Author Archives: kyleserikawa

Reining in Hyperbole About the Role of Drug Development

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All opinions expressed are my own and do not necessarily reflect those of Novo Nordisk

“The traditional pharmaceutical research and development operating model is no longer sustainable,” says Dennis Liotta, PhD, founder of the Emory Institute for Drug Development (EIDD) and co-inventor of multiple approved drugs. “The marked decrease in the development of new therapeutics is having a uniformly negative effect on global health and threatens life expectancy, quality of life, economic development and national security. Emory’s new public-private enterprise is a bold new approach that can help solve this problem.”  From a press release from Emory University

Yesterday Emory University announced the creation of a non-profit entity, Drug Innovation Ventures at Emory, LLC (DRIVE), that aims to take discoveries made by Emory scientists and bring them to the point of proof-of-concept clinical trials.  I think this is a great idea.  While this press release is what I would call a bit overstated (while at the same time understating the real problems involved in translating discovery science into actual drugs), drug development is in need of different ideas and different approaches, and I’m all in favor of various organizations trying different things to develop drugs.  I’m also in favor of any system that gives academic researchers exposure to the steps leading to a lead candidate drug.

What concerns me, though, is the quote above.  Again, this is a press release and some hyperbole is to be expected, but at the same time is it fair to say that the reduced number of new drugs being developed is having a “uniformly negative effect on global health?”  Digging into DRIVE’s webpage, it’s clear the organization plans to focus on viral diseases, which makes the connection to global health direct.  However, I can’t help thinking that there’s a lot more involved in helping the health of people in developing countries than new vaccines and antivirals, and that while new drugs could help, the lack of new drugs doesn’t condemn those populations into some kind of downward spiral.  I doubt Dr. Liotta meant this explicitly, but his comment supports a view of a specific kind of technological innovation–drug development–as providing a cure, when I’d rather see expectations managed with a little more circumspection.  I think the industry suffers when presenting cures as being accomplished with a simple pill or a shot.  Many times, maybe most times, health problems are best viewed as the result of multiple, intertwined factors, of which biology is just one.

The Global Alliance for responsible sharing of genomic and clinical data: an Asilomar conference for today?

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All opinions are my own and do not necessarily reflect those of Novo Nordisk

I’ve been mulling over the recent announcement by several prominent genomics organizations of a set of standards for the generation and sharing of genomic data.  This is a fantastic development in the field, and one with great implications for the future of genomics data research.  It’s also particularly apropos given the recent news that the US government has been collecting internet-based metadata broadly, in a previously secret program to detect signs of terrorist activity.

People are waking up to the idea that we all produce data of all kinds, and that advances in technology now make gathering that data as easy as getting wet in the Seattle winter.  Whether that data is created digitally and automatically throughout our day-to-day life, or via an action as simple as sending a cheek swab to a company, there are some deep questions that are just beginning to be asked, by the government and other organizations, as to how the use of these data best serves the public good.

As a UC Berkeley graduate student in the late 80s and early 90s, I heard the lore about the Asilomar Conference on Recombinant DNA.  I think it was part of our standard indoctrination package, along with instructions on how to navigate Telegraph Avenue and reasons why Berkeley was superior to Stanford and UCSF.  That conference, in the early days of the age of gene splicing technologies, was an amazing example of self-regulation by a group of scientists who had the forbearance to actually stop and think about the possible implications of what they were doing,  The Asilomar conference led to a set of standards for the practice of recombinant DNA technology, and an overall greater mindfulness of what we were actually doing when we moved genes around among organisms.

The announcement of the Global Alliance has a similar flavor to me.  Again, technological advances have opened a huge window of potential research opportunities that were not possible before.  The implications, however, will be unclear for quite some time, and the effect that cheap genome (and other kinds of) sequencing will have on research, public health, ethics, medicine, and many other fields is unknown, other than that it will be huge.  We were already seeing the beginnings of chaos in terms of data repositories, standards, and practices, but this Alliance suggests that, at least at the level of key players like the Broad Institute and the Wellcome Trust, there is a commitment to taking  a step back and trying to find a good answer to the question of how to do this well, to best serve the public good, and to try to minimize harm.

I wish them luck.

Supply chains in Drug Development?

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This is a response I made to a recent post at Xconomy about the idea of drug development adopting a supply chain approach.  http://www.xconomy.com/san-diego/2013/05/31/test-the-supply-chain-model-this-market-driven-relationship-is-a-fail/.  All opinions are my own and do not necessarily reflect those of Novo Nordisk.

I really appreciate the ongoing conversation about how to fix the problems that appear to be facing drug development–specifically a lack of truly transformative, life- and health-changing new drugs.  I think the idea of a supply chain process in drug development is worth looking at.  However, I am not convinced it will actually fix the problem.

In this piece, Standish Fleming suggests a market driven process isn’t meeting the needs of drug development because the potential suppliers in the market (the startup biotechs) don’t have a clear view of what the eventual buyers (the pharma) really want as part of their strategic goals.  Alignment is often a good thing.  I believe many startups may not have a clear idea of what actually constitutes a good drug as many of them arise out of academia. This is not a criticism, just a statement of how the academic and industrial systems have different cultures, goals and knowledge bases. I also appreciate the point that, with capital harder to get via venture funds, pulling pharma in to replace that investment at an earlier stage requires some sacrifice of control on the part of the biotech, with a corresponding gain in risk sharing and predictability.

But I don’t think alignment is enough.  I worry instead that the key problem is one that’s been suggested by David Shaywitz and others–we just don’t understand enough about diseases to make the next generation of drugs.  It seems that the buyers themselves don’t have a clear idea of what is most likely to make a good drug.  As evidence, I’d suggest that if pharma really knew what they wanted, failures in Phase I-III would be far lower since drugs would never be tested in humans until pharma were sure of an 80-90% success rate.  Baseball aside, a 30% or lower success rate generally doesn’t make for a good business strategy, but that’s what we’ve got.  And I agree with the point that there are a lot of smart people working on the problem across pharma, so it’s not just a question of brainpower.

If pharma can’t easily predict what kinds of drugs will succeed, then this model may just swap out VC funding for pharma funding with the same net effect.  Also, the development of a drug is an incredibly long process.  For a pharma to be able to predict the market ten or more years ahead of time is adding another uncertainty yet.

Since I live in Seattle, I’d like to throw out the analogy of the Dreamliner.  A key reason the Dreamliner exists is because of 9/11.  Before that, Boeing was designing a supersonic passenger jet.  After 9/11, the pressure for nations to become more fuel-efficient to allow less involvement in the Middle East led Boeing to change course and design a plane that would instead be a model of efficient design.  So there’s an example in which changes in the market outside of a company’s control can render all its best plans moot.

Another point about the Dreamliner is that that project relied on a supply chain that ended up delaying launch for over a year.  I know people at Boeing and they have good project managers and good communicators and they told their suppliers exactly what they needed, and problems still arose.  Ever after launch, unexpected issues with batteries grounded the jets again.  How much messier might a supply chain relationship be between biotech and pharma?  Can deadlines and milestones be guaranteed when we won’t know until Phase I if we’re dealing with the next best thing in air travel or a flaming battery?

All this is not to say it couldn’t work; just that I’m skeptical.  I agree the current method seems inefficient and difficult to make work in the current funding environment.  I just wonder if maybe there is a third way.  Now, if only Bill Clinton could get into drug development…

Sea turtles: Nature’s smartphone

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The recent publishing of the green sea turtle genome brought back memories of my first encounter with baby sea turtles, and one of the most fun and astonishing examples of hardwired behavior I know of.  I had the good fortune to travel to Heron Island in the Great Barrier Reef during my undergraduate days.  We were there in March and April, the Down-Under Fall, when the sea turtles hatch and begin their journey to–well, to be eaten, frankly, although a few percent do make it to adulthood.

The first nest that I saw hatch emerged in the afternoon on a rainy day.  Normally sea turtles come out of the nest and make their way to the water at night, and use cooling temperatures as a cue.  Rain fools them into thinking it’s dark, and this hatch was making their break in broad daylight.  We watched the baby turtles–each no bigger than a big kiwi fruit–flop awkwardly towards the water, alternating their flippers and dragging themselves forward.  We shooed away the seagulls who watched us with petulant expressions, since the normal fate of a baby sea turtle hatching during the day is a short trip down a seagull’s throat.

But none of this is the behavior I was thinking of.  Rather, the amazing thing is what happens when you pick up a baby sea turtle.  Once the pressure of the sand beneath its belly is gone, the motion of its flippers magically switches from alternating to synchronized, both flippers flapping in unison like the oars of a sculler on Lake Union.   Even more remarkable is what happens when you tilt the turtle from side to side, or front downward or upward.  The rear fins, useless on land, become rudders, turning in just such a way as would correct the turtle’s posture in the sea so as to keep it level and moving straight ahead.

Tilt the turtle head down, both rear fins bend up.  Tilt it to the left, the left rear fin bends down and the right fin bends up, while one front flipper stops moving and the other churns frantically.  The newly hatched sea turtle needs to get out to sea fast, to avoid the predators in the reef along the way, and its coloring (dark on top, light on bottom) are optimized to make it difficult to see as long as it remains level.

This is what evolution does.  It takes random variation and selects for those combinations that lead to reproductive success.  If those variations have their root in genes, those genes get passed along.  I’m curious to see if anyone tackles the question of how the turtle keeps steady, now that we have the tool of its genome to help.  I’d love to learn what goes into hardwiring this kind of behavior and who knows?  Maybe nature’s figured out some tricks that the cellphone makers don’t know.

I-5 as a metaphor for targets in drug development

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All opinions are my own and not necessarily those of my employer.

Yesterday a jack-knifed FedEx truck heading south on I-5 crashed as it passed Seattle’s downtown.  Traffic backups spread for miles north, and spilled onto all the other routes leading from the north of the city.  Tens and maybe hundreds of thousands of people had their days disrupted.  My commute, which should have taken 15 minutes, took most of an hour.  It occurred to me, as I sighed and listened to KUOW, that the situation was a nice metaphor for how I’ve been thinking about drug development lately.

We work to discover targets that will have a substantial effect on human biology, hopefully in the direction of improved health.  But health is a complex phenotype, arising from a network of interactions at all kinds of levels–molecular, cellular, physiological.  One thing we know from network theory is that interconnected networks are stable and redundant.  Seattle, or any city, is also a network of networks, and for the most part damaging one part of the network (pothole repair in Ballard, say) might cause some local effects but no real change to the overall phenotype. But there are a few nodes, like I-5, that can have a substantial effect on the whole when something happens to affect  them.

I’m starting to think of drug targets this way.  We talk about finding better targets with fewer side effects, but I wonder if that’s possible.  It’s kind of a yin-yang thing.  Any gene with a large enough effect when targeted  to disrupt the networks and subsequently the phenotype will by its nature have multiple effects.  I’m probably wrong, but it will be interesting to see what new drugs and new approaches come out in the years ahead.