Novelties of biomedicine

The most important biopharma news for the 2nd half of 2017

Ilya Yasny, XX2 century
For references and references, see the original article

The outgoing year was rich in real scientific breakthroughs, deep failures and bright news in the field of drug development and healthcare. Let's look at the most interesting and important of them.

To begin with, a review of new drugs registered by the FDA (US Food and Drug Administration). In 2017, 48 new drugs entered the market (as of December 25), which is an absolute record since 1996 (when 53 registration certificates were issued). However, there are only 9 drugs with a new mechanism of action (Fig. 1), which is inferior to last year's quantities (at least 33%) and makes one think about the productivity of the biopharma as a whole – a recent analysis was devoted to this, saying that investments by large pharmaceutical companies in the development of new drugs threaten to become unprofitable, which causes the need to look for new forms of evolution of the industry as a whole.

Fig. 1. The annual number of new registered drugs (orange curve) and drugs with a new mechanism of action (blue columns).

Nevertheless, there were enough innovations and news in the outgoing year. Let's talk about the most notable drugs with a new mechanism of action.

• Two CAR-T drugs that we often write about – Kymriah (Novartis International AG) and Yescarta (Gilead Sciences, Inc. / Kite Pharma) – received registration for various B-cell lymphomas ahead of schedule. The FDA noted that this is a "historic milestone" in our ability to treat and even completely cure previously incurable diseases. The cost of new products is high – $400-500 thousand, but Novartis plans to apply the so-called outcomes-based approach for the first time, when treatment will be paid only if the patient has responded to it. In addition, the analysis just conducted showed that even at such a price, the use of new drugs is economically justified.
• Spark's Luxturna Therapeutics gene drug for the treatment of a rare eye disease – retinal dystrophy caused by a mutation in the RPE65 gene. This is the first drug of its kind registered by the FDA, but the price for it will not be small – most likely, $ 1 million. However, another company's gene drug for the treatment of hemophilia A did not show a sufficient level of recovery of the necessary factor VIII in the blood of four treated patients.
• Rhopressa, a Rho kinase inhibitor of Aerie Pharmaceuticals, Inc., has been registered for the treatment of elevated intraocular pressure, including glaucoma. This substance modulates the contractility of smooth muscles in the eye muscles, contributing to the outflow of fluid from the eyes [1].
• Genentech, Inc., a member of the Swiss pharmaceutical conglomerate Hoffmann-La Roche since 2009, has received registration for the drug Hemlibra, which is a bispecific antibody against factors IXa and X. The drug is indicated for patients with hemophilia A who have developed antibodies against factor VIII, and thus injections of factor VIII have ceased to be effective.
• Ultragenyx Pharmaceutical has received registration for an enzyme replacement therapy drug for one of the accumulation diseases – Sly syndrome, in which the beta-glucuronidase enzyme gene is disrupted. This is a rare disease that affects one newborn per 250,000. The drug Mepsevii, like Elaprase in Hunter syndrome or Cerezim in Gaucher's disease, allows you to improve the symptoms of the disease with regular injections.
• Another drug to relieve the symptoms of a very rare childhood disease – Batten's disease, released by BioMarin Pharmaceutical Inc., was approved this year. The drug Brineura is also an enzyme, tripeptidyl peptidase 1, the genetic deficiency of which leads to the deposition of lipofuscin in the lysosomes of nerve cells. Injections of the drug can slow down the loss of the ability to walk.
• Celgene Corporation for the first time registered Idhifa, an inhibitor of the mutant enzyme IDH2 (isocitrate dehydrogenase) for the treatment of acute myeloid leukemia with IDH2 mutations – this is 9-13% of patients with such leukemias, approximately 1,500 patients in the United States who did not have standard therapy options. Isocitrate dehydrogenase is one of the main enzymes of the tricarboxylic acid cycle, and plays an important role in cell metabolism. Mutant forms lead to an increase in the concentration of 2-hydroxyglutarate, an oncometabolite that stimulates the survival and proliferation of leukemic cells [2]. The short period of this drug's release to the market is remarkable – only 3 years from the beginning of clinical trials to registration. He also has the potential to enter the first line of treatment for acute myeloid leukemia.
• Another antibody for the treatment of moderate and severe psoriasis, Tremfya, was released on the market by Johnson & Johnson. It is directed against another cytokine that plays a role in the development of inflammation – IL-23. There are already antibodies on the market against other proteins-regulators of inflammatory and autoimmune reactions – TNF-alpha (these are the leaders of the drug market in general), IL-17, IL-12/23. The new antibody has not been compared directly with existing agents, but according to historical data surpasses them in effectiveness, not inferior in safety.

Success of RNA drugs

This year, several antisense drugs were expected to be successful at once.

Fitusiran (Alnylam Pharmaceuticals, Inc.) is a double-stranded RNA for inhibiting the expression of serpin C1 (antithrombin), which contributes to an increase in activated factor X necessary for the transition of prothrombin to thrombin (Fig. 2). Thus, the drug increases blood clotting and can be indicated for both types of hemophilia (A and B). Currently, a number of plasma and recombinant intravenous coagulation factors are used in patients (factor VIII is used for hemophilia A, and factor IX is used for hemophilia B), but fitusiran has several advantages over them. In addition to the convenience of use (the drug is administered subcutaneously once a month), protein preparations also have an important disadvantage – many patients develop neutralizing antibodies, and the drugs cease to act. Since fitusiran has a non-protein nature and acts by a different mechanism, it will potentially help those patients who have developed similar neutralizing antibodies.

Fig. 2. Mechanism of action of the drug Fitusiran [3].

According to phase 1/2 data, the drug showed signs of efficacy and safety: half of the patients had no bleeding at all, and 69% had no spontaneous bleeding during the follow-up period. But in September 2017, what everyone feared happened: one of the patients in the study died of thrombosis after using fitusiran. The FDA suspended the study, but in December, after analyzing the causes of the patient's death and correcting the protocol, allowed it to continue.

Another Alnylam drug, patisiran, is a liposome-packed small interfering RNA (siRNA, or miRNA), a complementary gene of the TTR protein (transthyretin, transthyretin). The drug is being prepared for registration for TTR-amyloidosis. TTR is the main transport protein of vitamin A. Normally, TTR forms tetramers, but mutations can lead to the formation of a monomeric form of TTR, which causes amyloid extracellular protein deposits in vital organs, for example, in the heart and nerve fibers. This can eventually lead to heart failure, polyneuropathy and death. Antisense reduces the synthesis of TTR in the liver and thereby reduces the deposition of mutant protein in organs. In September, the results of phase 3 were published, in which the drug reached all primary and secondary endpoints. Compared with placebo, it significantly improved the neuropathic scale and the quality of life of patients. After entering the market, it will be the first registered drug that works on the principle of RNA interference. A drug against the same target, but based on a DNA antisense, inotersen, is being developed by Ionis Pharmaceuticals.

Fig. 3. The scheme of RNA interference. The double-stranded RNA is processed by the Dicer enzyme, then short fragments are incorporated into the RISC nucleoprotein complex, which destroys the mRNA containing sites complementary to the RNA in the complex [4].

Success in the treatment of cystic fibrosis

Earlier we wrote about Vertex Pharmaceuticals' drugs that help some patients with cystic fibrosis. The already registered Kalydeco and Orkambi, as well as the tezacaftor-Kalydeco dual combination entering the market, cover about 40% of patients with certain mutations. The new drug VX-440, added to tezacaftor-Kalydeco, will bring the number of patients who can be helped to 90% – and this is tens of thousands of patients in the USA alone. The drug has so far performed well in phases 1 and 2, but even if something happens, the company has spare versions of the molecules. Like the company's previous drugs, VX-440 is a modulator of the CFTR chlorine channel, the incorrect folding of which as a result of mutations is the cause of the development of cystic fibrosis. This protein plays an important role in the functioning of the epithelium of the lungs, pancreas and other organs. Its insufficient activity leads to the formation of mucus, inflammation, and an increase in the frequency of bacterial infections in the lungs and gastrointestinal tract. Vertex's drugs bind to CFTR and partially compensate for the effect of mutations, allowing the protein to function. This is expressed primarily in the indicator FEV1 (Forced Expiratory Volume in 1 second – the volume of air exhaled during the first second of forced exhalation). In the majority of patients in the studies, this indicator improved clinically significantly.

Fig. 4. A cell with a defective chlorine channel. Kalydeco is a "potentiator", that is, it binds to CFTR, which is located in the membrane and normalizes its function, and tezacaftor and VX-440 are correctors that stabilize the channel inside the cell and deliver it to the surface [5].

Another antibody conjugate with a toxin has been approved

Pfizer, Inc.'s Besponsa drug expands the spectrum of proteins on the surface of malignized B cells, against which antibody drugs are now available. The most famous of them, CD20, is the target of the drug rituximab, which has become the standard therapy for a wide range of leukemias and lymphomas. A new drug acting on CD22 is indicated for those patients who have not been helped by previous lines of therapy. This is an antibody with a bacterial toxin sewn to it. True, 4 years ago the drug failed in phase 3 for non-Hodgkin's lymphomas, but now it has shown impressive results in patients with acute lymphoblastic B-cell leukemia resistant to previous therapy. The proportion of complete responses was 81% in the drug group versus 29% in the chemotherapy group.

The CD22 receptor is expressed on the surface of immature and mature B cells, as well as transformed blast cells of a number of B-cell leukemias and lymphomas. Besponsa binds to CD22 on the cell surface, is dragged inside and the toxin kills the cell. This principle of antibody-drug conjugation (Antibody drug conjugation, ADC) was developed several decades ago, and for the first time the first drugs of this type were registered back in 1999. However, these drugs were withdrawn from the market due to toxicity, as a free toxin was split off from the drug under the action of plasma proteins and destroyed healthy cells. Now, after some progress in the development of linkers (the part of the molecule connecting the antibody and the toxin) that are more resistant to cleavage, 5 drugs of this type have entered the market and dozens are in development.

Fig. 5. The principle of action of drug conjugates with antibodies. The antibody part of the drug (lilac color) selectively binds to its receptor (blue) and gets inside the cell. There, the drug (yellow) splits off and acts inside the cell, usually killing it [4].

Malaria control

Although most of the drugs in development are expensive drugs for the treatment of diseases in developed countries, some Big Pharma companies do not forget about tropical diseases that affect up to 10% of the world's population (in 2015, malaria claimed the lives of 438,000 people). In particular, the portfolios of GSK (GlaxoSmithKline), Sanofi S.A., Takeda Pharmaceutical Company, Novartis International AG and other companies have funds for both prevention and treatment of malaria. The standard of malaria therapy is artemisinin-combination therapy (ACT). Artemisinin, a drug isolated from wormwood, acts very quickly, but alone is not able to cleanse the body of malarial plasmodium, as it is quickly excreted. It is combined with other drugs that linger in the body longer. Although ACT helps most patients with timely and proper administration, there are also cases of drug resistance, therefore, the search and development of new drugs is required. The mechanism of resistance to artemisinin is very interesting. The molecular mechanism of action of artemisinin is very complex and includes an effect on dozens of parasite proteins, but critically depends on the activation of the drug, which occurs after interaction with heme (an iron–containing oxygen carrier molecule in humans). Normally, in human cells, heme is in complex with the protein hemoglobin, and therefore the effect of artemisinin on human cells is minimal. Malarial plasmodium at one stage is located inside red blood cells, and free heme accumulates inside the parasite, causing activation of artemisinin. However, one of the mutations leads to the fact that plasmodium is delayed in the phase where there is still little heme in its cells, and artemisinin acts poorly.

Fig. 6. Scheme of artemisinin activation (lilac) by heme (brown) in a malarial plasmodium cell inside an erythrocyte [6].

Finally, to the news. This year, Novartis has started phase 2b of a new anti–malaria drug, KAF156, with a new mechanism of action, which may make it possible to cure many types of malaria, including artemisinin-resistant ones, in one dose of the drug. The drug will run into competition in the form of drugs from Sanofi and GSK, which are also in the late stages of development. However, the need for such drugs will begin to decrease after new vaccines and preventive means enter the market.

The cost of drugs is also a problem: in many countries where the malaria problem is particularly acute, even $1 is a high price for a medicine. They are partly trying to solve the problem with the help of charity, for example, the Bill and Melinda Gates Foundation spends more than a billion dollars annually on the fight against tropical diseases [7]. GSK, releasing its vaccine to the market, announced that it would sell it with a 5% markup to the cost price, and the added value would go to the development of new antimalarial drugs [8]. It is possible that the ambitious goal of WHO to get rid of malaria by 2030 will not be fulfilled, but it is for sure that there will be great successes.

The success of gene therapy

One of the largest studies of gene therapy was conducted in 17 patients with cerebral adrenoleukodystrophy (cALD) – showed stabilization of the disease in 15 patients. cALD is a rare genetic disease that leads to the loss of myelin sheaths around the nerve fibers of the brain and then to death, previously had no other therapy options other than stem cell transplantation. The bluebird bio, Inc. product is a lentivirus (a viral construct derived from HIV) carrying a working copy of the ABCD1 gene, while in patients this gene is defective. The lentivirus is treated with the patient's own bone marrow stem cells isolated from the patient, after which they are injected back. In this phase 2/3 study, patients were observed for more than three years after a single injection. The FDA allowed the study to continue and recruit more patients.

This is good news for bluebird, especially after a similar drug for the treatment of sickle cell anemia has not shown sufficient effectiveness.

Transplantation of genetically modified skin

Italian and German scientists have achieved tremendous success in the field of gene and cell therapy by transplanting 80% of the skin to a boy with epidermolysis bullosa. This terrible disease, also known as "butterfly syndrome", is characterized by structural and mechanical fragility of the skin, in which the slightest effects lead to peeling and erosion of the skin. The disease is caused by mutations in several genes encoding structural proteins of the skin – laminins, collagens and integrins. There are no treatment methods for this disease and more than 40% of patients die in childhood. Two years ago, scientists took 4 square centimeters of skin from a 7-year-old boy, obtained keratinocyte cultures and transformed their laminin genome using a retroviral vector. Then the grown crops were transplanted to the child.

Fig. 7. The picture of the patient's skin lesion before treatment. Red zones – exfoliation of the epidermis, green – swelling. The new skin material was transplanted to both red and green areas [9]. The observation period at the time of publication of the article (November 2017) was 21 months. Neither by external signs, nor by morphological analysis, there were no symptoms of the return of the disease.

This remarkable result will allow treating children with newly diagnosed epidermolysis bullosa, and will also probably be applicable to a number of other skin diseases of a genetic nature.

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