Bigfarma-2017, the first half of the year

The main news of "Big Pharma" for the first half of 2017

Ilya Yasny, XX2 century
For links, see the original article – VM.

We present to your attention the traditional semi-annual review of the most important news of the pharmaceutical industry and medical biotech, prepared by our expert Ilya Yasny.

CAR-T successes

In the field of CAR-T, which we have repeatedly written about, several high-profile events have occurred over the past six months. Company Juno Therapeutics stopped its CAR-T program due to the death of 7 patients in 2016. Closest to the finish line in the race for the company's FDA registration Kite Pharma and Novartis International AG, which continue to fuel public interest with news about successes.

Kite in February reported 6-month study data in patients with aggressive B-cell lymphomas resistant to therapy. More than a third of the patients were cured after a single injection of the drug, almost all were alive. This is an amazing result, since usually only half of such patients live up to 6 months. The picture was somewhat overshadowed by the death of one of the patients due to brain edema (as in Juno), however, the company and the regulator claim that the patient was extremely severe. The meeting of the FDA commission to review the application for registration is scheduled for November 29.

Novartis has published similar data on the effectiveness of its product, and no cases of neurotoxicity have yet been observed in its study. The FDA meeting is expected at the end of September, about 2 months earlier than Kite.

Kite is somewhat superior to Novartis in terms of product production speed. Now the production of these products takes 3-4 weeks and costs tens of thousands of dollars. This is due to the fact that the cells are taken from the patient himself, modified by genetic engineering methods and injected back into the patient. For some patients, it is impossible to get a product at all, and an individual approach is the reason for such a high price.

To solve this problem, Cellectis develops cells taken not from the patient himself, but from donor material. The cost of this technology, as the company promises, will not exceed $ 10,000. However, clinical data have so far been obtained on only 2 patients, of whom one had a "graft versus host" reaction – fortunately, it was managed to cope with it.

All of these products are directed against the same protein on the surface of B-cell precursors – CD19, therefore they are used only in patients with B-cell lymphomas and leukemias. At the ASCO (American Society of Clinical Oncology) Clinical Oncology conference in June, data on products against BCMA, another protein characteristic of multiple myeloma, were presented for the first time. For a long time, the well-known American companies bluebird bio (whose capitalization is about $ 4 billion, despite the lack of products on the market) and Celgene Corporation (one of the biotech giants) were the leaders in this area, but this year the Chinese startup Nanjing Legend Biotech suddenly burst into the circle of competitors, reporting 100% objective answers there are 35 resistant patients with multiple myeloma for therapy. 5 patients have been observed for a year without signs of illness. Almost no one has ever heard of this company before, and there is an assumption that this is not the last surprise that the Chinese biotech will present.

Figure 1. The chimeric receptor is shown as a green-blue-red "fork" on the surface of the T cell. It binds to the yellow CD19 protein on the surface of the tumor cell, which leads to the activation of the T cell, its multiple division and attack on the tumor. The chimeric receptor has been genetically engineered, and it does not need intermediary cells (APC - antigen presenting cells in the inset on the left) to train an attack on a tumor, unlike conventional T cells.

CAR-T is likely to take its place in the treatment of patients with hemo-oncological diseases (which are sometimes incorrectly called "blood cancers"), but there has been no success in the treatment of solid tumors (such as breast, lung, prostate cancer) yet, despite numerous attempts.

Genetic modification of humans

The panel of the National Academy of Sciences of the United States (United States National Academy of Sciences) in February issued an unprecedented recommendation that in exceptional cases it will be allowed to modify the human zygote to prevent the birth of children with serious diseases. The recommendation was made on the basis of a 216-page report and contains many moral and technical reservations. In particular, it says that the reliability and safety of genome modification technologies, such as CRISPR, is not yet sufficient. Therefore, genetic modifications are possible only if there are no "reasonable alternatives" and if they are aimed at eliminating serious diseases, and not, say, improving intelligence.

One of the factors contributing to the adoption of such a bold decision was the beginning of clinical trials using CRISPR technology in China. There is still no federal funding for such programs in the United States, and the States are certainly afraid of falling behind in this race.

Opponents of such solutions, as one of the arguments, in addition to potential insecurity, express concern that the technology will be used to "improve" the parameters of healthy children: for example, clinics may begin to offer a muscle strengthening service using technology designed to treat patients with hereditary muscular dystrophy. In this case, there is a danger of a dystopian division in society into those who can afford to improve beauty, strength or mind at the expense of new technologies, and everyone else. In a number of countries around the world, editing of the embryo genome is banned, including most of Western Europe.

Recently, there was a loud news that CRISPR-Cas9 technology is too dangerous, because it leads to a lot of mutations in the genes of mice in which it was used. However, then methodological shortcomings were found in the article, which is why its conclusions cannot yet be recognized as fair.

Millions of people on Earth suffer from rare genetic diseases, there are about 7000 such diseases in total. Current medications, as a rule, alleviate the condition of patients, but only for a very small proportion of diseases, and are not able to cure them. Let's hope that in a few years we will hear about the first genetically modified people freed from these serious diseases with the help of new genome editing technologies.

Figure 2. Micrograph of manipulations with a human egg.

Blood-brain barrier

Blood-brain barrier (BBB) – a system that does not allow most molecules to pass freely between the blood and the brain, and does not let toxins and microbes into the brain is a problem for drug developers. And if this problem is solvable for many small molecules, the situation is quite difficult for proteins – large protein molecules cannot penetrate the undisturbed barrier by any means. To get around this problem, various tricks are being attempted – drugs are injected intrathecally (under the membranes of the spinal cord) or directly into the cerebral ventricles. However, with this method of administration, the drug is quickly excreted into the blood and often does not have time to exert its effect.

Figure 3. Diagram of the BBB device. The barrier is formed by endothelial cells,
dense contacts between them, the capillary membrane, brain cells (astrocytes).

For the first time, ArmaGen managed not only to deliver a protein molecule beyond the BBB, but also to show in a clinical study that patients with a rare hereditary disease – Gurler syndrome – improve nervous activity indicators. Gurler syndrome (mucopolysaccharidosis-I H) is caused by a hereditary defect of the enzyme iduronidase, which leads to the accumulation of polysaccharides in cells and damage to organs, including the brain. There is a drug on the market – a replacement enzyme of the company Sanofi Genzyme – Aldurazim (laronidase), which facilitates muscle and respiratory functions – but does not affect cognitive decline.

ArmaGen has developed a technology that uses insulin receptors, which are in large numbers on the walls of blood vessels of the brain. To iduronidase, the developers "sewed" a section of insulin that binds to its receptor, and then the whole structure is dragged behind the BBB. The results of the 6-month study showed that four out of five patients had improved cognitive and neurological parameters, and the fifth stopped the deterioration of these functions.

This drug is only the first swallow. If a drug created using such technology is registered, it will open up wide opportunities for influencing targets in the brain with the help of biological molecules, which will allow more effective treatment of not only rare diseases, but also Alzheimer's disease, Parkinson's disease, multiple sclerosis, brain metastases and many others.

A new approach to testing cancer drugs has borne fruit

Traditionally, cancer patients were classified according to the location of the tumor: lung cancer, liver cancer, colon cancer, etc. Accordingly, depending on the location of the tumor, the patient is referred to an oncologist specializing in this type of tumor, and according to the same principle, the patient is included in the research of new drugs.

However, with the accumulation of knowledge about the cellular types of tumors, and then about their genetic features, it became clear that such different tumors as liver cancer and melanoma can combine a similar set of genetic anomalies. And if we develop a drug that purposefully acts on tumors with these anomalies, then it makes sense to recruit patients with this anomaly into research, regardless of the type of tumor. Such studies were called basket trials (from the English basket – basket), and this year the first studies of this type gave positive results.

Keytruda drug (pembrolizumab, antibody against PD-1) companies Merck & Co – the flagship in the world of immuno-oncology, was registered by the FDA not for any specific indication, like all oncological drugs before, but for any tumors with microsatellite instability (MSI, microsatellite instability). In the cells of such tumors, the process of DNA sequence repair (correction) is disrupted, which leads to the accumulation of mutations in many genes – in such tumors, mutations are 100-1000 times more than in ordinary ones. These tumors respond worse to chemotherapy, probably because their cells are capable of faster evolution – they have more options to escape from the action of drugs. However, it turned out that they, on the contrary, respond better to immunotherapy. Most likely, the reason is that a large number of mutant tumor proteins causes the formation of T-lymphocytes against this tumor, but they are inactive due to the immunosuppressive action of PD-1 and other similar tumor proteins and its environment. The introduction of an anti-PD-1 antibody, such as Keytruda, removes this block, and an immune response is formed against the tumor, which may even lead to the complete removal of the tumor and the patient's cure. Of the 149 patients with MSI who received Keytruda, a complete response was observed in 11, a partial response in 48. At the same time, in 78% of the responding patients, the tumor did not grow for 6 months. Most often, tumors of this type occur in patients with cancers of the colon and rectum, endometrium, gastrointestinal tract, less often - with cancers of the breast, prostate, thyroid gland, bladder. The drug has been registered according to preliminary results, and it will require additional studies for full registration.

Another example of this kind is the successful study of the company's larotrectinib drug Loxo Oncology. It is an inhibitor of the TRK kinase family (tropomyosin receptor kinase) – signaling proteins, mutations in which cause uncontrolled growth and increased survival of cancer cells. This study also recruited patients regardless of the type of tumor, but with a mutation in Trk proteins. As a result, 50 patients were recruited, both children and adults, with tumors of 17 types. Of these, 6 responded to treatment completely, and 32 partially, 91% of those who responded had a duration of remission of at least 6 months. However, as is known from previous experience with kinase inhibitors, some patients develop resistance to them, and the tumor begins to grow again. Therefore, Loxo immediately took care of creating a next-generation inhibitor, and has already tested it on two patients with resistance to larotrectinib.

Figure 4. The so-called waterfall-plot ("waterfall graph", histogram), illustrating the responses of patients to the drug larotrectinib. The color indicates different types of tumors, the percentage of change in tumor size relative to the initial one is postponed along the ordinate axis.

Such approaches are examples of successful application of the concept of personalized medicine in its modern form, when patients are treated depending on the individual parameters of their genotype and tumor genotype.

The success of prevention of cardiovascular diseases

Despite modern treatment regimens, 25% of people who have experienced a heart attack have another case of a heart attack or stroke over the next 5 years, which patients often do not survive. The cause in many cases is inflammatory atherosclerosis – the formation of plaques on the walls of blood vessels, accompanied by inflammation.

Figure 5. Canakinumab binds to IL-1ß
and prevents it from interacting with the receptor on the cell surface.

Novartis has announced the first successful trial of the direct anti–inflammatory drug Canakinumab, an antibody against interleukin-1-beta (IL-1ß), for this indication. IL-1ß, a protein produced by activated macrophages during the development of an inflammatory reaction, is one of the main mediators of inflammation, has multiple effects on cells of the immune system and blood vessels. Canakinumab binds to IL-1ß, preventing it from interacting with its receptors, thereby reducing inflammation, normalizing the structure of the vascular wall, and ultimately leads to a reduction in the risk of heart attacks and strokes. However, like any effective drug, it has side effects, the most serious of which is an increase in the frequency of infections – this is logical, given that the inflammatory reaction is just one of the lines of defense against pathogens.

The study lasted more than 6 years and included more than 10,000 patients. Now Novartis plans to process the results of the study and submit documents for registration for a new indication.

Canakinumab has already been registered in many countries (including Russia under the name "Ilaris") for the treatment of a number of inflammatory diseases – gout, juvenile arthritis and some others. Registration for the prevention of recurrent heart attacks and strokes can significantly expand the scope of the drug, since, according to some estimates, 7.29 million heart attacks occurred in the world in 2015.

Another potentially bright event in the field of cardiology is the success of the company's CETP inhibitor Merck & Co Anacetrapib. This medicine is intended to prevent not only repeated, but also primary heart attacks in those who take atorvastatin to reduce LDL-C (low-density lipoprotein, low-density lipoprotein, the so-called "bad cholesterol"). Such patients are at increased risk of heart problems, and a study on 30,000 people showed a significant reduction in risk compared to the placebo group.

CETP (Cholesterol ester transfer protein – cholesterol ester transfer protein) – plasma protein responsible for the transfer of cholesterol esters and triglycerides between lipoproteins. Its inhibition has been shown to reduce LDL and increase HDL (high-density lipoprotein, high-density lipoprotein). It would seem that this should lead to a decrease in mortality from cardiovascular diseases, which is associated with high LDL and low HDL, but in fact this has not yet been demonstrated. This proves once again that we are still very poorly versed in the mechanisms of pathology of complex diseases and simple mechanistic approaches, as a rule, do not work here.

Before the publication of the full results of the study, many are skeptical of Merck's success – it looks very unusual against the background of numerous failures of other CETP inhibitors in similar studies. It may well turn out that the effect is statistically significant, but small, and then the new drug will not find a place on the market. There may also be problems with the safety of the drug, since such molecules tend to accumulate in adipose tissue, causing side effects.

Successes in the treatment of migraines

Migraine is the third most common chronic disease in the world, it affects about a billion people. Existing means of preventing migraine do not help many patients, and more than half refuse treatment due to side effects.

In the coming years, the situation in the field of migraine prevention may change dramatically – positive results of key studies have been published by several companies involved in the development of anti-CGRP drugs, including Teva, Eli Lilly, Alder, Amgen (all have antibodies) and Allergan (small molecule).

CGRP is a peptide that is secreted in the fibers of the trigeminal nerve in patients genetically predisposed to migraine, and is the strongest vasodilator (vasodilating substance). Vasodilation leads to local edema, attraction of cells involved in the inflammation process to this place, release of pro-inflammatory molecules. This stimulates the painful endings of the meninges, which leads to additional activation of the trigeminal nerve, and the vicious circle closes. Thus, a decrease in the level of CGRP or its receptor plays an important role in interrupting the pathological process.

Figure 6. Scheme of migraine development. Isolation of peptides by nerve tissues (blue dots)
leads to vasodilation and inflammation.

We have previously written about some of these drugs when they were at an early stage of research. Now they all showed very similar results – in patients with 9-12 days with migraine per month, the number of days with migraine decreases by 3-4, whereas in the placebo group by 1-2. All new drugs are tolerated much better than existing anti-inflammatory and triptans. Of course, it is not yet possible to completely cure migraine, since the mechanisms of its occurrence are too complex and poorly understood, but these successes are an important step forward in the fight against the disease.

Since none of the new drugs were compared with each other directly, in one study, it is difficult to say which one is better. Presumably, they will enter the market next year, and the marketing departments of the companies expect fierce competition.

Portal "Eternal youth" http://vechnayamolodost.ru  04.07.2017