I have been looking into potential competitors in the severe...

I have been looking into potential competitors in the severe COVID-19/ARDS space. I previously posted on the topic of Jakafi as a potential competitor. Jakafi is the subject of two large Phase 3 trials being run by Incyte and Novartis. In the case of the Incyte trial involving ventilator dependent patients, we have been told that there won’t be a read out before the end of the year.

I have now taken a look at CytoDyn’s leronlimab (also known as Pro 140) which has been developed by CytoDyn (and the company from which it bought the rights) for use in combination with other treatments in HIV-AIDS. In that space, Pro 140 was designated a fast track product by the FDA in 2006. For the scientists, Pro 140 is described by the company as a humanized Ig64 monoclonal antibody that blocks CCR5, a cellular receptor implicated in (among other things) “immune signalling”.

As @LeftYahoo has mentioned, the BLA was a long time coming (about 13 years). Relevant portions of the BLA were submitted in April and May this year which was followed in July by a “refusal to file” letter that was issued by the FDA. So CytoDyn will need to file a revised BLA once it works out what is wrong with the first one and what needs to be done to correct it.

CytoDyn has sponsored three trials of Pro 140 as a treatment for COVID-19. The third of these is being run in Mexico. The company calls it a Phase 3 but it will have only 25 patients and is aimed at securing emergency use approval in Mexico. I won’t discuss it further because it seems to be the least important of the three.

The first trial (called CD10) is a Phase 2 randomised & blinded trial involving 86 patients for the treatment of mild to moderate COVID-19. Enrolment was completed in July 2020 and the company says that it has forwarded a report of topline results to the FDA and that it has also submitted an application for an emergency use authorisation for mild to moderate cases. CD10 had a primary endpoint and 12 secondary endpoints. The company says that it missed the primary endpoint but that it achieved a statistically & clinically significant result using NEWS2 {secondary endpoint no.2).

I will say a bit more about the way in which the company has gone about presenting these results later in this post. But the most important thing to notice about the Phase 2 study is that it is directed to mild-to-moderate cases of Covid 19, and not Covid 19/ARDS. So even if this proves to be a successful treatment in this patient population it would not be competing with remestemcel for the most severe cases in which the patients develop ARDS. At best it could have an indirect impact on the size of the market if it reduced the number of severe cases, as would also be true of any other effective therapy or vaccine.

The second trial (called CD12) is the more important of the three. It is a Phase 2b/3 randomised, blinded, placebo-controlled multi-centre study to evaluate the safety and efficacy of Pro 140 in 390 patients with severe or critical symptoms of respiratory illness caused by Covid 19. It commenced in April and data collection for the primary endpoint has an estimated completion date of 31 December.

The primary endpoint is all cause mortality at day 28 -- very similar to MSB’s Phase 3 which is all cause mortality at day 30. (The Incyte Jakafi Phase 3 for ventilator dependent patients uses the 28 endpoint also. The other Jakafi Phase 3 run by Novartis uses a slightly different measure which includes mortality at 29 days but, unlike the Incyte trial, patients there need not be ventilator dependent.)

The DSMC reviewed safety data after 149 patients had been enrolled and recommended the Phase 3 trial continue. But the data was not reviewed for efficacy. According to the CEO speaking during a conference call held on 12 August, the company will conduct a full interim analysis once 195 patients are enrolled. I presume he meant the DSMC would do this. At the time of the conference call there were 175 patients enrolled. Asked how long it would take to get to 195, the CEO would not be drawn. But you would think they must be getting close to enrolling 195 given their progress to date.

Here’s some more interesting information on CytoDyn:

· Market Cap US$1.95B. Trades in the over-the-counter market but has recently applied to “uplift” its listing to NASDAQ. For regulatory purposes, CytoDyn is currently classified as a “penny” stock. It doesn’t have a lot of cash (around $14M at last count). I suspect it needs to get onto the NASDAQ to raise some serious capital.

· The CEO felt compelled to say during the recent conference call that he did not say that the company would sell US$2.5B worth of product this year (or US$9.0B next year). Apparently some had understood him to say just that! The company does not generate any revenue currently.

· The company is involved in two law suits one by a well-known Australian oncologist based in the USA (Professor Richard Pestell AO) who for a short time was on the board of directors (as Vice-Chairman) and also Chief Medical Officer. He claims he was improperly pressured by the current CEO and also the Chairman (both are defendants) to approve trial protocols for submission to the FDA without sufficent regard for safety issues. Both cases raise questions about corporate governance. The company also paid US$22.5M earlier this year to settle another claim.

Now, back to the Phase 2. The company announced its Phase 2 “results” on 17 August via a press release that you can find online. Nothing is said in it about the primary endpoint. They focus on the NEWS2 endpoint but without being specific as to the result. Also, they point to safety data (ie. fewer adverse events in active arm compared to placebo) which is then spun into an important efficacy outcome. What about all the secondary endpoints that relate to efficacy besides NEWS2? As best I can tell, no written record (even a high-level summary or power point) of any of these Phase 2 results has been made public. All there is the press release and the discussion that occurred during the conference call and company promoted media interviews (on the Proactive Investors YouTube Channel).

During the conference call the CEO Dr Pourhassen (whose PhD is in mechanical engineering) said that during the Phase 2 trial “something fantastic happened”. The Chairman & CMO (Dr Kelly) described the results as “incredible”. The Chief Science Officer Dr J Lalezari) was equally ecstatic, and totally dismissive of the missed primary endpoint, saying (I kid you not) that he had been involved in its selection and that it was “plucked out of the air”. He claimed that the result for the NEWS2 secondary endpoint was incredible – all that remains to be seen, he said, was whether Pro 140 was “a double, triple or home run” and that the Phase 2 showed that it definitely works in Covid-19. So these as yet unpublished results are being pumped by the company like you won’t believe.

NEWS stands for the National Early Warning Score developed in 2012 by The NHS England and the Royal College of Physicians. NEWS2 is the 2019 update. It measures a set of standardised basic physiological parameters (eg. pulse rate, blood pressure, respiratory rate, temperature) and is used in assessing the seriousness of a patient’s condition particularly in a hospital setting. A NEWS2 based metric is being used by Novartis in its Jakafi trial measuring “time to discharge or to a NEWS2 score of ≤2 maintained for 24 hours…”. So we can’t be dismissive of NEWS2 as an endpoint. But please let’s see the actual results for it and all other endpoints!

We should be looking out for the CytoDyn’s Phase 3 interim read-out, but anything that is presented by the company needs to be scrutinized with great care. I suspect the company already has a serious credibility problem at the FDA. I suspect it is also in the SEC's sights.

Until yesterday I would have said that I’d be amazed if CytoDyn gets the emergency use authorisation it is seeking based on its unpublished Phase 2 results. But yesterday's announcement at the White House, coupled with President Trump's recent tweets, show just how crazy things have become.

I still expect MSB will have its own emergency use approval (if not a full approval) for the use of remestemcel in ventilator dependent COVID19/ARDS patients very soon, and long before CytoDyn. On the other hand, if CytoDyn gets genuinely positive Phase 3 results then that would be a very significant development.

I wasn’t intending to look at CytoDyn other than to see whether Pro 140 (leronlimab) was a serious potential competitor to remestemcel as a treatment for severe Covid19/ARDS. But when looking into the company I couldn’t help but see a number of red flags. As a potential competitor, although it has an interim read out of its Phase 3 coming up fairly soon, I can't see CytoDyn posing a serious threat to MSB’s first mover advantage in the severe/critical Covid19/ARDS space. That said, if President Trump and Dr Pourhassen were to hook up, then almost anything is possible. They are both very quick to talk up unproven therapies based on the slimmest evidence and desperate to make a deal.