Orphans on the market of medicines

The pharmaceutical industry's response to rare diseases
Anna Shibaeva, "Weekly Pharmacy" No. 2-2011

Currently, more than 6,000 rare diseases are known, which are noted only in 6-8% of the world's population, including 27-36 million patients with similar diseases in the EU countries. About 80% of all rare diseases have a genetic nature. The remaining cases are predominantly degenerative or proliferative in nature. With the improvement of diagnostic medicine and the deterioration of the environmental situation, the number of rare diseases is steadily increasing, 5 new rare diseases are described weekly in medical publications. Due to the low level of spread of these diseases, diagnosis is complicated, since many specialists have never encountered such a pathology before in their practice, their treatment is also problematic – modern medicine knows methods of treating only a few hundred such diseases.

The term "orphan diseases" (orphan diseases, rare diseases) first appeared in the USA in 1983 with the adoption of the Orphan Drug Act. In the USA, the orphan drug status is assigned to a product if it is intended for the treatment of a disease that has been detected in no more than 200,000 people in the country. In Europe, the criterion for classifying the disease as rare is its prevalence – no more than 5 cases per 10,000 people.

The main purpose of the Orphan Drug Law is to encourage pharmaceutical companies developing medicines for the treatment of rare diseases. In the West, states provide manufacturers of orphan medicines with preferences at all stages of the drug's life cycle. The main advantage that a pharmaceutical company provides orphan status for its drug is exclusivity regarding medical indications, that is, after marketing approval of the drug for a certain number of years, no other medicine will be registered for this indication. For example, in the USA, a drug with the status of an orphan can be sold for 7 years in conditions of complete lack of competition. Such stimulation is associated with the peculiarities of the initial stages of the life cycle of orphan drugs, the development of which takes much longer than for other drugs - on average about 10 years. In addition, the recruitment of patients for clinical trials, which can last for years, is also problematic.

The legislation also provides for various tax benefits for orphan drugs at the stage of clinical trials and in the process of marketing approval.

This approach is due to the insignificant volume of the orphan drugs market, respectively, their development, production, sale are not of commercial interest to pharmaceutical companies. It should be noted that such drugs do not need marketing promotion.

In the years since the adoption of the law, significant progress has been made in the development of orphan drugs. If in the period 2000-2002 the FDA assigned the "orphan" status to 208 drugs, then in 2006-2008 this figure was 425.

According to the report of the American research company "BCC Research", published in May 2010, the volume of the world market of orphan drugs by the end of 2009 amounted to 84.9 billion US dollars. With an average annual growth rate of about 6%, it is expected that by 2014 the volume of this market will reach 112.1 billion US dollars accumulate a share of 51% of the total global market of orphan drugs, and with an average annual growth rate of 8.9%, it is predicted that the volume of this segment of the pharmaceutical market in the United States by 2014. it will reach $65.9 billion.

The lion's share in the total global sales of orphan drugs in 2009 was accumulated by biological drugs - 64.3%. For comparison, a year earlier, this figure was 51.4%. According to forecasts, the volume of the world market of orphan drugs of biological origin by 2014 will amount to 76.2 billion dollars with an average growth rate of 6.9% per year.

In the context of therapeutic groups, the maximum share in the global sales of orphan drugs in 2009 was noted for antitumor drugs - 36% ($30.6 billion). According to forecasts, sales in this segment will increase to $49.7 billion by 2014, with an average growth rate of about 10% per year.

Let's focus in more detail on 5 rare diseases.

Severe combined immune deficiency (TCID), or "Bubble Boy Syndrome". The disease is a genetic defect of the immune system caused by a relatively rare mutation of the X chromosome, due to which the body is unable to produce mature T-lymphocytes responsible for resisting pathogens of various infections.

Thanks to the efforts of the media, this is one of the most famous rare diseases, despite the fact that it is noted only in 1 person per 100-200 000 births. The public first learned about this disease from the story of David Vetter, which was perpetuated by numerous mass media. American boy David Vetter spent all 12 years of his short life in a plastic "bubble", which ended in 1984 after an unsuccessful bone marrow transplant.

Traditionally, bone marrow transplantation is used in the treatment of this disease, which produces stem cells, which, in turn, are designed to produce new healthy hemocytes. In case of successful surgery, the disease ceases to progress, however, a patient with imperfect compatibility with the donor bone marrow subsequently needs chemotherapy, and he also faces numerous other problems.

Modern medicine focuses on the development of gene therapy designed to strengthen the stem cells of patients' own bone marrow. This method of treatment does not require additional supportive treatment, in particular chemotherapy.

Currently, GlaxoSmithKline, together with Fondazione Telethon, Fondazione San Raffaele, Genetix Pharmaceuticals, and Targeted Genetics Corp. are developing gene therapy for the treatment of TKID.

With the financial support of the Boston Children's Hospital in the world, it is planned to conduct a small study of gene therapy, which will involve 20 children with hereditary TKID. Seven years earlier, a similar study was conducted in Paris and London with the participation of 20 children, but it was temporarily suspended because 2 of them were diagnosed with leukemia, 3 developed blood cancer, and one died.

In the bone marrow cells extracted from the study participants, an intact copy of the gene whose defect caused the disease was injected in the laboratory, and then the normally functioning cells were returned back to the patient's body. The successful implementation of this procedure assumes that the injected cells will begin to produce the protein necessary for the normal functioning of the immune system.

Gaucher disease (glucosylceramide lipidosis) is a hereditary disease that develops as a result of insufficiency of the enzyme glucocerebrosidase, which leads to excessive accumulation of lipids in many tissues, in particular bone marrow, spleen and liver. Glucosylceramide lipidosis is divided into 3 types. The most common is the first type, which is detected in 1 person out of 50,000 born, and this disease is most often noted among Ashkenazi Jews.

This pathology was first described in 1882 by the French physician Philippe Gaucher.

Treatment of Gaucher's disease consists in the appointment of enzyme replacement therapy with intravenous administration of glucocerebrosidase. Currently, several market operators are represented in this segment. The Genzyme company, under the trade name Cerezyme, markets a recombinant form of the enzyme imiglucerase on the global pharmaceutical market, also intended for long-term enzyme replacement therapy. The approval of the US Food and Drug Administration (FDA) for this product was obtained in 2001. Under the action of imiglucerase, glycolipid glucocerebroside is hydrolyzed to glucose and ceramide along the usual path of membrane lipid metabolism, as a result of which the intensity of symptoms of the disease such as hepatosplenomegaly, anemia decreases, platelet count normalizes, and the quality of life of patients improves. It's no secret that the treatment of rare diseases is very expensive. Thus, the annual course of treatment of Gaucher's disease with Cerezim® is estimated at $200,000 for children and $ 600,000 for adults. for adults.

Cerezim's predecessor was Ceredase (CeredaseTM), also manufactured by Genzyme, obtained from placenta and approved by the FDA in 1991.

In February 2010, the biopharmaceutical company "Shire" received FDA approval for the sale of Vpriv™ (velaglucerase alpha), intended for long-term enzyme replacement therapy, and on August 27 of the same year, approval was received for the promotion of the drug in 30 EU countries.

In 2009, halfway through clinical trials, the drug of the British pharmaceutical company "Amicus Therapeutics" for the treatment of Gaucher's disease left the distance due to inefficiency - the drug improved the condition of only 1 out of 18 study participants.

Currently, Protalix and Pfizer are jointly developing Uplyso® (taligurase alpha) for the treatment of Gaucher's disease. Taligurase alpha is a recombinant form of glucocerebrosidase derived from plant cells.

Violations of the urea cycle are associated with a deficiency of one of the enzymes responsible for the normal metabolism of urea. Certain enzymes are responsible for the conversion of residual nitrogen in the blood into urea, which is excreted from the body with urine. Violation of the processes of urea synthesis leads to excessive accumulation of ammonia in the blood, which often leads to serious consequences, including brain damage, coma and death. In the USA, this disease is noted in 1 out of 10,000 births.

The American company Hyperion Therapeutics is developing a new drug glycerol phenylbutyrate (HPN-100) for the treatment of urea cycle disorders, which is at the final stage of phase III clinical trials. According to the company's representatives, this segment of the pharmaceutical market is estimated at about $ 200 million.

Currently, the combined preparation Ammonul® (sodium phenyl acetate/sodium benzoate) of Ucyclyd Pharma, which is a division of Medicis Pharmaceutical Corporation, is used in the treatment of urea cycle disorders. The drug was approved by the FDA in 2005 and received the status of an orphan drug.

Fabry's disease is a rare hereditary pathology related to lysosomal accumulation diseases (diseases with impaired lipid metabolism). 5-10 000 people suffer from this disease in the world. Violation of lipid metabolism is caused by a deficiency of the enzyme alpha-galactosidase A. This enzyme is responsible for the destruction of the lipid – glycosphingolipid globotriaosylceramide (GL3), the accumulation of which over a long period can lead to renal failure, increased risk of heart attack and death.

The American company Amicus Therapeutics, mentioned earlier in connection with an unsuccessful attempt to develop a new drug for the treatment of Gaucher's disease, together with the global pharmaceutical giant GlaxoSmithKline, is developing the drug Amigal™ (migalastate hydrochloride) for the treatment of Fabry's disease. Currently, the drug is in phase III clinical trials. According to the terms of the agreement, GlaxoSmithKline will pay Amicus Therapeutics an initial payment of $ 60 million, and the amount of subsequent payments is estimated at approximately $ 170 million.

Since 2001 and 2003, drugs for the treatment of Fabry's disease have been available on the global pharmaceutical market, respectively, from the companies "Shire" and "Genzyme" – Replagal® (agalsidase alpha) and Fabrazyme® (agalsidase beta).

Ectodermal anhydrotic dysplasia is a hereditary disease (type of inheritance – X–linked recessive) characterized by congenital disorders of the development of ectodermal structures, including skin, hair, nails, teeth and sweat glands. The disease is accompanied by a lack of sweating and a corresponding increase in body temperature at the slightest overheating. Ectodermal anhydrotic dysplasia is noted in 1 out of 17,000 people.

Edimer Pharmaceuticals and CMC Biologics are working together on a drug for the treatment of this disease. Ectodysplasin-A1 (EDA-A1) is a signaling protein responsible for the formation of sweat glands, teeth, hair, etc. However, in patients with anhydrotic ectodermal dysplasia, this protein is absent. The drug EDI200 is a form of EDA-A1.

P.S.
Despite significant progress over the past decade, the global orphan drug market, due to its specifics, still remains by no means the primary springboard for the development of pharmaceutical companies, which consider more massive market segments as priority areas of their activities. Therefore, the main driver of the development of the market of medicines for the treatment of rare diseases are state preferences to pharmaceutical companies operating in this segment.

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20.01.2011