Lessons from COVID-19 Clinical Trials
Nate Hughes, MPH, MPP
South San Francisco, CA.
November 20th, 2020
« Dear Dean Klag, Lisa, Marie, Nate
I trust you are all doing great! I have been talking with couple of people including folks from CDC working with Ministry of Health in Liberia. We are tackling the Ebola epidemic here in Liberia since March and the entire region. Since we got the promising news about the ZMAPP product use on the Americans the population here has been so concern.
These are few things I need answers if possible: They are:
1. Is ZMapp available in significant quantities for use in Liberia. Liberia will give expedited review and approval for clinical trials with the antibody. I know I can work with researchers at Hopkins like Dr. Moss and the rest of the folks to jump start this.
2. Even thought the safety and efficacy is not confirmed, Liberians are willing to sign consent for experimental use.
3. The Ministry of Health of Liberia would like to know if there is any way for rapid mass production of antibody in short time.
4. The greatest public health school in the world JHSPH need to work with me and the Government of Liberia to find some solutions and get to play an active role in this. Liberian I really dying in their numbers including health workers, prominent Doctors.
I am okay and doing my best to mobilize local and international support. I miss all of you! Lisa thanks for your help!
Find attached the latest Sitrep 84.
I look forward to hearing from you. I am extremely overwhelmed with this outbreak.
Tolbert G. Nyenswah Esq, BSc, LLB, MPH
Legal & Senior Public Health Specialist
Assistant Minister of Health & Social Welfare/Deputy Chief Medical Officer-Preventive Services
1000 Monrovia 10, Liberia, 9009
It was a little past midnight on Saturday, August 9th, 2014 when I woke up to a series frantic text messages from my friend and Hopkins colleague, Tolbert Nyenswah, who had been recently appointed as the Assistant Minister of Health by Ellen John Sirleaf, who was then serving as the 24th President of Liberia. It had been only two years earlier when we were still attending Johns Hopkins for our MPH degree, and found ourselves sipping on beers at the local Happy Hour in East Baltimore. I remember Tolbert shrugging me away, as I hurriedly attempted to grab us two Flying Dog IPA’s. I could tell he was talking to someone important on his cell but did not know it was President Sirleaf. Tolbert had been perhaps the most dependable study buddy I had at Hopkins, and when we were faced with both failing “Principles of Epidemiology” and retaking the course, we would meet at 6 a.m. at the library and study for 8 hours straight, memorizing odds ratios, relative risk fractions, and Epi case studies. We relied on each other. Both of us took “Public Health Preparedness” not knowing that we would both use this class later in life, and its coveted lessons, against two global pandemics. We both eventually passed Epi solely because of our intense friendship and declaration to help each other get through the challenging Hopkins coursework. Little did we know that the discipline of Clinical Epidemiology would shape our professional and public life.
When Tolbert informed me about Ebola for the very first time, and the few cases that were emerging in Liberia, I immediately alerted my public health heroes and first-responders, then Johns Hopkins Bloomberg Dean Mike Klag and Chair Marie Diener-West, Paul Farmer at PIH, Raj Panjabi a Last Mile Health, and even Tony Fauci at NIH. How can we respond effectively to something so scary as Ebola, in real-time? Tolbert needed medical supplies, he needed ulnar gloves, he needed ZMAPP, an experimental therapy comprised of 3 chimeric monoclonal antibodies. Where would we get this from? Johns Hopkins Hospital? I jumped in my car that Monday and drove to San Diego, desperately trying to find a company called MAPP Pharmaceuticals. When I entered the small office, I saw a man by the computer and introduced myself hurriedly. “I need ZMAPP.” The CEO, Kevin Whaley, and I connected since him and his wife were both Hopkins trained scientists and he was familiar with my academic advisor at JHH, Dr. Charles Flexner. “I can’t give you ZMAPP,” he said. “You will have to go through the CDC in Atlanta.” I felt like I was on a treasure hunt, and one request led to another bottleneck and so on. But the point is that when public health crisis hit, you have to assemble the right folks at the right time, and follow a pattern similar to discrete event simulation: time, resources, and finding bottlenecks and removing them to increase speed and capacity are all at stake to save lives. There is a rush, but there is a desperation as well. Eventually, Tolbert was able to help control Ebola, and eliminate all active cases from his native country.
The Ebola lessons of 2014 are fundamentally different from the emergence of COVID-19. First of all, Covid-19’s spread was much greater than Ebola, which was largely contained to West Africa region. So Covid has become more politicized with the requisite participation of more stakeholders at international levels, e.g. controlling trafficking of passengers, wearing masks, the advent of contact tracing, and public policy interventional mechanisms to control community spread.
But there are also similarities. Covid-19 and Ebola affect the poorest of the poor. How can you quarantine when you are a family of 5 living in a studio apartment in East LA with nowhere else to go? When your grandmother is living with you, and she gets sick, and transportation is lacking, or the distance from your apartment to a local hospital, or there is a cultural fear of getting sick, or so on? How do you a convince an undocumented immigrant who lives with the fear of being deported by ICE to go in for a test? It is impossible to separate out public health discrepancies and illness. “Of all the forms of inequality, injustice in health care is the most shocking and inhumane.” This quote by MLK rings shockingly true, especially when considering the public health pandemics of Ebola and Covid-19.
I have been working on Covid-19 trials, from a business development perspective, since March 2020. Since that time, our own federal government’s Operation Warp Speed, has picked up the pace on vaccines, where both Pfizer and Moderna have released critical efficacy data in their vaccine studies. BNT162b2 is a COVID-19 vaccine candidate developed by BioNTech and Pfizer, and given by intramuscular injection, with 90% efficacy. While certainly not a panacea, Moderna’s mRNA-1273 Phase 3 trial reported similar efficacy with their vaccine at 94.5%,
The trials I have been managing from a purely BD perspective, along with ClinOps teams, has been on the therapeutic and not vaccine side of the business. I wanted to share a few perspectives from these trials, one of which is in the public domain, a monoclonal antibody for Acute Respiratory Disease (ARDS) called Lenzilumab.
There is a trend with biotech’s submitting an IND (Investigational New Drug) for a drug in trial that could potentially be used as a therapeutic agent against ARDS; mAb’s and small molecule programs in IPF (Idiopathic Pulmonary Fibrosis) come to mind. That is, a company might have a drug under investigation for another therapeutic indication and will reach out to a CRO to re-write the IND (and eventually submit a new one) for Covid-19. The purpose of this is two-fold; one, to create a blue oceans strategy for the company’s shareholders where they can have a linchpin on the Covid market as it develops rapidly. Two, submitting an IND for Covid-19 is expeditious because the biotech does not have to write a completely new IND. It is just amended for Covid, and then once approved through expedited timelines, a company can seek expanded access through the FDA pathway. This is what happed with Humanigen. They had submitted an IND to FDA Oncology division for their Phase 1b/2 ZUMA19 CAR-T study (cytokine storm; cytokine release syndrome or CRS affects CAR-T patients as does Covid). This was a pre-IND/IND (or PIND) for their Kite CAR-T trial.
Now would submit the same IND to Infectious Disease experts, John Farley and Janet Woodcock for Covid-19. Eventually there would be a completely new IND for the proposed Covid use. But for the time being, what we did was suggest that Humanigen use their current IND for the 5 completed/ongoing multicentre trial for the prevention of CRS in patients receiving CAR-T for relapsed or refractory cancer (Kite-Gilead trial). We successfully received compassionate use/expanded access from the FDA. We started the trial in the USA with 10 proposed sites, and expanded sites across Russia and LATAM. Currently, according to Humanigen’s corporate website, they have a total of 53 sites including 30 in USA.
When I was awarded the Humanigen Phase 3 trial for ARDS, I sent out a press release to local Bay Area companies and one of them contacted me with a similar interest. They had a program already in a Phase 1 with 2 adult patients, for IPF, and the board decided to submit that IND, also for ARDS Covid patients, and apply the same strategy Humanigen had. I had done this previously with a Real-Time Scheduling software (discrete event simulation) 3 years earlier for NOVARTIS Morris Plains when I put together their Kymriah (the first CAR-T approved therapy in the USA) deal. Along with my CEO at the time, I discovered a new vertical for our optimization platform – cell & gene therapy. I took the Kymriah deal that I put together and immediately scheduled meetings with Kite’s biomanufacturing team (under Tim Moore at the time) in Santa Monica. In this industry, if you have a template of a deal that worked in the market, as a first-mover advantage (or blue oceans) strategy, so to speak, you have to immediately iterate and replicate that in the market as soon as you can. That is what I did for Covid IND’s in ARDS (CAR-T and IPF).
Another fascinating trail, also out of the San Francisco area, is through a biotech called DURECT. DURECT is currently conducting a double-blind, multi-center, placebo-controlled, Phase 2 study to evaluate the safety and efficacy of DUR-928 in approximately 80 COVID-19 patients with acute liver or kidney injury to evaluate multi-organ failure in Covid patients. According to Johns Hopkins, Doctors and researchers are finding that this coronavirus — officially called SARS-CoV-2—can also cause severe and lasting harm in other organs, including the heart and kidneys. C. John Sperati, M.D., M.H.S., an expert in kidney health, often discusses how the new coronavirus might affect kidney function as the illness develops and afterward as a person recovers.
While I am extremely proud of the biotech and pharma industry’s response to Covid-19 (including the critical role that CRO’s have played in these large Phase studies) – and am impressed with aspects of Operation Warp speed (although the transference of BARDA funding away from therapeutics and into vaccines completely I was not in agreement with several weeks ago) – I nonetheless find it imperative to remind ourselves how the poorest of the poor will be relieved of this public health emergency and burden of illness. The mistrust in vaccines in the African American and Latino community, along with the scaling of capacity of these vaccines – chain of custody and chain of identity – and the phases of distribution, will be critical aspects (and potential bottlenecks) which will shape how we defeat this deadly disease. The current mistrust in our medical system by underserved patient populations that are the hardest hid by Covid mortalities and morbidities is intrinsically tied to a historical pattern of disenfranchisement and systemic racism in American public health.
We can’t take our eye off these communities that are the most impacted by the prevalence of Covid. In the final analysis, we must go back to the initial definition of public policy, in general, and public health, in particular: when markets fail, we must rely upon evidence-based approaches that protect the most vulnerable patient populations within our society. That is what the Ebola crisis taught me back in early August 2014, and what Covid-19 teaches me every day.