Biopharmaceuticals on the rise

Ilya Yasny, XX2 CENTURY 

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

The boom in biotech and pharmaceutical financing continues. In the first half of 2015, investors invested more money in these areas than in the whole of 2013. Companies working in the field of immunotherapy and other modern biomedical approaches attract the most attention. 

 

PCSK9 binds to low-density lipoprotein receptors on the cell surface, which leads to the entry of receptors into cells and their degradation. As a result, low-density lipoproteins (LDL) in combination with cholesterol (LDL-C) remain circulating in the blood. As it was shown earlier, it is their increased level that is associated with an increase in the frequency of cardiovascular diseases. Antibodies against PCSK9 bind this protein, and the receptors remain on the cell surface, which reduces the level of LDL-C in the blood.

Mechanism of action of antibodies against PCSK9 (1)

However, before the new class of drugs are widely recommended for use for the prevention of heart attacks and strokes, it is necessary to prove their influence on these events during long-term observations, which will be completed no earlier than 2017. Until then, they are likely to be prescribed only to patients with rare hereditary hypercholesterolemia who do not respond to statin therapy. 

Nevertheless, a battle for dominance in this field broke out between pharmaceutical giants Amgen and Sanofi: both companies almost simultaneously completed studies that showed a significant decrease in LDL-C when taking new drugs simultaneously with statins or ezetimibe (a cholesterol-lowering drug that reduces the risk of cardiovascular diseases). The drug Repatha (evolocumab from Amgen) received registration in Europe in July and at the end of August – in the USA, and Praluent (alirocumab from Sanofi) – so far only in the USA (registration in Europe is expected this year). According to analysts, the new drugs will be very expensive, $14,000–$16,000 a year, which has already caused a wave of outrage from doctors, patients and insurance companies. 

The third giant, Pfizer, is catching up with the two leaders with its antibody "bococizumab" (bococizumab), which is in the last, third, phase of a clinical trial before registration. High competition in this area will allow payers to bargain about the price, as happened in the case of hepatitis C drugs registered last year (2).

Obama asked Congress to allocate $215 million under the Precision Medicine Initiative program for sequencing (that is, sequencing) the genomes of a million Americans for subsequent use of this data in biomedical research. However, skeptics say that, despite some successes achieved in oncology and the treatment of hereditary diseases, personalized medicine based on genomic data is not yet a panacea. Obtaining new genomic data raises more questions than answers, since medical problems and the biological processes underlying them are far from linear mechanistic models. For example, deCODE sequenced the genomes of 2636 Icelanders and discovered new mutations that increase the risk of Alzheimer's disease (3). However, what to do with this data is still unknown, since there are still no drugs that prevent or treat Alzheimer's disease, and probably will not be in the near future (Some encouraging there is still news – VM).

The company Calico, funded by Google, has agreed with a database of genetic information Ancestry.com about access to DNA sequences stored in the database in order to find correlations between gene sequence and longevity. This is one of the steps that, according to researchers, will one day lead to the creation of drugs that slow down aging (4).

Sequencing of the entire genome allows us to obtain information about both the sequences of all genes and non-coding DNA (5).

The company 23andMe sets itself more realistic tasks. She received approval from the FDA (US Food and Drug Administration) to sell a genetic test for a rare disease – Bloom syndrome – and signed an agreement with Pfizer to create a database that will link the medical records of patients with systemic lupus erythematosus with their genomic data (6).

Other major companies, such as Biogen, Roche and Amgen, have also launched genomic sequencing projects in an attempt to improve the process of drug discovery and development. This trend became especially fashionable after the cost of sequencing one genome fell below $1,000 (whereas it took about $3 billion to decode the first genome). 

In June, the annual conference of the American Society of Clinical Oncology ASCO was held, at which new data on the combination therapy of metastatic melanoma were published. The combination of antibody drugs Opdivo (nivolumab) and Yervoy (ipilimumab, both Bristol-Myers Squibb, BMS) surpassed the effectiveness of each of the drugs individually. The drugs act on the receptors of tumor cells and the immune system, which suppress the immune response against the tumor. Opdivo and Yervoy block various mechanisms of this process, and the immune system effectively fights the tumor. In a study on 945 patients, the combination resulted in a decrease in tumor size in 58%, while for Opdivo this figure was 44%, and for Yervoy – 19%. This unprecedented success is likely to lead to the approval of the combination in 2015 and the beginning of its use in patients. However, a fairly high level of side effects and a high price may limit the use of a new therapy (7).

Opdivo's lung cancer and kidney carcinoma studies were stopped prematurely, as the drug has already shown its effectiveness. Opdivo received approval for lung cancer from the FDA in March, overtaking its competitor Keytruda (Merck & Co.'s pembrolizumab) with the same mechanism of action and setting an FDA record for the speed of approval of a new drug (data was obtained by the agency in December 2014). Both drugs are currently being tested in dozens of studies on thousands of patients (8).

T cells attack the tumor cell. Photo from the journal Science.

The drug Atezolizumab (Roche) with a similar mechanism of action in a study on 439 patients with late–stage bladder cancer who did not respond to platinum agent therapy showed previously very good efficacy and safety - better than competitors who have already entered the market. Currently, the drug is being investigated for about ten very severe oncological indications, and its approval is expected in 2016 (9).

An extreme example is UniQure's Glybera drug for gene therapy of a rare disease – lipoprotein lipase deficiency – worth $1.4 million. 

Vertex Pharmaceuticals in July received FDA approval for the use of a combination of two drugs in patients with cystic fibrosis – the new lumacaftor and ivacaftor, previously released on the market under the name Kalydeco. A combination called Orkambi is indicated for 8,500 cystic fibrosis patients in the United States, that is, it covers more such patients than ever before (10).

The expensive drug, Sovaldi (sofosbuvir) by Gilead Sciences, was copied in Bangladesh and will be sold almost 100 times cheaper than the original. Gilead has already been criticized for the too high price of its hepatitis C drug ($84,000 for a 12-week course), as a result of which it introduced a flexible pricing policy and, for example, in Egypt it sells sofosbuvir at a price of $10 per tablet, and not $1,000, as in the USA. The Bangladeshi manufacturer Incepta Pharmaceuticals has developed its own version of sofosbuvir worth $10 and intends to sell it in Africa and Southeast Asia, where Gilead does not have a patent. Bangladeshi companies are not required to comply with patent restrictions in accordance with WTO rules, and the World Health Organization is only concerned about the quality of production of the drug, which will be properly tested, after which WHO may purchase the drug from Incepta for distribution in poor countries. 

Gilead responds by licensing its drug to Indian generic manufacturers, who will sell it at $11 per tablet and pay Gilead deductions (12). 

The therapy is aimed at restoring vision after eye injuries and burns. In case of serious damage, the cornea loses its ability to recover on its own, so scientists have developed a technique for collecting the remaining cells capable of regeneration and obtaining patches from them to treat the defect. The development of Holoclar, which took more than 20 years, was carried out by scientists from the University of Modena and Holostem Terapie Avanzate and funded by a large Italian company Chiesi Farmaceutici. 

Stem cells that allow the cornea of a healthy eye to regenerate are located in the corner of the eye between the cornea and the conjunctiva – the so-called limbo. With severe damage, the cornea does not regenerate, and the eye is covered with an opaque white layer of conjunctival cells. If the patient has at least a few stem cells left, they can be selected using Holostem technology, grow something like a contact lens and transplant into the affected eye. Rejection is unlikely, since the patient's own cells are used. In a clinical study on patients who had previously experienced vision loss for an average of 18 years, 51 out of 104 patients had an improvement in their vision (13). 

Parts of the eye

At the end of August, the Belgian company TiGenix announced the success of a phase III clinical trial in patients with Crohn's disease, a chronic autoimmune intestinal disease. The study was conducted on 212 patients who did not respond to anti-inflammatory antibody therapy. In this most severe patient population, remission was achieved in 49.5% of cases by week 24, while in the placebo group - in 34.3%. Adipose tissue stem cells of other people (so-called allogeneic adipose stem cells) were used for treatment. This is the first major success of allogeneic stem cell therapy, opening the way for the company to register in Europe and the USA. In 2017, the company plans to start selling its product, which can be shown to more than 100,000 patients annually (14).

Bluebird bio has announced its first success in the field of gene therapy for sickle cell anemia, a hereditary disease in which a hemoglobin mutation causes red blood cells to take the shape of a sickle and cannot normally carry oxygen. In June, the company reported that a 13-year-old boy, who previously constantly needed blood transfusions, has been without transfusions for three months and his normal hemoglobin level has reached 45%. Although it is customary to treat the results obtained on one patient with caution, in this case optimism is justified, since sickle cell anemia cannot go away by itself. There are 7 more patients in the study, data on which will be available later. Bluebird bio also reported that two patients with another hemoglobin synthesis disorder – beta-thalassemia – have been without blood transfusions for 16 months (15).

The vaccine was developed by NewLink Genetics back in 2010, but clinical trials began only in October 2014 after the Ebola outbreak in West Africa (16). 

More than 9,000 volunteers have already received the vaccine, and none of those who received it immediately became ill, whereas in the control group, where people received it three weeks after contact with the patient (the incubation period of the virus is 10 days), there were 16 cases. The first part of the study was carried out fantastically quickly by the joint efforts of many organizations – only from April to July 2015. The study will continue, all new participants will receive the vaccine immediately (18). Another study of a similar vaccine on 28,000 patients, apparently, will be stopped, as the peak of the Ebola epidemic has passed and patients are increasingly difficult to recruit into the study. 

Studies of drugs against Ebola virus infection were not so successful: Tekmira Pharmaceuticals stopped the study of its drug TKM-Ebola, based on the principle of RNA interference, because, according to preliminary results, the effectiveness was insufficient [19]. The study of a cocktail of three ZMapp antibodies from Mapp Biopharmaceutical against Ebola virus proteins is ongoing, but the results have not yet been published.

The 300-page bill concerns both indisputable points, for example, an increase in funding for the National Institutes of Health system by $1.75 billion per year, and a number of very dubious points that have caused sharp public criticism. For example, the project proposes to simplify the procedure for registering medicines with the FDA by reducing the requirements for the quality, quantity and duration of clinical trials. It is proposed to rely more on scientific background, preclinical data (on animals, cell cultures and in vitro) and modeling. This is done in order to speed up patients' access to new medicines, especially in areas where there is an acute shortage of effective and safe drugs (for example, in the development of antibiotics against resistant bacteria), but experts fear that such steps may lead to the emergence of insufficiently studied therapies on the market. There are examples of how side effects became known only after large-scale qualitative studies. For example, only after carefully studying and summarizing long-term data on the use of nonsteroidal anti-inflammatory drugs, the FDA agency required to indicate in the insert that they contribute to an increased risk of strokes and heart attacks, especially in patients with cardiovascular complications. Such drugs include diclofenac, ibuprofen (Nurofen) and meloxicam (Movalis), which are popular with us.

Another proposed innovation concerns orphan drugs (for the treatment of rare diseases) and drugs that satisfy a high need for medicines. Orphan drugs now enjoy a seven–year period of market exclusivity after approval, and new biological drugs enjoy a 12-year period. This period, during which other manufacturers cannot produce generics of the drug, is planned to be increased to 15 years for most categories of highly demanded drugs, which, of course, will greatly appeal to pharmaceutical companies, since it will allow them not to reduce drug prices during the entire period of exclusivity. Such measures will stimulate the development of new drugs, but will also increase the burden on the budget and the pockets of patients.

Another rather strange suggestion is that it is not necessary to inform the patient about participating in a clinical trial if such participation involves "no more than minimal risk". Nowhere is it specified what the "minimum risk" is, who and how will determine the level of risk. At the same time, it should be understood that clinical research is not an attempt to cure a patient, but a scientific experiment, and the inclusion of a patient in such an experiment without his knowledge looks like a violation of basic human rights (21).

Antibiotic-resistant staphylococcus and human cell (22).

A study published in June showed that Gardasil 9 (Merck & Co.) vaccination, which protects against 9 strains of human papillomavirus and prevents several types of cancer, is effective and well tolerated. The study involved 3066 boys and girls aged 9-15 years. More than 99% developed antibodies against all 9 strains of the virus after 4 weeks, which persisted throughout the 2.5 years of the study. It has already been shown that the vaccine protects against cancers and precancers of the cervix (preventing up to 90% of cases of cervical cancer), vulva, vagina, anus, penis, oropharynx, as well as genital warts and warts caused by HPV. It is estimated that with universal use in the United States, the vaccine is able to reduce the incidence of cervical cancer by 23,000 cases per year. The vaccine is well tolerated – among the side effects, mainly painful sensations, redness, swelling at the injection site. The only possible serious complication is an allergic reaction to the components of the vaccine, which is less common than one in a million, and does not pose a danger to life if the vaccination is carried out under the supervision of a doctor (23).

Another welcome news is related to the FDA's plans to introduce stricter regulations for homeopathic medicines. Their market in the US is $2.9 billion, and their development is not subject to the same strict control as in the case of conventional drugs. At a meeting with the FDA in April, a member of the Homeopathic Society of the USA stated that high quality standards are observed in this area and nothing should be changed. Critics object that the sale of homeopathic medicines on the same shelves with medicines misleads consumers who may not know that these products, unlike medicines, do not pass the FDA's inspection for compliance with characteristics, purity, effectiveness, quality and stability. In 1988, the FDA issued guidelines according to which a company can sell homeopathic products without checking their effectiveness and safety and, unlike dietary supplements, can indicate on the insert that the drug treats certain diseases, such as sprains, colds or allergies. However, in the 2000s, the agency began to independently monitor the quality and safety of such products, having already issued more than 40 warnings about exceeding the permissible concentrations of certain substances (for example, zinc or alkaloids) in homeopathic preparations (24).

Homeopathic medicines

However, the biggest concern is the use of homeopathy in severe cases instead of a really effective medicine. Doctors complain that some patients cannot be persuaded, and ask for help from the FDA. It is unclear exactly what changes will be made to US legislation, but, at a minimum, it will be necessary to indicate on the inserts the actual mass of the active substance in milligrams, and not the number of ritual dilutions.

The drug is a synthetic deoxycholic acid (one of the bile acids) that destroys fat under the chin, practically without affecting the surrounding tissues. Previously, the only way to cope with this ailment, which torments 68% of Americans, was liposuction costing $ 2700-5100 in the United States. However, the drug in clinical trials in 4% of cases showed an unpleasant side effect that could reduce its attractiveness – damage to the facial nerve (25).

The results of the use of the drug Kybella.

Unlike viagra, the drug does not act on the vessels of the genitals, but on the brain (being an agonist of serotonin receptors), and requires several weeks of daily intake. According to the agency's comment, the effect of the drug is minimal, but significant for some patients. On average, the number of satisfactory sexual acts increased by 0.5–1 per month (with an initial level of 2-3 per month). However, the drug has serious side effects in the form of fainting, injuries due to fainting and a decrease in blood pressure, especially when taken simultaneously with alcohol. Therefore, if the drug is approved, measures will be required to collect additional information about the benefit/risk ratio. For example, in case of loss of consciousness at the wheel, the consequences can be the most tragic. 

The agency made a positive decision only for the third time, after several months of lobbying by the manufacturer and feminist activists who accused the FDA of sexism for the fact that Viagra and other drugs for men have been approved for a long time, but there is still nothing like it for women. The FDA rejected this accusation, but on August 18, it still approved the drug, providing its insert with a "black rectangle" - a warning about severe side effects (26). 

Previously, medical devices created in this way were approved, but the medicine for oral (through the mouth) reception is registered for the first time. The advantage of this form is that the porous structure of the drug allows you to dissolve even large doses – up to 1000 mg – in a sip of water. Due to the fact that many patients, especially the elderly, have difficulty swallowing, they skipped taking medications, which led to an increase in the frequency of seizures. The company intends to release such versions for other drugs intended for the treatment of the central nervous system (27).

About the author

Ilya Yasny graduated from the Chemical Faculty of Moscow State University in 2002, defended his thesis on protein engineering. He worked at Algodign, where he was engaged in computer design of medicines. Then he was engaged in the organization of a laboratory for the expression of recombinant proteins. Since 2010, he has been working as a scientific expert of the biopharmaceutical company Generium, since 2014 – head of the expert department of Inbio Ventures, a management company of a venture fund that invests in drug development.