Last week a story on NPR’s Morning Edition reminded me that while sickle cell disease (SCD) is a serious but medically-manageable disease here in the US, in the developing world it is probably a major contributor to childhood mortality and deserves more attention (NPR blog). As I learned when I wrote my first post on SCD in 2010 (“A Really Neglected Disease”), SCD is a genetic disease that results in an abnormal hemoglobin and distorted and fragile red blood cells with the primary bad results of anemia and fatigue, but also an occasional blockage of blood flow by the inelastic red blood cells, resulting in pain and organ damage (especially in the spleen), stroke, and decreased resistance to infection (see NHLBI and Sickle Cell Disease Association). Since the genetic variation also confers resistance to malaria, its incidence is highest in Africa, and WHO estimated in 2006 200,000 affected children are born each year, about 3% of all births. The NPR story reported on a recent publication by epidemiologists who calculated that, due to population growth and improved survival of SCD carriers into adulthood, this number will likely increase by more than 30% over the next 40 years (Piel et al 2013) and add to the burden on the public health systems of these low-income countries.
But, as Piel et al. pointed out, while studies show that SCD contributes to childhood mortality directly or indirectly by reducing resistance to infection, the data on the magnitude of the effect are lacking. The authors cite Grosse et al 2010 who concluded: “The probability of early death among children … might be as high as 90% in rural areas where access to health care is limited, but closer to 50% in populations with better access to health care and lower exposure to infectious diseases” (Grosse et al 2010). Using the WHO 2006 estimate and a reported urban/rural distribution in Africa of 40/60 (Geohive), my wild guess at the annual co-morbidity of SCA is about 150,000 children. But this may be low. Ware 2013 noted that SCA contributes to 6.4% of under-five mortality across all of Africa which suggests the number may be closer 320,000 based a total of 5 million under-five deaths (WHO data). This would put the contribution of SCA to child mortality about three times greater than that due to HIV infection which was about 90,000 in 2009 (UNAIDS fact sheet). Needless to say, HIV/AIDS patients have received much more attention than those with SCD.
So what is to be done? Clearly, as has happened in the developed world, better diagnosis at birth will help, but the common test to detect the sickle hemoglobin by differential electrophoresis requires a lab setup so a point-of-care (POC) test is needed for under-resourced settings. Ware reported that Ghana is making progress at instituting a country-wide screening program but few others are. He also wrote that private-public partnership by the Republic of Angola, Chevron Corporation, and Baylor College of Medicine in 2011 conducted a newborn screening and follow-up program in which the families of affected were provided with including penicillin prophylaxis, pneumococcal immunizations, malaria bed nets, and education about seeking treatment for fever; the survival of affected infants exceeded 95% in the first year of life. There are no treatments that cure SCD, and the symptoms are treated with drugs, like hydoxyurea, to increase the production of normal red blood cells, or with blood transfusions or bone marrow transplants. These have worked well in the developing world but clearly are less frequently used in the low- and middle-income countries.
So for the developing world, a POC diagnostic and an affordable therapeutic specific to children is needed. SCD and pediatric medicines in general have had a low profile in the pharma industry and except for big pharma’s recent interest in acquiring drugs for orphan disease, little has been done by the pharma industry to address SCD. Here is an update on the few biotech companies I found that have advanced drugs into clinical trials.
–AesRx, in my neighboring town of Newton, MA, has a small molecule in development called Aes-103 that is intended to increase the affinity of the deviant hemoglobin for oxygen, thus reducing the tendency for the red blood cells to sickle. A Phase I trial was completed and reported last year. The company was unable to raise venture funding in 2008 and has been subsisting on $1.5 million in angel funding, US government grants, and a state loan (Xconomy article).
–Emmaus Medical has a dietary supplement (L-glutamine) to minimize “vaso-occulsive crises” (VOC) that cause pain and organ damage, and it is in a Phase III trial that will end in 2013. The company has spent about $36 million and needs another $4-5 million to get the product to market according to its most recent 10K filing.
–GlycoMimetics is also targeting VOC with a selectin antagonist (selectin is a cell-surface receptor involved in cell adhesion). Its GMI-1070 is starting a Phase II study this year, and the company succeeded in licensing the drug for all indications to Pfizer in 2011 for $340 million in milestones and royalties (GlycoMimetics press release).
-HemaQuest Pharmaceuticals has a short chain fatty acid derivative called HQK-1001 that induces fetal hemoglobin and red blood cell production; it entered a multicenter, placebo-controlled Phase IIb study in 2012 (HemaQuest). The company raised $20 million in a Series A round in 2007 and closed a B round for $29 million last year. Interestingly, the drug substance was licensed from Boston University which is a signatory to a statement intended to assure equitable access to medical technologies.
-Another local company, NKT Therapeutics (NTK), has a humanized, monoclonal antibody targeting inflammatory natural killer T-cells and the chronic inflammation of SCD. The company stated that trials will start in 2013 (NKT press release). The company has two top-tier VC firms as investors that, as near as I can tell, have put in $14 million to date.
–Selexys Pharmaceuticals has an anti-P-selectin antibody (SelG1) in development for addressing VOC that is entering a Phase II trial this year. The company made headlines last September when Novartis purchased an option to buy the company after completion of the Phase II study for cash and milestones totaling $665 million. At the same time the company announced it closed a $23 million A round (Selexys News).
Of this bunch I like Emmaus Medical’s drug since it is cheap and orally delivered, but it’s not clear if it will have funding to prove the drug’s worth. I also like HemaQuest’s HQK-1001 and AesRx’s Aes-103 since the drugs target the proximal effect of the deviant hemoglobin rather than subsequent symptoms. And there is a chance the HemaQuest license from Boston University requires access in the developing world. As for the 200,000 or so kids born in Africa each year, diagnosis and treatment is (too) many years off.