2 century
Let's start with what worries, probably, everyone without exception: how the Russian Federation 's military actions in Ukraine and the subsequent sanctions have affected access to medicines in Russia and affected the global development of new drugs?
Will the medicines be lost?
The initial surge of excitement has passed, when some drugs in Russia disappeared, and then reappeared, but at increased prices. On average, by the middle of 2022, prices have increased by 5-15%, but for some imported medicines — by 40-50%. By the middle of 2022, many medicines have returned to the shelves, but some important items are still missing and, in general, 70% of the surveyed doctors say there is a shortage of important medicines — most often there are not enough antiepileptic drugs that lower blood pressure, insulins and hypoglycemic, psychotropic drugs and drugs for the treatment of thyroid diseases. Traditionally, there are not enough medicines to treat HIV and hepatitis C. Separately, there is a shortage or even a complete absence of preferential drugs for children. At the same time, all foreign pharmaceutical companies either announced that they would not stop supplying vital medicines to Russia, or sold the Russian business to local legal entities like Bristol Myers Squibb, so that the shortage of preferential medicines is connected either with logistics or with failed state tenders. What awaits the pharmaceutical sector next?
About 50% of the names of medicines are produced in Russia, and from the list of vital and essential medicines (VED) — and even more, about 80%. However, this means that even in this list, 20% dependence on imports remains. In addition, even if the medicinal substance is produced in In Russia, the raw materials and consumables are still 90-95% imported. True, most of these imports come from China, but there is also dependence on European manufacturers. A very important aspect is the excipients: the quality of medicines critically depends on them, and they often cannot be replaced with Chinese or Indian analogues without loss of quality. There is also dependence in the field of medical devices: as officials found out, 1,500 necessary medical products are not produced in Russia and "friendly countries", of which about 800 cannot even be started in the near future.
Problems with import dependency have arisen in unexpected places: thus, it was reported about the shortage of cardboard for packages, vials, lids, interruptions in the supply of carriers and columns for chromatography, which are necessary for the analysis of drugs. All these problems are solved by importing similar products from China and other countries that have not imposed sanctions on In Russia, however, this leads to higher prices and in some cases requires additional research to prove that the medicinal product is similar to the old one. In order to learn from the experience of working under sanctions, Russian specialists are sent to Iran. An important problem is the lack of Russia standard samples for most drugs, the originals of which are developed in the USA and the EU: they are necessary to check each batch of the reproduced medicine and were previously purchased abroad. It is possible that Russian working samples will be used to solve this problem, but this may have an unpredictable effect on the quality of generics.
To reduce dependence on imported medicines, many Russian pharmaceutical companies have started developing generic drugs those names that do not yet have Russian analogues — the number of relevant clinical trials increased by almost 90% from January to May. However, this is not a quick matter: it takes about a year and a half to develop and register one generic, if you do everything according to the rules. In addition, since in In Russia, the regulation of the development and production of medicines is inferior to Western European practices, the quality of Russian generics is still not always up to par.
And what about innovation?
But with the development of new drugs, it's really bad. All the companies of "big Pharma" announced the termination of new clinical trials in Russia, and some stopped ongoing research. They are under political pressure, and logistical constraints also affect them.
Global drug development has also suffered losses: Russia and Ukraine were important territories in terms of recruiting new patients. Research on some drugs will slow down, since now you will need to look for where to recruit the same number of people — we are talking about thousands of research participants. According to Russian law, conventional medicines (not for rare diseases and not for combating epidemics) can be registered in In Russia, only if at least one center on the territory of the EAEU took part in a registration clinical trial. So either legislators will have to change this law, or Russians will be left without new medicines. Now they are transported individually from abroad, as the employees of the Circle of Good Foundation do, but you don't get manure for everyone in need. Of course, without paying attention to patents, you can try to reproduce these drugs in Russia, but there will be questions about the quality of such drugs, and the reproduction of biological products is a task for five years at all.
And, of course, the biggest loss is people. Many researchers and competent specialists in drug development have left Russia, and isolation from Western countries will contribute to a decrease in the qualifications of Russian manufacturers. The only way to catch up with the Western biopharmaceutical industry was the integration of Russia into international processes, internships of specialists abroad, adopting the best world practices and experience. Now this road is mostly closed.
As a result, we can conclude that Russians will not remain completely without medicines, but their price will increase, the quality is very likely to decrease, interruptions with individual positions will continue, the emergence of innovative medicines will be difficult.
Now let's move on to the biopharma world news.
Another breakthrough in the treatment of breast cancer
Breast cancer is generally treated well until it reaches the metastatic stage, when many tumors become immune to treatment. The situation is especially difficult with the so-called "triple negative" breast cancer, in which three receptors are missing in cancer cells: estrogen, progesterone and HER2 (human epidermal growth factor). At the same time, drugs literally have nothing to cling to, and cancer cells continue to survive and divide. There are only very non-specific options for radio and chemotherapy, which do not help much.
The drug acting on the HER2 receptor is known to many — it is the antibody Herceptin (trastuzumab), first approved in the USA in 1998. In 2010, several more improved anti-HER2 antibodies and antibody drug conjugates were released. However, if the patient has little or no such receptor, such drugs were not used because they did not expect effectiveness. And one of them, Enhertu (Daichi Sankyo/Astra Zeneca), was tried in women with low HER2 expression — and it worked! The median survival of patients receiving Enhertu was 23.4 months compared to 16.8 months in the control group, which corresponds to a 36% reduction in the risk of death. In addition, there were fewer adverse events in the Enhertu group, because the patients did not receive chemotherapy.
Where does such efficiency come from? The fact is that ordinary antibodies bind to the HER2 receptor and block it, but the cancer cell may not die at the same time. But an antibody conjugate with a drug, such as Enhertu, binds to the cell and delivers a toxin inside, which leads to its death.
Figure 1. Mechanism of action of Enhertu (trastuzumab-deruxtecan). The antibody part of the drug is the same as that of Herceptin (trastuzumab). With the help of peptide linkers, the toxin deruxtecan (yellow stars) is attached to it. The antibody binds to the HER2 receptor, enters the lysosome, where the toxin is released and enters the nucleus, irreversibly damaging the DNA of the cell.
The new result changes the paradigm of treatment of metastatic breast cancer. Previously, with HER2-positive status, the patient was treated with anti-HER2 antibodies, but with HER2-negative there was no such option. Now it has become clear that it is necessary to introduce a new HER2-low status, in which to give Enhertu, and this greatly expands the number of women who will be shown targeted therapy. Enhertu and other similar drugs are now being investigated in patients with even lower HER2 expression, so further success is possible.
Virus-"computer" kills cancer (in mice)
Such targets as HER2, so that there are few of them on healthy cells and many on cancer cells, are few. It often happens that the drug affects healthy cells too much and it is not possible to find a suitable dose that would not be too harmful.
It would be great if the drug could "distinguish" cancer cells from normal ones with a specificity close to 100%. Scientists were able to get closer to this cherished goal with the help of viruses with programmable gene sequences. They can be configured for several targets so that cancer cells fit the criteria for destruction, but normal ones do not fit.
Figure 2. The general principle of the organization of logical elements in a cell.
In the current version of the virus, there are two logical components — "AND" and "NOT". In other words, a virus can kill a cell only if it contains an x signal and a y signal, but NOT a z signal. In this case, proteins, mRNAs, peptides and other intracellular molecules, including previously inaccessible ones, can act as signals. In this case, the researchers took an adeno—associated virus (AAV, it is already used for gene therapy of rare diseases) as a virus, and liver cancer as a disease. A reasonable choice, given that this virus prefers to infect the liver. Further, transcription factors (proteins that control transcription, that is, the synthesis of RNA on the DNA matrix) specific for liver cancer were chosen as x and y signals. And as a signal, z is micro-RNA, which is present in healthy liver cells, but is almost absent in cancer cells.
Using a "NOT" signal is an interesting move, given that all previous therapies are aimed at what is in cancer cells, and not at what is NOT in them.
From these logical elements, a gene construct was assembled, which was packaged in AAV (it had to be minimally optimized, just like computer code on ancient computers, because the capacity of the virus is limited). When this construct is injected into mice with a liver tumor, the virus mainly infects liver cells, including cancer cells, but only in cancer cells the logic circuit is triggered and starts the production of HSV-TK protein. If such mice are given ganciclovir, the cells producing HSV-TK turn it into a toxic drug and the tumor size decreases.
There is still a long way to go before testing the new technology on humans. The experiment was conducted on mice without an immune system, so immunity against the virus has not been studied. And in general, it may turn out that the specific designs that worked in mice are unsuitable for humans. But there is no doubt that conceptually logical switches that take into account cellular characteristics are an important tool for future therapies.
A new type of immuno-oncological medicine is already on the market
Immuno-oncology is experiencing a rapid flourishing: almost every year new drugs are registered that directly or indirectly affect the immune system in order to fight tumors. However, we still have a poor understanding of the details of the most complex mechanisms of interaction between the tumor and immunity, so each fundamentally new approach in this area, which has proven its effectiveness, becomes an important event.
The approval of Immunocore's tebentafusp drug was such a milestone because it is the first example of therapy aimed at HLA proteins on the surface of malignant cells, and even for the treatment of a terrible, albeit rare disease — eye melanoma. This cancer is often asymptomatic, but in rare cases it gives metastases to the liver and brain, and then there is no effective treatment for it.
Tebentafusp is the first approved targeted therapy for metatastic uveal melanoma. It is a protein product consisting of two parts: antibody fragment against CD3 T-cell protein and extracellular part of T-cell receptor (TCR) specific against gp100 HLA fragment complex. Malignant cells, like most other cells of the body, expose fragments of their intracellular proteins on the surface (in combination with the HLA protein) so that the immune system can "check" them and make sure that the cell is in order. Otherwise, the cell is ordered to self-destruct (this is called apoptosis). Cancer cells avoid apoptosis, but many of them still carry fragments on the surface (in this case, the gp100 protein specific for melanomas was selected), by which they can be recognized, but the patient's immune system is unable to cope with it. When the researchers scouted the details of these processes, they came up with the idea to help the immune system. Tebentafusp does this: with one of its "ends" it binds to T cells and activates them, and with the other it binds to a cancer cell. The activated T-cell, getting closer to the cancer cell, kills it (see video).
In a comparative phase 3 study, which included people who had already unsuccessfully undergone at least one course of treatment for unresectable metastatic uveal melanoma, the median overall survival in the tebentafusp group was 21.7 months. compared with 16.0 months in the control group, which corresponds to a 49% reduction in the risk of death.
The drug is not suitable for everyone, since it is specific to a certain type of HLA on cancer cells (HLA-A* 02:01); for example, in the USA, about 45% of such people. The instructions of the drug contain a warning about a serious undesirable phenomenon — cytokine release syndrome, but this is a common thing for immuno-oncological drugs, and doctors, as a rule, are able to cope with it.
It is hoped that this drug is only the first swallow in a series of similar drugs and there will be others aimed at new targets and new indications.
A new target for immuno-oncology
The most powerful breakthrough and the biggest achievements of immuno-oncology began in 2011, when the first drug from the checkpoint inhibitor class was registered, about which the XX2 century wrote a lot. We are talking about antibodies against receptors on the surface of immune or cancer cells that "prevent" the immune system from performing its functions to destroy a cancerous tumor. Thus, these antibodies remove the "brakes" from the immune system, and in many cases it turns out to be able to cope with the tumor. So, if earlier patients with metastatic melanoma or lung cancer were practically doomed, now 20-30% are cured completely. And the question arises — how to help the remaining 70-80%?
The first target of this type, CTLA-4, eventually turned out to be not very promising: there were too large adverse events due to excessive activation of the immune system. But the antibodies Opdivo (nivolumab) and Kitruda (pembrolizumab), directed against PD-1, have become megablockbusters (their sales amount to tens of billions of dollars a year and are constantly growing) and have entered the standards of therapy for a number of cancers. The third target, PD-L1, PD-1's binding partner, predominantly expressed on cancer cells, also proved promising. At this point, until 2022, the arsenal of targets was exhausted — attempts to create antibodies against other targets failed, as a rule, due to insufficient effectiveness. So, already this year, studies of antibodies against TIGIT failed, on which high hopes were pinned.
And now — the long-awaited success. The Bristol Myers Squibb relatlimab antibody against the LAG-3 receptor has shown efficacy in combination with nivolumab. Median progression-free survival was 10.12 months versus 4.63 months in the group of patients receiving only nivolumab. The data are promising, and the drug has been registered by the FDA, but it has yet to prove a positive effect on overall survival — so far only a 20% reduction in the risk of death has been shown.
The path to the effect on the target of LAG-3 was not short: like other immune checkpoint receptors, this one was discovered in the 1980s and did not attract much attention for a long time, but already in 2001 a company was founded to develop drugs against it. After a number of unsuccessful attempts, it became clear that the LAG-3 blockade alone does not work, a combination with an anti-PD-1 antibody is necessary. By the way, the anti-CTLA-4 antibody is also combined with PD-1 blockade, but this combination, together with an increase in efficiency, gives a strong toxicity that many patients do not tolerate. In the case of LAG-3, it turned out that the combination with nivolumab is not much more toxic than nivolumab alone.
Figure 3. The combination of nivolumab and relatlimab blocks two receptors at once, with the help of which the tumor cell does not allow the T-lymphocyte to kill itself.
Scientists hope that the approach will be universal enough, and it will be possible to extend it to other tumors — in the case of CTLA-4 and PD-1, too, everything started with melanoma.
An analgesic, but not an opiate
Pain management is one of the most difficult areas in drug development. On the one hand, painkillers are a dime a dozen, on the other, not all needs are met. First of all, nonsteroidal anti-inflammatory drugs such as ibuprofen, ketorolac or etoricoxib are used to relieve pain. However, they are not sufficient to treat really severe pain, such as neuropathic pain in cancer patients, various postoperative pain or diabetic neuropathy. Here opiates come on the scene, which are effective, but have a number of well-known problems: addiction, abuse, severe adverse events (in particular, respiratory depression), difficulty with access due to legal restrictions. Therefore, the search for substances no less effective than opiates, but safer, does not stop. Minimum program — substances that reduce the effective dose of opiates.
The development of new drugs against pain encounters a number of barriers. Firstly, the pathogenesis of pain is very diverse and has not been fully studied. There are a huge number of types of pain (dozens or even hundreds), and almost always pain has a central, subjective component. That is why it is so difficult to study it in clinical studies: where one person answers that the pain is tolerable, the other will scream from it. And after all, you can't check what a person feels "really"! So, many researchers note that in Russia has an increased pain threshold on average, and international studies of analgesics have to take this into account. In addition, mouse models of pain are very imperfect — a number of mouse proteins involved in the pathogenesis of pain differ from human ones, and methods of measuring pain (for example, by pulling the paw away from a hot plate) also differ from human ones (where questionnaires are used).
Therefore, it is clear that any message about success in this area is received with enthusiasm, and this time it came from an unexpected side: Vertex, the famous developer of drugs against cystic fibrosis, announced the success of two phase 2 clinical trials of its analgesic. The drug was studied in patients who underwent surgery to correct the shape of the abdomen (abdominoplasty) or to remove one of the metatarsal bones (bunionectomy).
The drug was compared with placebo and with the opiate analgesic hydrocodone. At a high dose, the drug surpassed both placebo and hydrocodone in effectiveness (measured on the pain scale).
The target of the new drug is Nav1.8, a sodium ion channel on the axons of nerve cells involved in conducting a nerve impulse. This is a large transmembrane protein (that is, it passes through the cell membrane), which contains a pore for sodium ions to pass from the outside of the cell to the inside in response to a change in the membrane potential. At rest, the potential on the axon membrane is -70 mV. In response to an increase in the potential to -55 mV (action potential), the ion channel opens and sodium ions enter the cell, increasing the potential to +30 mV, which is called membrane depolarization. Then the ion channel closes and remains inactive for a while. This ensures the propagation of an electric pulse along the axon in only one direction. Other channels are also involved in conducting the pulse, for example, potassium channels, which pass potassium from inside the cell to the outside. After the pulse is carried out, ion pumps pump sodium ions out of the cell and pump potassium into the cell to restore the resting potential.
Figure 4. Schematic structure of the sodium ion channel. It consists of four similar subunits (I—IV), each of which contains a potential-sensitive domain 4 (green) carrying many positive charges. The picture shows a side view. Four subunits form one pore (see Fig. 5).
Figure 5. Structure of the sodium ion channel obtained by X-ray crystallography. View "from above". In the center, a pore is visible through which sodium passes.
It turned out that it is the selective suppression of Nav1.8 that can affect the occurrence of neuropathic and inflammatory pain due to the nature of expression of this receptor. The difficulty is to develop a sufficiently specific inhibitor that will suppress the protein exactly as needed, and at the same time will not affect the conduct of normal nerve impulses too much. Previously, such attempts were made, but all research was stopped. Hopefully, Vertex will turn out no worse than with cystic fibrosis.
"Google Maps" of human cells
Decoding the human genome 20 years ago, although it did not solve all the problems of biology, but greatly advanced us in understanding how genes and cells are arranged. About 10 years ago, scientists thought about the next level of complexity, fortunately, technology already allows. This is how the Human Cell Atlas project was born to solve the ambitious task of conducting a census of all cells of the human body. This is done using single cell RNA sequencing, RNA sequencing at the level of individual cells. This makes it possible not only to classify cells more accurately by type, but also to obtain a lot of useful information about the structure and functions of each specific cell, both in a healthy state and in various pathologies.
A project of this scale cannot be implemented by any laboratory alone — coordinated efforts of scientists from all over the world are required. Now the project employs more than 2,000 scientists from 83 countries, including Russia. Sponsors are government and non—profit organizations, for example, the Chan Zuckerberg Initiative.
In the spring of 2022, the first draft version of the atlas and four articles in the journal Science with interim results were published. To date, several tens of millions of cells have already been sequenced, which has made it possible to build a map of approximately 500 types of cells in 33 organs. There was also a study of the development of immune cells during embryonic development. Another article is devoted to the definition of cell types associated with 8000 genetic diseases.
The work on the creation of the atlas has already brought several discoveries: a new type of cells in the lungs, called an ionocyte, has been discovered, the difference in the cellular composition of the heart in women and men has been studied, studies of rare types of intestinal cells, such as enteral neurons, and so on have been conducted.
The aim of the project is to further accumulate data and process them, which will deepen the understanding of the work of organs, create new diagnostic and therapeutic tools. The main problem that has not yet been solved is the work of which genes and when makes each cell exactly what it is. What is published now is only the first draft and the tip of the iceberg. There are many more important discoveries ahead of us on this path.
Figure 6. Crypts (recesses in the wall) of the intestine, stained by histological methods. Blue, red, green and yellow are marked with different types of cells.
The US Antimonopoly Agency took on the culprits of high prices
The United States has the highest drug prices in the world. At the same time, insurance coverage there is far from ideal: millions of people do not have insurance at all, and, consequently, access to expensive modern medicines, and the rest have to pay extra for them out of pocket despite having insurance, and this situation causes fair indignation among many. Drug costs account for about 15% of all healthcare costs in the United States, which are huge there: almost 17% of GDP (for comparison, in the Russian Federation in 2019 they amounted to 5.65%). But, unlike the costs of hospitals, equipment, and doctors' salaries, which are only growing, the costs of medicines fall sharply after the expiration of the patent, when reproduced drugs enter the market.
High prices during the patent period allow us to pay for the development of new drugs, because, recall, 90% of drugs for which clinical trials begin fail. Actually, this is partly why the most new drugs are being developed and registered in the United States, and those who say that the United States, in fact, sponsors the development of drugs for the whole world are right.
But prices are rising even for old drugs, such as insulin. At first glance, greedy pharmaceutical companies are to blame, driven only by the thirst for profit. This is a convenient target: they are in plain sight, they really have sins, especially in the past, before 2010, for which they are still paying, and even now there are abuses — people are people. In the political struggle, both Republicans and Democrats regularly attack bigpharma and demand either legislative price restrictions, or permission for parallel imports from countries where the same drugs are cheaper, or some other simple measures that voters like to hear about. At the same time, opponents of such measures argue that there may be a short-term effect, but access to medicines will become worse, and most importantly, the pace of innovation will decrease so much that the world will miss many new medicines.
The real problem, they say, is not pharmaceutical companies, but intermediaries, primarily PBM (pharmacy benefit managers). This is the layer between drug consumers (hospitals, pharmacies) and manufacturers (pharmaceutical companies), which in the United States has become the main force influencing drug pricing. Formally, their task is to bargain for the best prices for consumers, and to take a percentage of discounts for themselves. It seems that this should lead to lower prices for consumers, but in fact it leads to an increase in purchase prices from sellers. Moreover, an opaque and very complex system of discounts, deductions and refunds (well, if not kickbacks) leads to the fact that pharmaceutical companies do not receive increased revenues — the entire margin settles in the pockets of PBMs.
And so, to the great delight of industry players, the US antitrust authority, the FTC, has launched an investigation into PBMs. The six largest companies must disclose their internal cuisine to officials. Senators of both parties who advocated such an investigation are confident that it will reveal the unsightly facts of price manipulation and lead to a ban on such practices.
It would seem that this is an internal matter of the United States, but drug pricing in the States affects the whole world: financial models of investors and pharmaceutical companies depend on forecast prices, and the intensity of new drug development depends on them, prices in all countries of the world for these new drugs, global initiatives, including charitable ones, and so on.
The first microbiome preparation
As probably everyone already knows, about 2.5 kg of bacteria live in the intestines of an adult. Of course, they affect our health, and the study of the microbiome has become a fashionable and promising scientific direction. But this is a very difficult object: the intestinal microbiome is extremely individual and changes literally during the day. The intestinal microflora affects everything: the psyche, the development of cancer, and, of course, obesity. True, reliable ways of influencing it with proven effectiveness are still almost unknown, but there is plenty of speculation. Sellers of various probiotics and prebiotics, dietary supplements and complexes will not fail to mention the effect on the microbiome as an intermediary for the effect of their miracle remedy, but only methods of evidence-based medicine can demonstrate whether this or that effect is really effective and safe.
At the moment, the first and only microbiome drug product with proven efficacy against a single indication is a Seres Therapeutics drug for the treatment of recurrent Clostridium difficile infection (C. Diff). This infection is the most common cause of hospital infections in the United States, and in the United States alone it claims about 20,000 lives per year. As you know, hospitals are hotbeds of antibiotic-resistant bacteria, so 20-60% of patients who have picked up an infection do not respond to antibiotic treatment (or the infection returns quickly, this is called recurrent).
C. Diff, like many other pathogens, live in the large intestine and in healthy people, but against the background of antibiotic treatment, the balance of microflora is disturbed and they can activate and begin to multiply, poisoning the body with toxins, causing diarrhea and intestinal inflammation — colitis.
In 2013, a small study showed the effectiveness of fecal transplantation (fecal transplantation) for the treatment of recurrent C.diff infection. Fecal transplantation is a long—known method (first described already in the IV century in China). But it is not too technologically advanced, although in the USA and Europe whole fecal storage facilities have been created, where healthy volunteers can donate it. The FDA has issued several warnings regarding the transmission of antibiotic-resistant bacteria through donor feces. The procedure is now allowed and practiced in the USA, but no manufacturer has registered a medicinal product based on a fecal transplant. In Russia, the procedure is available as part of the "research program".
Seres has taken a more technological path: their product is purified bacteria isolated from the feces of healthy donors, in a capsule for oral use — unlike fecal transplantation, which is usually performed rectally. Despite the initial failures in clinical trials, the company did not lose its head, increased the dose of the drug and conducted a phase 3 study, which turned out to be successful. Among the patients taking the drug, after 8 weeks, only 12% of C. Diff infection recurred, whereas in the placebo group there were 40% of such. The safety of treatment did not differ from placebo.
Figure 7. The general idea of Seres is to plant healthy bacteria in the intestines of a patient with a disturbed microbiome, so that they populate it, multiply and have an impact on the course of the disease.
The company is going to submit documents for FDA registration in mid-2022. The question is, which doctors will use more likely — fecal transplantation or a new drug that will probably cost more.
So far, we repeat, this is the only microbiome drug with proven clinical efficacy. Seres' program for ulcerative colitis has failed, and fecal transplantation has not yet shown effectiveness either in inflammatory bowel diseases or for the treatment of obesity or autism. However, scientists do not lose hope in the future to learn how to influence the microbiome for the treatment or prevention of diseases.
Hepatitis B seems to be amenable
The best protection against hepatitis B is vaccination. And although the vaccine began to be introduced in the 1980s, there are still many unvaccinated in developing countries and among the elderly population. As a result, hepatitis B affects more than 350 million people in the world, and 1.4 million people die from it a year. There is no effective treatment for this disease, and the transition of the disease to a chronic form threatens the development of cirrhosis and liver cancer. The existing therapy — interferons and nucleoside analogues — are toxic, and they must be taken constantly to control the disease: the cure rate does not exceed 5%.
The development of hepatitis B drugs is very difficult: the life cycle of the virus is complex, and it has learned to hide from the immune system and drugs. Therefore, despite numerous attempts, it was not possible to achieve even a functional cure — a steady decrease in the viral load after the end of the course of treatment, so that the immune system could continue to cope with the control of the virus itself.
Figure 8. The life cycle of hepatitis B virus. Like the human immunodeficiency virus, the hepatitis B virus has a reverse transcription stage, but its genome is represented by DNA (not RNA, as in HIV).
GSK announced the successful results of the phase 2b study, which recruited both untreated patients and those taking nucleoside analogues. In both groups, after 24 weeks of treatment, the virus was not detected in 28% of patients. Now it remains to wait for the results of long-term follow-up after drug withdrawal, but such data are impressive.
The drug belongs to a new class of RNA therapy - it is an antisense oligonucleotide specific to the RNA site of the virus. GSK licensed it from Ionis in 2019. There are other RNA drugs against hepatitis B in development, but so far only data from earlier stages of clinical trials are available for them.
This is good news for patients with hepatitis B, but there is still room for improvement — after all, more than 70% did not respond even to this modern therapy.
Some patients with hepatitis B are also infected with hepatitis delta — this is not even a virus, but a virusoid, which in some sense parasitizes the hepatitis B virus, because it requires part of the proteins encoded by the genome of the hepatitis B virus to reproduce. Hepatitis delta is characterized by an even more severe course of the disease - half of the patients die within 5 years.
In June, Gilead published data from a 48-week follow—up of patients receiving bulevirtide, a new and only proven anti-hepatitis delta drug. In 45% of patients receiving the drug, a virological response was observed, whereas in the placebo group there were only 2% of such patients.
Figure 9. Boolevirtide, a synthetic peptide preparation, is a fragment of the human protein NTCP, which the hepatitis delta virus uses to penetrate the cell.
The fate of this drug is interesting. It was invented by scientists from the University of Heidelberg and INSERM (France), had difficulties with financing, and even at the stage of the beginning of clinical research, the subsidiary fund of RVC — Maxwell Biotech invested in it. The Hepatera Company was established, and with the support of the Skolkovo Foundation, Phase 1 and 2 clinical trials were conducted in Russia, Ukraine, Germany together with MYR GmbH. According to these studies, the drug was registered in Russia, and also received conditional registration in the EU (the condition is further continuation of research) In 2020, MYR was bought by Gilead for 1.15 billion euros, and new data opens the way for the drug to full registration.
Thus, bulevirtide became the only drug in the development of which Russian specialists and investors played a significant role, and at the same time registered in the EU (and, hopefully, in the near future in the USA).
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