The term rare applies to those diseases affecting a limited number of people with a prevalence below a given cut-off point, which is codified by the legislation of each individual country. The EU sets this threshold at 0.05% of the population, i.e. when it affects less than 1 in 2000 inhabitants, while a disease or disorder is defined as rare in the USA when it affects fewer than 200,000 Americans at any given time. There may be as many as 7,000 rare diseases.
Rare diseases are characterized by a broad diversity of disorders and symptoms that vary not only from disease to disease but also from patient to patient suffering from the same disease.
Relatively common symptoms can hide underlying rare diseases leading to misdiagnosis and delaying treatment and they are often chronic, progressive, degenerative, and frequently life-threatening.
The lack of scientific knowledge and quality information on the disease often results in a delay in diagnosis. Moreover, it is equally difficult for patients to access effective treatment and receive social and medical care for the disease. This often results in heavy social and financial burdens on patients.
This explains why we focus particularly on treatment and assistance for rare disease sufferers; our commitment concentrates in this field as we believe this therapeutic area to be of great importance and social impact.
We are dedicating our efforts in two main areas: Advanced Therapy Medicinal Products (ATMPs) and lysosomal storage disorders (LSDs).
Advanced therapy medicinal products (ATMPs) are medicines for human use that are based on genes, tissues or cells. They offer ground-breaking new opportunities for the treatment of diseases and injuries. ATMPs can be classified into three main types: gene therapy medicines, somatic-cell therapy medicines and tissue-engineered medicines. The development of ATMPs is a dynamic, innovative and fast-growing field.
The cornea is a transparent front segment of the eye that covers iris, pupil, and anterior chamber; protects the eye against insults such as injury and infection and provides most of an eye’s optical power.
The cornea can be damaged and loose transparency, which is fundamental to maintain a correct visual acuity. Corneal epithelium renewal and repair is dependent upon the cells present in the basal epithelial layer of the limbus, which is found in a small area of the eye between the cornea and the conjunctiva.
Thermal or chemical ocular burns can destroy the limbus, causing a limbal stem cell deficiency (LSCD). If this happens, the cornea is invaded by the conjunctiva epithelium. This process leads to cornea opacification and neovascularization.
This condition can cause pain, burning sensation and photophobia causing most of the time loss of vision.
LSCD due to ocular burns is rare: it affects approximately 0.3 / 10,000 people in the EU, meaning a total of about 15,000 people.
If you want to discover more on limbal stem cell deficiency please visit www.limbalstemcelldeficiency.com
How is LSCD treated?
The treatment of LSCD requires a stepwise approach: after the damage, the initial phase aims at stabilizing the ocular surface; surgical interventions are rarely used during this acute phase as the inflammation must settle for a period of time. Subsequently, surgical procedures, indicated as follows, can be considered.
CLAU (Conjunctival Limbal Autograft), CLAL (Living-related conjunctival limbal allograft) and KLAL (Keratolimbal allograft) are traditional surgical techniques, using autologous or allogeneic limbal tissue transplant.
SLET (Simple Limbal Epithelial Transplantation) and CLET (Cultivated Limbal Epithelial Transplantation) are more innovative techniques, which need a smaller portion of preserved limbus. In particular, CLET entails cultivation and expansion in laboratory of cells retrieved from a small biopsy and subsequent transplantation in the patient’s damaged eye.
HOLOCLAR® is indicated for the treatment of moderate-to-severe patients affected by LSCD due to ocular burns. It consists in ex-vivo expanded autologous human corneal epithelial cells containing stem cells.
Lysosomal storage diseases (LSDs) are a group of about 50 rare inherited metabolic disorders that result from defects in lysosomal function. They are characterized by an abnormal build-up of various toxic materials in the body's cells as a result of enzyme deficiencies. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases.
Our mission is to improve the lives of people with rare diseases and we are dedicating our efforts in 3 different Lysosomal Storage Disorders: Alpha mannosidosis, Nephropathic cystinosis and Fabry disease.
Alpha Mannosidosis is a rare genetic disease, caused by the impaired function of the lysosomal enzyme alpha mannosidase. Due to this deficiency, oligosaccharides are only partially broken down, and over time build up in the body, causing increasing damage to cells and leading to medical problems in many body systems.
Alpha mannosidosis is a very heterogeneous disease, presenting with a wide range of symptoms: the most frequent are recurrent chest infections and problems with hearing loss, distinctive facial features, cognitive impairment and progressive muscular weakness. Lack of voluntary coordination of muscle movements and skeletal and joints abnormalities could occur. In adulthood few patients manage to be completely independent socially, needing help with many activities and possibly requiring a wheelchair.
High levels of oligosaccharides in urine is suggestive of alpha mannosidosis. Testing of the Mannosidase enzyme residual activity and genetic analysis are used to confirm the diagnosis.
Alpha mannosidosis is a rare disease, affecting approximately one in every million babies born worldwide.
If you want to discover more about alpha mannosidosis please visit www.alphamannosidosis.com
How is alpha mannosidosis treated?
The supportive treatments aim at controlling symptoms and they involve several medical specialties.
Hematopoietic stem cell transplant (HSCT) can be a treatment option for some patients, however the risk-benefit profile is more favourable in younger patients therefore ensuring an early diagnosis is critical for this to be a real option for patients.
Lamzede® is the first enzyme replacement therapy for the treatment of Alpha-mannosidosis (AM). The active substance of Lamzede® is velmanase alfa, a recombinant form of human alpha-mannosidase. The product is indicated for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. Lamzede® therapy, administered via weekly intravenous infusions, is intended to provide or supplement the natural enzyme, which degrades the mannose–rich oligosaccharides within the lysosomes and thus prevents their accumulation in various tissues in the body. Lamzede® obtained the EMA centralized approval in April 2018 and it is commercialized in an increasing number of European countries.
LAMZEDE® was designated as an orphan medicinal product on 26 January 2005.
Nephropathic cystinosis is the most common and severe form of cystinosis, a metabolic disease characterized by accumulation of the amino acid cystine within lysosomes in the cells, leading to several damages in many organs and tissues.
Nephropathic cystinosis usually presents in early infancy as renal Fanconi syndrome, a serious disorder of the proximal tubules of the kidneys involving excessive excretion of nutrients and minerals such as glucose, amino acids, phosphates, potassium and sodium. This can lead to excessive urination, resulting in acute dehydration. The loss of nutrients impairs growth and may result in soft, bowed bones. Untreated children will experience complete kidney failure by about the age of 10. However, nephropathic cystinosis is not only a renal disorder, but a multisystemic disease that could lead to ocular and neurologic impairment, muscle deterioration, diabetes, thyroid and nervous system problems, and infertility in affected men.
Transmission is autosomal recessive: two altered copies of the gene from both parents are needed to manifest the disease.
It is an ultra-rare disease, with an estimated incidence of around 1/100,000- 1/200,000 live births.
How is nephropathic cystinosis treated?
The main treatment is cystine-depletion therapy (the pharmacological lowering of the cystine content in the lysosomes), through cysteamine that, when initiated early, can slow or even stop the progression to renal failure and the development of extra-renal manifestations.
PROCYSBI® (cysteamine bitartrate) is the first EMA-approved cystine-depleting therapy dosed every 12 hours for nephropathic cystinosis. PROCYSBI® is a delayed-release form of cysteamine bitartrate that works by continuously reducing the toxic concentration of cystine in the cells. The product is indicated for the treatment of proven nephropathic cystinosis. PROCYSBI® is intended to keep cystine concentration under control to limit or prevent the damage too much cystine can cause to cells, tissue, and organs. Chiesi Farmaceutici, after the acquisition of the European subsidiary of Horizon Pharma in June 2017, owns the marketing rights for PROCYSBI® delayed-release capsules in Europe, the Middle East and Africa (EMEA). Horizon maintains marketing rights for PROCYSBI® in the United States, Canada and Latin America.
Procysbi®, delayed-release cysteamine bitartrate capsules, is indicated for the treatment of proven nephropathic cystinosis. It is orally administered every 12 hours due to the delayed-release,
In addition to cystine-depletion therapy, electrolytes and vitamin supplements are administered. Hormons and specific treatments are administered to support growth and to limit hypothyroidism, diabetes and hypogonadism. Renal transplantation is the treatment of choice for end-stage renal disease in cystinosis.
Fabry disease is a progressive, inherited, multisystemic lysosomal storage disease. It is characterized by the accumulation of sphingolipids, due to the inherited deficiency of the enzyme alpha galactosidase A.
In fact, Fabry disease is caused by mutations in the GLA gene, encoding the alpha-galactosidase A enzyme. This gene is located on chromosome X, therefore males are affected while heterozygous females are carriers, but may show a wide range of clinical manifestations.
The clinical picture covers a wide spectrum ranging from mild cases in heterozygous females, to severe cases in classically affected hemizygous males with no residual alpha-galactosidase A activity. It is characterized by specific neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and cerebrovascular manifestations.
Annual incidence is reported to be 1 in 80,000 live births but this figure may underestimate disease prevalence.
How is Fabry disease treated?
Nowadays, the enzyme replacement therapy (ERT) is considered the standard treatment for Fabry disease. The recombinant alpha-galactosidase A enzyme is administered with intravenous injections. The earlier the therapy is initiated, the better are the treatment results.
Recently, enzyme’s residual activity enhancement with oral pharmacological chaperone has been approved for patients carrying specific amenable mutations.
Conventional management consists of pain relief with analgesic drugs, nephroprotection and other symptomatic treatments. Some patients require dialysis and kidney transplant.
In October 2017, Chiesi announced an Ex-US license and collaboration agreement with Protalix BioTherapeutics, Inc. for the development and commercialization of PRX-102 (pegunigalsidase alfa), the Company’s chemically modified version of the recombinant alpha-Galactosidase-A protein for the treatment of Fabry disease. In July 2018 Protalix and Chiesi entered into an exclusive U.S. license and supply agreement which grants to Chiesi also the United States rights for the development and commercialization of PRX-102.
Inflammatory bowel disease (IBD) involves the chronic inflammation of all or part of the digestive tract. IBD primarily includes ulcerative colitis and Crohn's disease. IBD can be painful and debilitating, and sometimes leads to life-threatening complications.
Ulcerative colitis is an inflammatory bowel disease that causes long-lasting inflammation in part of the digestive tract. Symptoms usually develop over time, rather than suddenly. Ulcerative colitis usually affects only the innermost lining of the large intestine (colon) and rectum. It occurs only through continuous stretches of the colon.
Crohn's disease is an inflammatory bowel disease that causes inflammation anywhere along the lining of the digestive tract, and often spreads deep into affected tissues.
Clipper (beclomethasone dipropionate) is an oral corticosteroid, indicated for the treatment of mild or moderate ulcerative colitis in the active phase, as add-on therapy to 5-ASA-containing drugs in patients who are non-responders to 5-ASA therapy in the active phase. It is formulated in gastro-resistant prolonged release tablets, with a once-daily posology.
Cystic fibrosis is a hereditary genetic disease. A mutation of the CF gene causes an alteration in a protein called CFTR, which is present in all the organs and regulates the exchange of sodium chloride and water through cell membranes. The organs most affected by the disease are the lungs and the pancreas; in the former, thick, sticky secretions occur, thus helping to create the ideal environment for the development of bacteria such as Pseudomonas aeruginosa, meaning that sufferers are prone to recurrent infections and inflammation, which can in turn also represent serious conditions such as pneumonia. Chronic inflammatory processes can damage lung tissue over the course of time and subsequently lead to impaired respiratory function. The symptoms of infection are numerous and the degree of severity varies from case to case and from moment to moment: persistent cough, breathing difficulties, expectoration, reduced stamina for physical activity, loss of appetite, a sense of feeling generally unwell and temperature.
Bramitob is a tobramycin formulation in sterile inhalation solution, indicated for the treatment of chronic pulmonary infections caused by Pseudomonas aeruginosa in cystic fibrosis sufferers (CF).
Hyaneb is a hypertonic solution for nebulisation, containing sodium chloride and hyaluronate.
Its formulation activates an osmotic mechanism: the high percentage of salts contained in the solution attracts water, and facilitates the mobilisation of the mucus by hydrating the viscous secretions in the airways. Hyaneb is indicated for cystic fibrosis sufferers and those with bronchiectasis.
Organ failure happens when an organ loses its ability to perform its physiological functions, and this creates a potential threat to both the quality of life and the survival of the patient.
The kidneys cover various physiological functions, ranging from filtering the blood to remove waste products to maintaining the electrolyte balance, and regulating the production of red blood cells via the hormone erythropoietin. Regarding renal impairment, its severity is usually quantified through laboratory analysis, ranging from mild (grade 1-2) to end-stage disease (grade 5). The latter has two possible therapeutic approaches, either dialysis or transplantation. The first is a palliative treatment where an external machine replaces the filtering function of the kidney. Although effective, in most cases this approach requires the patient to return frequently to the hospital for long and unpleasant sessions. In the event of transplantation, however, a new and functioning kidney (a graft) is added through a surgical procedure to recover the lost function.
For patients with liver failure, the situation is even more complex. A functioning liver is in fact absolutely essential for survival and, at the moment, there is no corresponding palliative therapy such as dialysis for patients with severe hepatic impairment. The only therapeutic approach is therefore represented by a transplant. Unlike renal transplant, the original liver is removed during the surgical procedure and then replaced by with new organ.
Two important limiting factors for transplants are represented by the availability of organs, which remains substantially inferior to the demand, and by the biological and immunological compatibility between the graft and the recipient. Physiologically, the immune system protects the body from external pathogens, by recognising what belongs to the host (self ) from what does not (non-self ). Though critical in defending a healthy individual, in a transplanted patient receiving a graft from a donor (thus, strictly speaking, non‑self ), this mechanism results in the immune system recognising and attacking the transplanted organ (rejection). Currently, the standard of care for the prevention of organ rejection is a combination of immunosuppressive drugs, aimed at lowering the reactivity of the immune system enough to avoid rejection, but at the same time not enough to expose the individual to an increased risk of opportunistic infections. The treatment is administered throughout the entire life of the transplanted organ. The average survival of a transplanted kidney is approximately 10 years, and is slightly lower for a transplanted liver.
The standard of care currently in use is based on a triple combination of immunosuppressant agents, of which tacrolimus represents the main pillar.