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More from the Drugs for Neglected Disease Initiative

My recent post on the Drugs for Neglected Diseases Initiative (DNDi) brought some emails from Robert Don at the organization. He has more details on the sleeping sickness project – pointing out, for example, that the contribution from Scynexis was not pro bono, as I’d assumed:

We actually contracted a team of 10 chemists at Scynexis for over 4 years at 320,000 USD per FTE p.a. plus additional for extraordinary expenses such as expensive starting materials. We also employed independent consultant medicinal chemists to challenge the team. They worked on a number of hit to lead projects but the contribution to SCYX7158 was the majority of the team for around three years. . .In addition we assigned all IP to Anacor and increased the size of their library with 20-30 FTE years of well annotated compounds. We retain a license to use the results for neglected diseases in our kinetoplastid disease portfolio. Since then, Anacor have also contributed very significantly in their own right to discovery research for neglected diseases in our portfolio as well as many not included in our portfolio.

I’m going to make a note of this in the earlier post as well. He he also provided many more details on how DNDi is trying to do what they do, and I thought I’d pass those along for comment as well:

Our ultimate goal is to provide modern medicines to neglected patients. We have short, medium and long term strategies and as you correctly stated we repurpose drugs, look for geographic extensions, prove and disprove the efficacy of treatments currently in use etc. In fact we look to any incremental change which can improve the lot of these patients in the shortest possible time. Our long term goal is development of field-suitable NCEs together with a guarantee of access to them. To ensure accessibility we seek an industrial/pharma partner who will file for marketing authorization and involve them from early in the development phase. These agreements delink the cost of research from that of manufacture and distribution. They ensure a low cost to patient and a small profit to the partner. We want sustainability and do not advocate agreements in which any player stands to make a loss e.g. donations. 
To delink the cost of R&D we need to find mechanisms for R&D in which the cost is not borne by the industrial partner – although we welcome any contribution if they are willing to do so. 
Fair enough, although those last two sentences might, at times, come into conflict. The next part of his email gets at the main problem I have with the publicity that often attaches to the DNDi efforts, the idea that they have some sort of cost-cutting magic when it comes to discovery and development. Here’s Robert Don again:
We do not harbor any pretension that we can do the science/black art of medicinal chemistry any better than an industry which has been locked in competition for decades although I must admit that when we employed our head of discovery he did say that if he proposed nitroimidazoles as anti-infectives he would receive a severe warning if not dismissal by his previous employer and to follow that by fiddling with oxaboroles would definitely be a career limiting move. (We have one of each in GLP tox for leishmaniasis but the pipeline of candidates, leads and lead series behind is much more conventional)
The nitroimidazoles would, I think, mostly be a problem because that area has been worked on so extensively over the years (and because the limitations of these compounds are well-known). Those include a number of side effects that limit patient compliance in less serious diseases – headache, dizziness, nausea, and especially severe reactions if taken with any alcohol. Other members of the nitroimidazole class are suspected carcinogens on long exposure and have been banned from animal feed and some other applications. So no, if you’re not working a severe and intractable tropical disease, a nitroimidazole may not be the best call, but at the same time there are a whole list of them in clinical use.
The oxaborole is another interesting case. It’s absolutely true that such boron compounds get the fishy eye from many medicinal chemists (although the success of Velcade did vindicate the idea that boron-containing therapeutics could be useful). GlaxoSmithKline, though, was willing to do a development deal with Anacor for a broadly similar boron-containing antibiotic candidate, though, so it’s not like everyone runs away automatically.
We screen both pharma and commercial libraries and place no financial value on these assets but do pay all screening costs. We do however appreciate their inestimable scientific value. Following screening, all pro bono work (hit to lead, DMPK, tox and CMC) is fully costed by our partners and included in our financial reporting as in-kind income and expenditure.
The core and bulk of my budget is medicinal chemistry, ADME, toxicology and CMC at the same CROs as contracted by pharma and at the same cost. It is supported by in-house medicinal chemistry and parasitology expertise, contracted medicinal chemistry support and retired mentors. 
Savings are made through novel partnerships. For example a multilateral agreement between five pharma covers much of our hit to lead at very little cost to them and us and in a period of a few months we get SAR around hundreds to a thousand plus compounds for each hit. (Don mentions that a manuscript on this process has been submitted – DBL). We also save considerably by not competing. We are not the only player in the field and if we become aware of others working in the same area we share our experiences and this is reciprocated by other PDPs. Our nitroimidazole currently in GLP tox grew out the TB Alliance program which yielded PA824. Within the industry for example, how many advanced DAA programs for HCV were dropped because one company got to market and a couple of others had good second generation pipelines? We have the capacity to go from screen to NDA and the only failures are scientific – never commercial.
Exactly – since DNDi is not a commercial organization, competing in commercial markets, those considerations don’t apply, and that is indeed a savings. But I do have to bring up the flip side of commercial competition. In HCV, the situation wasn’t that everyone else dropped out because one company got to market – that’s not how it works. Two companies got to market, and after that happened Gilead was able to make it through with a combination therapy that the first two (and many others around the industry) were also trying to put together. This combination was, in fact, superior to the earlier iterations, and some companies dropped out of the area because they felt that they money was better spent elsewhere than trying to beat what was, in fact, a very good therapy. But even so, Gilead still has people coming after them with competing products, and the only way those will get a foothold in the market will be if they’re very effective themselves. The end result is that HCV patients benefit from some highly optimized therapeutic options, far better than they had ten years ago.
So what I’m trying to say is that sufferers from tropical diseases not only are being harmed by a market failure when no one is developing a drug for their condition – they’re also being harmed by a market failure when only one drug is being developed. That’s a lot better than no drug at all, God knows, but if this were a viable commercial market the situation for the patients would end up being better yet. Having a number of companies going after the same market is (from one perspective) wasteful, but at the same time, anyone who does drug discovery for a living knows well that it’s impossible to say which approach (and which drug even inside one mechanistic class) will prove to be the best. The only way to find out is to get them into patients, which costs a good deal of money. Some will work, and some won’t, and among the ones that work, some of them will definitely be better than others. And even among those, some patients will respond better to one drug, and some to another.
But I want to finish up with another quote from Don’s message:
In addition to providing modern relief to neglected patients, DNDi is a test-bed for new forms of collaboration between all players in the business of drug R&D. It is my joy to have tremendous freedom to experiment with this and my hope that some outcomes may stimulate a broader discussion on how we might reduce the costs for all drugs in a sustainable manner. I would certainly welcome any ideas, suggestions or offers from you and your readership on how we might constructively challenge the status quo.
I’m fine with that, of course. And I know exactly what he’s talking about when he mentions the joy of being able to freely experiment on an important topic – I’m glad that DNDi is doing what they’re doing. The only thing that’s irked me is the publicity around them that has suggested (at times) that if the rest of the industry weren’t so greedy and slow that they could do things the exact same way. I still don’t think that’s true, but I would second the call above for new ideas about how best to do what they’re actually doing.

10 comments on “More from the Drugs for Neglected Disease Initiative”

  1. Anon says:

    Unfortunately, market potential is defined by *ability* to pay, not just unmet need, or even willingness to pay. And in some areas, people just don’t have the money to cover the basic R&D costs let alone allow any kind of profit.

  2. fish eyes says:

    another benzoxaborole … GSK2878175 has good HCV coverage (EC50 ~ 1nM) and excellent human PK (14-day study in healthy humans). the only problem was that it was late getting to the party.

    249th Am Chem Soc (ACS) Natl Meet (March 22-26, Denver) 2015, Abst MEDI 38
    Title: First structural disclosure, discovery, preclinical characterization, and FTIH pharmacokinetics for GSK2878175, a second generation boron-based inhibitor of the HCV RNA-dependent RNA polymerase

    http://www.gsk-clinicalstudyregister.com/compounds/gsk2878175/rs/#

    .

  3. Dionysius Rex says:

    Why the hell did they pay so much for a US CRO when could get equivalent quality in the EU for less than half that?

  4. anon the II says:

    This was a long and informative post. Unfortunately, I don’t really remember much of it because the whole time I was reading it I, like Dr. Rex, was thinking, “Did they really pay $320K/FTE/year?”

    I thought the going rate peaked at $250K before the job market starting falling apart for chemists in the US.

    When I worked at Scynexis, given my salary, that would have left a lot of room for profit.

    1. Xplodyncow says:

      Maybe the $320K includes salary as well as a fee to Scynexis for letting DNDi “borrow” scientists?

    2. Wei says:

      Could be wrong, but I understand the 320k/year to include salary+research costs (consumables/equipment/instrument time)

      1. bad wolf says:

        Overhead for contract research adds up quickly. Industrial positions I had in the past estimated having a chemist and a bench cost the company at least $250k/yr, and that was many years ago with me getting a pretty modest salary.

  5. Magrinho says:

    Fully burdened cost of $320K per year is old school + inflation.

    When med chem outsourcing to US biotechs was in full swing (late 90s), the biggest number I saw was $275. Typically, the spread was $225(offered) and $250(asking price).

    Today, ex-US CROs (mostly China) are making money by charging $80-100K per FTE.

    Depending on site, fully burdened costs (divide total costs by number of scientists) within big pharma tend to be about $200-225K. Lots of variability in how you calculate that number but you can’t get to $100K!

  6. MFernflower says:

    Boron seems like a promising area to explore, but it will be out of reach for many academic institutions until the process and reactions simplify and cheapen

  7. tangent says:

    Tangentially to the subject at hand, I looked up tavaborole, which is approved for toenail fungus. After daily application for a year, their primary endpoint “complete cure” is, in two trials, 6% or 9%? Even understanding that this is a stubborn infection, my mind is pretty blown that this is a good result. Wikipedia adds that a 10ml bottle runs $1359 per empr.com.
    http://www.jaad.org/article/S0190-9622(15)01512-1/
    (The study has various other endpoints I don’t really follow — “negative mycology” seems like that should suffice but no?)

    So wow. Yeah. Tough job. What the hell compartment is that fungus hiding out in?

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