Yesterday's Email from Dr. Jay Lalezari: From:

Yesterday's Email from Dr. Jay Lalezari:

From: Jay Lalezari <drjay@questclinical.com>

Subject: Leronlimab for critical Covid

Date: December 8, 2021 at 3:15:23 PM PST
_______________________________________________________________
To: "joseph_eron@med.unc.edu" <joseph_eron@med.unc.edu>
Cc: mike saag Saag <msaag@uab.edu>, "FEINBEJ@ucmail.uc.edu"
<FEINBEJ@UCMAIL.UC.EDU>, "Kuritzkes, Daniel R.,M.D." <dkuritzkes@bwh.harvard.edu>,
Jonathan Schapiro <jonathan@jmschapiro.com>, "hmasur@nih.gov" <hmasur@nih.gov>,
"mellors@dom.pitt.edu" <mellors@dom.pitt.edu>, Steven Deeks <sdeeks@php.ucsf.edu>, PaulVolberding <paul.volberding@ucsf.edu>, "Schooley, Robert" <rschooley@health.ucsd.edu>,Stephen Becker <stephen.becker1@gmail.com>, "wdavidhardymd@gmail.com"
<wdavidhardymd@gmail.com>, harish seetham <seetham1971@yahoo.com>, Bruce Patterson <brucep@incelldx.com>, "Yang, Otto O." <oyang@mednet.ucla.edu>, Christopher Recknor <crecknor@cytodyn.com>, "Kimberly.Struble@fda.hhs.gov" <Kimberly.Struble@fda.hhs.gov>,
"Debra.Birnkrant@fda.hhs.gov" <Debra.Birnkrant@fda.hhs.gov>, "Murray, Jeffrey S" <Jeffrey.Murray@fda.hhs.gov>, "Janet.Woodcock@fda.hhs.gov"
<Janet.Woodcock@fda.hhs.gov>, Jay Lalezari <drjay@questclinical.com>
__________________________________________________________________
Dear Colleagues and Friends,

I’ve had the privilege of collaborating with you for 30+ years and now kindly ask for a few minutes of your time. I don’t know who has followed the twists and turns of the leronlimab story for Covid, but, with all the uncertainty in the air, I feel it's important to provide this group with an overview. Thanks for indulging me. It’s important and I’ll be concise. Here goes...

In March of 2020, Dr. Harish Seethamraju at Montefiore in NY treated 10 ICU Covid patients with leronlimab (aka PRO 140; CCR5 mAb) given through an EIND process as two weekly 700 mg SQ doses. These patients were severely ill: all but one intubated, on dialysis, liver failure, on pressors, etc.

Dr. Bruce Patterson at IncellDx received blood from these patients and generated striking lab results showing rapid (Day 3) decreases in IL-6, increases in CD8+ cells, normalization of CD4/CD8 ratios, and even decreases of plasma viral loads (Day 7) in association with CCR5 receptor occupancy by leronlimab and against a back drop of extremely high baselineelevations in RANTES. Taken together, Bruce’s data provided a credible story for how leronlimab might work in critical Covid by interrupting chemokine-driven migration of inflammatory cells into the lungs as well as reversing severe CD8+ immunosuppression. I've attached Bruce’s paper below.

I’ve heard a couple criticisms of the paper. Some complain that since most of the patients Harish treated eventually succumbed, the laboratory changes Bruce observed were of no clinical consequence. I disagree and believe the lab results starting as early as Day 3 in an essentially terminal population only underscores how relevant the RANTES-CCR5 pathway can be in critical Covid. A second criticism is that Bruce's data has not been reproduced or confirmed by another lab. I believe that is correct. CytoDyn ended their relationship with IncellDx in the summer of 2020 and, unfortunately, didn’t have a lab with similar capabilities in place to support their RCTs described below.

In March of 2020, Dr. Otto Yang also started using leronlimab in severe and critical Covid patients treated at UCLA. Otto treated about 30 patients through the EIND process (until the FDA shut it down in May of 2020 in an effort to promote recruitment into the RCT). Otto's case series from the first 23 patients, (including 6/7 ICU patients who recovered), is attached below. I believe Otto has now treated more Covid patients with leronlimab than anyone else. He once told me that he thought the real question is not whether leronlimab works in severe and critical
Covid but why it doesn’t work in everyone.
Before we leave the realm of anecdotes, just one more. There was a man in London named Tunde who was intubated for several weeks and then and on ECMO for an additional 61 days before receiving his first of 4 weekly doses of leronlimab. His wife Sohier sued the hospital to get leronlimab after the ICU docs wanted to withdraw support. Tunde had a striking response to leronlimab given on Day 79 of his ICU stay and started to wean off ECMO 4 days after his first dose. Unfortunately he suffered an MI during later rehab and never left the hospital but, like some of Harish and Otto’s patients, and consistent with the Day 3 lab data generated by Bruce, Tunde's response was quick and dramatic. There are maybe 10 patients in total who have come off ECMO after receiving leronlimab, but I believe the 61 days in this case report is the longest.

The case report is attached below.

Thank you for making it this far; we are halfway done.

CytoDyn ran 2 placebo-controlled RCTs in acute Covid: CD10 in 84 mild/moderate patients and CD12 in 394 severe/critical. Neither study has been published with top line results only made public through press releases.
CD10 missed its primary endpoint of change in Total Symptom Score at Day 3, but about half of the patients had essentially no symptoms at baseline. Given the proposed MOA and role for leronlimab in the hyperinflammatory phase of Covid, this small study targeted the wrong population. But, to be fair to CytoDyn, it was the first study FDA would allow them to perform in Covid after initially placing them on clinical hold (possibly over concerns around potential immunosuppression with CCR5 blockade).
The CD10 study continued to demonstrate the safety of leronlimab. Altogether, over 1,200 patients have now received the drug, including HIV+, Cancer, and Covid patients, without a discernible safety signal.
CD10 did provide a couple of interesting observations. The National Early Warning Score (NEWS) 2, developed by the Royal college of Physicians to identify patients at risk of pulmonary collapse, was an important predetermined secondary endpoint. The NEWS2 score combines parameters like O2 sat, oxygen requirements, respiratory rate, BP, etc. Subjects on leronlimab were more than twice as likely to improve their NEWS2 score compared to placebo at both
Days 3 and Day 14 (p < 0.05 for both). The CD10 results also demonstrated that patients on leronlimab experienced fewer AEs and 63% fewer SAEs compared to placebo. Maybe a nothing burger, but I’ve never seen a 63% reduction in SAEs before.

The CD12 study in 394 s/c patients was pivotal and, unfortunately, we made some mistakes (Iuse the word “we” because I was an advisor to CytoDyn for 6 months on Covid back in 2020).

First, we thought the results in critical patients would translate into benefit for hospitalized patients on oxygen but not yet intubated. Well such severe patients may indeed benefit from leronlimab, but it will require a larger study to prove it. There were also unforced errors like not stratifying for age > 65 which resulted in a significant randomization imbalance working against the drug.

The biggest mistake, however, was on dosing. The original CD12 protocol proposed to give s/c patients 4 weekly doses, in part because of data Bruce generated showing RANTES levels remained elevated in some ICU patients beyond day 14. Unfortunately, FDA saw Covid framed Covid as an acute viral illness and would only allow the same 2 week dose regimen as the m/m patients received. CytoDyn, fresh off clinical hold, wasn’t in a great position to push back and capitulated.

Unfortunately, CD12 study did not meet its primary or secondary endpoints and larger separate studies of severe and critical patients given 4 weeks of dosing (with first dose administered IV) and appropriately stratified for risk factors are underway. One of the reasons for taking you on this journey, however, is to look at outcomes in the subgroup of 62 critical patients enrolled.

In these 62 critical patients given leronlimab at Days 0 and 7, There was an 78% and then 82% reduction in mortality at Days 7 and 14 in patients receiving drug compared to placebo. There was an absolute reduction in mortality at Day 14 of over 20% and hence a possible Number Needed to Treat of less than 5. Of note, the mortality benefit tapered off to 30% by day 28 which, unfortunately, remained the primary endpoint despite only dosing at days 0 and 7. The raw data for Day 14 is below:

Of note, 12/43 patients on leronlimab + SOC were discharged alive by Day 28 compared to only 2/19 patients on SOC alone (an improvement of 166%). Also, the tapering of the mortality signal as drug levels fell between days 14 and 28 could be construed as indirect evidence that the drug was actually working while patients were receiving it at days 0 and 7 and maintaining full receptor occupancy. I know it's only a subgroup, but, given the proposed MOA of the drug and enormous toll of this pandemic, it is also the subgroup that matters most.

So where are we now?

To my knowledge, leronlimab for Covid is not on the radar at NIH. And FDA is not buying any of this. Indeed, FDA released a statement in May dismissing any claim of benefit with leronlimab in Covid until CytoDyn repeats more robust studies to prove it. I agree that larger follow up studies are urgently needed, but advocated for approving an EUA now for critical patients based on the efficacy signals described above, limited treatment options for these patients, and demonstrated
safety of the drug. One thing is for sure: FDA wants CytoDyn to definitively settle this issue asap.

Unfortunately, that doesn’t appear likely to happen quickly. Cytodyn is a tiny company with extremely limited resources. It took them about a year to enroll and analyze the CD10 and 12 studies. To their credit, they’ve identified their endpoints and target population in a new disease after only 2 studies. The recent addition of Dr. Chris Recknor has brought much needed experience in drug development and clinical research to the management team. But, since the onset of the pandemic, CytoDyn has lacked the resources and in house expertise to meet the
urgency of the moment. The company has other problems including various lawsuits and constant attack by a relentless group of short sellers. The drama of all this, in the context of a lethal pandemic, has been painfully surreal. And eight months after the FDA letter and 2 months after launching a follow up study of critical patients in Brazil, the company just announced it has enrolled a total of 4 patients.

So, why did I need to reach out to you?

First off, this has been exhausting. I realize now that during the dark days of HIV, the frequent meetings and Ad Boards gave me the opportunity to feel supported by colleagues and learn to trust the process. The experience with leronlimab in Covid has been the opposite and very isolating. So, on some level, I just wanted to reach out and share this story with colleagues I trust.

Second, we are entering an uncertain phase with Omicron and I wanted to provide this group with an overview of the leronlimab landscape for Covid. It's not clear to me who (or if anyone) in the virology world is paying attention to this. However this unfolds, I need to tell myself I’ve done everything possible to help patients, their ICU teams, and everyone under siege at the moment;
and honor the 1,200 nurses and millions of others who have died from Covid including my own dear mother.

That’s it. Thanks for your time and attention and please feel free to forward to anyone you think appropriate.

I like transparency so have taken the liberty of cc’ing Harish, Bruce, Otto, and Chris, as well as our colleagues at FDA.

With Gratitude,

Jay

Jacob Lalezari, MD

Medical Director,

Quest Research

SF, CA

415-353-0800

ps-Quest Research receives financial support for studies with leronlimab on HIV and cancer. I

don’t own/never owned any stock or have any other financial stake in CytoDyn.

My comments are just my opinions and should NOT be taken as investment advice.