Rare diseases affect a small percent of the population. In the United States, a rare disease is a condition that affects fewer than 200,000 people in the US (Orphan Drug Act ). In the European Union, a rare disease affects fewer than 1 in 2,000 people. Similarly, different federations follow different definitions to label a condition as a rare disease. There is no denying that individual rare diseases affect less than 5 to 7 individuals in 10,000; however, the collective burden of rare disease is quite high and shocking. Approximately, 300 million people, round the world, are living with one or other 6,000 identified rare diseases. 

Below are some of the Rare indications, their signs, symptoms, affected population, available treatment modalities, and upcoming therapies.

Synovial sarcomas

Synovial sarcomas (SyS) are rare entities of Soft tissue sarcoma. It has a special predilection for extremities and joints; however, despite what the name suggests, synovial sarcoma does not necessarily originate from actual synovial tissue. Researchers do not know what kinds of cells develop into this cancer. Its origin remains unclear. These can develop from anywhere in the body.

The exact cause of Synovial sarcoma is not clearly understood. However, studies point towards the translocation between chromosome X and chromosome 18 behind the development of sarcoma, which is identified in more than 90% of cases. 

  • How rare is Synovial sarcoma?

Synovial sarcoma mostly affects adolescents and young adults. It accounts for about 8–10% of soft tissue sarcomas. As per DelveInsight estimates, the total number of incident cases of Synovial sarcoma in 7MM countries was 1,610 in 2020. It has also been seen that males constitute a higher patient pool than females.

  • What are the signs and symptoms? 

Signs and symptoms of Synovial sarcoma occur near the area of origination of sarcoma, including 

  • Swelling appears near the affected area, which is often painless
  • Problems in using one or both limbs i.e., legs, feet, arms, or hands
  • If the sarcoma seeps deeper into the areas near the nerves, it can be excruciatingly painful. 
  • Problems in breathing, if the tumor is near the neck. 
  • How are Synovial sarcomas diagnosed?

Synovial sarcoma stays inactive in the body for a long time before it starts to proliferate gradually. Thus, it is necessary to keep a check on bodily changes and get regular scans. It often appears as a painless, harmless lump in the beginning. It progressively grows can be diagnosed by looking and examining the tissue samples using MRI, X-ray or CT scan and through biopsy or surgery respectively.

  • How is it typically treated?

At present, surgery is the most effective treatment for Synovial sarcoma. It is the only curative locoregional approach of localized resectable STS including SS cases. However, radiation and chemotherapy help to extend the time before recurrence and metastasis when used in conjunction with surgery.  

Doxorubicin and ifosfamide constitute the first-line approach. Pazopanib is an oral multitarget tyrosine kinase inhibitor (TKI), and is the first and only tyrosine kinase inhibitor approved for the treatment of multiple histological subtypes of soft tissue sarcoma and demonstrated promising OS in SS related studies.

  • What are the lags in the Synovial sarcoma treatment? 

Owing to the diverse and dispersed nature of the Synovial sarcoma, its heterogeneity, complexity, and rarity, it becomes quite challenging to manage and treat the tumor. The number of treatment options available in the Synovial sarcoma treatment landscape is limited, and there is a dire need for extensive R&D to better understand the patients’ needs, identify predictive biomarkers and improve end-outcomes. 

  • What are the emerging therapies in the Synovial sarcoma market?

Chalking out the developments over the past several years, it is clearly visible that effective and less toxic therapies are available for Synovial sarcoma. However, still, off-label chemotherapeutic agents continue to rule the therapeutics market. 

This is set to change in the upcoming future as several companies, including GlaxoSmithKline, Adaptimmune, Advenchen Laboratories, intend to bring revolutionary therapies in the market for Synovial sarcoma. 

Advenchen Laboratories is running a global Phase III trial of its candidate, AL3818 (Anlotinib) for Synovial sarcoma. It is an orally administered receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR1, VEGFR2/KDR, and VEGFR3), stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFβ), and fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3). Adaptimmune’s ADP-A2M4 (MAGE-A4) SPEAR T-cell therapy is under investigation to test its affinity-enhanced SPEAR T-cells in synovial sarcoma and Myxoid/round cell liposarcoma (MRCLS). Furthermore, GlaxoSmithKline is developing GSK3377794 (NY-ESO-1 T-cells; GSK ‘794), a NY-ESO-1-directed genetically modified autologous T-cell immunotherapy and is an engineered T-cell therapy.

  • What can be expected from ongoing clinical trials in the Synovial sarcoma landscape?

The upcoming therapies in each segment are measured to transform the Synovial sarcoma market scenario. DelveInsight expects a humble surge in the growth of the Synovial sarcoma market, which was estimated to be USD 35.0 million in 2020 in the 7MM.

Multiple biomarkers are associated with Synovial sarcoma that is being vigorously investigated for their molecular pathways having MoA. Extensive R&D, as well as a focus on rare diseases, have helped facilitate a better understanding of the molecular and immunologic characteristics of Synovial sarcoma. It has also led to the identification of new potential targets and the development of novel biology-driven therapies such as targeted agents, immunotherapy, and metabolic therapies that DelveInsight estimates are in different clinical stages of development and are expected to fuel the market size growth.

Biliary Atresia

Biliary atresia is a rare disease of bile ducts that affects only infants. It is a consequence of a blockage in the ducts or tubes that are responsible for carrying bile from the liver to the gallbladder. It develops due to abnormal functioning of the bile ducts inside or outside the liver. 

The actual cause of Biliary atresia remains unclear. Researchers believe that auto-immune mechanisms may be partly responsible; recent research suggests that biliary atresia could be triggered by a viral infection in susceptible infants.

  • How rare is Biliary atresia?

The total Biliary atresia incident population in the 7MM countries was estimated to be 613 cases in 2017. Biliary Atresia is slightly more common in female infants.

  • What are the signs and symptoms? 

Babies with Biliary atresia usually appear healthy at the time of their birth. However, within two-three months of life, symptoms of the disease start to appear. The signs and symptoms of Biliary atresia include:

  • Dark-colored urine
  • Pale-colored stool
  • Yellowish colored skin (jaundice)
  • Large liver 
  • Slow growth
  • Large veins visible on stomach
  • Large spleen 

In lack of proper treatment, infants with Biliary atresia develop cirrhosis within 6 months and liver failure within 1 year. By the time untreated infants turn 2, they require liver transplantation to survive. Complications of Biliary atresia include failure to thrive and malnutrition, cirrhosis and related complications, and liver failure. 

  • How is Biliary atresia diagnosed?

Biliary atresia is diagnosed with the help of blood tests that measure liver function and blood clotting factors, as well as a CBC (complete blood count). Further, liver biopsy (bi-op-see), and ultrasound help to detect abnormalities in the liver or in other organs. Then, a nuclear scan can be performed to track the flow of bile from the liver.

  • How is it typically treated?

Biliary atresia has no cure as of now. However, timely diagnosis and surgical intervention can improve patient outcomes, and with treatment, most infants with biliary atresia survive to adulthood. Further, special attention to nutrition, diet, and living style of children is also necessary. 

Surgery for Biliary atresia is referred to as the Kasai procedure. It helps in removing obstructions, thereby, facilitating the smooth flow of bile into the bile ducts and small intestine. It can also act as an early intermediate intervention to support the child’s growth. In cases of serious Biliary atresia complications, where surgery does not prove to be beneficial, the infant or child undergoes a liver transplant. Long-term antibiotic therapy helps to reduce the risk of infection, and additional medications may be used to promote bile flow and maximize the success of the operation. Genetic counseling and other symptomatic treatment also help. 

  • What are the lags in the Biliary atresia treatment? 

Owing to a lack of proper cause, and understanding of the rare disease, there is no way to prevent Biliary atresia. The available treatment options temporarily address complications. The preferred treatment is the Kasai procedure, and without it, Biliary atresia can be fatal. Thus, there remains a treatment gap in the form of lack of approved therapy, lack of understanding, and high mortality rates.  

  • What are the emerging therapies in the Biliary atresia market?

To overcome the challenges in the Biliary atresia market, the scientific community is working to identify the exact cause to ease earlier diagnosis and prescribe new treatment strategies. At present, a few companies are only investigating therapies in different stages of development. Albireo is developing a therapy, odevixibat in phase III clinical trial which is expected to be completed by June 2024. Besides, many academics and institutes are also working in the Biliary atresia market. Some of the therapies include Autologous BMMC transplantation (Vinmec Research Institute of Stem Cell and Gene Technology, Phase II), N-Acetyl cysteine (Baylor College of Medicine, Phase II), Filgrastim (T Rose Clinical, Inc. / Big Leap Research, Phase II), Oral Vancomycin (Sacramento Pediatric Gastroenterology, Phase I) among few others.

  • What can be expected from ongoing clinical trials in the Biliary atresia landscape?

The present Biliary atresia market homes a limited number of pipeline therapies in clinical development. The Biliary atresia market in the 7MM was found to be USD 2.9 million in 2017. However, increasing awareness about available treatments, a better understanding of disease pathogenesis, a collective database of clinical information as well as serum and tissue samples from children with biliary atresia by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) shall help encourage and perform clinical, epidemiological and therapeutic research. 

Argininosuccinic aciduria

Argininosuccinic aciduria is a rare disease that is genetically inherited.  It belongs to a group of Ural cycle disorders because the disease is an outcome of the improper running of the urea cycle in the body. 

Aberrations in the ASL gene result in Argininosuccinic aciduria. It is caused by the deficiency or lack of the enzyme argininosuccinate lyase (ASL), one of the six vital enzymes that break down ammonia and remove nitrogenous waste from the body. 

  • How rare is Argininosuccinic aciduria?

Argininosuccinic aciduria is inherited as an autosomal recessive trait and affects both sexes equally. It is estimated to affect approximately 1 in 70,000 to 1 in 218,000 live births.

  • What are the signs and symptoms? 

Argininosuccinic aciduria becomes evident in the first few days of life. The signs and symptoms of the disease vary from person to person depending upon the severity, which is decided on the basis of an accumulation of ammonia in the blood. 

An infant with the disease:

  • Is usually low on energy
  • Has irregular breathing rate and body temperature
  • Is unenthusiastic to eat 
  • Experiences seizures or jerks
  • May also go into comatose

Complications from argininosuccinic aciduria may include developmental delay, intellectual disability, progressive liver damage, high blood pressure (hypertension), skin lesions, and brittle hair.

  • How are Argininosuccinic aciduria diagnosed?

Elevated levels of argininosuccinic acid in blood or urine samples form the basis of a confirmed diagnosis of Argininosuccinic aciduria. Further, molecular genetic testing that detects the gene alteration can also officiate the presence of the disorder in an infant.

  • How is it typically treated?

The Argininosuccinic aciduria treatment aims to prevent excessive build-up of ammonia during a hyperammonemia episode. Long-term therapy combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy). Arginine supplementation helps to promote the excretion of nitrogen, however, its impact on the long-term, chronic complications of the disorder are not fully understood. Prompt treatment is necessary in cases of extremely high ammonia levels (severe hyperammonemia episode). 

However, unlike the rare conditions mentioned above, the Argininosuccinic aciduria market has a few approved therapies. While Hyperion Therapeutics has one approved, Ravicti (glycerol phenylbutyrate); Ucyclyd Pharma has two therapies namely Buphenyl (sodium phenylbutyrate) and Ammonul (sodium benzoate and sodium phenylacetate) approved. 

  • What are the lags in the Argininosuccinic aciduria treatment? 

Hyperammonemic episodes that have progressed to vomiting and incessant lethargy require aggressive treatments.  Affected individuals require hospitalization and a diet that is completely evasive of proteins for 24 hours. Despite such treatments, there are chances that patients’ outcomes do not improve and they fall into a  hyperammonemic coma. In this condition, Hemodialysis is also used to remove wastes from an individual’s blood. However, patients still continue to experience progressive liver disease, recurrent medical crises, and hospitalizations. In the last-ditch effort, liver transplantation is done.  

  • What are the emerging therapies in the Argininosuccinic aciduria market?

Pharmaceutical companies and institutes are actively seeking novel technologies and approaches to present effective and standard therapies in the Argininosuccinic aciduria market. Pharma companies such as Takeda, ACER Therapeutics, Evox Therapeutics, and others are developing novel therapies in different stages of clinical trials. ACER-001, a candidate of ACER Therapeutics, is a fully taste-masked, immediate-release formulation of sodium phenylbutyrate (NaPB) developed using a microencapsulation process. The therapy is under investigation in two parts in the pivotal trial. If approved, ACER-001 is anticipated to emerge as a compelling alternative to existing NaPB-based treatments, which have an unpleasant taste associated with NaPB.

Takeda is forging relations with Evox Therapeutics to develop novel protein replacement and mRNA therapies and explore targeted delivery of these payloads using Evox’s proprietary exosome technology. Not long ago, Evox Therapeutics managed to nab £1.5 million worth of funding from Innovate UK, the UK’s Innovation Agency, through the Biomedical Catalyst Early Stage Award. The company plans to use the sum to augment its pre-clinical development of an exosome-based therapy in the Argininosuccinic aciduria market.

  • What can be expected from ongoing clinical trials in the Argininosuccinic aciduria landscape?

DelveInsight analyzes that the current Argininosuccinic aciduria pipeline is limited and exhibits several medical unmet needs. The Argininosuccinic aciduria market size in the 7MM was found to be USD 40.3 million in 2017, which owing to the launch of new therapies shall increase further by 2030. The treatment landscape needs better treatment alternatives with prominent emerging drugs in the future. However, researchers are examining nitric oxide supplementation and enzyme replacement therapy for Argininosuccinic aciduria that projects a good sign. 

Rare Disease is still a field that remains largely unexplored owing to rarity and dispersed patient pool. However, with an increase in awareness, and collective efforts from private and public enterprises, Rare diseases are getting much wider attention at the world level. Medical research has paved the way for instrumental therapy options from traditional paradigms. Precision medicines have recently been targeting Rare diseases keeping in mind individual’s susceptibility and compliance to particular therapy options. However, the lack of an epidemiology database and misclassification of disease that poses a huge burden largely goes untraceable as many rare disease cases do not get reported in the healthcare system. The cost of conducting prevalence studies, and the uncertainty of the availability of enough subjects, ultimately hamper the overall advancement in the understanding of the rare disease. Thus, there is a need to recognize and broaden the knowledge base, trials, studies, and pipeline landscape in the pre-clinical and clinical course to bring out better outcomes in the Rare disease market.