- Mark Noe shares the importance of distinguishing the difference between drug discovery vs. the invention of drugs
- How Pfizer/BioNTech managed to invent a COVID-19 vaccine within less than a year
- Challenges Pfizer/BioNTech confronted in developing the COVID-19 vaccine
In an online video, “Mini-Doc: Pfizer Medicinal Chemist Mark Noe”, you said that ‘drug discovery’ is a bit of a misnomer. “Drugs are not simply found – drugs are invented.” Why is the distinction important to you?
Technically, the definition of the word discover is to find something unexpectedly or in the course of a search. It implies that the object being discovered already existed. However, medicinal chemistry at its core involves processes of design and synthesis to make new drug candidates – with significant creativity and problem solving required to overcome the numerous challenges associated with making a new medicine.
A new medicine needs to have sufficient potency, maximized safety, persist for an appropriate time in the body, be administered conveniently, and distribute to the appropriate tissue(s) to have a therapeutic effect. The new medicine also needs to be easily manufactured. It is exceedingly rare that all of these properties are found in compounds that exist in nature or in corporate compound collections.
Therefore, teams of medicinal chemists spend years thoughtfully designing compounds using experimentally determined structures of their target and computational models for safety, metabolic stability and permeability. Newly made compounds are tested using a myriad of assays that indicate whether changes being made to lead compounds are delivering the expected profile.
This information is provided by teams of scientists in pharmacology, structural biology, drug metabolism and safety science to inform the next cycle of design, ultimately leading to the drug candidate for clinical testing. Along the way, synthetic chemists creatively optimize the route and develop new methodology to expand the chemical space that can be quickly explored. These scientists are highly creative in solving problems, and that creativity manifests itself in the invention of a new medicine. This creative invention process is what attracted me to a career in the pharmaceutical industry.
In the same video, you assert that creating a medicine is like solving a very complex jigsaw puzzle.” Roughly speaking, what percent of the ‘puzzles’ that your team starts conclude with all pieces in the right place?
Our mission is to bring breakthrough medicines to patients, medicines that provide transformational benefit beyond what is currently available in the human pharmacopeia. Therefore, most of our research programs focus on novel mechanisms for treating disease (aimed at targets that we call “first in class”). Because these targets and the mechanisms they control are novel to us, we often begin the design process with an incomplete understanding of their role in disease and how best to modulate them.
For example, we may begin with some genetic information associating a protein with disease. We then might use that background to inform studies in cellular systems or animal models, which then guide drug design and dose projection. For the majority of programs that begin in this manner, the big questions of how best to design a medicine are not completely answered until it is tested in patients.
For that reason, our drug design efforts focus on maximizing the amount of target modulation we can safely achieve in the clinic – to see whether a differentiated therapeutic effect can be delivered. Fewer than 5% of lead optimization programs deliver an actual marketed medicine. For this reason, it is important that we understand as early as possible which mechanisms could potentially deliver transformative medicines and which are flawed. In doing so, we minimize the cost of failures and can redirect our resources to programs which have a higher chance of success.
How did Pfizer and its partner, BioNTech, invent a COVID-19 vaccine in less than a year, “… shattering all speed records for vaccine development,” as the New York Times wrote on December 10, 2020?
Three elements were critical to rapid development of the CoV2 vaccine: (1) mRNA vaccine technology, (2) A novel approach to clinical development, (3) A strong sense of purpose among our scientists.
The availability of mRNA vaccine technology, which was heretofore unprecedented for human use, was critical to delivering the COVID-19 vaccine in record time. Prior to that advance, vaccines were generally derived from attenuated or inactivated pathogens or antigenic proteins and carbohydrates. These vaccines take years to develop because each antigen has unique chemical characteristics. To elicit a durable immune response, the antigen may need to be engineered, and unique processes and formulations must be devised to confer appropriate chemical and conformational stability. Protein antigens can also be challenging to produce, as cellular systems are involved.
However, mRNA vaccine technology uses the cells in the inoculated person, rather than cells in a lab, to produce the actual antigen. As a result, mRNA constructs can be explored much more rapidly in the preclinical stage than protein antigens, and design can begin once the genetic sequence of the pathogen is available.
Another critical component to delivering these vaccines rapidly was a novel approach to clinical development. In particular, we evaluated 4 different candidates in a single study, and had ongoing, often real-time, dialogue with regulators. We knew we had to move fast and think differently about vaccine R&D to identify areas where we could we save precious time.
We worked with regulatory authorities to compress into months stages that have historically taken years, and those that have taken months into weeks. We decided to take steps in parallel instead of sequentially, testing four vaccine candidates simultaneously in our phase 1 studies to understand which one would likely have the strongest benefit-risk profile. Pfizer made the early decision to begin clinical work and large-scale manufacturing at its own risk to ensure that product would be available immediately upon Emergency Use Authorization and potential approvals.
Finally, an unprecedented marshalling of resources within Pfizer and BioNTech made this all possible. Everyone on the project worked with tremendous purpose and a sense of urgency given the pandemic crisis and the opportunity to make a significant contribution to humanity. More information on our work can be found at Pfizer’s Five Point Plan.
What was the biggest challenge Pfizer/BioNTech confronted in developing its COVID-19 vaccine? And what did you do to overcome it?
Oligonucleotides are hydrophilic and negatively charged; therefore, they do not readily penetrate the plasma membrane of human cells, which is required to produce antigen and elicit the protective immune response. This is the biggest challenge associated with oligonucleotide therapies and mRNA vaccines.
We overcame this challenge by optimizing a proprietary nanoparticle formulation, licensed from Acuitas. Also, because the mRNA is not the actual antigen that elicits the immune response, we invested substantial effort in characterizing the protein produced by the mRNA vaccine after uptake into human cells. This information helped select candidates for clinical studies.
What was behind the decision to opt for a two-dose treatment rather than a one-dose?
The two-dose treatment elicited the strongest immune response against the virus. It is not uncommon for vaccines to require a two dose (prime and boost) sequence as is the case with the CoV2 vaccine.
Would you expect the frequency and the manner in which pharma companies collaborate with one another to change as a result of the shared successes of 2020? If so, how?
The complexity associated with inventing medicines and bringing them to market necessitates cross-industry collaborations. Pfizer has been involved in several collaborations, including precompetitive work with the Innovative Medicines Initiative, the RESOLUTE consortium on solute ligand carriers, partnerships with biotech companies to facilitate their innovative technology platforms for drug design and collaborations with academics to bring new design and synthesis methods into the public domain.
The COVID pandemic has certainly provided a catalyst for further collaboration, some elements of which are outlined in our CEO Albert Bourla’s 5 Point Plan for addressing COVID19. We are also exploring opportunities to share non-competitive clinical information across the industry, as proposed by our Chief Development Officer Rod MacKenzie. I think you will see more exploration of pre-competitive collaboration opportunities across the industry to help reduce some of the cost and risk associated with bringing new medicines to patients. We are also taking knowledge gained from the unprecedented speed of our CoV2 vaccine program and applying it to other severe disease areas in our portfolio to more broadly accelerate our pipeline.
How have your parents influenced your leadership style?
My father is a physician and retired C-suite hospital executive, and my mother was a practicing nurse, so I always had a strong interest in health care. They always brought a strong work ethic and a deep concern for others that has influenced me profoundly.
I will share with you one example. Being from Buffalo, NY we have a lot of snow, and I remember one February there was a massive blizzard that stranded hospital workers and prevented people without 4-wheel drive vehicles from getting in to work. My father brought my brother and me to the Buffalo General Hospital where we worked to fold and sort freshly cleaned hospital linens because the laundry room was short staffed.
He then drove around downtown Buffalo to shuttle nurses between the hospital and their homes in his Jeep because that is what needed to be done. In this way he set a great example of facilitating the work of others in a time of crisis, and he did this regularly in many other ways during his career as a senior leader. I believe the role of a leader is to facilitate the work of the group, and that is what I have always tried to do.
What are some personality traits that have been most instrumental in your career success?
I am generally outgoing, am open to different perspectives and enjoy working on complex problems. These traits have helped me work with diverse teams, learn new things and interact with others informally. I think these elements have been important to my career advancement and also help me in my current role.
But because of the complexity of problems we encounter in drug discovery, and the diverse disciplinary expertise needed to solve them, there’s no one trait that I believe predicts success. Our project teams are comprised of biologists, chemists, pharmacokineticists, structural biologists, safety scientists, process chemists and many others needed to design, synthesize and characterize potential candidate medicines.
Their expertise in different areas of science brings unique perspectives to solving problems, understanding our targets and designing new medicines. I enjoy working with and learning from people with diverse scientific backgrounds, and these individuals have taught me a lot about different areas of science.
With respect to your scientists at Pfizer, what non-technical skills do you most highly value?
One important facet of work at Pfizer is our ability to work as part of diverse teams. Pharmaceutical research and development requires strong teamwork owing to the complexity associated with designing a new medicine that has all the properties required to be a transformational medicine. As such, our scientists need to be open to others’ perspectives, willing to share their own ideas and able to constructively challenge others regardless of their level in the company.
In doing each of these things, we ensure that the best ideas are considered and implemented. I think it is important for our scientists to expand their professional network inside and outside the company, which requires a willingness to go beyond their own laboratory or local work environment and learn about the scientific challenges that others are facing – as well as share their own. Doing so can bring diverse and often valuable outside perspectives to solving problems, without some of the blinders associated with working on a project for a long time.
Finally, because we work in an industry that thrives based on innovation, the ability to think creatively about how to solve a problem is crucial. Often, innovation requires taking a step back and discarding assumptions that limit how one approaches solving a problem, and as mentioned above, being open minded to new thoughts that you or others might generate.
What technology trends are you following most closely, with an eye toward how they may impact the work of your scientists, and Pfizer’s future growth?
One of the things that excites me most about my current role and my team is the diversity of science that we pursue toward designing and developing new medicines. I will mention three areas that get a lot of attention in our group.
One is non-traditional modalities for drug design. The area of targeted protein degradation is particularly exciting because it offers the potential to address biological targets that were once considered intractable for small molecule drug design. By recruiting E3 ubiquitin ligases to those biological targets, they become marked for destruction by the proteasome, yielding advantages in efficacy, selectivity and duration of action. We have an active collaboration with Arvinas exploring this technology.
Another area that we have been pursuing is phenotypic screening as a method for identifying novel mechanisms for treating disease. While phenotypic screening is not new, it is undergoing a revival prompted in part by newer techniques for perturbing cellular systems and uncovering the mechanism of action for phenotypic screening hits. We are particularly interested in functional genomic technology that for the first time enables one to probe large portions of the human genome for disease-modifying phenotypic effects. We can use these tools to confirm the mechanism of action for small molecule hits in a phenotypic screen, or we can generate confidence in a biological target and then deploy traditional high throughput screens to find chemical matter.
Finally, Cryo-electron microscopy (Cryo-EM) is driving a revolution in structural biology. The mainstay for determining the high-resolution structure of biological targets has traditionally been X-ray crystallography. This tool is very effective for low molecular weight, soluble proteins that can be readily crystallized. However, membrane proteins and multiprotein complexes are quite challenging for this technique because it can be difficult to get high quality crystals.
Technology advances in crystallography have enabled Herculean challenges to be solved – like the determination of G-protein coupled receptor structures bound to antagonists or agonists, which gives us the ability to do structure-based drug design. Cryo-EM offers the ability to study protein structure at high resolution without the requirement of protein crystals. There are limitations with this technique – namely, the requirement for high quality samples and a lower limit on the size of protein that can be studied. However, advances in experimental technique and instrumentation are pushing back some of those barriers.
What’s the one piece of advice you wish you had received when you began your current role with Pfizer in May, 2016?
Expect the unexpected! I had the advantage of working at Pfizer for 20 years when I began my current role as the head of Discovery Sciences in Medicine Design, so I already had built a lot of relationships and knew many people in the group. However, looking back over the last two years, I would have appreciated being more prepared for the highly unexpected, high impact pandemic event.
The COVID pandemic took many of us by surprise, and it has turned out to have significantly more impact on our lives and the way we do business than I expected. The closest analogy in my lifetime was the SARS epidemic in 2003, which was tragic but was relatively contained compared to the event we are experiencing now. This pandemic has required us to operate completely differently for a long period of time. Most of our business continuity exercises map out events that last a few days to a few weeks. This pandemic has significantly impacted how we work for over a year, and while we responded quickly, my being more open to that possibility early on would have changed some aspects of how we responded initially.
The pharma industry comes under frequent criticism by politicians and the media. If the vaccines are as successful in combatting COVID-19 as we all hope, would you expect to see greater appreciation for pharma and its scientists?
The pharma industry has, for a long time, delivered significant value to patients and to society by delivering innovations that treat or prevent disease. Early examples of innovations include the introduction of antibiotics to treat bacterial infections, the invention of antiviral agents such as those used to treat HIV, and numerous medicines for treating different cancers. The value of the industry’s innovation was brought more prominently into the public spotlight through the delivery of coronavirus vaccines to combat this awful pandemic. These vaccines have brought hope to many that we will be able to soon return to a more normal way of life.
I have seen an outpouring of support from family members, members of my community and members of government for the work that Pfizer and the industry does, and I am glad that we were able to be part of the solution to this global crisis. While I believe the public now has a greater appreciation for the innovative work that we do, the pharma industry is very focused on expanding access to medicines to all those who need them. As an example, Pfizer partners with global health institutions and implements novel pricing structures to blend philanthropy and business approaches that increase access to our medicines and vaccines where they are needed most.
What have you learned about yourself since the start of the pandemic?
I very much enjoy going into work and being with our team of scientists who work hard every day to deliver life-changing medicines to patients. I value spontaneous interactions with my colleagues, which is where I most often learn about new scientific advances, but is also where I establish personal connections with people at work.
While I have learned that there are many aspects of my job that I can do remotely, this element is missing due to the fact that nearly every interaction needs to be scheduled. It is often said that you rarely miss something until it is gone. Thankfully, in this case, the separation we are feeling is temporary, but it has brought me an appreciation of how important it is to interact with people in person. While I do go into the office on a weekly basis, it is different working with people when you have to maintain social distancing constraints and wear masks. I look forward to the day when we do not have to do that regularly.
I have also learned – about myself and others – how much more flexible we can be in applying our skills to very challenging problems when motivated by a sense of urgency and purpose. I have been amazed by the dedication of people at Pfizer and our willingness to take on very difficult scientific problems with a sense of courage and hope.
Every time we asked for volunteers to work on our COVID vaccine or therapeutic agent programs, we have always had more than we could accommodate – even when the task meant significant personal sacrifice or challenge. I suppose this experience really reinforced the reason I went into the pharmaceutical industry in the first place: to be part of a team that could really make a difference in peoples’ lives.
Mark Noe is Vice President of Discovery Sciences. This is a department that includes six functions supporting small molecule drug design: Primary Pharmacology, Structural and Molecular Sciences, Cellular Genomic and Protein Sciences, Design and Synthesis Sciences, Hit Discovery and Optimization, and Compound Management and Distribution. Working collaboratively with other groups in Medicine Design and Therapeutic Area Research Units, this group helps progress preclinical projects from idea to first in human studies.
Mark grew up in Western New York just outside the Buffalo/Niagara Falls area. He received his bachelor’s degree in chemistry from the University of Michigan, Ann Arbor in 1991, and his PhD from Harvard University, where he worked with Professor E.J. Corey.
Mark joined Pfizer in 1996 and worked as a medicinal chemist in the Oncology and Inflammation therapeutic areas and worked with teams that delivered several INDs. In 2003, he joined the Antibacterials group where he helped evolve the research portfolio from a focus on precedented agents for community respiratory infections to an emphasis on new mechanisms for treating hospital-based gram-negative infections. Two compounds from that portfolio have been licensed for further development: sutezolid for MDR tuberculosis and sulopenem prodrugs to treat Gram negative pathogens.
Mark has co-authored over 75 publications and patents. In addition to his interests in science and technology development, Mark sponsors the Groton Chapter of Pfizer’s Global Asian Alliance. He also serves on the Connecticut Site Leadership Team and has led Academic and Industry Relations for Pfizer Chemistry over the last 15 years. He serves on several scientific advisory boards for universities and biotechnology companies in the anti-infective area. Mark serves as the American Chemical Society Corporations Associates Representative for Pfizer and is a member of the Editorial Advisory Board for ACS Medicinal Chemistry Letters.
This article has been edited for length and clarity. The opinions expressed in this article are the author's own and do not necessarily reflect the view of their employer or the American Chemical Society.
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