When the pandemic started the United States government sought to protect its citizens with travel bans. That quickly escalated to quarantines and contact tracing on those affected. Cruise ships were quarantined and passengers held in military bases. Once the community spread started there was a run on PPE and masks. At first Fauci said “there's no reason to walk around with a mask” many speculated he was worried about a shortage of masks for healthcare workers. A look back at that policy; what was he thinking! Novel antivirals like Gilead Science’s remdesevir which was used in China moved onto center stage using the logic that if it works on ebola maybe it will work on COVID-19. Then Italy and Iran exploded with new cases and deaths. Then came the lockdown coupled with a stimulus package. The government’s answer was flattening the curve. To prepare for the wave of infected, ventilators were ordered en mass. Without solid clinical trial results remdesivir won Emergency Use Approval(EUA). The country started to come out of lockdown and the primary plan to deal with the virus was to develop a vaccine as quickly as possible and have Operation Warp Speed (OWS) ensure a ready supply of the most promising treatments upon approval.
Early Convincing Therapeutic Evidence - IGNORED
Not once did the government, key opinion leaders, or the media ask if there is a safe drug that could be repurposed for COVID-19 that takes people off the ventilators, gets them out of the hospital quicker, and is easy to administer. Before OWS was founded on May 15th 2020 here is a timeline of a therapeutic that was ignored by almost everyone.
Early Media Framed the Messaging - Take Dying off the Table
In the beginning stages of the pandemic Jim Cramer gave almost daily commentary that we need to get people out of the hospital and that people need to not fear that they are in danger of dying if they go back to work. The genesis of his ideology started on March 3rd after a surprise interest rate cut. On CNBC he said “If you got a drug, something that allowed you to get out of the hospital, if we had a vaccine, anything, then you won’t need this rate cut.” As the pandemic progressed he refined his stance and believed that scientists would solve it. Cramer said
“One of these things is going to stick as antiviral to get people out of the hospital faster,” he added. “That would be a major change in psychology in this country if you did not think a death sentence meant going to the hospital.”
On April 23rd, Cramer added that a COVID-19 antiviral would bring down the “fear level” in the US.
“If we get a vaccine, we will have some degree of normalcy and return to the American way of life.
During this time frame Cramer was pulling for a mortality benefit from the antiviral remdesivir. On May 1, 2020 when the FDA announced Emergency Use Authorization (EUA) of Remdesivir the mortality rate was not 8% versus 11.6% and failed to be statistically relevant. In the interim leronlimab was racking up compassionate use cases and saving lives and ultimately ended up with 70 Emergency IND’s before the FDA pulled the plug and told them that they needed to focus on completing their trials. One such study of eIND patients held at UCLA had saved 23 of 30 patients. Eligibility into an eIND means that there is a very high likelihood of death and it's so life threatening that there isn’t time to convene an Investigational Review Board (IRB). This was a very sick patient population that appeared to do better than regular hospitalized patients. A clear sign of anecdotal efficacy, but multiplied by 70.
The Curve Flattened - No Therapeutic Approved Yet
The whole idea behind flattening the curve was to not exceed the healthcare system capacity because that would result in poorer patient care and ultimately more deaths. The lockouts were supposed to reduce the amount of daily contacts and buy the country valuable time to get PPE gear, ventilators, and most importantly buy the scientists time to come up with a solution. Trump touted Hydroxychloroquine early and then a number of studies surfaced that debunked the effectiveness of the drug leaving him without a therapeutic. Everyone was hoping for a therapeutic that takes dying off the table and thought remdesivir might be it, but remdesivir was literally rammed through the approval process after STAT News announced an early peek at the data. This forced Fauci’s hand to quickly announce it was the standard of care before any more studies could debunk it. The early peek actually compromised the blinded nature of the trial results, but too many people were happy that they had something even though remdesivir didn't do much.
The unintended consequence of the EUA approval for remdesivir was that it crowded out other therapeutics including leronlimab despite its stout safety and efficacy profile. EUA approval of remdesivir took the heat off the administration and the FDA to find a therapeutic that worked. The EUA announcement had a calming effect on Americans that were crying out for the government to “do something!” It was relatively impractical for physicians to use because of all the limitations placed on its use especially those with underlying liver disease. The EUA approval placated the country long enough for the government to come out with Operation Warp Speed (OWS) and show its citizens the path through the pandemic was a therapeutic or vaccine. However, based on the level of funding, the government was clearly betting on a vaccine all along. Reviewing this sequence of events before OWS was announced reveals that one of the most promising therapeutics for COVID-19 was under development and not part of the national dialogue thanks to STAT News.
Despite its EUA for all hospitalized patients, it's very clear now that remdesivir is a failed drug. The WHO’s Solidarity trial enrolled over 11,300 patients in 30 countries and used different combinations of drugs which include redesivir,hydroxychloroquine, lopinavir, interferon or interferon plus lopinavir. The conclusion was that no drug or combination of drug reduced mortality. Many pundits point to a lack of a control arm, poor procedures, and a mixture of drugs. What is utterly amazing is that none of these pundits said that it just doesn't make sense as to why this antiviral is being given in the hyperinflammatory stage of the disease. Remdesivir might actually work early in the disease, but we will never find out because what person in their right mind is willing to accept a 25% chance of severe side effects like organ failure, septic shock, liver damage, or kidney injury when they have a 97% chance of recovering on their own.
The problem with a vaccine is that the FDA is only shooting for 50% efficacy. It won't take dying off the table. Only a therapeutic option like leronlimab can take dying off the table. There are about 9 vaccine candidates in phase 3 clinical trials. One of the top contenders in the vaccine race is AstraZeneca, but it was recently put on hold in the United States due to an adverse reaction. The study in the US is still on hold since September 8th, and the FDA wants to see data from similar trials before lifting the hold. J&J and Eli Lilly were co-developing a vaccine and it “temporarily paused further dosing” in its clinical trials while it investigates an unexplained illness. These pauses or holds for safety highlight just how challenging it is to make a vaccine.
Other vaccine makers like Moderna which is using messenger RNA (mRNA) to trigger the immune response in order to make a lasting vaccine and Pfizer with its partner BioNTech are also reporting serious side effects in their trials. Five patients across two studies reported intense chills, high fever, exhaustion, and pounding headaches. These perceived failures are wearing on public opinion. In a recent CNN poll only 51% of respondents said they would try a vaccine if it were available. While the government may be planning for a vaccine the American people seem to want a therapeutic that takes dying off the table.
The first major failures were in IL-6 inhibitors that were sponsored by BARDA. Roche Holdings tocilizumab was a repurposed arthritis drug. In late July it failed to meet its endpoints in a phase 3 trial. Sanofi and Regeneron’s drug sarilumab failed to meet its endpoints and raised additional concerns about safety. These were IL-6 inhibitors that were designed to quiet the cytokine storm.
Big Pharma Candidates - Flash then Fizzle
The Regeneron cocktail taken by President Trump claims to reduce viral levels and improve symptoms in non-hospitalized COVID-19 patients. The drug cocktail consists of two monoclonal antibodies that attach to the COVID-19 protein spike and target the virus for destruction and prevent cell entry. The interim trial results were based on 275 patients non-hospitalized COVID-19 patients. The patients were stratified into three groups seropositive (producing antibodies), seronegative (no measurable antibodies), and unknown. Approximately 45% were seropositive and 41% were seronegative, and 14% were unclear. The seropositive group was likely to get better without treatment and reached the lowest levels quantifiable (LLQ). The seronegative benefited the most and reached a key virological endpoint through day 7. The trial was looking for a change in the nasopharyngeal (NP) viral load from baseline. Patients with the highest viral loads at baseline benefitted the most. These findings are in line with the theory behind antibodies and their effect on viral load. There was also a slight benefit in alleviating symptoms in these seronegative patients from 13 days on placebo to 8 days in the high dose and 6 days in the low dose. Now this doesn't make any sense that a low dose would do better but that was the purpose of the study which showed that the antibodies were saturated and they had a maximum benefit. This allows them to use the low dose and treat more patients. This is an expensive drug that seems to work but there are 50,000 doses available and at the current infection rate that could be gone in days.
The other big pharma drug that recently made a splash was Eli Lilly. They too came up with a neutralizing antibody and demonstrated they reduced viral load at day 3, 7, and 11. The drug also lowered the hospitalization rates to .9% vs 5.8% in placebo. There were no treatment adverse effects so they filed for EUA. Within days the NIH paused the study for safety concerns following the DSMB recommendation to pause enrollment. This is yet another blow in the quest for a treatment.
Leronlimab to Take Dying off the Table
The DSMB recommendation after interim analysis of the severe to critical trial COVID-19 patients is set to be released after the bell today. The range of possible outcomes is a recommendation to stop the study based on efficacy to a recommendation to continue the study and increase the enrollment. Eliminating the two extremes and focusing on the middle options leaves 2 possible scenarios, a reduction in the number of patients which is very rare or continuation of the trial. Since both of these options have endpoints of mortality the company is likely to argue for an EUA with the FDA. They will cite that since they are on track or ahead of their plan to meet their statistically significant endpoint the FDA should move for immediate approval.
Major Medical Breakthrough - Unnoticed
A medical breakthrough in COVID-19 was discovered in March at Montefiore Medical Center using a repurposed HIV and cancer drug. The first two critical patients with hours to live and comorbidities were dosed with leronlimab. Both were off the ventilator in 2 days. For some reason mainstream media never picked it up. This lack of media coverage has probably cost Americans 10’s of thousands of lives if not 100’s of thousands of lives. Fauci wanted proof from a randomized double blind placebo controlled trial. Proof in a form of an interim readout is likely coming hours away. This clinical trial’s endpoint is a reduction in mortality which is considered the gold standard of clinical trials. If the DSMB reports that the clinical trial is likely to meet its endpoint and that they should continue the trial, CytoDyn will likely immediately apply for Emergency Use Authorization from the FDA. Their case will be simple because some analysts have estimated that over 30,000 lives may be lost while waiting to finish the trial. The company might claim that due to the pandemic there could be a huge loss of life while spending the time to complete the study. The drug has one of the best safety profiles and actually filed a BLA earlier in the year so the FDA is well versed on its safety.
If leronlimab works and gets approval, the notion that only big pharma has good ideas is a dangerous ideology that may have ultimately cost tens of thousands of American lives. Operation Warp Speed has ignored this drug, Trump has ignored this drug, Fauci has ignored this drug, media has ignored this drug, and the sensationalist STAT News Analysts that brought America remdesivir has berated this drug, but the American people know better and will stand united as they demand approval.