Bytes from the Info-stream (No. 1)

Although I haven’t taken the time necessary for any original thinking recently, I have been tapping the info-stream for items relevant to the business of global health. Here is a brief summary of several stories I have noted over the past few weeks (mostly from the Fierce newsletters) and a bit of commentary.

In early July, FierceBiotech reported that Newton, MA-based AesRx was purchased by the health care giant, Baxter, for an undisclosed amount (FB AesRx story). AesRx is developing a molecule to prevent the sickleling of red blood cells and mitigate the effects of the genetically-caused sickle cell disease, which, as I noted my post, Still Neglected, is a major contributor to childhood mortality in Africa, possibly great than HIV. The good news is that apparently Baxter will continue the candidate drug’s development, but, given that Baxter seems to have little to no interest in emerging markets, it is not clear if the company will market the drug, if approved, in Africa.

Various concerned parties in the US are now waking up to a health care challenge that is common is the rest of the world: drugs, especially new ones, are priced beyond the ability of a society to pay for them (see my post, The Price is Right). Recently a Senate committee sent a letter to the CEO of Gilead requesting justification for the pricing of its new HCV drug, Sovaldi, and noted the potential for conflict of interest by physicians who were both writing treatment guidelines and consulting for Gilead (FP Sovaldi story). Also recently, Fierce reported that the managers of the Arkansas Medicaid program may be restricting access to Vertex’s cystic fibrosis drug, Kalydeco, in part due to its cost ($300k per year for treatment, FP Kalydeco story). FB provided this quote from the original Wall Street Journal article: “We have this public health mentality that all people have to be cured no matter what the cost, and also let the innovators charge whatever they want,” Matt Salo, executive director of the National Association of Medicaid Directors, told the WSJ. “Those are fine theories independently, but when you combine them together in a finite budget environment, it’s not sustainable.” As stated by an executive of CVS Caremark, major pharmacy chain, in a recent JAMA editorial, it is time to price drugs appropriately: “Effective approaches to control costs for high-priced medications need to be developed and evaluated to ensure broad, equitable, and appropriate use of these new interventions in an already stressed health care system.”

A new report on the market for biosimilar drugs (generic biological drugs) noted that it may top $35 million in the year 2020, growing at a CAGR of 60.8% from 2014 to 2020, in part, driven by sales in the developing world, especially China and India (FB press release and author summary). As I have noted in several posts (e.g., Biosimilar Fever) this growing market is a major opportunity for companies, both US and rest-of-the world.

Finally, some good news on the development of drugs for neglected diseases. The Global TB Alliance, a NYC-based product development program, reported that a new combination of three already-approved drugs (two antibacterials and pyrazinamide, a standard first-line treatment) yielded a 72% cure rate in TB-infected AIDS patients in a Phase II trial (FB TB story).   The combo is compatible with standard HIV therapies, works more quickly than current therapy (important for decreasing the chance of the development of resistance), and will likely be one-tenth the cost of current therapy. For more on TB drug development, see my post, Mix and Match.

Still Neglected

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.

Virtual Reality Biotech Reprise

In my post last week, I played a numbers game to test out my contention that starting up a biotech company aimed at developing a drug for a rest-of-world (ROW or non-US market) disease isn’t that much more risky than a “traditional” biotech start-up.  I tried a similar exercise in March when I wrote about what potential market size may be used to justify a global health start-up, specifically one for sickle-cell disease.  I thought that post was worth regurgitating.

In July 2011, I wrote about a type of “virtual” biotech company that is formed to focus on a single product and use minimal financing to generate sufficient data to validate the drug and attract an acquirer  and whether this model could be used to commercialize products for the neglected, global diseases (“Backyard Biotech”).  For one company I mentioned in that post, FerroKin Biosciences, virtuality became reality.  To recap, until recently FerroKin was a San Francisco-based company with six employees, 60 contractors, and $27 million in private equity capital developing an iron-chelating drug to be used against the iron overload that anemic patients can suffer after repeated blood transfusions (FerroKin and FierceBiotech article).  And, thanks to positive mid-stage Phase II data, it was acquired two weeks ago by Shire PLC for an upfront payment of $100 million and  potential milestone payments of up to $225 million (FierceBiotech article).  I mention FerroKin’s success (at least from the viewpoint of its investors), because, as a company with a single product with a well-defined market, I think the company’s acquisition provides useful guidance for the investment decisions investors and companies may make in considering funding a start-up biotech that may have a product with a global health application.

So how did Shire arrive at a value for FerroKin of $213 million ($100 million cash and $225 million in milestone payments which I am converting to $113 in cash by assuming the likelihood of Shire paying out all the milestones is 50%)?  One way is to base a potential product’s value, in this case, the FerroKin’s value since it is a single-product company, on the expected maximum annual revenue from sales of the product.  Shire stated in its press releases that the annual worldwide market for iron chelation drugs is $900 million (Burrill report).  I found that the leading drug of the three sold in this category is Novartis’s Exjade and it has sales around $652 million per year, so the Shire number seems right, if not an underestimate.  Using the (very) rough heuristic of valuing a product opportunity at one year of peak sales, it underpaid since at a conservative a 30% market share (could be more if the drug has a superior clinical profile to Exjade) the gross peak sales value is $270 million per year.  Another addition to the value of FerroKin is that its product had received an “orphan” condition designation, i.e., treating fewer than 200,000 patients, in the US and the EU (FBS0701 status), so Shire will have seven years during which the FDA/EMA will not approve a competing drug.  Of course, Shire will bear the considerable cost and some risk of completing the trials and product registration.

Next, what is a comparable global health market opportunity for investors seeking to turn a $27 million dollar investment into $213 million (about an 8X ROI)?  Sickle cell disease (SCD) would be a good choice.  SCD is a genetic disease with its primary bad results being anemia and fatigue and an occasional blockage of blood flow by the inelastic red blood cells, resulting in pain and organ damage (especially in the spleen leading to decreased resistance to infection) and stroke (NHLBI).  It is an orphan disease in the US (70,000 to 100,000 prevalence) but a major problem in Africa where the gene persists since the trait confers some resistance to malaria during childhood.  As I noted in my posting, “A Really Neglected Disease” (7/29/10), recent studies show that SCD is a major factor in childhood mortality and may be a cofactor the 500,000 annual deaths in African children under 5 years old, more than HIV/AIDS at 370,000.  So the potential US market is good (my guessimate is $300 million since a low-ball price for an orphan drug is $10,000 per year and a modest number of patients at 30,000); what about in Africa?

The WHO gives the prevalence of SCD in sub Saharan Africa as 2% (WHO sickle cell disease), so if I assume the continental prevalence is 1% in Africa’s 1 billion people, a 30% rate of market penetration, and an “affordable” price of $.30 per day or about $100 per year, I get a market of $300 million/year.  (By comparison, Novartis gets about $70 per daily dose of Exjade [AVHLaw article].)  Of course, the skeptic will say the average per capita health care spending is less than $30 per person in countries with the most SCD so there seems to be no money for an SCD drug, and I, the optimist, will point out that African governments have been able to provide HIV/AIDS treatments at about $900 per patient (but with lots of outside aid and treating fewer than half of those who need treatment), but who/how pays for an SCD drug is worthy of another post.  So with some squinting, the African market for an SCD drug is about the same size as the US, if albeit, with much lower-priced drug.

Finally, my point in this meander is that my calculations support the idea that investors and companies should be looking seriously at creating single-product virtual biotechs in which the candidate compound (plus its backups) may work against an US orphan indication and a neglected/global health disease.  The route is for an established, or struggling, biotech, pharma company, or university to find a successful serial entrepreneur who believes in doing well by doing good, back her/his virtual start-up with a bit of capital (like $5 million) to develop a single product for a dual orphan/global indication, and hope to cash out at an 8X ROI.  The additional $10-20 million needed could come from far-sighted VCs (not likely), foundations (a bit more likely), or research grants (lots needed).

I agree that this route is speculative and risky but that’s what venturing is about.  Just for the heck of it, here’s a table of SCD drugs in development:

Company/Org. Product Stage Reference
AesRx Aes-103, small molecule Starting Phase I AesRx product
Celgene Pomalidomide, small molecule Starting Phase I ClinicalTrials.gov
Georgia Health Sciences University Pomalidomide, small molecule Starting Phase I GHSU PR
GlycoMimetics GMI-1070 In Phase II PR on license to Pfizer
Government of Nigeria Niprisan, plant extract Premarket Nigerian Ministry of Information PR
HemaQuest HQK-1001, short chain fatty acid Phase I completed HQ product
Selexys SelG1, antibody Phase I completed Selexys PR

Virtual Reality Biotech

Back in July 2011, I wrote about a type of “virtual” biotech company that is formed to focus on a single product and use minimal financing to generate sufficient data to validate the drug and attract an acquirer  and whether this model could be used to commercialize products for the neglected, global diseases (“Backyard Biotech” 7/7/11).  For one company I mentioned in that post, FerroKin Biosciences, virtuality became reality.  To recap, until recently FerroKin was a San Francisco-based company with six employees, 60 contractors, and $27 million in private equity capital developing an iron-chelating drug to be used against the iron overload that anemic patients can suffer after repeated blood transfusions (FerroKin and FierceBiotech article).  And, thanks to positive mid-stage Phase II data, it was acquired two weeks ago by Shire PLC for an upfront payment of $100 million and  potential milestone payments of up to $225 million (FierceBiotech article).  I mention FerroKin’s success (at least from the viewpoint of its investors), because, as a company with a single product with a well-defined market, I think the company’s acquisition provides useful guidance for the investment decisions investors and companies may make in considering funding a start-up biotech that may have a product with a global health application.

So how did Shire arrive at a value for FerroKin of $213 million ($100 million cash and $225 million in milestone payments which I am converting to $113 in cash by assuming the likelihood of Shire paying out all the milestones is 50%)?  One way is to base a potential product’s value, in this case, the FerroKin’s value since it is a single-product company, on the expected maximum annual revenue from sales of the product.  Shire stated in its press releases that the annual worldwide market for iron chelation drugs is $900 million (Burrill report).  I found that the leading drug of the three sold in this category is Novartis’s Exjade and it has sales around $652 million per year, so the Shire number seems right, if not an underestimate.  Using the (very) rough heuristic of valuing a product opportunity at one year of peak sales, it underpaid since at a conservative a 30% market share (could be more if the drug has a superior clinical profile to Exjade) the gross peak sales value is $270 million per year.  Another addition to the value of FerroKin is that its product had received an “orphan” condition designation, i.e., treating fewer than 200,000 patients, in the US and the EU (FBS0701 status), so Shire will have seven years during which the FDA/EMA will not approve a competing drug.  Of course, Shire will bear the considerable cost and some risk of completing the trials and product registration.

Next, what is a comparable global health market opportunity for investors seeking to turn a $27 million dollar investment into $213 million (about an 8X ROI)?  Sickle cell disease (SCD) would be a good choice.  SCD is a genetic disease with its primary bad results being anemia and fatigue and an occasional blockage of blood flow by the inelastic red blood cells, resulting in pain and organ damage (especially in the spleen leading to decreased resistance to infection) and stroke (NHLBI).  It is an orphan disease in the US (70,000 to 100,000 prevalence) but a major problem in Africa where the gene persists since the trait confers some resistance to malaria during childhood.  As I noted in my posting, “A Really Neglected Disease” (7/29/10), recent studies show that SCD is a major factor in childhood mortality and may be a cofactor the 500,000 annual deaths in African children under 5 years old, more than HIV/AIDS at 370,000.  So the potential US market is good (my guessimate is $300 million since a low-ball price for an orphan drug is $10,000 per year and a modest number of patients at 30,000); what about in Africa?

The WHO gives the prevalence of SCD in sub Saharan Africa as 2% (WHO sickle cell disease), so if I assume the continental prevalence is 1% in Africa’s 1 billion people, a 30% rate of market penetration, and an “affordable” price of $.30 per day or about $100 per year, I get a market of $300 million/year.  (By comparison, Novartis gets about $70 per daily dose of Exjade [AVHLaw article].)  Of course, the skeptic will say the average per capita health care spending is less than $30 per person in countries with the most SCD so there seems to be no money for an SCD drug, and I, the optimist, will point out that African governments have been able to provide HIV/AIDS treatments at about $900 per patient (but with lots of outside aid and treating fewer than half of those who need treatment), but who/how pays for an SCD drug is worthy of another post.  So with some squinting, the African market for an SCD drug is about the same size as the US, if albeit, with much lower-priced drug.

Finally, my point in this meander is that my calculations support the idea that investors and companies should be looking seriously at creating single-product virtual biotechs in which the candidate compound (plus its backups) may work against an US orphan indication and a neglected/global health disease.  The route is for an established, or struggling, biotech, pharma company, or university to find a successful serial entrepreneur who believes in doing well by doing good, back her/his virtual start-up with a bit of capital (like $5 million) to develop a single product for a dual orphan/global indication, and hope to cash out at an 8X ROI.  The additional $10-20 million needed could come from far-sighted VCs (not likely), foundations (a bit more likely), or research grants (lots needed).

I agree that this route is speculative and risky but that’s what venturing is about.  Just for the heck of it, here’s a table of SCD drugs in development:

Company/Org. Product Stage Reference
AesRx Aes-103, small molecule Starting Phase I AesRx product
Celgene Pomalidomide, small molecule Starting Phase I ClinicalTrials.gov
Georgia Health Sciences University Pomalidomide, small molecule Starting Phase I GHSU PR
GlycoMimetics GMI-1070 In Phase II PR on license to Pfizer
Government of Nigeria Niprisan, plant extract Premarket Nigerian Ministry of Information PR
HemaQuest HQK-1001, short chain fatty acid Phase I completed HQ product
Selexys SelG1, antibody Phase I completed Selexys PR

No Kiddin’

Last week I was pleased to attend the 5th anniversary reception for the Cambridge MA-based Institute for Pediatric Innovation (IPI), a not-for-profit founded by one of my technology transfer mentors, Don Lombardi.  After a career in business and technology transfer at Children’s Hospital Boston, Don started IPI to address the lack of new technology and therapies to treat children.  Its mission is “to identify which new devices and drugs clinicians need to provide better pediatric health care, and strive to turn those into available products,” and to date, the IPI has built a network of hospital and clinicians as sources of technology but has the ongoing challenges of funding and converting prototypes into products.

Of course, improving pediatric health is not a problem of the US only.  In developing world, in addition to the dangers of birth (the main cause) and inadequate nutrition causing children’s mortality, infectious diseases like pneumonia, diarrhea, HIV/AIDS, malaria, and rabies take their toll resulting in about 8 million children under the age of five dying each year (Global Health Council summary).  Aarthi Rao summarized the problem succinctly in a recent post (Center for Global Health Policy Assessment blog, “But What About the Kids,” Rao post), noting three needs:  access to and application of existing tools and methods (a problem in health care delivery), adaptation of existing technology and treatments for pediatric use (e.g., development of pediatric dosing and safety data for drugs, see WHO’s Essential Medicines for Children, WHO Meds for Kids), and development of new technologies specific to kids.  NGOs, international agencies, and foundations are focused mostly on the first area and somewhat on the second, and so I see a need and an opportunity for companies in the third, applying technology to improve ROW (rest-of-world) pediatric health.  Here are a few specific needs I have noted:

  • Tuberculosis diagnostic: since children cannot cough up enough sputum for an adequate standard diagnostic sample, a better method is needed (Rao above and WHO Fact Sheet);
  • Diagnostic to differentiate fever:  sick kids have fevers but proper treatment requires knowing the cause, so a diagnostic that can differentiate between malaria and pneumonia, for example, is needed (see BVGH IQ Prize Case Statement);
  • Pulse oximetry and oxygen delivery:  studies have shown that a reliable system of measuring blood oxygen and delivery of oxygen as needed can reduce child mortality from pneumonia by 35% (Duke et al 2009) and some simple oximeters have been prototyped (e.g., Zaman lab);
  • Sickle cell treatment:  as I mentioned in a previous posting (“A Really Neglected Disease,” 7/29/10),  underlying sickle cell disease in children in Africa is likely a contributing factor to upwards of 250,000 deaths per year, so a treatment will be life-saving (see All Africa article); and
  • Vaccines:  some infectious microbes have serotypes that are specific to kids whose developing immune systems make them vulnerable, so new vaccines are needed (e.g., bacterial meningitis and dengue).

But getting new technology development funded is the rub.  In the pediatric disease field there are huge donor-funded programs to improve health care delivery (as there should be), but few funders who understand the risks and rewards of technology development.  The Bill and Melinda Gates Foundation is one of the few foundations that is trying to and recently announced that one of its Grand Challenges will be for “scientists, innovators and entrepreneurs to seize the opportunity to contribute to the field of family health through the discovery and development of medicines, medical devices, diagnostics and other lifesaving tools.”  It will be funded at $35 million (Gates press release) and I hope will have advice from successful entrepreneurs.  There are currently small grants are available through the Grand Challenges Explorations program in which Round 6 included maternal and infant health as a goal (Explorations), but as I have noted previously the grantors favor academics.  Also recently the Gates joined USAID, the governments of Norway and Canada, and the World Bank to launch the Saving Lives At Birth Grand Challenge (Saving Lives) to fund innovations in both delivery and technology.  Of 19 finalist organizations under consideration for a share of $14 million in funding, seven have a technology component (Finalists), and if a few of these receive adequate funding and help from experienced product developers, one may actually create something that saves lives at birth.

One would think that companies with global health corporate responsibility programs would have an interest supporting technology development for neglected pediatric disease.  Two candidates are Alere, an international diagnostics company that has donated HIV/AIDS diagnostics (Alere), and Laerdal Global Health, which sells maternal and neonatal health products and training (Laerdal).  As for the big corporations, in 2010, the Johnson and Johnson Company made a five-year but unspecified dollar commitment to the WHO’s “Every Woman, Every Child” program (JnJ press release).  Although the press release mentions research and development of new medicines as a goal, the program website does not (Every Woman).  This month the General Electric Foundation provided Jhpiego, a Johns Hopkins University affiliate, with $1.6 million to “develop low-cost, lifesaving technologies that can transform health care for women and children in developing countries” (Jhpiego press release).  That is generous but limited to JHU and not much money for the intended “early-stage innovation and then, for selected projects, field-testing and product introduction.”  Bottom line:  cultivation of the corporate sector is needed.

Meanwhile back at the  Institute for Pediatric Innovation,  there is one project with a global health slant which is to perform a “detailed review of the medical anthropology” to “help advance pharmaceutical reformulation for children by sensitizing drug developers and marketers to important cultural and social issues” (Evaluating Global Reformulation Needs, IPI project).  I’m unclear on the concept and the results are still forthcoming.  My suggestion to Don to have a bigger impact on global pediatric needs:  review the IPI technology portfolio for opportunities that have global health relevance, write-up development, funding plans, and strong arguments to convince potential licensees that products for kids can have profit margins, and start knocking on doors in the for-profit world.

A Really Neglected Disease

Sickle cell disease is a textbook example of evolution at work.  It results from a single gene mutation that allows hemoglobin to polymerize, leading to a number of bad results for the person unlucky enough to get two copies of the mutant gene (homozygotes), but in those with only one copy (heterozygotes), it confers a selective advantage in regions where malaria is endemic since the polymerized hemoglobin and fragile red blood cells make it harder for the malaria parasite to reproduce in the blood (Wikipedia article).  Hence, in people whose forbearers moved out of historically malarial regions a few generations ago (Africa, Central and South America, the Mediterranean, Middle East, and India), the incidence of the mutation is many times higher in indigenous people than in emigrants (e.g., 4% in West Africans vs. 0.25% in African-Americans).  The primary bad results for the afflicted are 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 (NHLBI).  In the US, the estimated 70,000 to 100,000 people with sickle cell disease manage their disease with palliative treatments for their acute pain episodes, which occur about once per year, close medical monitoring, and maybe bone marrow transplants, hopefully paid for through their insurance plans (c.f., Sickle Cell Disease Association).  What about the rest of the world?

Worldwide prevalence data are lacking.  The WHO reports incidence data; each year over 300,000 babies with severe forms of sickle cell and another hemoglobin disorder, thalassemia, are born worldwide, the majority in low and middle income countries (WHO Fact Sheet).  In Africa, a 2006 WHO report states that 200,000 sickle cell infants are born each year and the disease contributes the 5% of the under-the-age-of-five deaths, to more than 9% of such deaths in West Africa, and to up to 16% of under-five deaths in individual West African countries (WHO 2006 Report).  However, there is evidence that sickle cell disease may be contributing to a greater percentage of childhood mortality, mostly likely by decreasing resistance to infection.  A study in Kenya that looked at hospitalized children under the age of 14 from 1998 to 2008 found that 6% those with bacterial infections were also sickle cell children (Williams et al. 2009).   Further, in an article on the publication, the authors note that one quarter of all child-deaths in the study region were attributable to sickle cell anemia (All Africa article).   Hence, using the WHO number that about 5 million under-five deaths in Africa each year (WHO data) and some loose extrapolation, the number dying attributable to the underlying sickle cell disease could be 250,000 to as many as 1.25 million.  This may be compared the under-five world-wide mortality that WHO attributes to:  respiratory infections (1.8 million), diarrhea (1.5 million), malaria (1 million), and HIV/AIDS (370,000).  To quote a quote from the study’s lead author:  “To date, sickle cell anemia has not enjoyed a high priority on African health agendas, despite the relatively high impact it has on childhood mortality, which far exceeds estimates for HIV.  HIV commands vast attention from the international community, yet sickle cell anemia is virtually invisible on the international health agenda (All Africa article).”

So what could be done to reduce the contribution of sickle cell anemia to childhood mortality in Africa, and the other places with relatively weak pediatric care?  Genetic screening and counseling of prospective parents would help, but this is a technology- and skill-intensive approach.  Pumping up public health through improved water quality and increased childhood immunizations clearly would help.  Post natal screening for anemia (low hemoglobin) or microscopic examination of blood cells would easily identify children with sickle cell and who are at risk of infection, and they could receive additional attention, e.g., vaccinations, dietary supplements like folic acid, and daily penicillin to prevent infections.  One study has suggested that education, screening, and follow up of the infants helps (Rahimy et al. 2008) and does mass vaccination against pneumococcal infection (Science News article).

As for a drug treatment, although hydroxyurea is used to treat adults, its long term consequences are suspect (c.f., US News article).  An affordable therapeutic specific to children is needed, but pediatric meds, in general, and the disease have had a low profile in the pharma/biotech industry.  There are a few companies working on drugs that address the condition (as opposed to its consequences).  Emmaus Medical has a dietary supplement (L-glutamine) in trials (Emmaus Medical).  HemaQuest Pharmaceuticals has a short chain fatty acid derivative in trials since 2008 that they claim induces fetal hemoglobin and red blood cell production (HemaQuest).   AesRx, in my neighboring town of Newton, MA, has a small molecule in development that is intended to increase the affinity of the deviant hemoglobin for oxygen, thus reducing the tendency for the red blood cells to sickle (AesRx).

As for the international health community, it is evidently focused elsewhere and the only major UN/WHO action I could find was declaration, in 2009, of June 19th as “World Sickle Cell Awareness Day’ (Children’s National PR).  Sickle cell disease did not make the recent G-Finder list of neglected diseases (Moran et al. 2009) nor does it qualify for the FDA’s priority review voucher consideration (FDA Priority Review Guidance).  And it’s not on BIOVentures for Global Health’s radar (BVGH Neglected Disease Pipeline).  Sounds like a double-bottom line business opportunity to me.