The corporate culture of CytoDyn Inc. (CYDY) has created an atmosphere where management is now able to realize the full potential of a drug that was essentially tossed in the garbage heap. That’s right, CytoDyn’s lead drug leronlimab was purchased from Progenics 8 years ago for only $3.5 million and it included all indications like HIV, cancer, stroke, Alzheimer’s Disease, Parkinson's Disease, Graft versus Host Disease (GvHD), NASH, and Multiple Sclerosis (MS). It’s hard to believe that Progenics spent over $200 million on leronlimab before the sale to CytoDyn.Leronlimab is quite safe, and has proved itself beyond a shadow of doubt in multiple indications, and is on the verge of FDA approval. Will the FDA finally approve it or will history repeat itself and tie it up in nonsensical bureaucracy? 

The Unlikely Journey

Leronlimab has survived the most unlikely of journeys and is at the finish line for approval in COVID-19. This is an unbelievable story because not one person could have predicted 8 years ago that leronlimab would be approved let alone take dying from COVID-19 off the table except CytoDyn’s dynamic CEO, Nader Pourhassan.In fact, leronlimab is the only pivotal phase 3 therapeutic candidate for COVID-19 that has mortality as its endpoint. 

The incredibly good reading from a recent Drug Safety Monitoring Committee (DSMC) said leronolimab was on track to meet its primary endpoint of a statistically significant reduction of mortality in its pivotal study. The study was just unblinded to the FDA yet there has been no public action as of yet. This is a drug that is non-toxic and has the potential to dramatically reduce the number of deaths from COVID-19. Despite the fact that the drug “does no harm” it is still sitting in clinical trials awaiting the recruitment of 140 more patients. Thousands of American lives could be saved daily if the FDA would green light leronlimab with an Emergency Use Authorization (EUA). Nothing can legitimately explain why a safe and effective drug has not been made widely available to the masses except politics and bureaucracy. Now that the election is over there is hope that the FDA will do the right thing and cut through the red tape and get this therapeutic in the hands of Americans before the United Kingdom takes all available inventory. The MHRA is considering approval via a BLA filing. 

The Series of Unfortunate Events

At the onset of CytoDyn’s development, a $28 million NIH funding was actually scrapped to pursue a multi drug resistant HIV indication with eyes on the final prize of a monotherapy for HIV patients in the form of a once a week injectable. Even in its infancy of development, HIV monotherapy was the vision of the company, and sure enough results confirmed as much. 

FDA Penalty for Running a Successful Trial

In July 2018 the company successfully met its endpoints in its pivotal Phase 3 Combination therapy (CD02) trial and showed a 48% viral suppression rate after 48 weeks. The higher the viral suppression and the longer it is sustained, the better the outcomes. In March 2018, which was 4 months before CytoDyn announced its results, another monoclonal antibody called Trogarzo obtained orphan drug approval with a 43% viral suppression rate after only 24 weeks. CytoDyn’s drug had a much safer profile and seemed to work much better but the FDA had other plans. 

Instead of approving the drug and granting orphan drug status, the FDA changed the rules after they heard the company announce a 70% responders rate in patients taking the next higher dosage of 525mg. The FDA had a very legitimate concern that if approved as an orphan drug, the doctors would be using it off label. In the pre-BLA meeting the FDA indicated the company should hold off on filing the BLA and jump the dosage from 325mg to 700mg. They thought that these highly experienced patients would greatly benefit from this higher dosage. This was probably the first time in FDA history that the drug was so successful that the FDA actually penalized the development.  In July 2020 CytoDyn received a Refuse to File Letter which was the FDA’s way of asking for safety data in a different format. Leronlimab would have likely been approved for HIV by now had this bureaucratic red tape not been thrown into the mix at the last minute.   

History Repeating Itself

Unfortunately in this pandemic history seems to be repeating itself again. Leronlimab is a cancer and HIV drug that was repurposed for COVID-19 early in the pandemic. The company has over 60 emergency IND’s (eIND) and a number of compassionate use cases. One early study from UCLA showed a 23% mortality rate in compassionate use patients. Compassionate use patients by definition have a “reasonable likelihood of death” without intervention.If you are in the camp that thinks that 75% represents a numeric value for a reasonable likelihood of death, then a COVID-19 drug that showed a 70% reduction in the death rate would awaken your sense of outrage of why something so effective is not being used already. According to the company they have the most eIND’s for a drug even more than Gilead Sciences (GILD) remdesivir. Anecdotally the high number of eIND’s indicate it works. One of the independent contractors for CytoDyn, Dr. Bruce Paterson was quoted extensively “Anecdotes don’t come off life support.”   

The anecdotal case to approve leronlimab is solid but the large randomized double blind controlled trial results represent the icing on the cake. The company finished its Phase 2clinical trial (CD10) which consisted of 87 patients with mild to moderate COVID-19.It met statistical relevance on one of its endpoints called NEWS2 (p<.023).This is an objective scoring algorithm which predicts whether a patient is likely to need critical care. A significant reduction in the NEWS2 score means that patients on the drug are less likely to get worse and need hospitalization. They also noted improvement in the clinical symptom score by day 3 for moderate patients that had an entry score ≥4.These moderate patients showed an improvement in their clinical symptom score at the rate of 90% versus 71% on placebo. To put these trial results into perspective if this trial had 100 moderate patients and been classified as a pivotal Phase 3 the FDA would have been forced to approve it.

The real question at hand is why Gilead got a relaxation of clinical trial procedure from Fauci during the pandemic, but since then nobody else has. The NIH fiddled with the endpoints midstream and did everything in their power to demonstrate some sort of efficacy. This study was later debunked by a much larger WHO Solidarity study yet remdesivir was approved exactly one week later as almost a political retaliation. Perhaps the estimated $7.4 million in Gilead lobbying this year paid a dividend of $873 million in remdesivir sales at the expense of American lives.      

CytoDyn’s Pivotal Phase 3 Severe to Critical Trial Status

Investors have been anxiously awaiting interim data that is currently blinded to them in their CD12 trial. The DSMB met for the second time and indicated that their drug was safe and that they should continue the trial as planned and expect them to reach their primary endpoint which happens to be 28-day all cause mortality. It's important for investors to understand that the company is 50% done with the trial. At the 50% point in Regeneron’s (REGN) and Eli Lilly (LLY) neutralizing antibody trials the DSMB halted both Severe to Critical trials. Both of these companies were so excited by the results they were seeking EUA approval of their drugs. 

It's very common to see clinical trials extended with more patients, but very rare to see them working so well they can cut them short. In the CD12 trial the DSMC requested another interim analysis at 75% enrollment.If the DSMC thought the efficacy was tracking on target they would not have suggested any more interim points and simply let the trial proceed. The study is still blinded to the company, but it's reasonable to think that the rationale behind the DSMC of adding an interim point was to take approval action. There is no reason to intervene for safety which only leaves efficacy as the primary variable affecting their decision. The DSMC also added an endpoint of 42-day survival which also suggests they saw efficacy in the 42-day survival rate. There is a very real possibility that the efficacy of leronlimab could be tracking ahead of the interim point. 

The Road Ahead

The issue is no longer if leronlimab will be approved but when it will be approved and how many American lives will be lost that could have been saved if the FDA used common sense.In a pandemic the FDA clearly has the power to balance between harming people and helping people. They have recently demonstrated that they will not let big pharma abuse the system. Both Eli Lily and Regeneron with their neutralizing antibodies were shut down in severe to critical covid. They should never have been allowed to do trials of what amounts to a viral inhibitor in the hyperinflammatory stage of the disease. 

MRHA Approval

The company finished its pre-BLA meeting and has a very aggressive plan moving forward. Within the next 10 days, CytoDyn is expected to file its BLA in HIV.The MHRA has a reputation that they are difficult to deal with, but the lack of red tape and the quick speed that has gotten leronlimab to this regulatory point is quite encouraging. Once the BLA is filed the MHRA will review it and then set the UK equivalent of the United State’s PDUFA date. The MHRA is a big deal for CytoDyn because it legitimizes their drug and will ultimately make it available to more than just patients with HIV.    

Call To Action

The FDA appears to be a wolf in sheep's clothing. While they seem all friendly on the surface they keep putting up the silliest of roadblocks that end up costing CytoDyn time and money trying to humor the whimsical requests of the FDA. It seems that CytoDyn is fighting back in their own way.CytoDyn clearly knows the drug can save lives, but seems to be unwilling to take the FDA’s statistical penalty. This is a smart tactical move. The data is unblinded to the FDA right now and they can tell the world if they want.CydoDyn would avoid the statistical penalty in this scenario.With so much on the line the company cannot make a misstep during these critical days, but they cant pander to the FDA either. If they unblinded the data and looked at it then they have to plead with the FDA for approval.  

The company has strategically put the FDA in a situation that forces the approval of the drug.  The FDA has seen the data and if this drug is a lot better than remdesivir, the current standard of care, the FDA is going to take major flak from the congressional investigations that are surely to follow. The FDA cannot sit on statistically significant mortality data. Congress will blame the FDA for the loss of thousands of lives for not making a timely approval. The DSMC said leronlimab was set to attain its endpoint, which was a much better outcome than remdesivir which just recently got approval. The second interim look on a drug with a spotless safety profile is a subtle indication from the DSMC that the data has to be good enough for an approval. It just makes sense that the FDA will be forced into action.

External forces are also pressuring the FDA. The MHRA has telegraphed they are ready to approve leronlimab for HIV. Once approved its likely to see off label use in COVID-19 and cancer. The BLA filing is coming in the next 2-4 weeks. Should leronlimab get approval, the United Kingdom would contract to buy as much leronlimab as possible. This threat puts tremendous pressure on Operation Warp Speed (OWS) to secure a purchase from CytoDyn and help them ramp up the supply of the drug. If the FDA stonewalls the company again with more bureaucracy the MHRA might step in, buy all the product leaving Americans in the cold.

 In the meantime, Cytodyn continues to get other countries to sign on to it as the global pandemic rages on. The past Administration showed little care for helping those already infected with Covid in its haste to try for a vaccine so that the economy could go back to normal. It is doubtful that this will be the case for and new administration, especially given the number of those already infected. This is an easy trigger to pull to show progress in the war against Covid. Although Cytodyn’s stock continues to limp on, it still has great prospects in not just Covid but primarily HIV and Cancer. The science should be what continues to hold investors to this stock and an approval which may be forthcoming should ignite the stock. Cytodyn’s field of science will be a great platform for building an amazingly expansive biotech company in the future. Whereas the USA should be a leader, it has not been here although I am hopeful that will quickly change. Whereas the USA should be a leader given this is from a US company, it has not been a leader here and may yet end up being a late follower, I am hopeful that will quickly change.