Bigfarma-2016

The most important news of pharmacology and medical biotechnologies for the second half of 2016

Ilya Yasny, XX2 century

For references to sources, see the original article – VM.

We offer you an overview of the most important, interesting and breakthrough events of "big pharma" for the second half of 2016.

New medicines approved by the FDA

This year, the FDA has registered surprisingly few drugs – only 21, which is in particular contrast to last year's figure of 45 new drugs. So little has the agency disapproved of since 2007. As can be seen from the FDA report, this is due to both a smaller number of applications submitted compared to last year and a large number of rejected ones, mainly due to manufacturing deficiencies (impurities, stability, reproducibility of analytical parameters), and not the drugs themselves. At the same time, the United States continues to be the leader in the number of approved new drugs – 65% of first-time registered drugs are approved in the United States. Of the 19 approved drugs, 7 have a unique mechanism of action.

Among them:

• medicine for the treatment of certain types of chronic lymphocytic leukemia – Venclexta (inhibitor of Bcl-2 protein, which blocks apoptosis of cancer cells),
• a new monoclonal antibody for the treatment of multiple sclerosis – Zinbryta (it binds to the interleukin-2 receptor and thereby reduces the activity of T cells),
• a drug for the treatment of a rare liver disease – primary biliary cholangitis – Ocaliva (binds to receptors on liver cells and accelerates the outflow of bile from the liver),
• a remedy for the treatment of dry eye syndrome Xiidra (binds to a protein on the surface of white blood cells and prevents their penetration into the cornea, thereby reducing inflammation),
• Zinplava antibody – to reduce the frequency of intestinal infections caused by Clostridium diffifcile,
• and finally, the most controversial drug of the year Exondys 51 (eteplirsen) by Sarepta Therapeutics, which we wrote about earlier (see below for details).

Dynamics of FDA drug registration by year, status as of December 9, 2016. Light green - biological preparations, dark green – small molecules, blue curve - submitted applications

The biggest success in the field of secondary progressive multiple sclerosis

There are four clinical forms of multiple sclerosis – remitting relapsing, primary-progressive, secondary-progressive, progressive-relapsing. Time is postponed horizontally, disability is postponed vertically.

Multiple sclerosis (MS) is a disease of the brain and spinal cord, in which the conducting processes of neurons – axons – are deprived of their myelin sheaths due to the malfunction of the immune system, that is, they seem to remain without isolation, cease to perform their functions and are destroyed. Multiple sclerosis has nothing to do with the everyday concept of "sclerosis", or "senile senility". It is so called because sclerotic plaques – areas of scar tissue – are scattered throughout the brain. The most common form of multiple sclerosis is remitting recurrent MS, in which periods of relapse are replaced by periods of remission. In recent years, drugs have been developed for this form that reduce the number of lesions in the brain and reduce the frequency of relapses. The other two forms, primary progressive and secondary progressive MS, are characterized by a much more aggressive course and practically do not respond to therapy (there is also a fourth form, progressive–recurrent, the most rare).

Last year we talked about the success in the treatment of primary progressive MS, and this year we published a report on the success of a study of a new drug siponimod (Novartis) for the treatment of a secondary progressive form. This, the largest, randomized controlled trial of this form of MS was conducted on 1,651 patients, and the new drug showed significant improvements compared to placebo: the risk of three-month disability was 21% lower in the drug group.

The drug is a modulator of sphingosine phosphate receptors on lymphocytes. Siponimod binding keeps lymphocytes in lymphoid tissues and thereby prevents their migration to the brain, where they contribute to the development of the disease. A drug with such a mechanism of action, fingolimod (also by Novartis), is already used to treat remitting recurrent MS, but it is ineffective in progressive forms. Apparently, the company managed to create a more selective drug.

Openness of clinical data in the USA

Earlier we wrote that the European Medical Agency EMA has overtaken the United States in terms of the open publication of the results of biomedical research. In September, the US National Institutes of Health (NIH) published new rules according to which information about an ongoing clinical trial should be available on the website ClinicalTrials.gov no later than 21 days after the first patient's appointment, and the results of the studies – no later than a year after the end (for new drugs, the period can be extended to three years). In addition, scientists should report on how they plan to conduct the study, disclose statistical methods of data analysis and all changes made to the research protocol during the experiment. The FDA has the right to fine violators up to $10,000 for each day of delay, and if the study is conducted on an NIH grant, the grant will be terminated.

The new rules will come into force on January 18, 2017, and organizations conducting research have time to prepare by April 18. The movement towards openness of clinical trials is of the utmost importance, since they are an experiment on people, which is carried out in the interests of all future patients, and for the completeness of the picture, experts need to know both positive and negative research results.

A dubious drug for Duchenne myodystrophy has been registered

We are closely monitoring the Sarepta – eteplirsen drug, which, under public pressure, was nevertheless registered by the FDA despite the negative conclusion of the panel of experts. However, the FDA required a clinical trial to confirm that the drug improves the physiological functions of patients, and not only increases the level of dystrophin in the muscles (a protein whose genetic deficiency is the cause of the disease). If the study does not show physiological improvements, the medicine will be withdrawn.

A serious scandal broke out at the FDA in connection with eteplirsen: the previous head of the commission for the approval of new drugs, who was against the approval of the drug, and some other officials resigned after the commission meeting, and the current director of the commission, Janet Woodcock, played a big role in the approval of the drug, despite open criticism from both superiors and subordinates. Officials at the FDA strongly recommend that other companies do not follow the example of Sarepta and provide only high-quality data to justify the registration of their products.

At the same time, the accelerated approval of eteplirsen is in compliance with the new 21st Century Cures Act signed by Obama in December. As we have already mentioned, one of the features of the new law is the simplification of registration and market launch of new drugs. As numerous critics fear, this may lead to a decrease in the standards raised by the FDA over the past decade to a very high level.

PARP Inhibitors against ovarian cancer

PARP (poly(ADP-ribose)-polymerase) is an enzyme that is activated in cells in response to DNA damage – breaks in one of the chains. In ovarian cancer cells, this enzyme is particularly active and is often responsible for the survival of cancer cells. The idea to suppress PARP led to the creation of its inhibitor olaparib and its launch by AstraZeneca on the market in 2014. However, it is approved only for patients with a BRCA mutation (this is the same mutation that made Angelina Jolie decide to remove her mammary glands and ovaries). The fact is that it works better in BRCA-mutant patients, since BRCA is another protein responsible for repairing damaged DNA, and when it does not work, the cell is forced to use workarounds such as PARP.

Schematic representation of the mechanism of action of PARP inhibitors from an article in Nature. Yellow – healthy cells, red – tumors with BRCA (without mutation), purple – tumors with BRCA mutation. SSB is a single–chain break, DSB is a double–chain break. LOH is the loss of both BRCA genes.

This year, two news in the field of PARP inhibitors were published: the results of a phase 3 study of the drug niraparib and the registration of rucaparib. Tesaro's niraparib drug has shown an advantage in relapse-free survival not only in patients with BRCA mutation, but also without it. In patients with the mutation, the drug increased the median progression–free survival time from 5.5 to 21 months compared to placebo, and in patients without the mutation - from 3.9 to 9.3 months. This result allows niraparib to cover a much larger population of patients, since only about 20% of patients are carriers of the BRCA mutation.

At the end of the year, the FDA registered another PARP inhibitor - rucaparib from Clovis Oncology for patients with BRCA mutation. At the same time, registration was issued for an accompanying diagnostic test for the detection of BRCA mutation. The test is based on the principle of next-generation sequencing (NGS, next–generation sequencing) and was created by one of the leaders in this field - Foundation Medicine. The drug is registered in an accelerated way, which means that for full registration, Clovis will have to provide data from clinical studies proving the benefits of the drug in terms of prolonging patient survival.

The registration of several new drugs in each area of cancer treatment is of great importance for patients and doctors, as it allows them to move on to the next therapy option after progression. In the case of ovarian cancer, this is especially important, since many patients have been going through the lines of therapy one after another for years. However, there is still little experience in the field of PARP inhibitors and many unclear questions remain: with which targeted drugs and chemotherapy drugs it makes sense to combine PARP inhibitors, why they work at all in patients without BRCA mutation, in which patients it is better to start therapy with new drugs - in newly diagnosed or already treated with other means, does it matter it makes sense to repeat therapy with this or another drug after progression on a PARP inhibitor and others. Some of the ongoing research may help answer these questions.

The first medicine against soft tissue sarcoma in 40 years

Soft tissue sarcomas are a group of oncological diseases that affect soft connective tissues, such as muscles, tendons, ligaments, etc., unlike osteosarcomas that affect bones. They represent one of the most deadly oncological diseases. The only medicine against this group of diseases was the chemotherapeutic drug doxorubicin, registered 40 years ago, which has a lot of side effects and, as a rule, is not able to ensure long-term survival, since in the end the patient still relapses. This year, the FDA for the first time registered a biological antibody drug olaratumab (Eli Lilly) for use in combination with doxorubicin in patients who were not helped by surgery and radiotherapy.

Olaratumab blocks the PDGFRa receptor, which is expressed on the surface of cancer cells and stimulates their growth. This is the first biological drug with such a mechanism of action that has entered the market.

In a study on 133 patients with 25 different types of metastatic sarcomas, olaratumab in combination with doxorubicin showed a median survival of 26.5 months compared to 14.7 months in the doxorubicin group. Such success in the treatment of a very resistant tumor with almost no drug options is rare, and we hope that this is just the beginning.

The success of antisense drugs

Until this year, all drugs of the class of RNA-antisense oligonucleotides failed in clinical trials (the exception is the very dubious eteplirsen, see above). Antisense drugs (antisenses) are a chain of RNA complementary to matrix RNA (mRNA), which binds to mRNA and modulates the expression of the protein encoded by this mRNA. If this protein is responsible for the development of a disease, a therapeutic effect is achieved. The concept looks very simple, much more elegant than attempts to block the action of an already synthesized protein with the help of small molecules or other proteins. However, until now, antisenses have encountered a number of difficulties that prevented their successful application in practice, and those that reached clinical trials failed either due to lack of effectiveness or unacceptable toxicity.

The scheme of action of antisense RNA drugs. It should be noted that with the help of antisense technologies, it is possible not only to reduce protein production, but also to stimulate it.

This year, Ionis Pharmaceuticals has demonstrated success in two areas at once: positive results of phase three studies on spinal muscular atrophy and hypertriglyceridemia have been published.

Spinal muscular atrophy is a rare genetic disease in which motor neurons that carry a signal from the spinal cord to the muscles die due to a defect in the SMN protein. As a result, the denervated muscles themselves gradually atrophy. To date, there has been no cure for this disease, and most patients die before they reach the age of 20. The drug nusinersen partially restores the expression of the SMN protein, and in phase 3 clinical trials, both in patients with early and late onset of atrophy, it showed a statistically significant superiority over placebo on the scale of motor disorders.

Hereditary hypertriglyceridemia is a rare disease in which the concentration of triglycerides and very low density lipoproteins (VLDL) increases in the blood as a result of a genetic defect. This leads to an increased risk of acute pancreatitis and coronary heart disease. The drug volanesorsen inhibits the synthesis of apo-C-III protein, which is synthesized in the liver and is one of the key regulators of blood triglyceride levels. In the phase 3 study, the drug showed a 71.2% decrease in triglycerides compared to 0.9% in the placebo group, and the effect persisted for six months.

Despite these successes, there is no guarantee that the drugs will be registered and will enter medical practice. The first results have been published so far, available so far only in the form of press releases. The FDA agency and the expert community have reason to fear the high toxicity of antisense, and full research reports will be the subject of scrupulous analysis.

Shocks in CAR-T research

T cells with chimeric antigen receptor (CAR-T), which we have repeatedly written about, are a promising means of cancer immunotherapy. However, this technology is at the very beginning of its development, and therefore tragic surprises associated with its application are inevitable. In July 2016, a study by Juno Therapeutics on patients with leukemia had already been stopped due to the deaths of two patients. The company changed the protocol of the study, removing fludarabine from the patient preparation scheme, presumably leading to brain edema. The FDA allowed the study to continue almost immediately, 3 days after the shutdown. However, it seems that such haste was premature – in November, the program was stopped due to the death of three more patients for the same reason - brain edema. Apparently, the swelling was caused by the cells themselves, since its severity correlated with their number, but scientists have not yet established the exact mechanism.

Very similar CAR-T of the same specificity (against CD19 protein on the surface of leukemia and lymphoma cells) are being developed by Kite and Novartis, but they have not yet identified similar problems. On the contrary, both companies have reported complete remission in more than 80% of severe patients and are going to apply for registration in 2017. These products also have quite severe side effects, but the companies hope that the benefits in this case outweigh the risk.

Juno will have to focus on other CAR-T products. Another player in this field, bluebird bio, has published the first positive results of CAR-T with a different specificity – anti-BCMA – in several patients with very severe multiple myeloma previously treated with an average of seven other therapeutic agents. One patient had a complete response, the others had a partial response or stabilization.

Hemophilia Gene Therapy News

BioMarin reported success in the treatment of hemophilia A. Its product, a viral vector (a means of delivering a gene to a cell) containing the factor VIII gene, was injected once into 9 patients. Of the seven people who received the highest dose of the drug, six had an increase in blood clotting factor VIII (a protein whose deficiency leads to hemophilia A, in which the main problem is internal and external bleeding) to 50 percent or more of the norm. The average frequency of bleeding decreased from 20 to 5 per year.

Spark Therapeutics and UniQure Biopharma B.V. presented data for similar products, but in the field of hemophilia B. Spark's study on 9 patients showed a recovery of factor IX levels to 12-65% of normal, UniQure's success is still more modest – 3-12% of normal in 5 patients. However, the average follow-up period for UniQure is still less. On the other hand, the UniQure product reduced the number of bleeds quite well: from 8.3 to 3.4 per year.

Thus, convincing evidence has been obtained of the possibility of restoring blood clotting in hemophilia due to gene therapy. However, the main question remains open – will gene therapy be able to ensure long-term expression of target genes in the human body? This is especially important given the huge cost of such therapy, which can reach $1 million per dose. The second very important point is security. Although the use of modern vector designs has not caused serious side effects so far, the story of the mid-2000s is still fresh in memory, when 5 out of 21 children had gene therapy for lymphoma that led to the emergence of secondary cancer. The fact is that a gene that is embedded with the help of a viral vector can get into the DNA regions responsible, for example, for controlling cell division and survival, which will lead to their oncological transformation.

Successes and failures of checkpoint inhibitors

Schematic representation of checkpoint inhibition. On the left is a T-lymphocyte, on the right is a tumor cell. In the absence of antibodies, PD-L1 binds to PD-1 on the cancer cell and suppresses the activity of the T-lymphocyte

The drugs that have revolutionized the treatment of certain metastatic diseases – immune checkpoint inhibitors – continue their victorious march in the areas of therapy, but not without some problems. We are talking, first of all, about the drugs Yervoy (ipilimumab, BMS, antibody against CTLA-4), Opdivo (nivolumab, BMS, antibody against PD-1) and Keytruda (pembrolizumab, Merck&Co, antibody against PD-1). Recall that these drugs, which entered the market in 2011-2015 according to the indications of metastatic melanoma and lung cancer, remove the block from the immune system, giving it the opportunity to attack the tumor. More than 800 studies are currently being conducted with drugs of this class: these are all kinds of combinations, new indications, and various lines of therapy.

In 2016, the list of competitors and indications expanded once again. According to the indication of bladder cancer, the FDA approved the drug Tecentriq (atezolizumab, Genentech/Roche). This is the first registered antibody against PD-L1, the ligand of the PD–1 protein, which is expressed not on the cells of the immune system that came to the tumor, but on the tumor cells themselves. Tecentriq has also been approved for second-line lung cancer.

Both PD-1 inhibitors – Opdivo and Keytruda – have expanded the list of approved indications, now they are also approved for use in patients with head and neck cancer resistant to platinum drugs.

Opdivo was the first checkpoint inhibitor to enter the field of hematooncology: it showed high efficacy in the treatment of Hodgkin's lymphoma, the response rate to therapy was 65%. The drug was accelerated approved for this indication and will receive permanent registration in case of successful completion of a randomized phase 3 trial.

However , in the rivalry between Merck & Co and BMS in the field of lung cancer therapy, the drug Opdivo has so far been defeated. If Keytruda successfully entered the first line of metastatic lung cancer, showing a 40% reduction in the risk of mortality, then Opdivo failed the study without achieving the primary criterion of effectiveness – superiority in progression-free survival compared to standard therapy. An important difference in the Keytruda study was the inclusion of patients with only high PD-L1 expression in tumors, more than 50%, whereas the Opdivo study included patients with an expression level of more than 5%. In other words, BMS tried to reach a wider population of patients and cruelly paid for it – the value of the company immediately fell by $ 20 billion.

A huge amount of research and a dozen new drugs that will enter the market in the coming years will certainly greatly change the practice of cancer treatment. Already 20-30% of patients with metastatic diseases achieve complete remission, whereas previously they had an average of a year to live. However, there are still a lot of questions, and the main one is how to cover the remaining 70-80% of patients? What will help them – new funds? Combinations of existing ones? The answer to this will be given only by future research.

Another important issue is the price of a new therapy. Now a year of treatment with one drug costs 120-150 thousand dollars. The cost of the combination can reach up to 300 thousand. Obviously, the majority of patients in need and the budget of most countries cannot afford modern treatment. However, the entry of new drugs into the market will exacerbate price competition and lead to a reduction in the cost of therapy.

The End of Theranos

The Theranos scandal, which we talked about a year ago, has almost ended. Recall that this is a company created by Elizabeth Holmes, a young charismatic woman whom journalists dubbed "Steve Jobs in a skirt" for her addiction to black turtlenecks and bright press conferences. In 2003, she dropped out of Stanford University, as she caught fire with the idea of creating a startup to develop diagnostic technology that would allow detecting dozens of diseases at once with one drop of blood. Such a statement of the problem can immediately cause skepticism in any specialist in the field of diagnostics, and very serious evidence is needed to justify such a development. However, Holmes managed to convince (non-specialized) investors to invest more than $400 million in the project. Then, during the mentioned speeches, the girl claimed many times that the technology has already been created and is working. In 2014, Forbes estimated the company at $9 billion and began calling Holmes the youngest billionaire in the world (she was 30 years old).

Everything began to fall apart in the fall of 2015, when, after a journalistic investigation by The Wall Street Journal, which revealed that the tests were not done at Theranos, but were outsourced to Walgreens, blood was taken not a drop from a finger, but the usual amount from a vein, and the cost of the test was no different from the average, the company was raided inspection bodies. Violations in the technological process were detected and the activity of the laboratory was suspended. Holmes has repeatedly made statements that these difficulties are temporary, "real innovators always have a hard time" and that the company will soon present all the evidence of its honesty. However, then it turned out that no revolutionary technology exists at all, and the test results provided to patients were of poor quality, which jeopardized their health. Elizabeth was banned from running the labs for two years.

In November, Walgreens filed a $140 million lawsuit alleging that Theranos misled them about the merits of the technology. Theranos was also sued by one of the investors, Partner Fund Management, who invested almost $100 million in 2014. To top it all off, it turned out that the investigation was launched after the grandson of one of the members of the board of directors (which includes elderly veterans of law enforcement agencies and politicians, such as Henry Kissinger) worked at the company and realized that something was wrong. He first turned to the management of the company, but, not finding their understanding, decided to attract the attention of the press.

Several instructive points can be extracted from this story. Firstly, it is too early to draw any conclusions about the prospects of the technology, if the details of how it works are unknown. Secondly, the absence of specialized investors and members of the board of directors in the company is a bad sign, as it means that an independent competent assessment has not been carried out. Thirdly, no matter how much you hide the lack of real achievements, in this area the truth will eventually be revealed, and the punishment will be the stronger the more brazen the lie was.

Portal "Eternal youth" http://vechnayamolodost.ru  26.12.2016