Global Health Business Weekly (No. 5)

What does it cost in time and money to run a crash vaccine program against a deadly but infrequent disease that occurs in uninsured and underserved people outside the US? The disease, of course, is Ebola, and the program was announced two weeks ago (GSK press release in FierceVaccines). The program’s goal is to complete safety and efficacy tests in about three months, and its costs will be met in part by a $4 million grant from private and government (UK) sources, GSK, and the US NIH. GSK will also receive funding to manufacture 10,000 doses of the candidate vaccine in parallel to be deployed by WHO if the trials are successful. Such success will not only save lives but may provide a model for crash vaccine development programs against other infectious diseases in the rest of the world which have no or limited vaccines like hepatitis C, malaria, and TB.

An effective drug for treating Ebola is also needed, and recently the US Biomedical Advanced Research and Development Authority announced commitment of up to $42 million (10x what is going into the vaccine program) to tiny Mapp Biopharmaceuticals, Inc. for further testing and manufacture of its candidate drug, ZMapp (FierceBiotech article).

At the other end of the funding spectrum, OncoSynergy, Inc. recently announced the start of a crowd-funding campaign to raise $5,000 to test an antibody it is developing to treat cancer against Ebola (FierceBiotech article FierceBiotech article, OncoSynergy press release, and Experiment.com funding page ). My skeptical side says “PR stunt” but I hope I’m wrong and the company has positive results in its in vitro demo.

In the “Nature doesn’t take a day off” category, FierceVaccines reported that an academic study of the polio virus associated with a 2010 outbreak in central Africa found a new, mutated form (FierceVaccines article). The scary part is that the mutated form was not neutralized in vitro by antibodies generated by the current vaccine. Even more scary was that the outbreak had a 50% mortality rate and it was estimated that half of those affected had been vaccinated. Of course, everyone knows that polio was common in the US with 35,000 cases per year in the 1950s and about 1% resulting in limb paralysis until almost universal vaccination was introduced (CDC Polio FAQ).

In the “lost in the noise” category, Gilead mentioned last week that it is in discussion with six generic drug companies about licensing its anti-hepatitis-C drug, Sovaldi (FiercePharma article and Bloomberg article). According to Gilead’s EVP Gregg Alton, the agreements will bring the drug to about 80 developing countries, and the licensing is in addition to Gilead’s plans to sell Sovaldi in India and other countries for $900 per treatment course. The noise, of course, is that Gilead has priced the same treatment in the US at $84,000 which has generated approbation by some payers and members of Congress. Alton noted, however, that this price is the same as that paid by the payers for the older, less effective regime. So I guess the payers are upset not by the cost of treating (and curing) a patient but by the potential demand for the drug. So the overall cost of the drug is the fault of patients and their doctors.

In the “emerging start-up opportunity” category, MIT reported that researchers of the Singapore-MIT Alliance for Research and Technology had built an MRI-like prototype device for detecting the malaria waste product, hemozoin, in blood (Fierce Diagnostics article and MIT press release). The team is starting a company to develop and test a cheaper, portable version that may be faster and more reliable than the current microscopy-based detection. Not mentioned was another diagnostics company founded by an MIT alum, Disease Diagnostics Group, that is using a simpler technology to detect hemozoin and that its prototype is in field testing (Boston Globe article).

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.

Revenge of the Microbes Replay

Last week, I saw a Bloomberg News story that a WHO surveillance program had found that antibiotics “now rank among the most counterfeited medicines in the world” and are contributing to global drug resistance.  It did not reference a WHO report and I was not able to find one which is unfortunate because although the link is logical, data are lacking. If anyone knows of this report, please share the link. The story reminded me of a post I wrote in April 2011:

It’s pretty well known, at least among those in the health care biz, that the problem of antibiotic-resistant, infectious, and deadly bacteria is growing. The problem certainly isn’t a new one (a perspective in the New England Journal of Medicine notes there was concern among docs starting around 1960, Moellering 2011), but the public media’s hysteria last fall about a gene for a new antibiotic-destroying enzyme highlighted another flaw in our drug development system, in addition to ignoring global health diseases (e.g., Boston Globe article).   The gene is called NDM-1 or New Delhi metallo-beta-lactamase-1 and confers to bacteria the ability to destroy beta-lactam antibiotics (e.g., penicillin, cephalosporins, and carbapenems) which are the backbone of anti-infective therapy. More scary is that NDM-1 has been found traveling about with several other genes for beta-lactamase inactivation (e.g., inactivating erythromycin, ciprofloxacin, rifampicin, and chloramphenicol), a gene for a “pump” to flush out antibiotics, and growth factors (for those who don’t remember their microbiology, bacteria have neat ability to share genes by putting them on small DNA loops and injecting them into each other, i.e., sex for bacteria). Even more scary is that NDM-1 was found in multiple types of nasty bacteria and in multiple countries, including India, Pakistan, Bangladesh, Britain, United States, Israel, Turkey, China, Australia, France, Japan, and Taiwan, although there is controversy about the soundness of the studies (Lancet article).   Will NDM-1 get into some easily transmitted and deadly bacteria like those that cause cholera or tuberculosis (which is already drug-resistant to line one and two of our drug defenses), run wild, and kill all humans? I dunno but it looks to me more effort needs to be applied to this global health problem besides using it in a disaster movie script.

Clearly, new antibiotics are needed but, as with the neglected diseases that afflict most of the world outside our expensive medical bubble, the pharma/biotech industry is mostly AWOL and has been for about 20 years. In a classic case of market failure, the problem is that the use of a new antibiotic would likely be restricted to patients who have failed standard therapy (a small number) and, if the drug is any good, used only for a short time, so the pay-back period for the (at least) couple hundred million dollars of R and D could be very long. PhRMA, big pharma’s trade group, doesn’t even mention the lack of antibiotic R and D as an issue (PhRMA issues). According to a Reuters article on the poor pipeline, AstraZeneca and GlaxoSmithKline and to a lesser extent Novartis, Merck, and Pfizer have active antibiotics programs, but the next new drug is about five years away from approval (Reuters article). By my guessimate, there are 10-20 biotechs world-wide with antibiotics programs but most have few drugs in development (e.g., Cubist pipeline).

So what should be done to save humankind from superbugs? There seem to be lots of recommendations but little action. The pharma/biotech industry thinks a clearer FDA regulatory approval and use polices and longer patents will help (Pharma Manufacturing article). The WHO is devoting its 2011 World Health Day to antimicrobial resistance and is recommending a number of solutions (WHO World Health Day policy briefs) which, not surprisingly, are all government-policy-oriented (“commit to a comprehensive, financed national plan”) or, to “foster innovations and research and development for new tools,” are not new and similar to those for stimulating neglected disease drug development: more basic government funding, advanced market commitments, and prizes (not a good idea, see my posting of 12/9/10). The Infectious Disease Society of America has been ringing the alarm bell for more than five years and in 2010 proposed global plan called “10 X ’20: Ten New Antibiotics by 2020” (10 X ’20 Plan). It is short on specifics however, citing only an increased R and D tax credit (like that recommended for neglected disease, see my posting of 3/10/11) and yet another global task force to mount a “man-on-the-moon” effort.

The US government has put money into infectious disease research at universities though the NIH, about $35 billion in 2007 (NIH Report) and the lead institute is the NIAID which has two task forces and sponsors a conference on microbial resistance (NIAID partnerships). And governments and donors are funding half a billion dollars of TB research, some of which is relevant to antibiotics for resistant TB (TDR press release). As for government support of companies which actually may develop a drug, thanks to our government’s pre-occupation with keeping us safe from terrorists, BARDA (Biomedical Advanced Research and Development Authority) has a Broad Spectrum Antimicrobial Program that is funding a few companies with multi-tens-of-millions of dollars (e.g., Achaogen Inc. of San Francisco, BARDA press release).

Are we headed into the perfect storm (c.f. David Dickman’s review of David Shlaes book of that name, Dickman blog) and are we ready for a world without antibiotics (c.f. The Guardian article of that name, Guardian article)? It is clear that bacteria evolve a lot faster than we humans can discover and develop antibiotics, and a lot faster than we invent policies and processes for discovering and developing needed but “uneconomical” drugs in general. So when Johnny and Sally come home from daycare with unstoppable ear infections and end up dead like the millions outside the US that die each year due to lack of medicines for their diseases, maybe we (the public and our representatives) will get serious about drugs for neglected disease.

Herd Wisdom

At the risk of adding another echo to the blogosphere, I am commenting on a recent editorial by John Carroll, chief of FierceBiotech, in which he noted the major pharmaceutical companies are now concentrating their research and development efforts on a few diseases (indications), apparently to reduce R and D risk but with the possible unintended consequence of increasing their market and competitor risk (“Assessing the Crowd Effect”). Mr. Carroll’s comment was initiated by Helen Thomas’s Heard on the Street column in the Wall Street Journal (“Beware the Thundering Pharma Herd” at WSJ.com for those with a subscription or at Innovator94 for those without). Ms. Thomas cited a report by Barclays (I assume written the bank’s market intelligence group and not publicly available) that the indications of oncology (cancer) and inflammation absorb one-third of big pharma’s R and D budgets although drugs for these indications are likely to account for only 17% of projected sales. The point of both writers is that big pharma, by focusing on indications with less risky and less expensive development efforts, is heading for lower profits when their “not-much-different-than-all-the-other” drugs hit the market. Mr. Carroll: this concentration “could set the stage for a migration [by innovative companies] to lonelier diseases or drug theories, where true pioneers can be years ahead of the next competing therapy.” Ms. Thomas: “Today’s R&D efforts are bearing fruit, but there is something to be said for standing apart from the crowd.”

Of course big pharma’s herd wisdom also includes a number of other rubrics as analysts, industry watchers, and I have noted:

  • R and D is expensive so needs to be down-sized into areas where a greater knowledge base exists to build on;
  • R and D on some indications like cardiovascular disease that require huge trials and are subject to closer scrutiny by the FDA and Alzheimer’s disease that has seen a large number of late-stage trial failures is too risky;
  • biotech companies will take on the riskier, more innovative research (ignoring that investors invest primarily in companies that can be sold to big pharma);
  • more money can be made in rare disease treatments where insurance companies tolerate astronomical annual per-patient costs;
  • although payers (insurance companies and the government) make sounds about paying only for demonstrably better drugs, it is marketing that sells drugs not benefit; and
  • there is no market and will never be one for new drugs to treat the diseases of poverty that afflict a large percentage of humankind.

As one may have noticed over the past four years in this blog, I have applied my small voice to refuting the last rubric, and anyone who is interested may read my rants in “Playing the Long Game”, “Missing the Boat”, “A Rare Request”, and “Throwing Darts”.  So what is my point? If the major pharmaceutical companies are plowing one-third of their current R and D spend (or $17 billion based on a $50 billion annual spend) into drugs that are projected to capture 17% of all sales (or $54 billion if one assumes annual US drug sales of $320 billion) (an approximate 1:3.2 ratio), I think at least one of the major pharma companies would find it an acceptable risk to put $100 million each year into R and D on a neglected disease with the assumption that eventually it would yield a drug with a $320 million market. That seems reasonable to me, given the company would likely have no competition and number of potential patients is in the tens or even hundreds of millions. The only barrier is that the world needs to find a way to pay for the new drug in the next five to ten years, the time it takes to develop it.

The most recent issue of Technology Review is about remarkably innovative companies, and in it I read about Mark Levin, a founding partner of the local venture capital firm, Third Rock (Tech Review feature story). Third Rock is known as a non-traditional VC firm, emphasizing early-stage investments in novel ideas vetted by its science team and acting more like an incubator than an investor (FierceBiotech article). And it has been successful as indicated by its raising of $1.3 billion in capital since 2007, including closing a $500 million fund in 2013. According to the article, Mr. Levin will back companies addressing challenging indications (like amyotrophic lateral sclerosis or ALS), can spot what will be an important product in five to ten years, is personally wealthy, and is “extraordinarily empathetic.” I wonder what he thinks, or if he has thought, about the investment potential of a start-up aimed at a global health disease.

 

Shameless Plug

As I noted in last week’s post, I reconnected recently with a colleague who has an interest in accelerating the discovery of drugs for neglected diseases via a data-sharing platform.  Michael Pollastri is an associate professor of chemistry at nearby Northeastern University and a ten-year veteran of the pharmaceutical industry, and I have mentioned him and his work on repurposing existing drugs to target parasites in previous posts (e.g., “A Rare Request, an Orphan Offer”).  Mike is starting a web-based portal for sharing of data and ideas among medicinal chemists trying to develop new drugs for the neglected diseases (ND), which in this case, includes the thirteen WHO-listed neglected tropical diseases and the two better-known global diseases, tuberculosis and malaria.  All are diseases of poverty, have low mortality but high morbidity with long periods of suffering and often a lifetime of disablement, and hence have a devastating effect on societies in the endemic areas (Kaiser Fnd Fact Sheet).  Although there are drugs to treat most of these diseases, new drugs are needed to cure rather than treat, to overcome or prevent resistance, and to make widespread treatment easier, affordable, and less toxic.  As for current efforts, the leading product development program, the Drugs for Neglected Disease initiative (DNDi) has programs for Human African Trypanosomiasis, Chagas, pediatric HIV, leishmaniasis, malaria, and filariasis, and the Gates Foundation has prioritized filariasis, onchocerciasis (river blindness), and soil-transmitted helminthic infections in a recent call for proposals in its Grand Challenges Round 10.

Mike’s reasons for the portal are sound.  A major bottleneck in finding new drugs (not only for neglected disease but all disease) is finding lots and lots of “maybe drugs,” chemical structures that have biological activity in predictive assays and can be run through more assays and tinkered with to find non-toxic, bioactive, and potentially therapeutic versions that can be tested in humans.  It is medicinal chemists that design and tinker with the structures to optimize their activities along the multiple parameters required by the desired drug.  So, since the universe of potential structures is vast, the number of possible targets immense, and the design and testing cycle fast, Mike wants to see more sharing of ideas, advice, and results, especially negative ones, early in the process, before the years of data accumulation needed for a publication.  He also sees the portal increasing opportunities to form collaborations; to share preferred assays, endpoints, and models; to bundle work to get better prices from contract research companies; to aggregate and organize data for extraction of insights; and to promote the drug profiles desired by organizations (and companies) looking for candidates to develop into products.  Mike also notes that the product development programs like DNDi, Medicines for Malaria Ventures, and the TB Alliance seem to have only modest pipelines and few or no back-up compounds for their clinical leads and need more maybe drugs.  Also getting industrial-strength collaborators to further test the maybes is getting easier now that a number of the major pharmaceutical companies are supporting ND drug discovery, e.g., by making their compound libraries available and participating in data- and resource-sharing efforts like Re:Search (see last week’s post) and GlaxoSmithKline’s Tres Cantos Open Lab Foundation.

As for models of collaborative ND drug discovery, Mike mentioned two to me:  the successful search for a synthetic pathway to make a pure form of the anti-parasite drug, praziquantel (Woelfe et al. 2011) and the on-going OpenSourceMalaria project (OSDD- Malaria).  As for the mechanics of the portal, he may utilize the software and considerable expertise of Collaborative Drug Discovery, Inc., a company in California I have mentioned previously (“Drug Development on the Cheap”) and which is the host of a public access “vault” of structure-activity data for ND research (CDD Public Access).  One big bug in the ointment of Mike’s proposed portal is intellectual property rights and whether/how to protect them.  He told me that access would be password-protected and limited to those who agree to confidentiality to assure that pre-patent-application disclosure did not occur (I think he may need a legal opinion on this).  Also, some academic research administrators get antsy about their researchers disclosing pre-publication data, as UCLA did when GlaxoSmithKline requested proposals for funding recently (“The Good, the Bad, and the Ugly”).  Other than the concern for obviating later patents, there is the problem of “confusion” of who invented what should any participant of the portal (really his/her institution or company) file an application.  Theoretically, a patent may have value; practically, it will have none (one of the reasons these diseases are neglected).  But for academic institutions that have over-staffed technology transfer offices and lots of money to throw at patents and for companies concerned that their own patents will be open to challenge, the problem needs to be addressed.  As I noted last week, the WIPO open innovation program, Re:Search, requires participants to agree to grant no-cost, limited licenses to the other participants, but this solution generates a huge overhead that Mike’s effort can’t afford.  I thought up three alternatives that kick the can down the road and require minimal bureaucratic involvement upfront.  The participating parties could agree not to assert any resulting patents against each other or they could agree that everyone is prospectively granted an non-exclusive license under any subsequent licenses that result or everyone agrees everything goes into the public domain and there are no patents.

Not surprising, the other bug is money and right now, like many entrepreneurs, Mike is taking the crowd-funding route to raise $25K to support a pilot version of the portal.  If you looking to increase your 2013 tax deductions, you should check out his site at Fight NTDs.  Long term support of the what are likely to be modest operating costs could come through participant fees (may be from a big pharma who sees the value) or from grants from the government (unlikely) or foundations (more likely).  One obvious source (for all things global health) is the Gates Foundation, but Mike says his approaches to Gates and two of the groups it funds, DNDi and BVGH/Re:Search, have not been fruitful.  I think more probing of Gates is warranted since it is heavily invested in PATH that has an open source ND project (OneWorldHealth Share) and at least one of its program officers has written about the value of medicinal chemistry and data-sharing in drug discovery (Elliott 2012).  Mike’s portal is too good an idea to flounder, but it needs money and a snappy name.

Better than Expected

Back in June, I wrote about GlaxoSmithKline’s (GSK’s) Discovery Partnerships with Academia program (DPAc) and its “competition” for participation called Discovery Fast Track (“The Good, the Bad, and the Ugly”).   In the latter, academic researchers were invited to submit a therapeutic hypothesis with supporting data that was to be judged by a panel of GSK scientists on several factors, including the potential for addressing an unmet medical need (Discovery Fast Track).  GSK would then use the researcher’s assays and its compound library and screening platforms to identify active compounds, and, if there were success, set up a funded, multi-year DPAc collaboration with the aim of generating a clinical candidate that GSK would develop.  GSK has been running DPAc for about three years and had collaborations with a number of university research groups (e.g., in the UK with the universities in Cambridge on alpha-1 antitrypsin deficiency and Edinburgh on severe acute pancreatitis and in the US with Vanderbilt on obesity and Fred Hutchinson Cancer Research Center on muscular dystrophy).  The Fast Track approach was aimed at expanding the program in the US and finding researchers who may have data leading to new mechanisms of action for drugs.  I opined that the program may also fund drug discovery for diseases of the rest of the world (and typically ignored by big pharma) and wished them well.

That was the good.  The ugly I mentioned was that at least one university’s administration (at UCLA) had taken umbrage at the program’s perceived lack of safeguards for university IP and had advised its researchers not to apply.  I noted the concern was unfounded and that GSK had modified the program to get the buy-in of university tech transfer offices.  Fortunately, many universities did not share UCLA’s concern, and, as was announced last week by GSK, the company evaluated 142 entries from 70 universities, academic research institutions, and hospitals that addressed 17 therapeutic areas (FierceBiotech article and GSK press release).  Eight projects were chosen, and I was pleased to note that five may result in therapies for diseases and conditions occurring partly or predominately in low- and middle-income countries (for a reason not given, the group at Harvard declined having its project described).  The projects are:

  • anti-microbial agents, Sarah Ades, Pennsylvania State University;
  • drugs for malaria, Myles Akabas, Yeshiva University;
  • treatments for leishmaniasis (a parasitic disease afflicting about 500,000 persons per year with a 10% mortality rate, Lauren Brown and Scott Schaus, Boston University, and Jim McKerrow, University of California, San Francisco;
  • antibiotics to overcome resistance, Rahul Kohli, University of Pennsylvania; and
  • regulation of male fertility for contraception, Deborah O’Brien, University of North Carolina at Chapel Hill.

The press release also noted that work on the projects will begin immediately and the first screens are expected to be completed in mid-2014, meaning to me that the preclinical phase may start in 2015 and resulting clinical candidates may show up by 2018.

Of course, it would be great if GSK decided to expand DPAc by adding a component that created start-up companies to further develop the academic research it finds, for example, projects that had advanced beyond the screening stage and/or had candidate compounds in hand.  And it would be great if GSK did this for global health start-ups and greater (for me) if GSK did so in the Boston area.  Connecting of a few dots suggested to me that GSK may be headed in this direction.  GSK is definitively putting major money into starting companies out of academia.  At BIO 2013 in May, GSK and Avalon Ventures announced they were creating an investment fund with up to $465 million from GSK and $30 million from Avalon to start perhaps ten companies over three years in the San Diego area but based on technology from “anywhere” (Xconomy article).  It was reported that the GSK spokesperson, Lon Cardon, senior vice president for alternative discovery and development, said that the new fund is modeled in part on DPAc (Global University Investing article).  Apparently, GSK will have offices in San Diego and Boston (actually Kendall Square in Cambridge) to “help manage current external relationships and collaborations as well as identify and review new opportunities,” according to a GSK blog post last month (More than Medicine blog).  Although the post provided few details of the Cambridge office, I found a position listing GSK put up in February for a “DPAc Entrepreneur in Residence – Biology,” who would be “a member of the Alternative Discovery and Development (ADD) Boston Incubator, a new collaborative pilot organization in Cambridge, MA” (Jobing.com posting).  One of the responsibilities of the new hire was “the creation of an exit strategy for the program [e.g., a DPAc project] to either transition into GSK or spin out into an independent entity.”  The job listing also indicated that each project would have an external funding of about $3 million (per year?) and an internal funding of $7.5 million, pretty substantial amounts.  So it is not unconceivable that, if the Boston Incubator includes an R&D facility (rather than only an office), global health-oriented projects in local academia, like the new DPAc-affiliated work at Boston University, could transition to it and eventually spin out as new ventures.  Cool.

 

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.