More on the Business of Global Health (No. 4)

Here are a few items I spotted over the past two weeks.

FierceDiagnostics reported on the clinical test of a concept for a new diagnostic to identify patients with arteminesin-resistant malaria (Fierce article). Almost all the patients studied (about 1200) had parasites with a unique gene, meaning that the quick test could be used to improve treatment (a longer course of arteminesin or combinations of drugs) or to monitor a population being treated prophylaticly (so-called mass drug administration or MDA). MDA is a controversial approach since it may generate stronger resistance (WHO 2011 report on MDA for malaria).

The ever-inventive research group at Harvard University led by George Whitesides is working on a new approach to portable diagnostics using electrochemical analyses. As reported in FierceMedicalDevices (another Fierce article) and published in the Proceedings of the National Academy of Sciences (Nemiroski et al. 2014), the team demonstrated the device’s function using four tests: the detection of blood glucose, trace heavy metals in water for environmental monitoring, sodium in urine for clinical analysis, and a malarial antigen in blood. Fierce also noted that the team wrote software that allows data transmission via basic, not-smart, cell phones and that the whole system is being tested in India. No word on whether Prof. Whitesides, on whose technology the company, Diagnostics for All, is based, has plans for commercial development.

The product development organization, the Global Alliance for TB Drug Development, and Novartis announced the licensing of all the assets of Novartis’s TB therapeutic development program to the Alliance (TB Alliance press release). The assets included a class of promising drug candidates called indolcarboxamides that the Alliance stated it will continue to study. Not addressed in the press release was why Novartis was giving up on TB therapeutics and whether the Alliance tried to get some cash from Novartis to support its work.

One may hope that the Ebola crisis in western Africa may increase the public’s awareness of the lack of foresight and investment by our global society in the development of treatments for neglected diseases, medical infrastructure in Africa, and international health organizations’ ability to response to infectious disease epidemics. And maybe awareness will result in change. A blog post by Julia Fan Li (Li blog post) and a follow up table of the Ebola product pipeline (Bioentrepreneur table) in Nature’s Bioentrepreneur provided concise and cogent statements of the problem and status of developing treatments for Ebola.

Scott Kirsner, the innovation economy correspondent for the Boston Globe, wrote a column recently entitled the “Losing strategy in Mass. on education and health care” (Kirsner column). His point is a valid one: “Where are the voices talking about expanding access to education and health care, and driving costs down? In Massachusetts, they’re scarce. And that’s a losing strategy.” It is a losing strategy for the long-term health of our local economy which is widely viewed as an exemplar for the future of the US economy. As some readers may remember, I have tooted my horn on the potential for profit in providing low-cost, affordable health care (e.g., my post “Missing the Boat”) and I thank Mr. Kirsner for adding his push.

Bad Air Replay

As with our national “leaders,” I am kicking the can down the road this with week with a replay of a posting from the first week of 2014.

Recently I got around to reading two reports that were released in early December [2103] on what funding levels and targets are needed to continue the progress toward eliminating one of the big three global diseases, malaria. The reports, “From Pipeline to Product: Malaria R&D Funding Needs into the Next Decade” and “Estimating Costs and Measuring Investments in Malaria R&D for Eradication” (copies here and here), were written by staff of Policy Cures, a global heath contract research group based in Australia and best known for its annual survey of funding for global disease product development, G-FINDER. Although Policy Cures’ focus is on governments, philanthropic funders (e.g., the Gates and Wellcome Foundations), and global health advocacy groups (their clients), the organization generates data and reports that can be used by companies looking for product and funding opportunities in global health. These reports provided me landscape view of malaria R and D and product development but unfortunately make recommendations aimed at their main clients and overlooked the role and value of commercial product development.

Here’s a quick summary of the “Pipeline” report. After noting the progress that has been made since 2001 (274 million fewer cases and 1.1 million fewer deaths, a reduction of 26%), the authors reported on the past funding on malaria R and D (which has increased from $131 million in 1993 to $610 million in 2011) and its distribution (25% in research and 75% into development). Of this amount, the public sector (governments, primarily the US) accounts for around half of all funding, the philanthropic sector for a third (primarily the Gates Foundation but also the Wellcome Trust), and industry for a fifth. The authors also stated in general but provide no specific details, that there are “at least 96 malaria products in development, including 13 new vector control active ingredients and new formulations, 37 drug candidates, and 46 vaccine candidates.” Then for each of four areas (basic research, diagnostics, drugs, vaccines, and control agents [insecticides]) the report provided a breakdown funding by product type or stage of development and the types of products needed based on “globally-agreed R&D targets.” The authors then summarize their projections of funding needs in each of these areas, but more useful to companies were the details of the projections were given in Annex 2.

In Annex 2, the authors listed the products (“ideal portfolio targets”) that are needed as determined by the main malaria research and public health groups: Foundation for Innovative New Diagnostics (for diagnostics); Medicines for Malaria Venture, Malaria Eradication Research Agenda Consultative Group, and Malaria Eradication Scientific Alliance Task Force (for drugs and vaccines); and the Innovative Vector Control Consortium (for control agents). Then using information the phase of development of the products, an estimate of the costs of completing each phase, and the probability of success at each phase (defined as percentage of candidates successfully reaching the next phase), the authors projected the required funding. To account for failures, the authors assumed that the goal was one successful product for each target within a decade and added in the cost of backup R and D required to account for attrition to reach desired number of successfully registered products. While this approach is sound, I did not verify the underlying data (e.g., probabilities of success vary by indication with cancer having a higher failure rate) and confirm that their methods were widely accepted (I noted that of the ten or so consultants used by the authors only one was from industry).

As for the recommendations made, not surprising, the primary one is that funders need to come up with an average of $700 million per year over the next decade, or about $100 million more than was allotted in 2011, with more of a slant toward product development. They also recommended that more coordination of basic research and product development is needed, but, again not surprising, made no recommendations on increasing incentives for involvement of companies. Although R and D spending by companies is only 17% of the total, companies like Novartis, GSK, and Ranbaxy have played and are playing key roles in the development and deployment of new drugs and vaccines and many smaller companies have made possible the widespread availability of inexpensive rapid diagnostics. Also, as the authors noted on page 39, public and private funders and need to act more like for-profit product developers: “Unfortunately, funding decisions are often disconnected from the product development occurring on the ground. Ideally, funding should be flexible and should respond to changes in the pipeline: if a malaria vaccine candidate enters late-stage clinical trials, then the funding required is significantly higher than in the earlier stages of the development pipeline. Industry, and to an extent, philanthropic funders (particularly those with the resources to closely follow R&D developments or whose funding contracts are milestone based) tend to be responsive to these fluctuations in the pipeline and in funding needs. Public funders, however, are often much less responsive. Funders should be aware of R&D developments in the global portfolio and progress against agreed-upon goals in order to direct their funds to the areas where they are most needed.”

The good news in the world of product development for malaria is that it has been funded fairly steadily over the past ten years by a diverse group of funders (pubic, private, and corporate) and that is likely to continue, and that there has been a lot of effort into identifying what products are needed. Less good news is that two of the funding groups (pubic and private) are also footing the bill for on-going malaria control efforts, now about $ 1.5 billion per year (said to meet only about half the need) and that up-coming stage of bringing products into use will require expensive trials and registration. Hence, some one or some group needs to make funding decisions based on return on investment and triage of less promising programs, something companies are good at but governments and foundations are not. My recommendation is that the global malaria eradication community would benefit from forming up a “commercialization agenda consultative group” soon.

A Long Strange Trip Continued

Back in November 2011, I wrote a post about the approval of a new drug for malaria by Ranbaxy Laboratories, an India-based generic drug maker and, since 2008, a division of the Japanese pharma company, Daiichi Sankyo Co. Ltd. (“A Long Strange Trip”). My point was that story of the drug, now called Synriam™, was an example of a mix of players cooperating for global health drug development: US academic medicinal chemistry researchers, a grant-supported product development organization (Medicines for Malaria Venture or MMV), a persistent big pharma willing to take a risk on a low-priced product (Ranbaxy), and a government agency willing to support a public health drug (the Indian government’s Department of Science and Technology). The trip continues, so here is an update with some clarifications of my original post.

In my first post, I missed the point that the approval granted Ranbaxy by the Indian government was conditional; an inspection of a Chinese ingredient supplier was needed. So it was not until last October that Ranbaxy announced receiving unconditional approval for India and that it was pursuing approvals in African, Asian, and South American markets with applications filed in several African countries (Ranbaxy press release). I also missed that Synriam is a “fixed dose combination” (FDC) drug being a combination of the novel, US-invented anti-malaria chemical, arterolane, and a known anti-malaria drug first developed in China in the 1950s, piperaquine. I have not found an explanation for Ranbaxy choosing to develop an FDC rather than a single active ingredient drug, but there could be several reasons, for example:

  • In its collaboration of with MMV, Ranbaxy found that arterolane alone did not provide as-good-as-expected clinical results;
  • The malaria-causing parasites are known to develop resistance to anti-malarial drugs and Ranbaxy wanted to reduce this risk by using two drugs with different mechanisms of action at the same time;
  • Ranbaxy wanted to develop a drug that was effective against both the major parasites, Plasmodium falciparum (causes 60% of cases worldwide) and Plasmodium vivax (causing 40% world wide but 50% in India), and this combination of drugs worked; and/or
  • Ranbaxy needed a stronger intellectual property position and patenting an FDC may help.

This last point did not occur to me until I read a posting at a website devoted to intellectual property issues in India (SpicyIP article). The writer, Prashant Reddy, noted that Ranbaxy’s license to arterolane is non-exclusive and therefore MMV could license competitors or may not enforce its patent rights. My guess is that Ranbaxy filed for patents on its FDC so that it had IP rights independent of those granted by the MMV license.

Since getting approval for marketing in India, Ranbaxy has been promoting the drug. The company has a website for it (Synriam) and a presentation for download (2013 Ranbaxy presentation). From these I learned that the drug has a number of attractive features:

  • Two mechanisms of action: arterolane kills parasites in the blood, providing fast relief of malarial symptoms, and piperaquine kills residual parasites, preventing disease recurrence;
  • Compliance-friendly dosing: one pill taken each of three consecutive days (compared to 6 to 24 for the drugs);
  • Kid friendly: a pediatric formulation and dose is being tested in Phase II trials;
  • Completely synthetic unlike the artemisinin-based, mainline drugs that are made from a wormwood extract;
  • Works well: 97.9% in uncomplicated falciparum malaria;
  • As fast-acting and safe as standard mainline drug, Coartum; and
  • Low price: it is sold for 130 Rs ($2.21) per 3-day course in India where there are 1.3 million cases per year.

Given these features, I imagined that the many not-for-profit, anti-malaria groups would be pleased that Ranbaxy had put in the $50 million or so to develop Synriam. But to my surprise, my review of the websites of the following found no mention of the drug and its approval:

I’m not sure why the lack of comment or interest. Is it because the drug has some fatal flaw that I am unaware of? Or it is because these organizations are invested in fighting malaria their way and Synriam doesn’t fit? I found an editorial published this week in the New Telegraph of Nigeria (“Towards Curbing the Malaria Menace”) that gives the perspective of a writer in a malaria endemic country and excerpted the following:

  • -Nearly all Nigerians (97 per cent) are at risk of at least one malaria attack per year.”
  • “… a princely N480 billion [about US$3 billion] is expended annually on antimalaria campaigns even when the impact is not altogether appreciable in the fight against the scourge.”
  • “Compared to other diseases, malaria is one of the most marketable diseases that shares a large funding pool by international donor agencies.”
  • “Thus for it to still remain a major killer disease in the country 14 years after a concerted campaign was launched in 2000 by African leaders, is an indication that perhaps, the various strategies adopted to eradicate the scourge are inadequate.”
  • “We strongly recommend that governments and corporate bodies take keen interest in research and adequately fund relevant institutions in the country to embark on manufacturing effective anti-malarial drugs.”

According to my math, Nigeria could treat its 100 million annual cases with Synriam at a cost of $212 million, and I think Ranbaxy would not be adverse to manufacturing Synriam in Nigeria. What am I missing?

Vector Vax

Malaria is a nasty disease resulting from an infection by the Plasmodium parasite that occurs via injection by an infected mosquito, and that, according the WHO, happened to about 200 million people in 2012 (WHO Malaria Facts).  Fever and chills ensue and, if untreated, death, and this happened to about 600,000 people, mostly children in Africa, in 2012.  While drug treatment exists and is being improved by newer drugs, combinations, and better distribution and measures like preventing bites with netting and killing mosquitoes and destroying their habitat are helping reduce mortality, a malaria vaccine has been a long-sought goal of the global health community.  A vaccine is a major challenge though.  The parasite goes through a number of stages in the human host and the insect vector (see a nice graphic at Malaria Vaccine Initiative) and how, when, and where the human immune system mounts a successful response are not known.

Vaccine developers have taken three vaccine approaches (also at Malaria Vaccine Initiative).  The first is to aim at the early stage of an infection when the parasite is infecting the host liver; the most advanced vaccine, GlaxoSmithKline’s (GSK) RTS,S AS01 in Phase 3 clinical trials, is of this type.  The second is to generate an immune response to the parasite while it is rapidly reproducing in the host red blood cells, reducing the severity of the disease and allowing time for the innate immune response to occur.  The third, using a transmission-blocking vaccine (TBV), is my favorite because it targets the parasite while it is reproducing in the mosquito using antibodies obtained from the host.  Essentially the vaccine turns a human into a system to deliver antibodies to treat the vector’s malaria.  The idea for a TBV has been around at least since 1987 when studies confirmed that the blood of malaria sufferers contained antibodies that reduced the number of parasites in mosquitoes (e.g., Mendis et al. 1987 in which the researchers dissected out the mosquito gut to look for parasites), but it has only been in the last three years that candidates have advanced into clinical trials.  The primary sponsors of the trials have been the Malaria Vaccine Initiate (MVI is run by the Seattle-based global health product developer, PATH, and funded by the Gates Foundation) and the NIH’s National Institute for Allergy and Infectious Diseases.

MVI’s lead TBV candidate was Psf25-EPA, so named because it consists of  antigens to a Plasmodium surface protein and a detoxified version of an immune-stimulating bacterial protein.  Unfortunately, it failed to generate a strong enough response in a Phase I trial in 2012 (MVI Call for Letters of Intent).  While a number of companies and academic groups have expressed a variety of the parasite’s surface proteins in a range of expression systems (I noted one in yeast and another in algae), the Fraunhofer Center for Molecular Biotechnology (FCMB) evidently had the best proposal and was selected by MVI to fill the gap left by the failure of Psf25-EPA.  Also apparently FCMB was able to move its candidate, Psf25-CP, into trials quickly.  Recruiting for Phase I started last November (Clinicaltrials.gov entry), and the trial got under way this past month (FierceVaccines iBio press release, FierceVaccines iBio press release).  Since I’m interested in how multiple parties collaborate to develop global health products, I looked into the background of this project and found not all the players on the same page.

The FCMB is part of the globe-spanning Fraunhofer Gesellschaft, a German-based research and development non-profit that has 67 institutes in Germany and offices and centers around the world including 11 in the US (Fraunhofer).  The Fraunhofer has 23,000 employees and $2 billion plus budget, 30% from the government and 70% from government and industry contracts (Fraunhofer Wikipedia article).  The FCMB is in Newark, DE, and has 90 employees focused on recombinant protein expression in a proprietary plant-based expression system (FCMB).  It has a GMP-compliant pilot plant and projects for vaccines and antibodies for influenza, Trypanosomiasis (sleeping sickness), yellow fever, hookworm, HPV, and malaria, the last supported by a Gates grant of $9.85 million received in 2009 (FCMB press release).

As noted in the above-cited press release, apparently FCMB has a commercial partner in the development of the expression system and in the malaria TBV project, a company called iBio, Inc.  iBio has a 2011-dated website (iBio Inc.), that seemed to be light on details, but since it is a public company listed on the NYSE, I looked at its SEC filings and analysts’ reports.  iBio appears to be struggling financially, facing delisting (see Middle Market article) and floating stock with the aim of raising $10 million but securing only $500K in 2013 (but had $5 million cash on hand at year’s end; see the latest iBio 10Q).  I looked at the US patents assigned to iBio and the three key ones are either co-assigned to Fraunhofer or have Fraunhofer employees as inventors.  I am guessing this co-ownership resulted from iBio’s sponsoring of the expression system’s development at FCMB (with FCMB scientists being the actual inventors).  Such an agreement and its recent modification to less expensive terms for iBio are mentioned in the company 10Q filing (iBio is committed to $1.5 million in payments to FCMB through 2015).  I also noted the company is co-located with the FCMB.

All this suggests to me that iBio is a shell company whose main assets are patents on the expression system and future revenues are dependent on FCMB’s success in using the system to develop products with partners like MVI and FioCruz (a Brazilian governmental institute with whom FCMB has a contract to build a plant for a yellow fever vaccine; see my post, “Procurement Power”) and those products being licensed to a commercial entity to conduct full-scale trials, registration, distribution, and sales.  If the FCMB wrote its contract with iBio correctly, or used the recent renegotiation opportunity correctly, it may have the right to pursue commercial partners independent of iBio, just owing a royalty.  I hope this is the case so that FCMB can find partners for the malaria TBV and other products that are committed to global access.  I assume that the FCMB management and  board has thought through its product development strategy perhaps with help from the Gates and/or PATH (the latter have successfully launched one global vaccine, MenAfriVac®).  There is no statement of a strategy on the FCMB website, and I noted its management team is all scientists (FCMB Leadership ) and its advisory committee is all solid citizens of Delaware with no pharma/biotech/medical experience (FCMB Committee).

Bad Air

Recently I got around to reading two reports that were released in early December on what funding levels and targets are needed to continue the progress toward eliminating one of the big three global diseases, malaria.  The reports, “From Pipeline to Product:  Malaria R&D Funding Needs into the Next Decade” and “Estimating Costs and Measuring Investments in Malaria R&D for Eradication” (copies here and here), were written by staff of Policy Cures, a global heath contract research group based in Australia and best known for its annual survey of funding for global disease product development, G-FINDER.  Although Policy Cures’ focus is on governments, philanthropic funders (e.g., the Gates and Wellcome Foundations), and global health advocacy groups (their clients), the organization generates data and reports that can be used by companies looking for product and funding opportunities in global health.  These reports provided me landscape view of malaria R and D and product development but unfortunately make recommendations aimed at their main clients and overlooked the role and value of commercial product development.

Here’s a quick summary of the “Pipeline” report.  After noting the progress that has been made since 2001(274 million fewer cases and 1.1 million fewer deaths, a reduction of 26%), the authors reported on the past funding on malaria R and D (which has increased from $131 million in 1993 to $610 million in 2011) and its distribution (25% in research and 75% into development).  Of this amount, the public sector (governments, primarily the US) accounts for around half of all funding, the philanthropic sector for a third (primarily the Gates Foundation but also the Wellcome Trust), and industry for a fifth.  The authors also stated in general but provide no specific details, that there are “at least 96 malaria products in development, including 13 new vector control active ingredients and new formulations, 37 drug candidates, and 46 vaccine candidates.”  Then for each of four areas (basic research, diagnostics, drugs, vaccines, and control agents [insecticides]) the report provided a breakdown funding by product type or stage of development and the types of products needed based on “globally-agreed R&D targets.”  The authors then summarize their projections of funding needs in each of these areas, but more useful to companies were the details of the projections were given in Annex 2.

In Annex 2, the authors listed the products (“ideal portfolio targets”) that are needed as determined by the main malaria research and public health groups:  Foundation for Innovative New Diagnostics (for diagnostics); Medicines for Malaria Venture, Malaria Eradication Research Agenda Consultative Group, and Malaria Eradication Scientific Alliance Task Force (for drugs and vaccines); and the Innovative Vector Control Consortium (for control agents).  Then using information the phase of development of the products, an estimate of the costs of completing each phase, and the probability of success at each phase (defined as percentage of candidates successfully reaching the next phase), the authors projected the required funding.  To account for failures, the authors assumed that the goal was one successful product for each target within a decade and added in the cost of backup R and D required to account for attrition to reach desired number of successfully registered products.  While this approach is sound, I did not verify the underlying data (e.g., probabilities of success vary by indication with cancer having a higher failure rate) and confirm that their methods were widely accepted (I noted that of the ten or so consultants used by the authors only one was from industry).

As for the recommendations made, not surprising, the primary one is that funders need to come up with an average of $700 million per year over the next decade, or about $100 million more than was allotted in 2011, with more of a slant toward product development.  They also recommended that more coordination of basic research and product development is needed, but, again not surprising, made no recommendations on increasing incentives for involvement of companies.  Although R and D spending by companies is only 17% of the total, companies like Novartis, GSK, and Ranbaxy have played and are playing key roles in the development and deployment of new drugs and vaccines and many smaller companies have made possible the widespread availability of inexpensive rapid diagnostics.  Also, as the authors noted on page 39, public and private funders and need to act more like for-profit product developers:  “Unfortunately, funding decisions are often disconnected from the product development occurring on the ground. Ideally, funding should be flexible and should respond to changes in the pipeline: if a malaria vaccine candidate enters late-stage clinical trials, then the funding required is significantly higher than in the earlier stages of the development pipeline.  Industry, and to an extent, philanthropic funders (particularly those with the resources to closely follow R&D developments or whose funding contracts are milestone based) tend to be responsive to these fluctuations in the pipeline and in funding needs.  Public funders, however, are often much less responsive.  Funders should be aware of R&D developments in the global portfolio and progress against agreed-upon goals in order to direct their funds to the areas where they are most needed.”

The good news in the world of product development for malaria is that it has been funded fairly steadily over the past ten years by a diverse group of funders (pubic, private, and corporate) and that is likely to continue, and that there has been a lot of effort into identifying what products are needed.  Less good news is that two of the funding groups (pubic and private) are also footing the bill for on-going malaria control efforts, now about $ 1.5 billion per year (said to meet only about half the need) and that up-coming stage of bringing products into use will require expensive trials and registration.  Hence, some one or some group needs to make funding decisions based on return on investment and triage of less promising programs, something companies are good at but governments and foundations are not.  My recommendation is that the global malaria eradication community would benefit from forming up a “commercialization agenda consultative group” soon.

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 Long Strange Trip

A couple weeks ago, Ranbaxy Laboratories Ltd. of Gurgaon, India (Ranbaxy) reported that it had received marketing approval in India for an new anti-malaria drug, a combination of arterolane maleate and piperaquine phosphate (Fierce Biotech article and Economic Times article).  The announcement was notable because Ranbaxy is a fifty-year-old generic drug maker (and since 2008 a division of the Japanese pharma company, Daiichi Sankyo Co. Ltd.) and the new, unnamed drug was its, and maybe India’s, first novel pharmaceutical.  The story of the drug’s discovery and development a good example of how a company can take on the risk of developing low-margin products for under-served markets with planning, persistence, imaginative public-private deals, and luck.

Clearly malaria is a major and continuing global health problem with more than 3 billion people at risk of infection, 250 million new cases annually, 900,000 deaths (mostly children in Africa), and $12 billion per year in direct costs (Roll Back Malaria facts).  And new drugs are needed since the parasites causing the disease, protists of the Plasmodium genus, have become resistant to both the traditional and the newer “first line” drugs, which use derivatives of the natural compound, artemisinin, by themselves and in combination with traditional drugs (Medicines for Malaria Ventures resistance research).  For the past 22 years, the Medicines for Malaria Ventures, a donor-funded product development program (MMV) has been a key player in promoting new drugs and has an important role in the discovery of the Ranbaxy drug.

As was described in a 2002 article (WHO Bulletin), the discovery of the new drug’s active ingredient, arterolane, started when John Vennerstrom, a medicinal chemist at the University of Nebraska, and colleagues received a small $70K grant from the WHO Tropical Disease Research Program, a collaborator of the MMV.  The group succeeded in finding bioactive compounds, specifically derivatives of artemisinin with reactive oxygen groups, and was granted $1 million by MMV who brought in the Swiss pharmaceutical company, Hoffmann-La Roche, for its past malaria drug development expertise.  Two other academic groups participated; the Swiss Tropical Institute tested the compounds in mouse models, and a researcher at Monash University in Australia did pharmaco-kinetic studies.  As for the intellectual property, the University of Nebraska did the right thing and assigned the rights to the compounds and synthesis method to MMV without payment (WHO Bulletin summary).  According to a recent Business Standard article (Business Standard article), Roche left the party in 2003 giving its “development and marketing rights” back to MMV, and shortly thereafter MMV found a new partner, Ranbaxy.  A 2007 article quoted MMV’s clinical development director, “We wanted to go with a partner based in a disease endemic country [and] Ranbaxy was the best company we talked to” (LiveMint.com article).

But as in wont to happen in drug development, the candidate drug delivered less than outstanding results in human studies, both pharmaco-kinetic and efficacy, and MMV pulled its support in 2007 to focus on more promising candidates, writing off a $15 million investment (LiveMint.com article).  Undeterred, Ranbaxy decided to continue, but to defray the cost of the Phase III trials, it struck a deal with the Indian government’s Department of Science and Technology (DST).  The DST agreed to partially fund the project, and Ranbaxy agreed to supply the (maybe) drug for domestic public health needs at a price just 10% more than its cost of production.  And the DST would also get a 3% royalty on sales outside of India (Business Standard article).  I can only dream that the NIH could be this imaginative.  I couldn’t find any reasons given by Ranbaxy for continuing, perhaps just it was just faith, or the desire to do good, since apparently arterolane’s overly-reactive, “ozonide” structure is risky for a drug candidate, at least according to the medicinal chemist and blogger, Derek Lowe.  In 2009, he noted that the drug had one of the “funkier” structures to make it to Phase III, but that “I have to congratulate the people who had the imagination to pursue these things.” (In the Pipeline).

So after ten plus years and about $30 million of its own and others money (my estimate), Ranbaxy has a novel anti-malaria drug that is potent (requires three doses over three days vs. four tablets taken twice a day for three days for the current best-in-class combo drug, Novartis’s Coartum) and is cheap to make allowing it to sell at an affordable price (Ranbaxy said one-third of Coartum’s already-discounted price).  And expected sales are decent; in India the market is about $90 million annually and growing at 20%, and the international market is between $400 and $500 million (Sharekahn.com).  And MMV has come came back on board and is testing the ability of the drug to avoid Plasmodium resistance (MMV research).  Kudos all around, to MMV for funding the work from discovery through Phase II and for partnering with Ranbaxy, to Ranbaxy and Daiichi Sankyo for altering course from making generics to pursuing a novel drug program and for striking a deal with the DST, and to the DST for doing a deal.

But the story hasn’t had its happy ending yet.

Getting affordable, effective drugs to the people who need them is a major challenge in global health, and a problem with which the international anti-malaria community is struggling, especially in Africa where 90% of the infections occur and almost all the deaths.  Because of the availability through local shops of really cheap, but useless or even counterfeit, drugs, any alternative drug needs to be equally available and nearly as cheap.  As I noted in a previous post (“AMFm: Not Your Ordinary Radio,” 6/10/10), the Global Fund to Fight AIDS, Tuberculosis, and Malaria launched the Affordable Medicines Facility-malaria in 2009 with about $225 million of donor (but not US) money as a way to subsidize and therefore lower the market price of retail, first line anti-malarials (AMFm).  So Ranbaxy needs to get approval by the WHO to participate in the AMFm and sell its drug in the largest market and that is apparently underway (Business Standard article).  Meanwhile, the AMFm may turn out not to be the best distribution channel.  Although the first review of the program, albeit by its backers, noted that its goals were being met, primarily bringing down retail prices (Last Mile Meeting 2010), there are indications of problems.  An organization outside the Global Fund sphere called Africa Fighting Malaria (AFM) reported some findings in a policy paper recently including:

-over-purchasing of the first line drugs by a few countries (four of the 12 eligible countries accounted for 70% of drugs’ production);

-diversion of AMFm-subsidized drugs to non-purchasing countries;

-selling of purchased drugs above the agreed-to ceiling prices; and

-a shortage of drugs in public clinics and for the US government’s President’s Malaria Initiative because most of the drugs are being bought by distributors for the private market (AFM paper and American Enterprise Institute article).

Bill Brieger, a Johns Hopkins professor of public health, noted drug availability problems in his blog posting of May 2011 (Malaria Free Future blog).  So will the AMFm sort out its problems, will Ranbaxy get its approval, and will people with malaria get a better, cheaper drug?  To be continued.