New achievements
The main news of "big pharma" and medical biotechnologies for the second half of 2018
Ilya Yasny, XX2 century
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We present to your attention the traditional semi-annual review of the pharmaceutical industry: new medicines for influenza and migraines and new orphan drugs, a new tuberculosis vaccine and new important steps in the fight against cancer, digitalization of biomedical technologies, medicines for the poor, new details about fish oil, as well as expanding the list of indications for already released medicines.
A new record has been set
This year, the FDA (US Food and Drug Administration) set an absolute record for the number of new registered drugs for the first time since 1996 – 59 compared to 46 last year and 53 in 1996.
Figure 1. Dynamics of the issuance of registration certificates for new products in the USA. BLA Approvals are biological products, NDA Approvals are small molecules obtained by chemical synthesis. Filings – the number of applications submitted. (The graph shows data for the end of November, on 26.12 there were already 59 drugs.)
The year coming to an end is also distinguished by other parameters: for the first time, the number of registered orphan drugs (for the treatment of diseases that affect less than 200,000 people in the United States) exceeded 50%. 35% of registered drugs have a new mechanism of action. Let's talk about some of them.
About one thing – Vitrakvi (larotrectinib; Loxo Oncology) – we have already written. This drug is indicated for patients with any solid tumors (that is, not related to the circulatory and lymphatic system), regardless of the affected organ. The main thing is that a genetic marker is present in the tumor – the fusion of the NTRK gene (encodes the protein neurotrophic receptor tyrosine kinase) with other genes. The approval of this drug is an important step in the transition from the treatment of tumors based on their localization to the appointment of therapy based on the genetic classification of the tumor.
Another landmark drug is Onpattro (patisiran; Alnylam Pharmaceuticals), registered for polyneuropathy in TTR–amyloidosis (transtiretin amyloidosis). We wrote about him last year. It is remarkable because it is the first ever successful drug of the class of small interfering RNAs. Before him, all medications of this type failed.
For the first time since Tamiflu, an anti-flu drug with a new mechanism of action Xofluza (baloxavir marboxil; Roche Group) has been approved, which reduces the duration of the disease. It does not differ in effectiveness from Tamiflu, but instead of ten tablets, only one is required.
During the year, three new drugs were approved at once to prevent migraine – antibodies against CGRP. We have previously written about the registration of the first of them and about the clinical success of the others.
The blockbuster status is predicted for the antibody against kallikrein Takhzyro (lanadelumab; Shire Plc) for the treatment of hereditary angioedema (NAO), which was registered in August. NAO is a rare genetic disease in which one of the enzymes of the complement system, the C1 inhibitor, is defective. Such patients have seizures several times a year, similar to a severe allergic reaction (Quincke's edema), which without relief can lead to death. For the prevention of seizures, the plasma-isolated C1 inhibitor Cinryze (Shire) is now used, which reduces the frequency of seizures by 50%. It is administered once every 3-4 days intravenously, the cost of treatment reaches $ 500,000 per year. Also last year, a subcutaneous form of the Haegarda C1 inhibitor (CSL Behring LLC) was approved twice a week, reducing the frequency of seizures by 84%.
Figure 2. Cascade of interactions between plasma proteins leading to angioedema. C1-inhibitors Cinryze and Haegarda act by interrupting several pathways at once (shown by arrows with stop signs). The antibody against kallikrein acts more selectively.
Lanadelumab is administered subcutaneously once every two weeks, and in a clinical study it showed an 87% reduction in seizures compared to the placebo group. It inhibits kallikrein, one of the proteins involved in the development of an attack. In addition to the rarer introduction, it also has the potential to reduce the price, because the production cost of a monoclonal antibody is much lower than that of a plasma protein.
Chemical Chaperone
Another interesting drug registered this year by the FDA is Galafold (migalastat; Amicus Therapeutics) for the treatment of Fabry's disease. This disease refers to hereditary diseases of lysosomal accumulation, in which, due to an inactive enzyme, the substrate of this enzyme accumulates in the lysosomes of cells - as a rule, fats and carbohydrates. This leads to dysfunction of various organs and premature death.
Figure 3. Transmission electron microscopy (TEM) shows the presence of inclusions of glycosphingolipids of various shapes and sizes in the cells of the distal tubules of the kidney in Fabry disease.
Now some such diseases (Gaucher, Pompe, Gurler, Fabry and others) are able to treat by introducing the missing enzyme. However, there are a number of problems here: the development of such enzymes is very expensive and complex; enzymes are expensive; in some patients they are ineffective, since antibodies are produced against them; they almost do not penetrate the blood-brain barrier, that is, they do not reduce neurological disorders. In addition, constant injections of these drugs are required. They are trying to solve the latter problem with the help of gene therapy, but these experiments are still at the very beginning of the path.
That is why the development of small molecules in the field of lysosomal accumulation diseases is so attractive. Migalastat is a so–called "chemical chaperone", that is, a molecule that changes the structure of a non-functional protein (in the case of Fabry's disease, it is α–galactosidase A) and allows it to do its job (chaperones are proteins that help proteins fold properly and protect them from harmful effects, for example, thermal - then they are called "heat shock proteins"). Migalastat is available as a tablet, taken every two days. In clinical studies, the drug has shown efficacy comparable to enzyme replacement therapy, and even surpassed it in reducing the mass index of the left ventricle, which should reduce heart problems in patients.
Figure 4. The mechanism of action of the chemical chaperone. It combines with a partially unfolded protein and restores its three-dimensional structure.
However, the drug turned out to have a difficult fate: migalastat was registered in Europe in 2016, but it did not receive approval in the USA – the FDA required another study on the gastrointestinal effects of the drug, which should have delayed market entry for 5-7 years. But the change of the FDA leadership at the end of last year led to a revision of the agency's position – in August 2018, migalastat received accelerated FDA approval. The new head of the FDA, Scott Gottlieb, has repeatedly stressed that his priority is to accelerate the development and market launch of new drugs without compromising the quality of this process, and we see that he is fulfilling his promises.
The drug will help about half of patients with Fabry's disease in the United States (there are about 3,000 of them in total) and will cost $315,000 a year. The price may seem high, but it is mostly covered by insurance, and modeling has shown that the use of pills is more profitable than injections of enzymes.
In Russia in 2015 there were 20 patients with Fabry's disease, but it is obvious that there should be much more of them, the disease is simply not sufficiently diagnosed. It remains to be hoped that someday a new drug will be available to them.
Is fish oil effective?
Amarin Corporation has published the results of a seven-year REDUCE-IT study showing the effectiveness of capsules with purified fish oil (Vascepa) in terms of preventing serious cardiovascular events – death, stroke, hospitalization due to angina pectoris. It turned out that the use of the company's drug together with statins reduces the risk of these phenomena by 25% compared with the use of statins alone.
Figure 5. Reduction of cardiovascular risk in the Vascepa group compared to the placebo group.
Earlier studies have already demonstrated that Vascepa reduces the level of LDL-C (low-density lipoproteins, increased levels of which are associated with cardiovascular diseases). However, as the failure of CETR inhibitors has shown, this decrease does not necessarily lead to a decrease in mortality.
There was no direct comparison with new drugs in this area – PCSK9 inhibitors (we wrote about them earlier), but an indirect comparison shows that they are slightly less effective – the risks of adverse outcomes are reduced by 10-20%, – less safe, and, importantly, very expensive.
Interestingly, almost simultaneously, the results of the ASCEND study were published in 15,480 people in the UK, dedicated to the study of a dietary supplement of fish oil to reduce the same adverse outcomes. It turned out that fish oil had no effect on these outcomes compared to placebo. What's the matter?
Omega-3, which is the main therapeutic component of fish oil, is not a single acid, but a complex of compounds, the main of which are alpha-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. According to Amarin, its drug contains 95% purified EPA, while the supplement investigated in ASCEND also contains DHA and other components. Amarin argues that it is high doses of EPA that reduce cardiovascular risks. The company reports that to achieve the same EPA level as in their study, you need to take at least 10 capsules of dietary supplements per day.
It has also been shown that DHA, but not EPA, can even increase LDL-C levels. In addition, the Amarin study was conducted in patients with initially higher cardiovascular risk and assumed mandatory statin intake, unlike ASCEND.
The company is coming on the heels of the pharmaceutical giant AstraZeneca plc, which is conducting a risk reduction study for a similar product (Epanova). The results will be published next year.
Medicines for the poor
Quite often, claims are heard against big pharma companies that, in pursuit of profit, they develop medicines only for the rich inhabitants of the first world and neglect the interests of millions of residents of developing countries. This is true, but only partially.
The non-profit Access to Medicine Foundation regularly examines the R&D portfolios of 20 major companies for the development of medicines for the poor and publishes reports on its website. In 2018, the Foundation identified 77 diseases with the highest priority. The assessment was carried out in 106 countries where the need for treatment of these diseases is highest.
A total of 298 research projects were identified, of which half (144) are aimed at 5 diseases: malaria, HIV/AIDS, tuberculosis, Chagas disease and leishmaniasis. On the contrary, no research project is aimed at solving the problems of 16 priority diseases at all. Among them are several types of hemorrhagic fevers, diseases caused by parasitic worms, syphilis, cholera and diarrhea caused by Escherichia coli.
63% of the projects are developed by five companies: GlaxoSmithKline (GSK), Johnson & Johnson, Sanofi, Merck KGaA, Novartis AG. Completing the list are Boehringer Ingelheim and Novo Nordisk, which do not have such projects at all.
Figure 6. Priority projects in the development of the top 20 pharmaceutical giants.
One of the projects in development at GSK is a new tuberculosis vaccine, for the first time in a hundred years after the discovery of BCG. It contains a recombinant protein – derived from two immunogenic epitopes of Mycobacterium tuberculosis – and is designed to prevent the transition of latent infection into the active form. In phase 2b, the vaccine was studied in Africa in 3,753 patients: 10 people in the vaccine group became ill with tuberculosis, and 22 in the placebo group within two years after vaccination. Latent tuberculosis infected 25% of the world's population, last year 1.6 million people died from the active form. Although the results are promising, a final conclusion about the effectiveness can be made in 2019, after all participants have completed a three-year follow-up.
The Foundation also assessed how much companies care about the availability of their medicines protected by patents – whether flexible pricing policy, licensing to local generic manufacturers and subsidized programs are applied. The Foundation has identified 53 medicines that require such measures. It turned out that at least one of these measures applies to 37 medicines from the list. The leader here is Gilead Sciences, a manufacturer of HIV drugs/AIDS and hepatitis C. Gilead takes an individual approach to pricing in all countries (although still in some cases price reduction is not enough), and in more than 100 countries the license for production has been transferred to a local manufacturer.
GSK was among the leaders here, too. Thus, for the company's product Ventolin (salbutamol), used in patients with lung diseases, flexible pricing has been established in 11 countries. In total, Gilead and GSK cover half of the list of medicines with access strategies (23 products out of 37).
Among the 16 priority drugs that do not have access strategies, the contraceptive Yasmin (Bayer AG) and the palliative prostate cancer drug Eligard (Sanofi) are named.
Digitalization of pharma
There is so much news about the use of digital technologies and artificial intelligence in pharma that it is already possible to allocate a special category for them. It is clear that there are quite a lot of inflated expectations, and a catchy title does not always correspond to a more modest essence. Let's try to figure out which AI-based products have really shown their usefulness this year.
In September 2017, the FDA approved the first application for patients with drug addiction by Pear Therapeutics, and now its version for the treatment of opiate addiction has entered the market. It is based on a kind of cognitive behavioral therapy – community reinforcement.
The new application, reSET-O, should be used together with a buprenorphine patch, and now its installation on the patient's smartphone is prescribed by a doctor. It is a tool for training, monitoring and reminders, including virtual rewards for fulfilling prescriptions – just like in a computer game. However, in a clinical study, the app did not reduce the amount of drugs taken by those who used it, compared with patients who did not use the app. But in the group of app users, the percentage of those who fully completed the 12-week drug withdrawal program was significantly higher – 82.4% versus 68.4% in the control group.
The processing of medical images using artificial intelligence is already being introduced into practice. Various studies show that artificial intelligence may not be able to replace a pathologist (or radiologist) yet, but certainly a pathologist with an AI assistant copes with the task of making a diagnosis better than a pathologist without AI. Thus, the FDA has registered Arterys Inc's online solutions for the diagnosis of lung, liver and heart pathologies using MRI images and CT and several Zebra Medical Vision algorithms for the diagnosis of intracranial bleeding, CT of coronary arteries.
Using deep learning algorithms and a database of 2,100 images taken from 1,000 patients, the researchers were able to diagnose incipient Alzheimer's disease on average 6 years earlier than the diagnosis made by radiologists. The algorithm showed 100% sensitivity and 82% specificity (that is, all cases of the disease were recognized correctly, and 18% of cases where there was no disease were incorrectly classified as a disease). True, there are currently no drugs that would prevent the development of Alzheimer's disease even at an early stage, but such a tool will certainly be useful when they appear.
There are already quite a few apps on the market that remind patients to take pills on time, but UCB has developed a tracker specifically for patients with Parkinson's disease. It not only allows you to record a medical history, reminds you about taking medications, contains medical information about the disease, but also makes it easier for the patient to control the smartphone, which is very important in the case of Parkinson's disease. Since it is often difficult for patients to type, the emphasis is on voice control. The program has a built-in AI module that adapts to the vocabulary and pronunciation features of a particular patient – because they can change over time.
Three patients with paralysis managed to control the tablet using electrodes implanted in the brain. In completely paralyzed patients (one had a spinal cord injury, and the other two had amyotrophic lateral sclerosis), an array of silicon microelectrodes measuring 4 by 4 mm was implanted into the motor cortex of the brain. The signals from them are transmitted via Bluetooth to the tablet, as from a wireless mouse. At first, the researchers "eavesdropped" on the signals exchanged by neurons around the electrodes and sent them to the decoder for training. Each patient visualized the cursor control process differently - one imagined that a billiard ball was rolling on the surface, the other that he was moving his thumb and index finger. However, at the end of the training, patients reported that the visualization was replaced by a feeling that they were controlling the cursor directly. The patients were then asked to complete a number of tasks, such as chatting in a messenger, shopping in an online store, and even playing a virtual piano.
Figure 7. Training of the tablet control system using an implanted microelectrode.
The printing speed reached 40 characters per minute, which is about three times slower than for a regular user, but faster than the currently available approaches. It is very important that a completely ordinary tablet was used without any additional options and special features. That is, the researchers managed to separate the learning process from the use of technology, and now microelectrodes in the patients' heads can be paired with any device that works with a Bluetooth mouse.
Among other news, of course, it is impossible not to mention the scandal with the editing of embryos in China, which we have already written about.
It is also noteworthy that this year the Nobel Prize in Medicine was awarded for a discovery that formed the basis of several revolutionary drugs that have already entered the market. These are Yervoy (ipilimumab; BMS), Opdivo (nivolumab; BMS), Keytruda (pembrolizumab; Merck), Tecentriq (atezolizumab; Roche), Imfinzi (durvalumab; AstraZeneca), Bavencio (avelumab; Pfizer). This year, they were joined by another antibody – Libtayo (cemiplimab; Sanofi / Regeneron Pharmaceuticals), registered for one of the types of skin cancer (metastatic squamous cell carcinoma). Dozens more products are in different phases of clinical trials.
The list of diseases for which these drugs have shown effectiveness is also constantly growing. The new readings added this year are shown in the table in red.
Table 1. Indications for which new immunotherapy drugs have been registered in the USA. Those approved in 2018 are marked in red
Fundamentally, the new drugs give some patients (unfortunately, not all yet) hope for a complete cure. We hope that in a couple of years it will be possible to add a few more rows to this table!
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