To learn something thoroughly often requires repeated exposure to the information. It is normal for some learners to not grasp the meanings despite multiple attempts. Not to worry though, they will follow the crowd of leaders. In a few hours we will see how the new leadership is step by step advancing one of the most remarkable new technologies to come along as we see in the monoclonal antibody called leronlimab. Here is a bit of history that does a good job of explaining about the drug. Also we see the failings of the FDA, and the failings of past company leadership though decisions made were based on the available conditions at the time and capital allocations working within a limited budget.
To the FDA: Approve Leronlimab Now for Critically Ill COVID-19 Patients – Article by Dan Elton
May 3, 2021 Dan Elton
Daniel C. Elton, Ph.D.
Author’s Note: This article is cross-posted from my Substack.
How does Leronlimab work?
Leronlimab is a humanized monoclonal antibody that antagonistically binds to the CCR5 receptor to block activation of immune cells and lower the release of cytokines. The development of Leronlimab started with mouse antibodies that bind to CCR5. Unfortunately, mouse antibodies can’t be directly imported into humans since they are attacked by the immune system as foreign invaders. That’s where next-level genetic engineering comes in. Researchers looked at the genes for human antibodies, identifying ones that were closest to the genes for the antibody that the mice produce. They then took the segment of DNA from the mouse antibody that coded for the antigen binding site and stitched that into the human antibody gene. (The antigen binding site is the key part of the antibody allows it bind to the CCR5 receptor). The result is a chimeric or humanized antibody which can be mass-produced in bacteria.
As alluded to, the specific place where these antibodies bind is the CCR5 (Chemokine Receptor Type 5) receptor, a “G Protein coupled” receptor that resides on the surface of cells, in particular immune cells such as macrophages. When the receptor is stimulated, calcium channels open up and Ca++ ions move into the cell, causing activation (movement) of the macrophages.
Leronlimab was originally developed to treat HIV, because the HIV virus uses the CCR5 receptor to get into cells. (By blocking the receptors, the HIV virus could be blocked.) Despite being under study since 2007, Leronlimab is still not FDA-approved for HIV, although it appears to be getting close. To treat HIV, it is given as a once-weekly at-home injection. Researchers have found many other uses, however. For instance, when Leronlimab blocks the CCR5 receptors on breast-cancer cells, it prevents them from moving around so that the cancer can’t move to other parts of the body, which makes the cancer easier to treat. Note that Leronlimab is not yet FDA-approved for any of these possible applications, so off-label use for COVID-19 is impossible.
In the case of COVID-19, infection by the SARS-CoV-2 virus induces stressed endothelial cells to produce CCL5. When CCL5 reaches T-cell and macrophage cells in lymph nodes and binds to their CCR5 receptors, it induces those cells to become activated and then move towards the source of the infection along the CCL5 gradient. Unfortunately, in severe COVID-19, the immune response can be so strong that it leads to tissue damage. CCL5 also induces the production of inflammatory cytokines including TNF and IL-6.
What do we know about the efficacy of Leronlimab?
CytoDyn Inc. published a press release on January 28th, 2020, announcing that it was beginning to evaluate Leronlimab’s use for COVID-19. In that press release, CytoDyn clearly explained the mechanism of action described above, noting that clinical experience in China found that many patients who died from COVID-19 did not die from the virus but from an overactive immune response causing inflammation and the infamous “cytokine storm”.
A study published in preprint form on May 5th, 2020, looked at 10 terminally ill COVID-19 patients on ventilators at the Montefiore Medical Center in Manhattan. The experimenters administered 700 mg of Leronlimab to each patient. Within three days they found that found that IL-6 had decreased in all of the patients, reaching healthy levels in two weeks. After two weeks six patients had recovered while four died (a 40% mortality rate). At that time the mortality rate for ventilated patients was said to be “as high as 88%” in New York City. So, while there was no control group in this study, one can argue there was an observed reduction in mortality here. While the results on reduced mortality are weak due to a lack of a suitable control, the biomarkers studied all showed a reduction of immune response. The researchers found a reduction of new immune cells manufactured in the bone marrow and a return of platelet cell counts towards normal levels. The researchers also found that the concentration of virus in the blood (viremia) decreased. In a TEDx talk, one of the authors, Dr. Bruce Patterson, claims that Leronlimab was responsible for the drop in blood virus concentration. He said this:
“Leronlimab restored CD8 T-cells and increased Granzyme A to better clear virally infected cells. It also inhibits Treg cells and repolarizes macrophages which both enhance the immune response against infected cells.”
I honestly do not understand these details or know how well they are empirically supported by this or other studies.
CytoDyn initiated two Phase IIb/Phase III clinical trials in mid-April 2020 to study mild-to-moderate COVID-19 and severe or critical COVID-19. To their credit in 2020 the FDA did provide about 60 emergency IND (eIND) authorizations that allowed patients to receive Leronlimab. However the company had to defer seeking eIND authorizations to accelerate the pace of enrollment in their clinical trials.
The mild-to-moderate trial did not meet its primary efficacy endpoint, but in a post hoc analysis in the subset of subjects with more severe disease, a higher proportion of Leronlimab-treated subjects (50%; 24/48) versus placebo-treated subjects (21%; 5/24) showed improvement in National Early Warning Score 2 – a risk score for “rapid clinical deterioration requiring critical care intervention” (p ?= ?0.0223).
The severe-to-critical trial also did not meet its primary endpoint — considering all patients, the difference in Day 28 mortality between Leronlimab and placebo was not statistically significant (N=384, 2:1 split, p > 0.05). (Update: a commentor pointed out that the placebo group ended up being younger and was small, so unfortunately they missed statistical significance. You can see all the details here.).
However, the researchers then analyzed patients on invasive mechanical ventilation or ECMO. They found that if Leronlimab was added to the standard of care, then on the 14th day there was a reduction in mortality of 82% (p=0.0233, N=62) and an average reduction in the length of stay of 5.5 days (p=0.005, N=62). They also found a 400% improvement on a 7-point ordinal scale for COVID-19 severity when compared with standard of care.
There have been several clinical reports and anecdotes about patients on ventilators or ECMO who rapidly recovered after receiving a single dose of Leronlimab (see here (N=1), here (N=4), here (N=1), and here (N=1)). A somewhat larger observational study with N=23 patients reported that after 30 days, 74% no longer required hospitalization. Six out of the seven patients that required ventilation survived. The biomarker results were somewhat mixed – while the researchers found evidence of reduced immune activation in the patients who received Leronlimab, they also found that the inflammatory marker CRP didn’t decrease until after two doses were given. Another small study on N=3 lung transplant patients with COVID-19 found a decrease in CRP after one week.
On March 29th, 2021, the Phillippines’ FDA began issuing compassionate use authorizations on a per-patient basis and for up to one year. Incidentally, one of first two patients was a former President of the Phillippines. In April compassionate use authorizations were given to 28 critically ill patients.
Why hasn’t the FDA acted?
CytoDyn’s failure to reach either their primary or secondary endpoints in their Phase II/III trial on critically ill patients is undoubtedly a major blow. The company has not yet applied for an Emergency Use Authorization (EUA), and it seems this failure is the reason why. (News reports from August 2020 saying that company had applied for an EUA turned out to be incorrect.) CytoDyn is moving forward, however, and has filed a new protocol with the FDA that will study four doses given over four weeks to critically ill COVID-19 patients.
The use of any immunomodulator like Leronlimab is clearly a double-edged sword. It makes sense that it would only be helpful in the most severe cases. This is what the two clinical trials showed – they showed a significant effect on mortality for patients on ventilators and no statistically significant effect on other patients. Unfortunately the analysis of the patients on ventilators was a post-hoc analysis, which is frowned upon in science due to the possibility of data dredging. So clearly the science is not settled here.
Let’s consider this from an ethical point of view. Patients who are in ICUs and on ventilators have a high chance of dying. Inflammation macrophage activity, and excess cytokines are implicated in many COVID-19 deaths. There is strong evidence, going back over a decade, showing that Leronlimab decreases inflammation, macrophages, and cytokines. Leronlimab is known to be a very safe drug (prior to 2020 no serious side effects have been found in nine clinical trials with more than 800 patients). Even if Leronlimab only saves 20% of those to whom it is given, then one can argue we have an ethical obligation to do so. It is a somewhat expensive drug (for HIV patients getting weekly therapy, it costs about $2000 per dose; another source suggests it would cost about $1100). However, keeping someone in the ICU costs around $3,000-$10,000 per day. So in addition to saving lives, Leronlimab could also save money as well by reducing the amount of time patients need to spend in the ICU. This could lead to second-order life-saving effects in places where ICU beds are in short supply.
Medical educator Dr. Mobeen Syed has said this:
“I believe that if there is a drug that can help someone who is on a ventilator or ECMO and it can save them, then whatever small population that is, it is useful — that is my opinion. I have no financial interest or commercial interest or any other interest of any sort with them (CytoDyn).”
I agree. While the evidence is not conclusive, we have good reason to believe Leronlimab can help very critically ill COVID-19 patients such as those on ventilators or ECMO. There are likely gains from receiving Leronlimab for such patients and very little downside, especially if the patient is considered terminally ill. So not allowing doctors access to Leronlimab risks many unnecessary deaths. The drug should be an especially impactful tool in places like Brazil and India, where there are currently shortages of ICU beds and ventilators.
Dan Elton, Ph. D.
For an overview of the possibilities of Leronlimab to save the lives of critically ill COVID-19 patients, watch this brief video by Random Ryman.
