SESSION V: CLINICAL CASE STUDIES AND COMMERCIALIZATION STRATEGIES

KD: Yes, the ALS Association has a whole funding program dedicated to support postdoctoral fellowships.  Here’s the link http://www.alsa.org/research/our-approach/attracting-bright-young-scientists/milton-safenowitz-postdoctoral-fellows.html. 

MZ: My academic laboratory developed a novel technology platform to enable selection of fully human antibodies to antigens of interest back in 2001. The technology had several advantages over existing alternatives, and we thought it could have commercial potential. Unfortunately, in spite of the advantages we offered, in 2001 we were already too late to compete with established methods for human antibody selection to soluble targets. We did eventually develop a novel and competitive selection technology applicable to the special instance of multi-pass membrane receptors such as GPCR and ion channels, but it took several more years.  In the meantime, we started developing specific antibodies of our own as novel therapeutics of which anti-SEMA4D is not the first, but is the most advanced.

There are two important lessons: (i) you need to understand the commercial market and the unmet needs, and (ii) you need to be flexible enough to respond to new conditions and information. The latter is difficult because it requires an investor base that is willing to provide the required funds and time to allow you to change strategy or direction. We were lucky, but I would not count on this again. I would make sure I knew enough to get the strategy right the first time.

MZ: I was very intrigued by the fact that SEMA4D regulates the cell’s actin cytoskeleton by binding to its high affinity plexin-B1 receptor. The cell cytoskeleton gives cells shape, but, more importantly, it makes it possible for cells to change shape. Cells need to change shape in order to extend projections that enable movement in a desired direction. We first discovered that tumors exploit this pathway as one of several means of evading anti-tumor immune responses. They express high levels of SEMA4D at their margin and this serves to immobilize and prevent infiltration of dendritic cells and macrophage that express the plexin-B1 receptor for SEMA4D. We found that we could block this pathway with antibody and promote immune infiltration. As a result, we are developing our anti-SEMA4D antibody in combination with a checkpoint inhibitor as immunotherapy for cancer.

Based on our understanding of the biochemistry and cell biology of the SEMA4D/plexin pathway, we came to recognize that similar cytoplasmic projections are required for cells to make contacts that enable direct interactions with other cells. Such contacts are central to the normal function of astrocytes and other cells in the brain. We determined that astrocytes do indeed express plexin-B1 receptors for SEMA4D and wondered whether SEMA4D binding to these receptors would trigger the morphological and biochemical changes associated with inflammatory transformation. It does, and this was the subject of my ADDF presentation.

MZ: I originally became an academic because I love the process of discovery research. Later in my career, I formed a connection with investors interested in founding a biotech company, and I thought this might be an interesting alternative to spending half my time writing NIH grants. I was not ready to abandon discovery research, and although, at the time, I suspected that industry has a different system of priorities than basic academic research, I did not yet understand the many implications. As it happens, I was very lucky to have a group of investors with a genuine commitment to innovation. They understood that innovation takes time and they were willing to allow Vaccinex the time required. I cannot emphasize enough how unusual this is. Investors generally have a short time horizon and discovery research is too risky and distant a reward. It is important to understand why.

By inclination and because of their responsibility to the people they represent, investors need to create wealth. There are two requirements to do this successfully: (i) you need to repeatedly engage in potential profit making opportunities, and (ii) you cannot lose your money. The second is most important, because, if you lose all or much of your money, you will not be able to engage in the first. The most efficient way to lose money is to take excessive risk. An investor can tolerate making money slowly, but absolutely needs to avoid losing money rapidly. Now you need to broaden this concept and recognize that businesses and industry are also investors albeit in different profit making opportunities. Every one of these parties seeks to take as little risk as necessary while preserving their profit making opportunities. For example, large pharmaceutical companies have increasingly become manufacturing and marketing organizations that in-license products from successful biotech. Why? They have huge manufacturing and commercialization infrastructures that can be reliably deployed to generate reasonable profit without large risks. Early development and discovery research are left to entities that have no other way of making a living. This includes start-up biotechs, and, at the very bottom of the chain, you, the academic scientist. This is not all bad news. The greatest excitement comes with the greatest risk. Like I said, I love discovery research.

However, like yourself, I understand and regret that pursuit of a long term academic career has become increasingly difficult and competitive. Many of us are disturbed by the fact that most young academic investigators do not get their first NIH grant until they are in their early 40s, and, for many of them, it is their last grant and last chance at promotion. I hope this will not dissuade people from pursuing graduate education, which I think is a marvelously enriching experience. But, at 40 years of age, many of you will have a spouse and children. You cannot feed them excitement. At some point, you may want to think about alternatives to an academic career. Among these is biopharmaceutical employment. The prospects for employment are very good. The tools of discovery in biomedical science are more powerful than ever, and the pace of medical advances continues to accelerate. Many existing and newly formed companies will seek to take advantage of this. They will need well-trained scientists to guide and execute their development. If you choose to work for a large biopharma, you will likely have less independence and need to learn to be productive in a large and sometimes inefficient environment. Smaller biotechs and start-ups have need for strong team players who can drive innovation anddevelopment. They may offer more leadership opportunities. On the other hand, biotech companies can come under financial pressure (see above) and are at risk of becoming insolvent. Most biotechs that fail do so because they run out of money not out of ideas. Anticipating this possibility, if you choose this pathway you need to either be geographically flexible (can your family move?) or you should seek employment at a major urban biotech center where people can more freely move between companies.

MZ: What is unique about our strategy is that we are targeting a specific pathogenic mechanism not just a biomarker of disease. Biomarkers are useful to identify disease susceptibility and progression, but, as we have seen in many failed Alzheimer’s disease trials, they are not necessarily effective targets. There is a lot of evidence for the pathogenic role of astrocytes and chronic inflammation in multiple neurodegenerative diseases and these research advances have informed our strategy for HD and AD.  One benefit is that there could be broad application to other neuroinflammatory indications including, for example progressive MS and ALS.

MZ: Drug development is very expensive and every new drug carries the risk of novel toxicity. I think it would be unusual for a company with a successful drug to invest in a replacement drug unless there was potential for greater efficacy and/or less toxicity. In general, antibodies have had less associated toxicities than small molecule drugs, possibly because they have greater specificity due to a larger interface of interaction and less toxicity because they do not, for the most part, penetrate into the cell cytoplasm.

ME: Thank you for your question! Intellectual property is an intangible product of a creative effort and IP rights are legal mechanisms by which you can protect IP. You can have limited protection for your IP without pursuing IP rights like patents. However, you could publish about the molecule (using your example) and prevent others from pursuing patent rights because the information is now in the public and no longer novel and/or non-obvious (two of the criteria for something to be considered patentable). At that point, you wouldn’t have the exclusive right to prevent others from making, selling, using, offering to sell, or importing the IP (rights associated with a granted patent), but no one else can seek that exclusive right and prevent you from doing any of those activities.

ME: Thank you for your question! Non-obvious is not quantitative and is subject to interpretation by a patent examiner. However, patent examiners are trained in a process to review patent applications, search prior art, and interpret case law. If an applicant receives an office action by the examiner stating that the application is obvious (or not novel or useful), the applicant is given a chance to argue that the examiner mis-interpreted prior art or perhaps did not appreciate an element of the invention that would overcome the objection.

ME: Thank you for your question! Utility patents include the opportunity to patent improvements to existing inventions, which could include drugs that are re-purposed. The starting point is to look at the patent (or patent family) that exists for the drug to understand what is covered by the patent rights and where there is room to seek patent rights. In addition, it can be helpful to examine patent applications that have been filed but not granted and review the examiner’s comments (office actions); you can do this through the USPTO Public Pair database. This may give you a sense of what is considered non-patentable and why, as well as other companies or institutions in the space.

ME: And thank you, as well, for your question! There is no guarantee that a patent will be granted, but there are steps that you can take to manage the risk, including: conducting (or contracting) a thorough prior art search for information that is publicly available and could cause a patent examiner to say that your invention is not novel or non-obvious (remember that publicly available information could come from conferences, publications, published patent applications, granted patents, commercially available products, etc.); constructing a patent landscape analysis (you can contract this service); maintaining thorough records; hiring a patent attorney with appropriate subject matter expertise; and coordinating the filing of the patent application with your business objectives – if you need to publish or make your invention publicly known, file earlier. If you can keep the information confidential, you may be able to wait to file (although be cognizant that others who are working in the same field may file first!).

ME: The Bayh-Dole Act of 1980 provides guidance for patentable inventions made with federal funds. An academic institution or small business (for example, if funded under an SBIR or STTR) takes ownership of IP created with federal grant or contract funds. The entity must report patentable inventions to the funding agency. Many agencies, including the NIH, use iEdison for reporting purposes; reporting is often done by the IP/Tech Transfer office for an academic institution or by Sponsored Research (Sponsored Programs). The entity can elect to take title to the IP and must pursue IP protection and/or commercialization within a certain period. If the entity elects not to take title or does not pursue IP protection and commercialization, then the IP rights revert to the federal government.

Typically, you can include confidential information and details in a grant application. The funding agency provides guidance on how to mark those specific sections of a grant proposal that contains the confidential information so that, if funded, those specific sections can be redacted before the application is made public. Please note that the agencies usually say they will attempt to redact the information but do not guarantee it. You should work with your Grants & Contract Administrator to review the agency’s instructions for marking the grant proposal. In my experiences, the proposals are considered confidential by the USPTO and proposal reviewers are under confidentiality agreements, so the information in the grant proposal should not constitute a public disclosure.

ME: The USPTO’s website includes a fee schedule related to patent filing, examination, granting, and maintenance of patent applications and patents (https://www.uspto.gov/sites/default/files/documents/USPTO%20fee%20schedule_current.pdf). Variable costs include whether you contracted services to conduct a prior art search and/or patent landscape analysis before deciding to file a patent application and the legal fees for a patent attorney. Some steps you can take to help reduce costs include conducting the prior art and landscape analysis yourself, providing thorough records to the patent attorney drafting the application, participating in the drafting process, minimizing the number of countries where you file the patent application, and deciding on your budget (you may not have the absolute best patent application on a budget, but it may still accomplish your purposes and objectives). It can be helpful to ask network or ask for references when selecting a patent attorney to understand how they work with clients, ways to constrain expenses, experiences with the subject matter and experiences with small businesses.

Many companies receive initial funding in part or in whole through investment by the founder(s) and/or friends and family.  This can be perceived as believing so strongly in your idea that your are willing to put personal skin in the game.  It can also be a way to lose friends and family if things go south.  It’s important that any investor (including yourself and especially your spouse) understand the risk of a personal investment, including the investment in time and attention.  The flip side of such an investment is that it is not really an external validation.  This is the reason I am a fan of grants from sources such as NIH and foundations- the money that comes from these sources also comes with vetting of your technology by a peer review panel, which can be a valuable attractor for other sources of funding.  The caution with these funding sources is that the time between writing and submitting a grant proposal and receiving funding can be long, and can often take several tries.  At one point in my career I inherited a next generation SERM for breast cancer that had a great preclinical package, but we could not interest anyone in licensing it because the set of grants that funded all the work ate up too much patent life for a licensee to recoup development costs.  Any funding source comes with pros and cons, including personal investments and friends and family investments.  Used strategically in the beginning of a company life cycle, such personal investments can play a critical role in getting you started, but they rarely provide enough funding to take you very far, so as usual you should have a plan for securing your next funding source while you are working on your current funding source.

Thank you for bringing this up, it should have been something I addressed in more detail in the talk.  A lawyer is important from the start as you deal with articles of incorporation and other issues around establishing your company as a legal entity.  It’s also important to codify issues such as percentage ownership amongst founding members from the start so there are no misunderstandings (or worse) down the line.  This doesn’t mean that you need a full time lawyer from the start, although sometimes a legal representative may be willing to do some part time work in return for equity.  In the case of my most recent company, we were established in the San Francisco Bay area through a state funded program called QB3 which supports spinouts from several California academic institutions.  Part of their ‘Start-Up in a Box’ program is provision of some hours of pro bono legal advice from a firm associated with the program.  One of the advantages of having a lawyer as part of your team is illustrated by the ham and egg breakfast- the chicken is involved, but the pig is committed.  If you have a lawyer as a member of your team, they may have more of a personal stake in your success and may have a longer history with your company and understanding of the issues and personalities- one of the challenges of engaging a law firm can be turnover of staff and periodically needing to bring a new person up to speed.  Been there, done that.  However, in a fledgling company you are unlikely to need a full time lawyer on your staff, so as with other roles you will likely want to balance the advantages and disadvantages of outsourcing versus building internal resources.

There could be two interpretations of this question, either working together in running a company or in securing funding.  As to the first, I have seen co-founders start as friends and end up at each other’s throats, but it doesn’t have to turn our that way.  Money and power can strain friendships, so my advice is to agree on a detailed contract from the start and understand that roles and pressures change as a company grows.  Working with known colleagues can provide a solid foundation of trust and established modes of communication, which can be a real advantage.  Keeping that trust and that advantage takes conscious effort.  When it works, and I have seen it work, you can achieve great things.  The other way your question might be interpreted is receiving early stage investment from friends and/or family.  This is one way to finance some of the early activities of a company, including completing articles of incorporation and providing for a thorough freedom to operate review.  It can be seen as putting a personal stake in the formation of the company.  There are several caveats to this type of investment.  If friends and family are involved, it is important that they understand the risk and have realistic expectations if you want to keep them as friends and family.  Also, it may complicate decisions that need to be made objectively.  In general, the level of funding available from friends and family won’t take you too far down the development path and growth curve of the company, but it can give you the time and resources to secure Angel or foundation or grant or VC investments.  I learned early on that when working with a CRO a detailed work plan is your friend and best protection when things inevitably go off rail.  Similarly, when working with friends and family a good legal document can prevent many (but not all) misunderstandings. 

I think a good place to start is to talk with local entrepreneurs and organizations, especially local chapters of BIO.  Here is where the unfairness of geography can make a difference and would affect my answer.  In the San Francisco Bay area where I live and have worked all my biotech career, we have several organizations that are incredible resources for people interested in starting a company.  The company I co-founded spun out of a local research institute and received initial assistance from QB3, a state funded innovation program designed to help academic spinouts from several University of California campuses.  The QB3 “Startup in a Box” program provides several hours of pro bono legal assistance on incorporation, workshops on SBIR grants, freedom to operate reviews, and discounts on some services, a no-fee bank account, and rentable incubator space.  The California Life Sciences Institute (CLSI), an affiliate of the California Life Sciences Association (CLSA), sponsors the FAST program that assembles a diverse team of experienced biotech professionals to advise qualifying startup teams- I have participated in multiple rounds of the program and can attest to the difference it makes in launching promising new companies.  If you are in other hotbeds of biotech such as Boston or San Diego there are likely similar mentoring programs.  Good ideas and experienced people are not exclusive to either coast, and translational support programs are flourishing in many locales.  If you would like to contact me through the ADDF or LinkedIn I would be happy to see if I can give more specific advice for your location.  As to finding a CEO, this is also a good question that gets the adult diaper response- it Depends.  Founders often try to assume this role, and that is often a mistake as founders may not have the experience or bandwidth or traits for the role.  Experience is important, but I would caution against the big league fallacy, akin to hiring a manager because he has big league experience and ignoring that he has never had a winning record.  That said, most entrepreneurs have failed in their career; if they haven’t, they may be too risk averse, because the risk of failure is high in drug development.  In the end, the biggest failure is not learning anything from a failure and repeating the cycle (and calling it experience).  For an early stage company, it will usually be challenging to find a very experienced CEO to come on full time, but you may be able to secure one as an advisor- the trade off is their attention will likely be split.  You may also find someone like a Sr. Director of Business Development who is looking to move into a CEO role.  Alternatively, if your goal is to secure venture funding it may be best to hire a head of business development and not fill the CEO role immediately.  Venture capitalists often prefer to install their own CEO, and sometimes other members of the senior management team as well- this is what happened in the start-up company I co-founded.  Again, the local chapter of BIO may be able to suggest advisors and candidates for CEO and other key roles that can help you get started. 

Although it is cold comfort to hear, you are not alone.  The longer I work in this field and talk with colleagues the more stories of broken trust and misused power I hear.  One of my best bosses years ago liked to paraphrase the Lily Tomlin line- no matter how cynical I become, I can’t keep up.  Still, I think as scientists we are optimists because most experiments fail and even knowing that we believe we can, and often do, find a path to success.  I remain optimistic that trust can be earned and kept, and that the next experiment will work.  So my advice is to try to stay on the sunny side of paranoia, and much as I hesitate to quote Ronald Reagan: “trust, but verify”.  When building your team, you can’t always hire people you know, nor is it sometimes a good idea.  Hiring is hard; reversing a hiring mistake is harder.  Take extra time to vet a person, and don’t ignore what your gut is telling you- I wish I had read Malcolm Gladwell’s book “Blink” before some of my hiring decisions (both as a hiring manager and as an applicant).  Networking can help in finding and vetting your team members.  In addition, a clear contract that is mutually understood and agreed to is important, especially in times of stress.  To me, trust is earned, not assumed, and one of the best ways to build it is through sharing the challenge and the credit.  I think it is also important to understand what motivates people, and to understand the effect that power and money have on trust.  I have seen companies fail on a breakdown of trust- co-founders driving one founder out, only to be driven out themselves by another founder or member of senior management.  I have seen trust broken through favoritism, through harassment that was condoned by management, by illegal activities that led to termination if they were not adopted.  And I have seen incredible unselfishness and mutual support through some very stressful times.  In the book “Innovation: the Five Disciplines for Creating What Customers Want”, Curt Carlson includes team alignment as one of the 5 keys to successful innovation and successful companies.  I think this is too often overlooked in biotech, and likely in many other fields.  When a team has trust and works in alignment, as I have experienced at times in my career, you feel what my wife called swing when she rowed crew in college- everyone pulls together and the boat rockets forward.  I think you are right to think about trust and to take the time to build it, and if you can build that alignment then treasure it and fight like hell to maintain it.  Also bear in mind that as a company grows this can be very challenging to maintain.  All very nice words, but back to your question, how do you build a team you can trust?  Especially bearing in mind that as a basic scientist (and a basic human being) you will need to / should bring in team members who are different.  I suggest that while you interview people about their basic skills for the roles you need, which are important, you also ask about situations they were in when the team was cohesive, and examples of when the team broke down; ask them both what they think caused it and how they handled it, and what they would do now if they were in charge.  Checking references is important; networking and checking independently is important too.  Work on communications styles, because trust can break down due to miscommunication; and remember trust is two-way, so make sure you build the trust that people can put in you.  Finally, have the courage to fire or walk away if a situation is beyond redemption.  Again, the more you build your network the more you will find that you are not alone with this issue, and there are a lot of people with scars who are willing and able to lend advice.  Finally, as a company grows your percentage ownership in the company and your control will inevitably be diluted.  This is not necessarily the same as ‘giving away’ your ideas or molecules, but it can be hard to experience.  Make sure you understand net present value and get good legal advice on what are reasonable expectations for ownership and control at each stage.  Also, not all sources of funding are equal; network to learn whether there are trust issues with a source of funding, just as you would try to establish the trustworthiness of a prospective hire. 

In my experience, and in discussions with colleagues, this is not an uncommon problem.  The reason I like to bring up the Myers-Briggs model is that it reminds us that different people have different ways of processing information, as well as difference processes for making decisions.  Good communication puts a burden on us to bear in mind the audience, even when it is an audience of one; the difference between talking and communicating lies in delivering information in a form that can be best processed by the recipient.   Not all CEOs are alike or fit a particular MBTI profile, so my main advice is to seek to understand how a particular CEO likes to receive and process information.  Many of us are trained to give seminars and to present information to our peers.  You may have a CEO who comes from this world and is accustomed to this format, but I think it is rare.  Also, in science we often follow discoveries in what I think of as an expanding pattern (which I symbolize as “<”, one observation leading to others, to more options, to new models), whereas in industry and in communicating with CEOs there is usually a drive toward closure (which I symbolize as “>”, a drive to a conclusion, to a decision, to a clinical lead, etc.).  Also, I have seen many seminars where the conclusion appears on the last slide.  In communicating, this can result in “burying the lead”, and your audience (CEO) may tune out and lose the key point buried under a pile of details.  I have found it useful to organize and present information in a series of bullet points, with the option of diving into greater detail if it is requested.  Borrowing from Myers-Briggs, many scientists fall within or near the INTP profile, and when they try to bridge communication gaps they can fall into several traps.  One is the tendency to present too much detail- we can bury the forest in a mountain of bark.  Another tendency related to the N, the intuitive leap, is to state a conclusion without providing a guide to how we got there. Many (but not all) CEOs and other business types collect information through an S (sensing) function, preferring to see evidence presented in a orderly, step by step fashion.  Again, this doesn’t mean you pile on the information, for the other S tendency is to prefer a delivery that is brief and concise.  Note also that the way you organize and present information may vary with its form- i.e. whether it is verbal or written, a report or an email, a quick verbal exchange or a formal presentation.  In an email or memo or PowerPoint presentation it may be easier to tier the information with a summary first, bullet points of what will be covered, and then deeper dive into the information.  It can be harder to organize this way in a conversation; when in doubt, keep it concise- you can always elaborate if asked.  One other thought on communication.   I once had a VP who kept checklists, and was driven by the need to check items off the lists.  If this is the case with your CEO or boss, it is helpful to see the list.  It is also helpful to know how well they are able to prioritize that list and to communicate it to you.  The trap with such lists is that sometimes list keepers get agitated if an item stays on the list too long, even if it is not a high priority.  Such an item, no matter how trivial, can become a burr under the saddle of such a person.  It can be a good strategy to define priorities and to check on their order periodically.  Also, it is helpful to define the deliverable, so there is a common understanding of what is considered a completed task or achieved goal.  You don’t have to process information the same way as your CEO- Myers-Briggs and similar systems teach us the advantage of a diverse team; but when it comes to communication, it helps to understand how the receiving party prefers to receive information and to accommodate that style without compromising the information.

No, the change of name was not related to funding strategies or any other sinister reason.  As often happens, once the company received additional venture funding we had a chance to do a more formal (i.e. expensive) search and found another name that was too close to the name MedaRed.  In a nod to our Greek academic founder the name Therini Bio was chosen; it is a combination of letters from the words Therapy and iniki, the Greek word for fibrin, our target molecule.  It may be a sign that all the good names are taken.  Company names are tricky- ask Ionis Pharmaceuticals, formerly known as Isis Pharmaceuticals, a name it had originally chosen before the terrorist group Isis became a front page feature.  My first company, initially named after a tolerance mechanism, shared its name with a dog food brand and reportedly also with an Italian manufacturer of prosthetics.  I have on occasion suggested that Sisyphus Pharmaceuticals would be a good name for a biotech company, but thankfully to date no one has taken me up on the suggestion.