The Case for Leronlimab
To the FDA, Janet Woodcock, and Peter Marks: how many more terminally ill COVID-19 patients will you let die before you act?
How does Leronlimab work?
Leronlimab is a humanized monoclonal antibody that antagonistically binds to the CCR5 (RANTES) 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 invades. 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). It is still not yet FDA approved, 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 indication, so off-label use for COVID-19 is impossible.
In the case of COVID-19, infection by the SARS-CoV2 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. released a press release January 28th, 2020 announcing they were beginning to evaluate its use for COVID-19. In that press release they 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. They 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 (40%). 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 due and a return of platelet cell counts towards normal levels. They 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. 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 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.
In Phase II the mild to moderate trial did not meet its primary efficacy endpoint, but in a 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). We are still waiting full results from the Phase IIb/Phase III trial but the company has released some promising looking results.
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 having less elderly and was small, so unfortunately they missed statistical significance. You can see all the details here.).
However, they 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=.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 they 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 and N=1 placebo patients with COVID-19 found a decrease in CRP after one week.
On March 29th, 2021 the Philippines’ FDA began issuing compassionate use authorizations on a per-patient basis and for up to one year. Incidentally, one of first two patients was the former president of The Philippines. 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 have filed a new protocol with the FDA that will study four doses given over four weeks to critically ill COVID-19 patients.
Using any immunosuppressant (*correction: immunomodulator) like Leronlimab is clearly a double-edged sword. It makes sense that it would only be helpful in the most severe cases that had gone into a late-stage hyperinflammatory phase. 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 a no-no 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 and 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 it is given to 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 is about $2000 per dose, another source suggest 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 effect 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 is currently shortages of ICU beds and ventilators.
Note: I am not invested in or affiliated with CytoDyn, although after writing this article I am considering investing in their stock.