Monthly Archives: January 2018

Linking the scientific and patent literatures

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LENS

The scientific literature and patent literature have for a long time been viewed as two different worlds, with publications in the latter one measure of a researcher’s translational activity. But a much larger cadre of researchers influence inventions beyond those who are named as inventors on patents. Within patent filings there is often an extensive list of citations to the non-patent literature, including peer-reviewed papers, monographs, meetings and more. In a Patent article, Jefferson Osmat and her colleagues have created a tool to mine an open database termed the Lens containing filings from the US Patent and Trademark Office, The European Patent Office, the World Intellectual Property Organization Patent Cooperation Treaty applications and IP Australia for the non-patent literature. This enables an assessment of individual and institutional contributions to the global patent literature.

Andrew Marshall

Gottlieb on pricing, competition and new therapeutic modalities

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While freelancing for Nature Biotechnology, I recently talked to US Food and Drug Administration (Rockville, MD) Commissioner Scott Gottlieb. The conversation ranged from pricing, to market competition to new therapeutic modalities like gene therapy coming down the pipeline. A more extended extract of our discussion is also available in the News Feature.

 

You’ve helped to insert FDA into the drug affordability debate in 2017, by emphasizing competition and, by extension, more approvals, as a means to reduced costs.

Scott Gottlieb: A lot of what FDA can do around competition comes down to what we can do on the generic drug side with respect to complex drugs that are hard to make generic because of scientific or regulatory obstacles. We also see companies sometimes taking advantage of certain regulations and policies to extend patents beyond the time Congress really intended. And built into the generic drug approval process is a sort of regulatory arbitrage, where a company can come in, pick off one of the 300 or so products that was typically a low-volume generic but didn’t face any competition and jack up the price. So we’ve been taking action to try to resolve what I think are regulatory policy obstacles to allowing more vigorous competition.

Focusing on complex drugs where the patents and exclusivities have lapsed but they don’t face any competition yet, companies maintain monopolies on these products. We will be putting out some analysis early in the year on what the total spend is on complex drugs that should be subject to competition but aren’t.

These are drugs like metered dose inhalers. Drugs that are hard to copy under the traditional framework of the generic drug approval process. When a drug can’t be easily measured in the blood or it acts locally on tissue because it’s a topical agent or it’s an eye drop, or it’s a metered dose inhaler, that framework doesn’t apply very well.

So we’ve committed to putting forward product-specific guidance two years ahead of the first potential patent expiry on any complex drug going forward. We’ve gone back and tried to revise guidances on existing complex drugs that aren’t subject to generic competition. We’ve revised general principles in various areas for demonstrating sameness when it comes to things like metered dose inhalers, or topical agents, or liposomal agents. We’ve also put forward changes in how we infer sameness in drug-device combinations when the generic device that delivers the drug might be slightly different than the branded device.

Would you have expected to see more biosimilar competition by now, given when that pathway was created?

SG: I think we’re going to. When we look at the pipeline we see a pretty robust pipeline of companies that have come in to us, starting to engage the agency on biosimilars they want to develop. We have to keep in mind, there’s a small subset of biologics that have come off of patent. And also the biosimilars that have been approved have been subject to litigation. I think that if you look back at the early days of Hatch/Waxman the experience that we’re having with the biosimilars isn’t that different. It took a while for firms to gain the sophistication to come through the regulatory process. It took a while for providers to gain confidence in adopting the generic drugs. And it also took a while for a lot of litigation to get settled. I think we’re basically in the early days of that. That said, the big initiative we’re going to announce next year on drug competition is a biosimilar policy initiative. It’s going to be a collection of policies that we undertake to try to loosen the framework for bringing biosimilars onto the market to try to instigate more competition. We’re also going to be spending money trying to help educate providers about biosimilars. We’ve done that on the generic drug side of the house where we do public service campaigns. We’re going to be undertaking and are in the throes of it right now a big public service campaign on adoption of biosimilars, trying to educate providers on using biosimilar drugs as well.

I think that we’re still in the early days for biosimilars. But I never had the expectation that this market would evolve in as robust a fashion in its early years as some of the initial policy estimates. There were estimates put forward in Washington that inferred and imputed enormous savings from biosimilars very early. I think it was always going to be the case that this is going to be a slower evolution. And I think we’re doing quite well. I feel pretty confident and I base that not on what’s been approved. I’m looking at what we see in terms of the action of companies coming in and engaging us.

How do you think about creating competition in areas like gene therapy?

SG: Right now we’ve validated a handful of tools and I think over time we’re going to validate more tools that are going to enable different ways to try to address the same disease through multiple modalities.

If you look at sickle cell disease, for example, there are people developing CRISPR/Cas9 approaches to it, people who are developing exogenous gene therapy, people doing in vivo gene therapy techniques, people who are using fetal hemoglobin, people trying to correct the underlying defect. There’s a lot of different approaches that will hopefully create some inherent competition in the market. Right now it’s early days because we’ve validated a handful of tools. –like antibodies I think the inflection point we’ve witnessed in gene therapy in the past couple of years is the advent of the AAV vector and more reliable vectors that don’t have any immunogenicity, and deliver the gene therapy products more reliably. And so I think we’re going to see other types of modalities come forward, just as we saw in the biologics space, where you saw multiple ways to humanize and develop fully human antibodies. I think the same thing will play out in gene therapy and you’ll see competition by virtue of that.

Chris Morrison

Synthetic Vaccines

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Traditional and novel forms of vaccines.

Traditional and novel forms of vaccines. {credit}Birgit Schmidt{/credit}

In 2010 scientists from the JCVI announced the creation of the first bacterial cell controlled by a chemically synthesized genome1. The ‘synthetic’ cell was mycoplasma, a bacterium with an exceptionally small genome of less than 1 million base pairs and without a cell wall. Carole Lartigue, one of the co-authors of that landmark paper, later returned to the National Research Institute for Agriculture (INRA) in Bordeaux, France, to continue working on Mycoplasma. In fact Mycoplasma is not just a beautiful model organism for synthetic genomics. Their small genomes make them also a great model for systems biology, a work that was spearheaded by Luis Serrano at CRG in Barcelona2, 3, 4, who characterized Mycoplasma in a quantitative manner to apply this knowledge to do a rational engineering for novel applications. Some mycoplasma, however, are pathogens affecting both human and farm animals (Table 1). The mycoplasma infections not only cause animal suffering and death, but also lead to epidemics, resulting in production delays, lower food-conversion rates and an overall decreasing efficiency and profit for farmers.

Table 1: Main mycoplasma infections of farm animals

Animal Mycoplasma species Disease Existing vaccines
Cattle   M. bovis Mastitis, Pneumonia, Arthritis Inactivated (not effective)
M. mycoides subsp mycoides Contagious bovine pleuropneumonia (CBPP) attenuated
Pig M. hyopneumoniae Respiratory disease Inactivated
Poultry   M. gallisepticum Chronic respiratory disease (CRD), sinusitis Inactivated
M. synoviae Arthritis, respiratory disease Inactivated
Sheep/goat M. agalactiae Contagious agalactiae, mastitis, pneumonia, arthritis none
M. ovipneumoniae Atypical pneumonia none
M. capricolum (subsp. capripneumoniae) Contagious caprine pleuropneumonia (CCPP) none

 

In the European H2020 funded project MycoSynVac (2015-2020), CRG together with INRA, the global healthcare leader MSD Animal Health, and other partners across Europe, are now working on the first synthetic biology-derived animal vaccine. Traditionally, bacterial vaccines are made from simply inactivated or attenuated pathogens, which are deployed to ‘train’ the immune system of the host. In many Mycoplasma species, however, these vaccines don’t work really well, because the inactivated pathogens don’t attach, for example, to the host epithelial cells, thus failing to trigger an appropriate immune reaction.

The goal of MycoSynVac is not just a mere attenuated pathogen, but a reprogrammed organism that has to be, so to say, ‘semi-infectious.’ In other words, the reprogrammed microbe should be able to ‘inhabit’ the host, to attach to host epithelial cells in the respiratory tract, but then refrain from causing cell damage and inflammatory response because the virulence factors had been removed5.

Re-programming this behaviour requires not only a deep understanding of the pathogenic life cycle and its cause on a genetic level6, but also reliable bioinformatics models7 and precise gene editing tools for Mycoplasma8,9.

Mycosynvac is also developing extra layers of safety with newly developed biosafety control circuits built into the vaccine. These and other challenges don’t exactly make this vaccine a low-hanging fruit, but when considering the impact and scope of a successful product, it immediately seems worthwhile. The reasons are manifold:

(A) The market for animal products and animal vaccines is huge, with M. hyopneumoniae vaccines alone currently topping $150 million annually.

(B) For many pathogens there is either no vaccine available or they don’t work very well, so new applications are in high demand.

(C) The designed vaccines will be based on a standardized ‘chassis’ that can hold several different types of pathogenic epitopes (the surface molecules necessary for the protective immune responses), so development of the next vaccine(s) will be much easier and faster.

(D) Making it easier to engineer novel vaccines will also allow for a systematic replacement of antibiotics in agriculture. Antibiotics in farming industry is already a serious concern in the surge of antimicrobial resistance (AMR) and so-called ‘superbugs’ (multi-resistant pathogens) affecting animals and humans alike. Vaccines as tools to reduce AMR have historically been under-recognized in these discussions, even though their effectiveness in reducing disease and AMR is well documented10.

(E) Last but not least, once approved for farm animals, the next goal will be synthetic biology vaccines for human infections with an even bigger market and impact.

Markus Schmidt

References:

  1. https://science.sciencemag.org/content/329/5987/52
  2. https://science.sciencemag.org/content/326/5957/1268
  3. https://science.sciencemag.org/content/326/5957/1235
  4. https://science.sciencemag.org/content/326/5957/1263
  5. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137354
  6. https://genomea.asm.org/content/4/2/e00263-16.long
  7. https://www.frontiersin.org/articles/10.3389/fcimb.2017.00031/full
  8. https://pubs.acs.org/doi/pdf/10.1021/acssynbio.5b00196?src=recsys
  9. https://pubs.acs.org/doi/abs/10.1021/acssynbio.6b00379
  10. https://www.nature.com/articles/nm.4465

Why Every Life Science CEO Needs a Leadership Coach

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table4

{credit}Emily Winiker{/credit}

The biggest graduation for an academic researcher comes without diplomas or Latin superlatives, caps or gowns. It’s the leap from academia to business, the shepherding of our beloved ideas and inventions out of the known world of the lab and into the strange land of the marketplace.

It’s a bigger jump than any researcher imagines. When my co-founder Sarindr (we call him “Ik” for short) and I graduated our bone-growth technology from a Columbia University lab to a startup company, we realized lab reports don’t translate easily to investor pitch decks, and hiring a lab assistant from within your university department does not prepare you to build a cohesive company staff. We knew how to respond to the requests of an academic lab director, but that does not equate to answering to the FDA.

In short: A science project does not a science business make.

That’s why I sought the guidance of leadership coach. I had discovered the benefits of coaching when I was a TED Fellow (through their SupporTED program) and transitioning my role from academic postdoc to EpiBone CEO. My coach, Mark Capellino, helped me find my best professional self, one session at a time, through self-examination, skill and connections to outside resources. I started to see clearly the overlaps (and gaps) between my dreams and my skills, to answer the essential question: “What kind of CEO do you want to be?” and then enact my answer.

I knew this kind of expert guidance was indispensable for EpiBone—not only for Ik and me, but for staff at every level. A startup company is strong and nimble only when every teammate gets the support they need to do their best work. When obstacles arise within the team, the right coach can teach you to solve thorny social dynamics and smooth communications. As you increase the trust in the organization, you increase speed and efficiency.

Ik and I wanted a New York-based coach who could embed with our team, and someone with the experience to guide us without getting dogmatic. We found Lori Dernavich, who has advised and coached a host of ex-academics before us. Lori, who previously worked as a high-tech recruiter and psychotherapist, specializes in leadership coaching at growth-stage startups.

I am happy now to be able to say something radical: every single person who joins EpiBone is supported with one-on-one coaching. Besides coaching founders, Lori provides three to five sessions for every employee who is new or in a new role, plus monthly sessions for each manager. While her individual conversations are confidential, her wisdom and observations about the company overall help me keep EpiBone thriving—to grow a strong business while growing strong bone.

I recently got Lori to go on the record about why every biotech startup founder needs a leadership coach. Here are highlights of our conversation.

* * *

NINA: Lots of life-science executives come from academia. We’re in a new world here, but we’re smart people. Leadership coaching is not remedial. If you just got into the Olympics, wouldn’t the expectation be that you would need an Olympic coach?

LORI: Yes. You hear all the time from investors that they invest in the people. They want someone with a lot of passion, resilience, grit, empathy—meaning they can really work with other people. But VCs don’t often put their money where their mouth is. They often only call me when there’s a problem, when damage has been done. Founders need someone to have their back as they’re leading and growing a team.

When everyone’s a scientist, there’s little understanding of what’s coming next, or even what questions to ask in building a company. You can do it by trial and error, but startups have just a couple chances to make things work. It’s better to make fewer mistakes, or to recover from mistakes faster.

With founders coming out of the sciences, there’s a natural desire to learn. You’re brilliant at what you do, but you’re willing to learn what you don’t know. I love that.

Skills for the Science CEO

NINA: I see the need for this in the life sciences only growing. The trend in the past 10 years is of Big Pharma getting their R&D off their balance sheets by buying startups. That has pushed people like me and Ik into the position of leading emerging R&D groups.

If our last graduation was out of the lab into our own space, and from having government funds to angel funds, now we’re graduating from pre-clinical into clinical, and we’re transitioning from angel investors to VC investors. So I want to proactively address the pitfalls that many startups face, to be sure we address our blind spots in business building. Why would someone in my position seek out a science-leadership coach rather than a VC entrepreneur-in-residence (EIR) or simply a lot of deep reading?

LORI: Lots of people I meet wonder about this. The answer is that a leadership coach—and, ideally, the startup leader—are after something deeper. An EIR is a subject-matter expert in science, operations, sales, or finance, but they usually don’t specialize in coaching or the human dynamics of organizational growth. A leadership coach works with startups on their day-to-day interpersonal issues and in the development of leadership skills needed to scale. Not only for the founders, but for employees at all levels (a.k.a. your future leaders). Plus, there are going to be some things you don’t want to take to your VC, like those moments of self-doubt and uncertainty that visit every founder. You can Google how to be a better leader all you want, but that’s not the same as having a coach there to be your mirror, to show you your blind spots. Blind spots are called blind spots because you can’t see them.

NINA: I’ve found, too, that those more visible skills are easy to commodify. The value of good leadership is in the subtler skill sets. There’s a huge upside for people who recognize that. So as a founder, you have to ask yourself who are you going to bare your soul to, because you have to if you’re really going to do this work.

LORI: Right. What’s needed in all startups are basics like hiring the right people, leading meetings well, articulating the big picture. Communicating everything, a lot. And delegating. Delegating is huge. This is my baby; how do I let it go, so that other brilliant people can take pieces of it?

In life sciences specifically, founders are going into an environment that’s far more collaborative than academia. Scientists can be more introverted than those in high tech, so communication is also a challenge. How do you focus on other people? How do you turn your language into something that someone on the outside can understand?

This is not soft stuff. It’s the team and the people that make your business. The quote-unquote softer skills are some of the hardest ones to learn.

NINA: It’s the same with hiring. We may have had experiences as grad students working with undergrads in the lab, and we’ve trained them on the thing we want them to do. So, we think we’re good at hiring, but we’re not. We may be good at testing for skills. We don’t realize that we should also be interviewing for flexibility, adaptability.

And we think we’re good at communication because we deliver a paper presentation twice a year. But we’re not. In a way, we’re being tricked. We think it’s the quality of the idea that carries the day and that we’re on an infinite timeline to get the right answer. In reality, by the time you figure that out the world has changed. We have to learn the 80/20 rule for startups, where the need for speed means you can sacrifice some accuracy. What’s the 80% correct answer that I can get to in 20% of the time? Because making an imperfect decision quicker is more important than making the absolutely correct decision too late. That’s the biggest shift.

Growing Leaders at Every Level

NINA: Lori, you led hiring and on-boarding workshops for our whole staff to help us figure out how to bring new employees into the company, in deeper ways than the standard paperwork. You helped us tailor our process to our company’s character. We got a chance to think tangibly about how to make sure we’re hiring the right people, what is our philosophy, what is the cost of getting it wrong. That was valuable. Instead of “the company culture is what it is because there’s only five of us and we’re all in the same room together,” now we’re 20 people, and you need to starting naming and codifying things to be sure they continue to live. You can’t just rely on osmosis and chance and serendipity.

LORI: That’s true. Plus, people tend to feel more engaged and motivated if they have ownership. It shouldn’t just be for hiring managers to define our values. Anyone who is going to be working with new hires should understand what are you looking for. You don’t have to be managing somebody to be a leader. You should all have leadership skills and be able to come up with different solutions.

Cultivating Culture

LORI: Compared to solo academic work, building a company culture is completely different. As a startup, you have to define that from the get-go: What are our values? And then you have to live out those values in every area and action of the business.

NINA: Yes. I’ve learned that every single thing you do is actually two things: you are transacting business and you are also demonstrating through your actions the norms through which your business should be conducted.

When you’re growing bone cells, you can’t have cell culture medium that’s undefined. The reason it’s called cell culture is you’re trying to create an environment that works for your cells. What are the key ingredients that you need to make the cells not just survive but thrive, to foster attachment, proliferation, differentiation, collaboration? If we have this idea down pat when we’re thinking about how to encourage cells to grow, how do we apply that thinking to our company?

Nina Tandon