Sickle cell disease (SCD) is a genetic, autosomal, recessive blood disorder caused by an abnormality in the hemoglobin molecule found in red blood cells which carry oxygen throughout the body. This abnormality is the result of a single point mutation of βGlu6 in the hemoglobin (Hb) of a normal red blood cell to βVal6 in the sickle hemoglobin (HbS) of a sickle red blood cell (SS). The mutation results in a tendency of the sickle cell to deform (polymerize) into the characteristic rigid “sickle” shapes which give the disease its name, especially with dehydration, infection or hypoxia (low oxygen states). SCD is one of the most prevalent hematological genetic disorders in the world.
Rigid, sickled red blood cells cannot pass through capillaries and may occlude capillaries and small blood vessels. This blockage can cause a wide range of serious, and sometimes life-threatening, conditions including: chronic hemolytic anemia, chronic pain and acute painful crisis, stroke, acute chest syndrome, and cumulative damage to tissues and organs.
Normal and Sickled Blood Cells |
Figure A shows normal red blood cells flowing freely in a blood vessel. The inset image shows a cross-section of a normal red blood cell with normal hemoglobin. Figure B shows abnormal, sickled red blood cells clumping and blocking blood flow in a blood vessel. (Other cells also may play a role in this clumping process.) The inset image shows a cross-section of a sickle cell with abnormal hemoglobin. |
Sickle cell disease leads to chronic injury to joints and major organs, causing serious damage particularly when it occurs in a major organ such as the brain (stroke) or the lungs (acute chest syndrome). The function of the spleen is frequently lost due to infarction in the first few years of life and as a result individuals with SCD are at increased risk of infections. In fact, in the US, current standard of care calls for children with SCD to be given penicillin from the age of six months as prophylaxis against these infections. Damage caused by SCD is cumulative and even in the US, with the best supportive care, SCD patients’ average lifespan is only approximately 40 years. The disease imposes an enormous cost on the health care system annually for treatment of its complications, mainly damage to the lungs, kidneys, liver, bones and other organs. Moreover, because of the effects of their disease, sickle cell patients tend to be at increased risk of cognitive disorders, perform less well in school and have increased difficulty in excelling in the work place. As a result, these patients suffer from a significantly lower quality of life.
Sickle cell disease is particularly common among people whose ancestors come from sub-Saharan Africa, India, Saudi Arabia and Mediterranean countries. This distribution reflects the fact that the sickle cell trait, in carriers of one abnormal or mutated copy of the hemoglobin gene, confers a survival advantage against malaria. Selection pressure due to malaria has resulted in high frequencies of the mutant gene especially in areas of high malarial transmission.
The diagrams below show the distribution of malaria and SCD across the globe.
| Distribution of Malaria | Distribution of Sickle Cell Disease |
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Patient Populations
AesRx believes there are several markets which could be addressed by a successful treatment for SCD.
Primary Market
The largest primary market by value for a treatment of SCD is in the United States. According to the National Institutes of Health, there are approximately 75,000 individuals in the US who suffer from SCD. Because of the small number of patients with SCD, AesRx’s drug candidate for the treatment of SCD, Aes-103, has already been granted Orphan Drug Status by the FDA in the US and qualifies for accelerated approval under 21 CFR 314 Subpart H.
In addition to the US, there are estimated to be approximately 40,000 individuals who suffer from SCD in the European Union. The target population in the EU consists of a combination of patients, the majority of whom are of sub-Saharan African origin or descendants of those of sub-Saharan African origin with particularly high concentrations in the United Kingdom and France. The EU target population also includes patients in the Mediterranean region of the EU where malaria has historically been prevalent. These patients are concentrated in Spain, Italy and Greece. Although application has not yet been made, AesRx believes Aes-103 will qualify for Orphan Drug Status in the European Union under the rules promulgated by The European Medicine Agency (EMEA).
Secondary Market
In addition to the US and EU, there is potential for Aes-103 in the Middle East and the emerging market of India. As in the Mediterranean region of the EU, malaria has historically been prevalent in those areas, and consequently the survival benefit conferred by the recessive sickle cell mutation has resulted in a significant population of individuals who suffer from SCD. In fact, there are an estimated 1,000,000 individuals in India who could benefit from a treatment for SCD, and AesRx believes there are over 100,000 individuals with SCD in the Middle East.
Tertiary Market
The largest market by numbers for a SCD treatment is sub-Saharan Africa where there are an estimated 12,000,000 individuals who suffer from SCD. The largest concentration of SCD patients in sub-Saharan Africa is in Nigeria. In that country, the frequency of the carriers of the trait is thought to be about 24 percent of the population, though in some states the frequency is much higher. As a result of the carrier frequency, the prevalence of SCD is about 20 per 1000 births. This means that in Nigeria alone, more than 100,000 children are born annually with SCD and more than four million Nigerians have SCD. In Nigeria, SCD accounts for more than 8 percent of the annual infant deaths, and in some rural parts of Nigeria only 20 percent of SCD patients survive to see their 5th birthday.
Given the complex dynamics of drug policy, distribution, and economics in sub-Saharan Africa, AesRx will seek to develop Aes-103 for that market through a distribution agreement with a third party. Third parties which could be potential development partners for the Company may include large, multinational pharmaceutical companies with an existing infrastructure in the region, regional distributors or charitable agencies, and foundations which have a mission to address widespread, life-threatening diseases in Africa. AesRx is committed to the development of Aes-103 in Africa, but sales of Aes-103 in the region are likely to be on terms and conditions which reflect the economic realities of the area.
The worldwide target patient population for Aes-103 can be summarized in the following table:
| Primary Market | |
| United States | 75,000 |
| Europe | 40,000 |
| Secondary Market | |
| India | > 1,000,000 |
| Middle East | 100,000 |
| Tertiary Market | |
| Africa | > 12,000,000 |
Total |
> 13,000,000 |