3月份读完的书，辉瑞CEO讲述的开发新冠疫苗的故事，可以说是当下最好的医药投资类读物了。疫苗的发明远不只是科学研究、和临床试验，生产也是巨大的门槛。需要巨大的资金、极度的好运气和持续的加班加点才可能把不可能变为可能。这是今天的登月工程，毫不夸张。照例做些摘录。
Kennedy said he chose the moon, not because it was easy, but because it was hard: “Because that goal will serve to organize and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win.”
More recently, Mariana Mazzucato, professor in the economics of innovation and public value at University College London, in her book Mission Economy: A Moonshot Guide to Changing Capitalism, writes that we saw many “spillovers” from Kennedy’s moonshot affecting life on Earth—technological and organizational innovations that could never have been predicted at the beginning. It was a “massive exercise in problem-solving.” These are the reasons I felt it appropriate to name this book Moonshot. Like Kennedy’s moonshot, the work to develop our novel vaccine against COVID-19 was indeed a massive exercise in problem-solving, an exercise that allowed us to consolidate scientific knowledge of a decade within nine months and that will have spillover effects in many other scientific areas, affecting life on Earth more than we thought at the beginning.”
明知山有虎、偏向虎山行。当年肯尼迪登月工程带来了巨大的技术溢出效应，相信这次的mRNA也一样。
What matters is not what happens to you, but how you react to it. Epictetus, AD 50–135”
You will never do anything in this world without courage. It is the greatest quality of the mind next to honor. Our problem is not that we aim too high and miss, but we aim too low and hit. — Aristotle, 384–322 BC
先哲的经典语录。关键的不是发生了什么，而是如何应对= 放下执念，认真应对；没有勇气什么都干不成，勇气是最大的美德。人类的问题不是目标太远大，往往是目标太渺小！
Clearly this is not business as usual. If we miss our budget for a year, no one will remember it the year after. If we miss the opportunity to do something for the world now, we will all remember it forever.
At the end of the meeting I went through the room to each of my executive leadership team members and assigned them specific tasks related to what we had agreed. I sensed the team’s resolve.”
危难到来时，即是难得的担当，也是对良机的充分把握，身在其中不错过。
And as usual in life, the most critical decisions were the most challenging to make. When I look back, the one that clearly stood out was the decision to use the mRNA technology to develop a COVID-19 vaccine. Not only because a different choice would have yielded very different outcomes. It was also because that particular decision was the most counterintuitive. The obvious option was not to use mRNA. It required a lot of forward thinking and eventually a lot of courage, but this is what gave us the vaccine.”
“In 2012, Phil and others published an article showing that self-amplifying RNA encapsulated within a lipid nanoparticle potently elicited antibody and T-cell responses. These findings were early signals of what was to come. Pfizer has been interested in RNA in part because of its ability to respond quickly to changes and be consistent. Although molecules of RNA also can vary in their behavior, one piece of RNA behaves a lot more like another piece of RNA in general than either viruses or proteins do. We liked the flexibility of the technology compared with traditional vaccine technologies. This flexibility includes the ability to alter the RNA sequence in the vaccine to potentially address new strains of the virus, if one were to emerge that is not well covered by the current vaccine.”
“Are you sure about this?” I asked. He was. Mikael was convinced through our work with flu that the technology was the right choice.“The technology is ideal for something like this. It is fast, and capable of being edited quickly for updates and boosters. Adenovirus or other viral vectors technologies could have difficulties with boosters because the immune system will create antibodies not only against the coronavirus but also against the adenovirus,” he said. Mikael knew from previous discussions that the speed of development and the ability to boost frequently were very high priorities for me.”
“What about using protein technology?” I asked. “We are good with proteins, and we could certainly make a vaccine with this platform, but with mRNA we would have both humoral and cellular immune responses. With proteins, we will have good antibodies, but I am not sure we would have T-cells,” he replied.”
选择mRNA技术对辉瑞来说要比Moderna等难得多，大公司更倾向选择成熟的技术路线，比如GSK、AZ和Sanofi等等。辉瑞的选择小心谨慎，也充满智慧，还没有依仗自己的资源多头并进。
“On April 9, we signed a collaboration agreement to codevelop a first-in-class, mRNA-based coronavirus vaccine, aimed at preventing COVID-19 infection. BioNTech received from us a $72 million up-front payment and was eligible for future milestone payments of an additional $563 million for a total consideration of about $636 million. In addition, we were going to provide $113 million in cash to them by buying equity from the company (bringing our total ownership of the company to about 2.3 percent at that time). Under the collaboration agreement, the two parties agreed to share all development costs and profits fifty-fifty, but Pfizer agreed to cover all these costs up front. If the project failed, Pfizer would bear all the losses alone. If the project succeeded, BioNTech would pay back to Pfizer its share of development costs from its profits from the commercialization of the product. ”
惊人、大方的合作条款了。
“I knew that a century ago, during the 1918 influenza pandemic, the second wave was much more lethal than the first. I also knew that during the coming fall we would face the double danger of a flu season amid the pandemic.“It is not good enough,” I told the teams. “We must have it by this October. And we must have hundreds of millions of doses by next year, not tens of millions.”
病毒的第二波冲击要比第一波狠，原来并非首次。
“The design of the Phase 1 and 2 programs was done in a very clever way. Instead of waiting to have all candidates released from the lab before they started the program, they would start the study immediately, when the first vaccine candidate became available. They would test it on multiple combinations at different doses, in different regimens, and with different age groups so they could develop a good understanding of how the candidate interacted with the immune system. Once the second candidate became available, they would follow a smart plan of targeted tests, comparing it with the first one. These tests would allow us to draw conclusions for the second candidate without repeating the entire set of tests we had done for the first. We would repeat the same with the third and fourth candidates. The idea was to quickly terminate the less promising candidates, concentrate on the best two, and with a few additional tests select the final candidate that would move to a Phase 3 study. ”
从构建的12个疫苗到选出4个候选进入临床，再到3期选中1个，每一步都要过关。
“The FDA had set a limit of at least 50 percent efficacy for a vaccine to be approved. Our team had designed the study to be able to demonstrate vaccine efficacy of 60 percent, an even higher internal standard. The FDA usually asks for two months of safety data for Emergency Use Authorization and six months of safety data for full approval. Regardless, our team would follow up with the enrolled participants for two years. The statistical analysis that our mathematicians performed indicated that for this level of efficacy (60 percent), they would need a total of at least 164 events of COVID-19 (participants who get the disease) to demonstrate statistically significant efficacy. A study size of ten thousand to fifteen thousand participants could potentially generate these results in less than a year (dependent on incidence rate of disease/infection). They decided to blow out the study size and go for thirty thousand participants so they could accumulate COVID-19 events faster (later we increased this number to over forty-six thousand).”
早期仅仅是60%的有效率预估。为了加速，只能扩大临床规模，都是钱啊。
“I told the global presidents of these business units that they should each consider their unit like an entrepreneurial biotech company, with the presidents of each business unit acting as CEOs and with me in the role of the CEO of a private equity firm that owns them.
“A private equity firm does three things with the biotechs they own,” I told them.”“First, it appoints their management. I have appointed you. Second, it agrees with their management on the strategic direction. We have discussed and have clear alignment on the strategic direction that each one of you should follow. Third, it allocates capital to them. You will have to compete for that. The best proposals will get the funding.”
不得不说这种灵活的组织安排犹如创业公司。
“We had developed four vaccine candidates, each representing a unique mRNA format and target antigen combination. Two of the four vaccine candidates included a nucleoside-modified mRNA (modRNA), one included a uridine containing mRNA (uRNA), and the fourth vaccine candidate utilized self-amplifying mRNA (saRNA). Each mRNA format was combined with a lipid nanoparticle formulation. Two of the vaccine candidates encoded an optimized full-length spike protein, and the other two candidates encoded the receptor binding domain (RBD) of the spike protein. The RBD-based candidates contain a piece of the spike that was thought to be important for eliciting antibodies that could inactivate the virus, while the longer spike protein was thought to be important for eliciting a broader or more differentiated antibody response. The first studies in humans were meant to compare the four candidates at different dose levels. The dose escalation portion of the Phase 1/2 trial included approximately two hundred healthy subjects ages eighteen to fifty-five and targeted a dose range of one microgram (µg) to one hundred µg, aiming to determine the optimal dose for further studies as well as evaluate the safety and immunogenicity of the vaccine candidates.
“We had two promising final candidates, two different vaccine formulations. The first (known as b1) was the one that used only the RBD of the SARS-CoV-2 spike protein. This candidate had the most data and appeared to be an excellent choice. The second (known as b2) was the one that used the full-length spike protein. It appeared to have a broader immune response with fewer tolerability issues, fewer chills, and fewer headaches. Very preliminary data was also indicating that it might be potentially more potent in older adults, who were more susceptible to severe COVID-19 in the first place and whose immunity was more difficult to boost.”
艰难的四选二、二选一，最难的成功了。
“From the ninety-four cases of confirmed COVID-19, ninety belonged to the placebo group.” I was shocked and felt I’d misheard, so I abruptly interjected.“Did you say Nineteen? One–nine?”“No. Ninety. Nine–zero!”“But what is the efficacy?”“Ninety-five-point-six percent, sir.”
Doug and I remained speechless for a few moments.“How conclusive is this number?” I asked.“The statistical significance is very high, sir,” one of them replied. “We do not expect this number to change much when we have all the one hundred sixty-four cases accumulated and proceed to the final readout.”
中期见到了95.6%的有效率，难以置信。当初的预估只有60%。
“For context, total vaccine production at Pfizer at this point, before COVID-19, was two hundred million doses per year, including Prevnar, a pneumococcal flu vaccine to protect infants, kids, and adults. Prior to the pandemic, Prevnar was our largest-volume vaccine, and it had taken ten years to get to that level of production. I knew that we would need to double our overall vaccine production in just nine months. And we would need to do so on an mRNA platform that had not been used at any scale, ever.”
“The key ingredient in our COVID-19 vaccine would prove to be lipids. Remember that our vaccine uses lipid nanoparticles to transport mRNA to instruct cells to make the SARS-CoV-2 spike protein. Lipids, which are chemically synthesized, became the most important constraint to solve for. They were a new ingredient, not used at scale in other vaccines.
To make matters even more complex, there are four different lipids needed. Two are proprietary and two are commodity. And so where does one go to buy large volumes of diverse lipids? It turns out, not many places. On the commodity side, niche chemical companies became critical partners. The term “working together” does not sufficiently describe the extreme collaboration we had with the entire biopharma ecosystem.”
关键原料：脂质体，还需要4种，供应链就很关键了。
“As we set our sights on producing larger and larger volumes of vaccine, we became concerned about the capacity of our already overburdened suppliers. The solution we landed on was to build our own capacity. This meant replicating the pumps and T-mixers dozens and dozens of times into lipid nanoparticle skids. The tech industry has seen warehouse-sized data centers with hundreds and hundreds of racks of network computers. Those racks of computers combine to form cloud computing. It’s a similar idea with our lipid nanoparticle skids. Combined, they can produce massive doses of vaccine. ”
“Of course, we are doing aseptic formulation and we cannot host our new formulation suites under a tent. But the concept is what is important here. We can order prefabricated modules that we can install in our Kalamazoo manufacturing site within months, not years. There is a producer in Texas that makes them. We can give him specifications, build them there, and transfer them to Michigan with special large trucks. We will have to do the transfer at night, and we would need the police forces of several states to cooperate with us for this operation, but it can be done. It would take us months instead of years,” Mike said.”
“This breakthrough in logistics will become increasingly useful in the future as we explore new mRNA technologies.
Vaccines have always faced a last-mile problem. We can ship the vaccine thousands and thousands of miles by planes, trains, boats, and automobiles, but that last mile into the center of a city or a remote community—all the while preserving a subfreezing cold chain—requires solving a snarl of complications. Inventing a therapeutic drug or a vaccine is the first mile, but there remain many miles to go. Medicines have always faced this challenge, which is why some companies and philanthropies have invested in mobile refrigeration. Cool.”
“Another challenge we recognized early on was to reduce waste and increase the number of doses per vial.”“Another challenge we recognized early on was to reduce waste and increase the number of doses per vial.
At the time we submitted our first regulatory applications, we knew that we were filling our vials with enough vaccine volume so that after dilution each vial would have approximately 2.25 ml. For each dose we needed 0.3 ml, so inside every vial we had volume for at least six doses. The challenge was that you cannot use all the volume all the time. After injection, some volume will remain unused, typically in the space between the needle and the tip of the syringe, as “dead volume.” There”
“He had noticed that we were significantly overfilling our vials and told me that according to his calculations we were wasting 40 percent.
“Albert, we must find a solution to this,” Ugur told me.
I brought it up to the team, and we started exploring solutions. We agreed to a plan that would allow us to test many different combinations of syringes and needles and find how many doses could be extracted with each. But at the time of the submission, we hadn’t done the work to determine the maximum number of doses that we could safely extract from each vial, and for this reason, we filed our application indicating only five doses per vial.”
“The way we price our medicines is by calculating the value they bring to patients, to the healthcare system, and to society. Unlike what some may believe, good medicines reduce, rather than increase, the cost of a healthcare system. We try to calculate this economic value. For example, if one hundred people take a heart medicine and as a result we have five fewer heart attacks, we calculate the cost that these five heart attacks would generate to the healthcare system (ambulance rides, hospital stays, tests, doctors, caregivers, work days lost, etc.) and compare it to the cost of the medicine for one hundred people. Of course, there are many more nuances to this economic value. How does one put a price on the avoidance of human pain? This, in my opinion, is truly invaluable.
I asked our pricing team to calculate the usual economics of the global COVID-19 crisis, and they came back with staggering numbers. For an assumed 65 percent efficacy, the reduction of hospitalization costs alone would be hundreds of billions of dollars. We could price the vaccine at $600 per dose, and still the healthcare system would pay less than it saves—not counting the value of human lives saved. I realized that this could become a gigantic financial opportunity for us but also that in the middle of a pandemic we could not use the standard value calculation for setting the price. I asked for a different approach. I told the team to bring me the current cost of other cutting-edge vaccines like for measles, shingles, pneumonia, etc. In the US they were priced between $150 and $200 per dose. It sounded fair to me to match the low end of the already existing vaccine prices. No one could say that we were using the pandemic as an opportunity to set prices at unusually high levels.”
“In the US, pharmaceuticals ranked near the bottom of all sectors, right next to the government, in terms of reputation. I again asked the pricing team to give me the current prices of the cheapest commodity vaccines. In the US, flu vaccines cost up to $70, but they also offered a low protection rate of around 50 percent. Their low end is around $20 to $30.
“We are changing course,” I told them. “For the high-income countries, the starting point should be the low end of flu pricing. We can still offer discounts for high-volume commitments.”
“Equity doesn’t mean that we give everyone the same. Equity means that we give more to those who need more. Therefore, we couldn’t have a single price for all. Instead, we decided to implement a three-tiered pricing approach. We used the World Bank’s classification of economies for our own analytical purposes. ”
“Most of the high-income countries were among the first to place orders to reserve doses of our vaccine through 2021. Europe, the US, Japan, and the UK were among the many that included us in their bets. Unfortunately, many other countries, particularly middle- and low-income, decided to go exclusively with other vaccines, either because mRNA technology was untested at that time or because other companies had promised local manufacturing options. ”
不容易的定价。特别时刻特殊定价，商业化要卖到600，为了大家最后实际美国采购价只有19.5。
“In the meantime, the US Trade Representative, Katherine Tai, announced suddenly that the US would support a waiver of the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement for COVID-19 vaccines at the World Trade Organization (WTO). The TRIPS agreement is an international legal agreement that was signed in April of 1994 and became effective on January 1, 1995. The agreement introduced intellectual property law into the multilateral trading system for the first time. India and South Africa had requested such a waiver from the WTO, but there was no traction for this request so far. Interestingly enough, both countries are among the largest generic medicine manufacturers in the world, and for many people the request looked quite self-serving.”
“The US made this a condition to COVAX and decided to purchase five hundred million doses with an option to procure more. It was a major step toward vaccine equity, and I was proud that we were leading the way. There was, however, one stubborn issue that needed to be resolved first with respect to liability-related provisions. ”
“ I called Netanyahu back. A few hours later, he returned my call. Ron Dermer, Israel’s ambassador to the US, was already on the line, together with Israel’s national security advisor. I looked at my watch and calculated the time in Israel. I was shocked. “Prime minister, it is two thirty in the morning!”
“Don’t worry about that. I don’t need much sleep,” he replied. “Look, Albert. If we leave this just to the lawyers, we will never get it done. I will conference our head lawyer now. Can you do the same?”
I felt a little bit uncomfortable, but I was also intrigued by his decisiveness and sense of urgency. ”
“The rise in infections was occurring with the introduction of the more infectious delta variant, and what we needed to determine quickly was whether the upsurge in cases was caused by lack of efficacy of the vaccine against this variant or the gradual loss of efficacy over time. This had critical implications not just for Israel but also for the world, because if the former was true, then a new vaccine tailor-made to prevent the delta variant needed to be developed immediately. Our analysis revealed that the efficacy of the vaccine was waning over time and most specifically among the individuals vaccinated in large numbers beginning in December. ”
“New mRNA technology could drive prevention and early detection of disease.
The breakthroughs we have made with mRNA vaccine technology may allow for one vaccine to provide protection for multiple diseases, decreasing the number of shots needed for common vaccine-preventable diseases. In addition, cancer research is studying how to use mRNA to trigger the immune system to target specific cancer cells. ”
“At the time of this writing, cumulative global mortality from COVID-19 has surpassed five million, a horrifying toll, and it will continue to rise. But each and every year, about seventeen million people die from cardiovascular disease and ten million from cancer. Are these patients somehow less deserving?”
“The first truth is that our breakthrough vaccine was the result of the rare combination of brilliant, cutting-edge science powered by the private sector alongside collaborative engagements with governments. It’s fascinating to see that in the last year “mRNA” became a household word. Laypeople followed the science as if it were a popular sport. It’s imperative that our society continues to respect and honor science. ”
“Let us always remember that businesses have the power to make a positive difference. Corporations play a vital role as engines of creativity and avenues of opportunity. Commercial pressures require businesspeople to quickly discover and adapt new technologies and boost efficiency and productivity. Entrepreneurship and innovation go hand in hand.”
“This culture that we created gave us the appropriate mindset and allowed Pfizer to move with the agility and speed of a small biotech and bring to the world a breakthrough vaccine that is dramatically changing the lives of so many. Whether you are a leader or a team member, I would encourage you to ask yourself the following three questions during every step of your journey:
Am I being true to my purpose?
Have I aimed high enough?
Do I have the right mindset?”