By Danielle Antoinette Young and Stephan Kutzer, AKDYS LLC
September 17, 2020
With almost 30 million infections and close to 950,000 recorded deaths worldwide (~200,000 in the US), the Covid-19 (SARS-CoV-2) pandemic developed into the third leading cause of death in the US for 2020 and has thrown life as we know it and the world’s economy into total turmoil. Governments and health organizations experience varying (and fluctuating) levels of preparedness and success in their testing, tracing, screening and containment efforts, while pharma & biotech companies are feverishly working on the development and testing of vaccines, plasma and antiviral treatments to prevent, reduce severity or even cure the still spreading viral infection.
The approximately 180+ global vaccine candidates, currently in various pre-clinical and clinical stages, range from investigational vaccine technologies to the repurposing of centuries old “tried-and-true” techniques. News outlets cannot allow these emotionally charged times go to waste, and immediately publish headlines for every positive or negative trial progress update, with people glued to their smartphones on the other end desperate for any answers they can get during this unending time. This is followed by an instant worldwide stock market reaction, keeping not only financial advisors and their clients, but also the general population, on edge as they watch their retirement accounts go on a roller coaster ride. All the while, families whose incomes have dropped from the pandemic are kept awake at night trying to figure out how to make their basic ends meet. More stress and uncertainty is added when people are faced with a barrage of conflicting or changing opinions from different “experts” and agencies (hydroxychloroquine anyone?) about what to do, what not to do, what the latest science and data are saying and when to expect to get back to pre-pandemic life, if ever.
The heightened sense of urgency, that is further increased by the aforementioned highly politicized, 24/7 media coverage, challenges the established “rules of engagement” of drug development instituted by the pharmaceutical and biotech industry and its regulatory agencies. Proven and preset guidelines based on product safety, efficacy and therapeutic benefit are questioned, challenged and changing in the race for needing approval “yesterday”. The broad and open public and private discussions about the pros and cons of making overnight changes to the development & approval process and taking calculated risks & shortcuts for Covid-19 vaccines are leading to an increasing vaccine hesitancy by the masses, even in potential high risk groups. The pledge by the leading innovators to only release safe and effective products is offset by breaking news of serious trial side effects on the same day.
Right now, the vaccine efforts can only be called a “Hail Mary” approach to vaccine development with countless moving parts and logistics that lead to unrealistic (or misleading statements about) launch dates for a mass produced, publicly available, long lasting, proven safe and highly effective vaccine.
While the approval and recruiting for the various clinical trials seemed to ramp up quickly, some drug companies disclosed their current trial patients lack the diversity required to represent critical at risk groups.
This leads to a slowdown of recruiting to focus on those populations that are underrepresented or an expansion of the trial patients (up to 50% increases in participants). Let’s also not forget, no children are being tested in the ongoing FDA Phase III trials as of date, with only one trial announcing they plan to include adolescents as young as 16 years old.
Digging further into the funding fine print, we see substantial portions of the money allocated for bioreactor and fill-and-finish capacity buildout, validation, qualification and approval. Skilled plant operators, technicians and lab personnel must be identified, hired and trained. The lead times for up and downstream single-use and stainless steel manufacturing equipment were a bottleneck before the Covid-19 crisis and the vial glassware, stoppers and caps supply situation was and continues to be a challenge. And then, there is still the question of visual inspection, stability testing and ultra-cold storage and the timely cold chain distribution of billions of vials worldwide that needs to be addressed.
Going through the endless list of risks, obstacles, challenges and problems should remind us that the safe development of new therapies, lifesaving drugs and vaccines, along with their temperature controlled distribution around the world, is a very time, cash and capital consuming process that requires a lot of hard work and even more patience. Let’s not forget, that the average drug success rate from Phase I to approval is still below 10% (19% for infectious disease candidates) and scientists, researchers and immunologists have advised that herd immunity against Covid-19 is not feasible without a vaccine. Even then, if the vaccines approved are on the lower end of FDA’s acceptable efficacy range (>50% primary efficacy endpoint) we might end up with a vaccine at too low efficacy level to reach herd immunity. Or a vaccine that requires rigorous, repeat administration if the effectiveness wears off.
According to latest announcements, the US government alone has invested north of $10 billion in Covid-19 vaccine development, clinical trials, manufacturing capacity, vial and syringe reservations for the 7 leading vaccine candidates and, along with other governments, has called “dibs” on hundreds of millions of doses to vaccinate their citizens. CMO/CDMOs are lined up, reservation fees are paid and accounted for in the 2020 & 2021 financial outlooks. Despite recent announcements about trial delays and holds, it is pointed out that the CMO/CDMO financial outlooks for 2020 and 2021 have a decent probability of being unscathed due to the contractual structure of their funding. Beyond that is yet to be seen if and when the additional milestones are met.
We will not debate these timeline assumptions by getting into topics like technology transfer, scale-up and GMP manufacturing – challenging project in their own right that manufacturers are facing on the march to large scale production.
Let’s also not lose sight of the potential safety stock depletion or development delays of other drugs who moved down the queue due to limited research and manufacturing capacity. And we will not touch on the topic of collaboration by competing vaccine companies to maximize output of a single vaccine candidate if proven to be the safest, most highly effective and distributable vaccine.
So, is there ANY good news?
The leading vaccine candidates had overall successful Phase I/II safety results with mild side effects. The data shows the creation of antibodies against SARS-CoV-2 (or its spike protein). Phase III trials are ongoing and continue to feverishly recruit diverse patients. There is hope that Phase III initial results will be available at the end of October. Health officials are still cautiously optimistic that a safe, effective and approved vaccine will be seen at the end of this year or early next year, with available doses for all Americans by the end of 2021.
As a refresher, the fastest vaccine developed (mumps vaccine, licensed by Merck) to date took 4 years to develop before its introduction in 1967. We are now ~7-8 months into the Covid-19 vaccine race and are seeing a lot of record breaking progress on a large number of candidates that give confidence that introduction of a vaccine(s) will beat the 4 years record by far. But bets on how fast and by whom are keeping the Russian bookies busy.
The ink on the first tech transfer protocols is drying, testing assays are developing. Stockpiles of vaccine-hopefuls are starting production, distribution channels are lining up to offer quick transportation at the required temperatures, new capacity is in the works with equipment on order and the FDA is adjusting their resources and focus to quickly review generated data. We are all hopeful that one or more of the vaccine candidates will make it.
While the ultimate goal is a one time, one shot solution, the current expectation for the most advanced vaccine candidates is a 2 shot solution. The length of time the vaccines are effective for will be determined through continuous monitoring of patients.
What is your point with all of this?
It is therefore fair to say that any predictions about the first vaccine launch date or future demand forecasts and, therefore, capacity requirements and future revenues for CMO/CDMOs, are a wide ranging hypothesis. As much as we all hope that we not only find the perfect solution to bring us back to life as we knew it ASAP and that the investments in capacity and supply chain will generate a payback, we simply just don’t know – yet. It’s virgin research!
One thing the vast majority of experts have a consistent response on is that for the foreseeable future, social distancing and covering of mouth and nose is the most readily available, widely accessible “vaccine” to bring down and keep low the number of Covid-19 infections.
As the director of the CDC said during his testimony before the US Senate, a face covering is the most important protection against COVID-19 that we currently have and may ever have.