GUD Knight

About a month ago, the US FDA announced that it had granted a Canadian company, Paladin Therapeutics, approval to sell a drug called Impavido® to treat leishmaniasis, a nasty, protozoan infection that occurs annually in about 1.3 million, mostly poor, people and causes 20-30,000 deaths (WHO Fact Sheet). The press release in FierceBiotech also stated that Paladin received a Tropical Disease Priority Review Voucher (PRV), only the third one granted. The PRV process is intended to encourage development of drugs for neglected diseases, and the FDA will expedite review of a drug submitted by the holder of a PRV, and the company has sales sooner as a result. And since it is transferable, the holder can also sell it, although none have been sold (or used) to date. I found it interesting that the FDA would make the announcement and not the company and was more perplexed when I found that Paladin was no longer in business, having been purchased in 2013. But before untangling that web, I looked up background on Impavido.

Impavido is the name trade-marked by the Æterna Zentaris Inc., a German company, for a drug with the generic name of miltefosine. Miltefosine was designed and developed in the 1980s as an anti-cancer drug, was found to be a broad spectrum antimicrobial, and developed as the first (and only) oral treatment for chronic leishmaniasis by ASTA Medica (later Zentaris GmbH), the WHO Special Tropical Diseases Programme, and the government of India in the 1990s. Subsequently, Zentaris got approvals for Impavido in Germany, India, and Central and South America (the last through licensees), and miltefosine is made by at least one Indian generics company for the domestic market (nicely summarized by Dr. Anthony Crasto in his blog, New Drug Approvals, and at docguide.com). So why isn’t Impavido/miltefosine being widely used to treat leishmaniasis (which has three forms- visceral, also known as kala-azar and the most serious form; cutaneous, the most common; and mucocutaneous)? I looked at the Drugs for Neglected Diseases Institute’s (DNDi) website since this grant-supported, not-for-profit has a major program to develop visceral and cutaneous leishmaniasis drugs (DNDi Strategy), but could not find a clear reason. My read is that DNDi believes that the drug’s course of treatment (28 days) and immediate improvement may result in poor patient adherence and development of resistance, the drug’s potential fetal toxicity makes it unsafe for reproductive-age women, and its cost is too high for monotherapy (about $80 per course at the current WHO-negotiated preferential price). Dorlo et al. had a more positive assessment in their 2012 review, concluding that, as a well-tolerated and oral drug, miltefosine should be a viable option for many patients.

What about Impavido’s use as a treatment? All rights to the drug were bought by Paladin, a successful, Montreal-based specialty pharma retailer founded by Jonathan Goodman, from Zentaris in 2009 (PRNewswire release). Paladin apparently continued Zentaris’s commitments to its licensees and WHO purchasers, selling about $2.5 million worth out of total annual sales of $200 million. In November, 2013, Endo Health Solutions, Inc., a US-based specialty pharma company, bought Paladin for about $2 billion in cash and stock (Reuters article), in part to extend its product line and in part to reduce its US corporate tax liability. Since the acquisition was done through an Irish holding company, some analysts call the deal an end-run around the IRS (e.g., Zerohedge.com blog), interesting but not relevant. What is relevant is that Mr. Goodman negotiated retaining Impavido ownership as one of the assets for his new company, Knight Therapeutics, which he founded just after the Paladin sale. Knight is off to a good start with $60 million invested by Mr. Goodman, another $180 million from other investors (Cantech Letter), and an IPO on the Toronto Stock Exchange in March (Waterhouse article). Why did Mr. Goodman keep Impavido as the company’s first product? It’s not clear to me. According the two above-cited sources, Knight licensed Impavido’s non-US rights to Endo so will get about $500K in annual royalties (peanuts for a company with a market capitalization of about $140 million), and Knight has the drug’s PRV (value to be determined). According to the company website (Knight Products), it is developing a commercialization plan for the drug for the US market, although leishmaniasis is very rare so revenues are likely to be small.

Mr. Goodman is clearly an experienced and successful entrepreneur, building Paladin from a start-up to a public company, and is wealthy from the Endo deal (he owned one-third of Paladin’s stock as reported in a Globe and Mail article). He also has a different perspective on life after an almost fatal bicycle accident in 2011 that I, as a road biker and commuter, can relate to. Two weeks ago, Mr. Goodman posted a note called To Define Success in which he wrote “Success is defined by the good we do for others.” He ended with:

The more you practice the cycle of giving, the easier and more rewarding it becomes – it is now my new addiction (I gave my bicycle to my cousin). Anyone can repair our world. Anyone can make a difference. Any currency can be used, whether it is money, knowledge or your time. Knight’s stock ticker is GUD, not derived from Goodman, but for the hope we all do good.

My humble suggestion is that Mr. Goodman use his money, knowledge, and time to get Impavido used to treat as many of the 12 million people with leishmaniasis as possible.

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A Rare Request, an Orphan Offer

A press release last week has prompted me to get on my “rare disease” soap box again.  In previous posts, I noted that drug development for rare and orphan diseases (but not the neglected diseases of poverty that are rare in the US) has become one of the saviors of the pharma industry (or at least its profits) with one-third of the drugs approved in 2011 being for rare disease (“Orphaned and Neglected” in February 2012).  Of course, the venture capital industry took note of this opportunity and has been investing in early-stage companies developing such drugs, but last week’s announcement showed that VC-types are also good at structuring new business models to accelerate and “de-risk” drug development.  My request (naïve hope) is that they apply their smarts to drug development for the orphan, neglected diseases (NDs) of the rest of the world and add some push for the pharma/biotech industry into the global health business.

The press release was from a new company called Cydan located in our local biotech hotbed of Cambridge.  While the company website has little additional information (Cydan), the release noted that Cydan will be “an orphan drug accelerator that identifies and de-risks programs with therapeutic and commercial potential” with such programs coming from academia and other companies but presenting “well-understood biology and proof-of-concept data in in vivo models” (Cydan PR).  Cydan will conduct its preclinical studies via contract development outfits to “inform definitive ‘go’ or ‘no go’ development decisions” and will start up companies based on the most promising programs.  Cydan’s management has strong drug development credentials.  Cristina Csimma, the CEO, has start-up and big pharma experience (I know her slightly from our overlapping stints at Genetics Institute/Wyeth) and James McArthur, CSO, and Deborah Geraghty, Vice President, Project and Portfolio Development, have multiple start-up company experience.  More importantly the company has good initial financial backing, $16 million led by the VC firm, New Enterprise Associates (NEA), which has the deepest pockets among the VCs for biotech investment.  NEA’s raising of $2.6 billion in 2012 means it could funnel more than $700 million into biotech companies in the coming years (FierceBiotech article).  The other participants are Pfizer Venture Investments, suggesting a corporate acquisition pipeline, and Alexandria Real Estate Equities, Inc., the dominant Kendall Square (Cambridge) lab space developer with more than 2 million square feet occupied and 1.7 million planned and approved (Alexander Real Estate PR).

Will Cydan refute conventional wisdom and take up ND projects where the profit margins are likely less than those for the rare diseases and more difficult to assess?  Not likely but NEA is not totally unfamiliar with the global pharma market, having offices in India and China and having made a investments in Chinese service companies, a few anti-infectives and needle-less delivery companies, and in one US company, Liquidia Technologies, that has a collaboration with PATH on pneumonia vaccines (NEA portfolio and Liquidia press release).  Also the NEA principals could be inclined to try a ND opportunity or two knowing that assessing commercial potential for programs that will result in drugs, even with accelerated development, in 6-10 years is difficult and a market for ND drugs could develop by then.  They are also likely aware that US insurers are increasingly expecting new drugs to provide measurable improvements in quality of life and that there will be competition even for rare disease drug price coverage (e.g., Sanofi and Agenion are competing on price for their recently approved products for familial hypercholesterolemia [FiercePharma article]).

Undoubtedly, the founders of Cydan have list of rare disease program opportunities they are working, but I read the press release as implying that interested parties may submit their nominees for consideration.  What global health/neglected disease opportunities are there that may meet Cydan’s criteria of having with well-understood biology, proof-of-concept data in in vivo models, and a “characterized genetic etiology?”  The last is a sticky point and the only one I can think of is sickle cell anemia in which suffers have retained expression of a form of hemoglobin which confers some protection against malaria but also decreases blood flow and increases the severity of infections in African kids (see my post, “A Really Neglected Disease”‘ July 2010).  However, if the last criterion includes diseases in which the target organism has genetic characterization, there are more opportunities.  One may be drugs for hepatic C virus infection for which there are many early- (and late-) stage drug development programs and for which I wrote up a not too-unreasonable justification of commercial potential outside the developed markets (“Rolling the Dice” Aug 2012).  There are also the several families of compounds being pursed by the non-profit neglected disease drug developers that may be stuck in the preclinical stage for lack of funding or expertise (e.g., DNDi portfolio and MMV portfolio).  There are also a bunch of academic labs trying their hand at drug development for neglected diseases, e.g. Michael Pollastri at Northeastern (Pollastri lab) and the many listed in the BVGH Global Health BVGH Primer (BVGH Primer).  If anyone has a program she/he wants to submit for Cydan’s consideration, I’m happy to help with the pitch.

 

Bottleneckrophobia

Thanks to serious international efforts and multiple years of funding from foundations like the Bill and Melinda Gates Foundation and US and European governments, the pipeline of new drugs and drug combinations to treat the big three infectious diseases (HIV/AIDS, tuberculosis, and malaria) is starting to pump out products.  As pointed out by researchers at Policy Cures, a non-profit consulting group in Sidney, Australia, the good news is that there are 20 or so new drugs for diseases of the developing world that have been or are in the process of being approved by several regulatory authorities (Moran et al. 2011).  The less than good news is that the national regulatory authorities (NRAs) in many of the countries where the drugs are intended for use (such as in Africa, the authors’ focus) are not sufficiently staffed and trained to render rapid approvals.  In the past the NRAs have relied on the approval process of the “stringent” authorities of the world, e.g., the US FDA and the European Medicines Agency, but this route has resulted in drugs being approved but not tested in the countries in need or being withdrawn based on first world risk/benefit ratios.  While this bottleneck is clearly a problem for the several non-profit drug developers, e.g., Medicines for Malaria Venture and the Drugs for Neglected Diseases Initiative, it is a strong disincentive for most for-profit developers, excepting the few multinational pharmas with deep pockets and vision, like Sanofi and GlaxoSmithKline.  To my (naïve) way of thinking, a clear path to approval and registration of new drugs (and vaccines, devices, and diagnostics) in the countries of need is required (along with patient investment and vision) for the many mid-sized, and maybe even small, companies to risk a try at developing new, affordable drugs for the neglected diseases.

Harmonization and coordination of drug approval processes is not a new problem, of course, and there has been a substantial effort, focused mainly in the major market, and more recently, emerging market, countries.  As noted recently by PharmaManufacturing.com (MPC article), the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and a working group of the US Pharmacopeia (USP), both which started 20 years ago, have achieved good progress on certain aspects of standardization like testing protocols and documentation, mostly in the past five years.  The challenge is large though; another group, the Pan American Network for Drug Regulatory Harmonization, has more than a dozen working groups including those on bioequivalence (to approve “follow-on” or generic drugs), counterfeiting, good clinical practices, good laboratory practices, good manufacturing practices, promotion, biotechnology products, and vaccines (PANDRH).   The MPC article also notes the cost of non-harmony is high; multiple regulatory filings and plant inspections can comprise tens of millions of dollars per product.

One approach to supplementing (or more politically problematic, supplanting) the country-by-country approval process would be an international approval agency.  A possible model for such an agency is the WHO’s Prequalification of Medicines Programme (PQP).  Begun in 2001, the program reviews medicines for treating HIV/AIDS, tuberculosis, malaria, and more recently for reproductive health for eligibility for purchase by international procurement agencies like UNICEF.  These purchases are made by the countries of need, are often subsidized by donors (governments and foundations), and run into billions of dollars per year (PQP Fact Sheet).  Although the PQP has approved 240 products, is low cost (free to applicants thanks to about $10 million per year given by UNITAID; see UNITAID Programs), and strengthens NRAs through a training program, it is slow (two-year average for approvals according to Moran et al.) and only evaluates generic drugs and new combinations and formulations of generics for which there are substantial data and sometimes stringent NRA approvals on the original product.  While the PQP’s approval of such generics is important in making needed treatments accessible and affordable, it would need substantial funding and political will to evolve into a novel drug registration agency.  The WHO also has a similar program to pre-approve vaccines from applicant manufacturers that is slightly different in that it relies on NRAs for initial approval but then requires the NRAs to meet a standard of competence (WHO vaccine program).

As is their wont, Moran et al. offer several alternatives to widen the bottleneck:

  • Include a representative of the endemic country NRA in the deliberations of stringent agency approval of a new neglected disease drug (NDD) [but who is the ultimately responsible party?];
  • Allow a NDD approved by a stringent agency to qualify for WHO prequalification status (this was done for generic HIV/AIDS drugs) [but still means that NDDs may not be reviewed with the appropriate criteria];
  • Use the “Article 58” process of the EU (in which an expert panel renders an “opinion” on the use of a drug outside the EU) but gie those drug developers a shorter path to EU market approval [as an incentive to developers of dual market drugs; but for ND-only drugs?];
  • Strengthen the WHO PQP with help from stringent NRAs or expert panels to allow it to recommend/almost approve new drugs [might work, see below]; and
  • Create regional regulatory agencies responsible for each of Africa’s main regions [sounds too bureaucratic and piecemeal to me].

Overlooked by Moran et al. is the deep expertise, experience, and possible motivation of the for-profit drug developers themselves.  After all, the major and mid-tier pharma companies spend billions of dollars conducting trials by themselves or through contract firms (CROs), more often in countries where costs are low but registration is not expected, and are willing to pay substantial “users’ fees” to the USFDA to make sure the agency does its job (about 60% of the FDA budget or $570 million in 2011 according to a Washington Post business blog, Klein blog).  While having such a financial dependency of a regulating agency on the regulated may not be a good idea, I think there is a concordance of interest between industry and the harmonization efforts of the ICH, USP, and others (like the Bio Supply Management Alliance I mentioned last week) on one hand and the WHO PQP and the NRAs of the rest of the world and given the right framework these groups may cooperate to build a better international registration system, one that provides a path and an incentive for the development and registration of NDDs.  I can see an upgrading of the PQP with regulatory expertise from stringent NRAs and industry to create an alternative path to country-by-country registration with the “qualified” products and manufacturers being eligible for purchase by “qualified” buyers, which would be any government or group able to commit to negotiated volumes and prices.  Another close-to-international registration program for NDDs could result from cooperation between the PANDRH mentioned above and the Pan American Health Organization’s Revolving Fund mentioned in my post, “More Bang for the Buck”.  Clearly, I need to do more research on this idea and get others’ input (policy wonks, speak up), but think it has merit.

See Change

The 15,000-plus presenters, exhibitors, politicos, scientists, execs, salespeople, and hangers-on who attended last week’s Bio Industry Organization’s (BIO) 2012 International Convention here in Boston have all returned to their regular jobs and I am back to scribbling this week’s post at the last minute.  The BIO convention (as is the nature of conventions) is all about selling products, making the connections that will lead to sales, and learning where the next sales may be made, so most BIO 2012 attendees were focused on the serving the health needs of those with high incomes, but this year I noted some change in the sea of selling.  By my casual survey of session descriptions and attendance and conversations with attendees and exhibitors, more interest was shown in opportunities outside the major markets than in the half-dozen conventions I have attended before.  Moreover, I noted investment analysts, execs, venture capitalists, reporters, and scientists (who invent and make products), not only non-profit types, participating the out-of-the-main-channel sessions.

Here’s a recap of the sessions I noted, seven of which I was able to attend:

  • Driving Innovation in Global Health:  Why Biotechnology is Key-  I did not attend this press briefing by BIO Ventures for Global Health (BVGH), the advocacy organization partly backed by BIO itself, at which the group brought attention to its finding that 40% of small-medium biotech companies are conducting some type of global health product development (I reviewed this report in my post, “BD Needy”).  I hope they got good attendance.
  • A Practical Guide to Global Health:  Shared Experiences from Biotech Companies on Making Global Health Work for You-  I commented on this session, also organized by BVGH, in last week’s post and add that the “shared experiences” were fine but a “practical guide” it was not (but I hope one is in the works).
  • Global Biotechnology Forum:  The BRICS and Beyond-  another session I missed but its theme was how governments in emerging market countries are supporting biotech companies (including funding) to address pressing health needs, and attendance list was more than 50 persons.
  • Exploring Innovative Models for Investment in Global Health:  A Discussion about Unique Partnerships in Working Towards Solutions for Global Health-  I’m sorry I missed this session since it explored “the various models available for engagement with these funding groups [venture capitalists, governments, non-governmental organizations, and companies] in the development of vaccines, therapeutics, and diagnostics and how companies are working across these funders to develop new models for investment in global health.”  About 50 people had signaled an interest in attending.
  • Vaccines Beyond 2012:  Sustainable Business Solutions to Accelerate Global Access- as I noted in my comments in last week’s post (“BIO Bits”), Sanofi’s commitment to global health and pediatric vaccines was evident at this session which had about 40 attendees including those from major (e.g., Merck) and biotech companies (e.g., Novadigm).
  • Increasing Cancer Drug Availability in Resource-Limited Settings:  Models for the Future-   as I noted last week, the situation is dire and requires innovation in funding and distribution, not so much new drugs (which compose the major of drugs being developed by the US pharma/biotech industry).
  • Leveraging New Development Paradigms to Address Infectious Diseases in the 21st Century-  this session (another I missed) addressed the need for new vaccines that can be made quickly (and cheaply) against agents with multiple variants.
  • Traditional Manufacturers Beware: How Disposable Technology is Changing the Biomanufacturing World-  this session spoke to the shift of the biomanufacturing industry (makers of vaccines and biological drugs) away from large volume, high capital factories to small volume, regional, and flexible (able to make many products) plants.  As I have written in several earlier posts (e.g., “More Grease on the COGs”), this trend is important in lowering the cost of products as well as addressing the public health needs of developing countries.  In a side conversation with a rep from Xcellerex, a disposable technology company recently purchased by GE Health, I learned their sales team has made and is making sales calls all over the world.
  • Innovative Approaches to Financing R&D for Global Health-  as noted last week, I had hoped to learn more about the Gates Foundation’s program-related investment program, now funded to more than $1 billion (to used for all the Foundation’s interests including global health), but was disappointed.  The program could be structured like an investment firm, doing due diligence, making significant inputs, gaining board seats, and in general being more proactive in starting up global health companies.  Perhaps the other 30 or so attendees learned more than I.
  • Biologics and Biosimilars in Latin America:  Are New Regulations and Guidelines in Brazil, Mexico and Argentina a New Model for Drug Regulation?:  biosimilars is a hot button issue for the industry since the established players want to limit competition (e.g., Amgen has a Director of Brand Protection) and the emerging biotech industry wants a piece of the action (and governments want cheaper drugs).  I assume (wasn’t there) the new regulatory policies spell out what level of proof is needed for establishing “similarity,” likely including some number of trials and manufacturing process approval, but not as high a barrier as that recently set by the USFDA.
  • Emerging Markets Become Strategic Markets:  Biotechs Looking Internationally for R&D, Manufacturing, and Market Opportunities-  another session I missed and based on my review of the almost 100 prospective attendees, there was a lot of interest among reps from companies in the mid-income emerging market countries like Russia and Brazil as well as US and EU companies looking to sell into these markets.
  • Building the Global Pathway for Product Safety and Quality Manufacturing of Biologics and Drugs- I attended this session because of the importance to companies that want to sell products outside their home country.  The session turned out to be quite technical but I came away with an appreciation of the complexity of the global supply chain for drug manufacture (80% of the drug ingredients for US drugs come from outside the US) and the need for better and more universal standards and inspections.  FDA, multinational pharma companies, and a logistics trade group (Bio Supply Management Alliance) are working on this but have a long way to go.
  • Thinking Outside the Box:  A New IP-Sharing Model Brings Biopharma, Government Agencies, and Non-Profits Together to Accelerate R&D Collaborations for Neglected Tropical Diseases-   the new sharing model was the BVGH-managed Re:Search database and partnering “hub” on which I have written previously (“Window Dressing”).  I garnered some new information on Re:Search, e.g., no announced partnerships have yet resulted but 15 are in discussion.  I also learned that a relatively new product development program (PDP), the Center for World Health and Medicine at St. Louis University, was making progress in new therapies for neglected diseases (and rare diseases) but is approaching a funding crunch.

Do fourteen sessions (including mine) on neglected diseases, emerging and public markets, and low-margin products out of 125 offered at BIO 2012 and several hundred attendees out of 15,000 indicate a sea change in the biotech/pharma industry?  No.  But the trend is in the right direction.

Climatic Change-Up

I’m not a fan of baseball, either to play (too slow) or to watch (really too slow), but over its 150-year-plus history its enthusiasts have generated an interesting lexicon.  A change-up pitch, as I learned from my more learned colleagues, is a slower-than-expected pitch that fools a batter into swinging early.  In a mix metaphors, I note that we here in New England are experiencing a climatic change-up with warmer-than-expected winter and spring, and, while I realize that our local change-up is only a small piece of the global climate, my global health alarm rang when I read that the incidence of dengue fever has increased a whopping 30-fold since the 1960s (WHO fact sheet) and one factor in the increase may be increases in rain and temperature brought by climate change (Intergovernmental Panel 2007 report).

Dengue is a mosquito-borne viral infection that causes fever, headache, muscle and joint pain, and a characteristic rash and, in a small proportion of cases, develops into a lethal hemorrhagic form.  WHO currently estimates there may be 50-100 million dengue infections worldwide every year and 15-25,000 deaths.  It is a leading cause of death in children in some Asian and Latin American countries and is considered to have an impact on global health similar to tuberculosis.  Defending oneself immunologically is challenging because there are four distinct, but closely related, serotypes of the virus and, while exposure to one provides immunity against that particular serotype, subsequent exposure to other types increases the risk of developing severe dengue (WHO fact sheet and Wikipedia article).  So more water and warmth, more mosquitoes, and maybe more severe dengue.  To add to the unpleasantness of dengue, there is no specific treatment and the carrier mosquito, Aedes aegypti, prefers to feed on human blood rather than that of other vertebrates.  The best defense to date has been a good offense via mosquito control measures like insecticides, reducing standing water, and bed-netting.  Dengue occurs in 110 countries, but in only a few places, like the US Gulf coast, have the control measures kept it completely under control.

It’s time for science to come to the rescue, and, as in the world’s response to HIV/AIDS, malaria, and tuberculosis but without the publicity and celebrities, researchers in academia, governments, and companies have been working on a vaccine.  There are currently eight products in clinical trials sponsored by the NIH, Merck, Inviragen, GlaxoSmithKline, and Sanofi Pasteur (see Dengue Vaccine Initiative development).  Sanofi’s ChimeraVax is in the lead with Phase III trials starting late in 2010 and a possible launch in 2014 (FierceVaccines article).  The Sanofi vaccine is quite impressive technically in that it is a live, attenuated (infectious but not disease-causing), “recombinant” virus in which the envelope protein genes from the four types of dengue viruses have been used to replace the corresponding genes in the yellow fever virus (both are the members of the same viral genus) (Guy et al. 2011).  And Sanofi has trod a long path, conducting trials in about 6000 persons in many countries (Mexico, Colombia, Brazil, Honduras, Puerto Rico, the Philippines, Indonesia, Vietnam, Singapore, Australia, Thailand, and Malaysia, Sanofi press release), and, at least according to its corporate responsibility site, is trying its best to have a successful launch:  “Sanofi Pasteur collaborates actively with the WHO, national governments, payors, and NGOs (Dengue Vaccine Initiative, Bill and Melinda Gates Foundation, Sabin Institute, etc.). These efforts aim to reduce insofar as possible any delays that might stand in the way of introducing the vaccine quickly once it has received authorization from national authorities” (Sanofi CSR).  But, as it is well-known, it is the pioneers that get shot by the arrows, and it will be interesting to see if Sanofi can avoid being scolded or worse by the various global health “advocacy” groups as it tries to recoup its substantial investment in a vaccine for a disease with almost no first world market.

Several problems loom.  One is Sanofi meeting demand for the vaccine.  The company has built a new plant with a 100 million dose per year capacity, but a study by the International Vaccine Institute estimnated an “upper limit” need of about 600 million doses per year for the first five years (3 doses given over 12 months to children under the age of 12 years, Amarasinghe et al. 2010).  A second loomer is that of pricing which Sanofi is likely negotiating with potential buyers now, but very quietly.  Third, the success of any vaccination program depends heavily on other players like governments, donors, and NGOs to:

-gather epidemiologic data that are needed to vaccinate the right populations;

-include the vaccine in national vaccination, control, and awareness programs; and, of course,

-pay by financing the budget needed for consumables, infrastructure, and training.

Lastly, Sanofi has a substantial task in conducting Phase IV trials to monitor safety, since there is a small possibility that the vaccine may mutate to a virulent form or increase the chance of the natural virus causing the hemorrhagic syndrome (Guy et al. 2011).  In the self-promotion department, I note that I think one of the key executives navigating these shoals is Alan Watson, Sanofi’s vice president for Vaccination Policy and Advocacy, who has kindly accepted my invitation to participate in a panel I am organizing for BIO 2012 called “Accelerating Access Public Sector Markets” (June 18 at 3:30 PM if you are there).  And the effect of the climatic change-up on the use of vaccines to reduce the impact of dengue is unknown.

Historical footnote:  the route from ChimeraVax concept to product has been a long one.  In the late 1990s, the idea and technology was invented by Thomas Chambers of St Louis University and scientists at OraVax, a Cambridge, MA, company founded in 1990.  Shortly OraVax licensed the university’s rights in 1999 (PR Newswire story), it was acquired by Peptide Therapeutics of Cambridge, UK, and the joint company was renamed Acambis (Inknowvation entry).  Acambis successfully completed a Phase I clinical trial of the dengue vaccine in 2002 (Vacination News article), I was interviewed but not hired for an Acambis business development position in 2005, and Sanofi partnered with Acambis on its ChimeraVax vaccine for West Nile fever in 2007 (FierceBiotech article) and acquired the company for $565 million in 2008 (another FierceBiotech article).

NTD TD

While viewing audience for the upcoming Souper-duper Bowl is likely to exceed 100 million, 16 times more people are afflicted with the world’s most disabling and disfiguring diseases, the “neglected tropical diseases” (NTDs).  These 1.6 billon and another 2 billion people at risk of infection are the target audience for last Monday’s “Uniting to Combat NTDs” meeting, a notable convocation of representatives of pharma companies, health agencies, disease advocacy groups, foundations, and governments (about 20 in all) who agreed to participate in the WHO-guided effort to substantially eliminate the NTDs by 2020 (Press release at FierceBiotech).  NTDs (ascariasis, hookworm infection, trichuriasis, lymphatic filariasis, onchocerciasis, dracunculiasis, schistosomiasis, Chagas disease, human African trypanosomiasis [HAT], leishmaniasis, Buruli ulcer, leprosy, and trachoma) are diseases of the impoverished, 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).  Fortunately, most can be treated effectively by inexpensive drugs.  But despite large qualities of donated drugs, foundation funding, advocacy and NGO participation, and several notable successes (e.g., 670 million receiving preventive treatments annually, elimination of onchocerciasis in West Africa, and 60% decrease in the incidence of HAT), according to the WHO (WHO 2010 Report) and critics (e.g., Molyneux 2010), the neglected diseases were still neglected.  (Additional background is in my previous post, “Brother, Can You Spare a Dime (or Five)?”  2/24/11.)

The attendees of the meeting agreed to WHO’s playbook, “Accelerating Work to Overcome the Global Impact of Neglected Tropical Diseases” (Roadmap for Implementation), but how will they score?  Here’s my play-by-play:

Expanding current drug treatment:  ten pharma companies (Bayer, Eisai, Gilead, GlaxoSmithKline, Johnson and Johnson, Merck and Co., Merck KgA, Novartis, Pfizer, and Sanofi) will expand their donation of 14 drugs in quantities sufficient to treat almost everyone who needs it through 2020.  The pharma industry trade group, the International Federation of Pharmaceutical Manufacturers and Associations, stated that the donations will amount to 1.4 billion doses per year, a substantial quantity (IFPMA press release).  The cost to the companies will be about $70 million per year, excluding opportunity costs, based on my guess of a $0.05 per tablet cost-of-goods (Wikipedia article on generic drugs).  A cynic will note that this is less than 2% of the $4.3 billion the multinational pharma companies spend each year on advertising in the US (FiercePharma article), including those 30-second spots for drugs for erectile dysfunction (not an NTD) we’ll enjoy when not watching the action during Sunday’s game.

Development of new treatments:  11 pharma companies will agree to provide the leading NTD non-profit R and D group, the Drugs for Neglected Disease Initiative (DNDi), access to compounds and data for testing for activity against the NTDs, and DNDi and several companies will continue their collaborations on possible treatment.  The companies gave no specific dollar amount for their commitment to spending on NTD research, although the GFinder survey, which tracks global health spending, reported that companies’ spending on both internal and external NTD R and D was about $400 million in 2009 (GFinder 2010 report) or about 0.5% of the total $70 billion pharma R and D spend (Reuters article), not strong offense.  For a critique of the WHO approach as being heavy on treatment and light on research, see Patrick Adams’ posting of last November (Tropika blog).

Funding:  the ever-generous Gates Foundation pledged to kick in another $386 million and the USAID ($90 million for FY 2012) and UK’s DFID ($200 million through 2015) ponied up as did the Lion’s Club International, the government of the United Arab Emirates, and Mundo Sano, a privately-financed NTD institute in Argentina.  More money is great; however, I note that, according to an NTD researcher and advocate (Molyneux 2010), only 0.6% of all international health development assistance is aimed at NTDs so one could argue the funding is not in proportion to their impact and more is justified.

On the ground:  the biggest challenge in tackling the NTDs has been operational.  Weak public health systems have typically been by-passed and marginalized by the aid groups, so critics have questioned the long-term effect and benefit of the NTD effort (e.g., Morris 2010).  The meeting’s most promising announcements were specific goals for NTD control and elimination set by the government of Mozambique and the statements  by the governments of Brazil, Tanzania, and Bangladesh that they will implement of plans to control and eliminate NTDs in their countries.  But as far as I could find, the Roadmap has no mechanism for reviewing, monitoring, supporting, or participating in these plans or the plans of the other 70 or so NTD-endemic countries.  According to the meeting press release, “partners will follow collective progress through a scorecard that will regularly and formally track progress including whether participating organizations are meeting their supply, research, funding and implementation commitments,” but the process is not provided in the Roadmap which defers to specifics given in an unpublished WHO report of an April 2011 meeting (Roadmap, page 2).  Ultimately, public health is the responsibility of the governments and without some mechanism for monitoring performance in providing treatments, vector control, and improvements to water and sanitation, governments will not be accountable and the goal of NTD eradication will not be met.  In response to the meeting, the well-respected global health group, Médecins Sans Frontières, cheered for its intent but was concerned WHO was underplaying the challenges, especially for Chagas disease, sleeping sickness, and leishmaniasis, noting more support for in-country programs and product development is needed (MFS briefing).

My half-time analysis:  WHO’s team leads the NTDs by a field goal, but it’s going to be a tough second half.  It should up its game and not be allowed to punt.

Too Big to Flail

In the biotech world, the acquisition of a company by another is an occasional but newsworthy event since it typically means that the acquired company has succeeded in creating sufficient value that an acquirer is willing to pony up significant cash (and/or stock) to buy out the acquired company’s founders and investors (e.g., Takeda’s recent purchase of Intellikine for $300 million plus, Fierce Biotech article).  And since the IPO market is pretty well closed to biotechs, acquisition is the primary way the investors can get their money out of one company and into others, thereby recycling capital in the entrepreneurial ecosystem.  But what does it mean when one granted-funded, global health product-oriented organization acquires (absorbs?) another?  An alert colleague brought to my attention the recent announcement that OneWorld Health (OWH), which calls itself the “first nonprofit pharmaceutical company in the U.S.” (OWH History), was becoming an “affiliate” of PATH, the Gates Foundation’s favorite conduit for global health technology development (PATH press release), or according to one source was being acquired by PATH (Humanosphere blog).

The PATH press release provided no clarity on what had happened and why, although it is clear OWH’s CEO, Richard Chin, is out.  But what will OWH do as an affiliate of PATH, who directs the programs and funds, does the hiring, calls the  shots?  Is the move driven by synergy?  Lethargy?  The PR language is opaque:  “By becoming a PATH affiliate, OneWorld Health will be able to scale and accelerate its successful drug development efforts,” which sounds to me like the plan will be to get rid of unproductive people and programs, which is often part of a for-profit acquisition.  OWH has always been a puzzlement to me since it called itself a pharma company but has never acted like a business, with a plan and accountability to its investors.  I reckon it is a global health product development program (so-called PDP), a grant-funded, primarily research-oriented, and academically-advised organization with a mission to develop new diagnostics or treatments for neglected diseases- a welcome addition in global health but not a company (for more on PDPs, see the DFID 2020 PDP report).

In one of my 2010 posts (“The Emperor’s New Clothes,” 6/17/10), I noted, while the OWH has been successful in garnering grants since its 2000 founding, more than $150 million primarily from the Gates Foundation and the UK’s Department for International Development, the organization had not developed and commercialized any drug (not-withstanding statement in the PATH press release, “OneWorld Health has a successful track record in developing and delivering effective, affordable drugs,”).  OWH’s lead product, an injected version of paromomycin, an off-patent aminoglycoside antibiotic, for treating visceral leishmaniasis (VL), a protozoan parasitic disease, had been approved in 2006 but its sale has been on hold pending completion of a “Phase IV demonstration program” to determine if the drug can be delivered and be effective in rural conditions.  I also noted according to the only financial data then available, a Form 990 which the IRS requires all 503(c) non-profits to file, OWH spent about $30 million in 2008:  $7 million on salaries, $3.7 million to its law firm, $1.3 million on travel, $7.6 million in contract labor and services (which, I am guessing, is for R and D), paid a “professional fee” of $2.7 million, and gave $5 million in grants yielding an uninspiring overhead rate of 50%.  In my post, I also noted that OWH had won a lot of awards and was offering two product tie-ins, a video camera and a charm bracelet charm.

I revisited the OWH website to see what has changed over the past year and half that may explain the PATH take-over.  The website is re-designed (as of June), the product tie-ins are gone, and apparently the lead drug is still in testing.  A November press release announced that OWH will be part of a new consortium with the aim of “establishing and implementing new treatment modalities as successful tools to support the elimination of VL in South Asia’s most endemic regions.” Then, “Upon completing the study, a feasibility report will be published, which will include recommendations for the private sector engagement using new treatment modalities,” more paperwork and no delivery (OWH press release).  As for financial accountability, OWH is still not doing annual reports, relying instead on the Form 990s to provide a snapshot of its finances.  The most recent (OWH 2010 Form 990) shows no financial problem:  expenses did not exceeded grant “revenue” ($27 million in and $19 million out for salaries, operations, and grants) and there is $26 million in assets “in the bank.”  And its large executive team was well-paid.  OWH also reported that CEO Chin got $400K in compensation and the top 10 salaried employees earned about $200K each.  I can’t help but note that, since the cost of treating one person with VL with the OWH drug is $20 (another OWH press release), for the cost of one its top-ten compensated employees, OWH could treat about 10,000 cases of VL, which is about 2% of the 500,000 new cases each year, possibly averting about 20% of the annual 50-60,000 deaths.

So what’s up with the acquisition?  Maybe someone in the Gates Foundation (like Trevor Mundel, the new head of global health, see my post, “Free Advice, Trevor,” 10/6/11) realized that OWH had not much to show for the $150 million it had received, that Dr. Chin was not a good choice for a CEO, or that OWH’s administrative expenses could be cut, fewer studies done, and more could be done to get a treatment to the people with VL.  As an indirect investor in both organizations (through the tax code and government grants), I’d like to know the rationale for and the expectations of the new OWH-PATH affiliation, but, unlike the acquisitions among for-profits, they are not obvious.