Anyone have a Seeking Alpha sub to post this article:
CytoDyn And Humanigen: Ticking Time Bombs, Impending Results Likely To Fail
Seeking Alpha
... in COVID-19 as a "priority program," namely CytoDyn (OTCQB:CYDY) and Humanigen (NASDAQ:HGEN), are reckless investments that are likely to ..
Summary
CytoDyn and Humanigen are running high-visibility trials focused on ameliorating COVID-19 acute inflammation.
Acute inflammation plays a major role in the hospitalizations and deaths of patients with COVID-19.
Despite monoclonal antibody drug approvals for 88 chronic inflammatory indications, warranted FDA approvals of monoclonal antibodies targeting acute inflammatory indications are almost non-existent, even though many have been tried.
It is reckless to invest in pre-commercial companies operating "priority programs" using monoclonal antibodies to fight COVID-19 acute inflammation.
Editor's note: Seeking Alpha is proud to welcome Saique Research as a new contributor. It's easy to become a Seeking Alpha contributor and earn money for your best investment ideas. Active contributors also get free access to SA Premium. Click here to find out more »
Recently there has been significant attention toward monoclonal antibodies (mABs) and their potential for playing a therapeutic role in the COVID-19 pandemic. In an effort to make better-informed biotechnology investment decisions during this time, we performed a review of every publicly disclosed monoclonal antibody to determine which settings they have succeeded in and found the following: monoclonal antibodies have proven therapeutically beneficial in targeting chronic inflammation but not in targeting acute inflammation. Because acute inflammation plays a major role in the hospitalizations and deaths of patients with COVID-19, pre-commercial companies using monoclonal antibodies to target acute inflammation in COVID-19 as a "priority program," namely CytoDyn (OTCQB:CYDY) and Humanigen (NASDAQ:HGEN), are reckless investments that are likely to crash upon realization of their therapies' ineffectiveness - among other unfavorable market factors becoming realized. To our knowledge, no such compilation of data and comprehensive review has ever been performed and reported on before.
Inflammation - The Body's Natural Response
To understand why their mABs are unlikely to work, we first need to understand inflammation. Inflammation is a normal response of the body's immune system that protects tissues from pathogens, traumatic injury, or disease. This immune reaction typically encourages healing, however, if uncontrolled, can become acutely harmful and persist as chronic inflammation.
The immune system naturally responds adaptively to insults and modifies its response over time, resulting in differences in the acute versus chronic inflammation settings. One of the differences is seen in the sets of leukocytes that are present in the tissues. Neutrophils, which express pro-inflammatory cytokines, are predominant in acute inflammation, whereas macrophages and lymphocytes are predominant in chronic inflammation.
An uncontrolled and overactive leukocyte migration to the site of injury, commonly known as a "cytokine storm," is associated with a number of acute problems, including COVID-19 viral infection. This hectic inflammatory response has caused COVID-19 patients to experienceinflamed lungs resulting in difficulty breathing and subsequent risk of death due to insufficient oxygen absorption. Problematic acute inflammation also occurs in acute diseases and traumas such as sepsis, organ transplantation, stroke, traumatic brain injury, non-COVID-19 acute lung injury, spinal cord injury, GVHD, heart attacks, and other acutely emergent events.
Problematic chronic inflammation can result from the aftermath of an acute disease or trauma, a non-instantly emerging problem, persistent pathogens, or a genetic disease. Chronic inflammation is often associated with diseases such as rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, lupus, HIV, ankylosing spondylitis, macular degeneration, multiple sclerosis, asthma, and other long-term conditions.
There have been many pharmacological interventions developed to target various biological pathways within the inflammatory process. One class of these pharmacological interventions are monoclonal antibodies. Monoclonal antibodies are, by definition, a single antibody cloned - a potentially insufficient remedy when targeting a multifaceted and complex inflammatory response such as in acute inflammation cytokine storms. Empirical evidence suggests that monoclonal antibodies are far more successful in achieving therapeutic benefit in chronic inflammatory indications than acute inflammatory indications.
Companies Betting Big on Mitigating COVID-19 Acute Inflammation
This empirical evidence has not stopped companies from developing monoclonal antibodies to target acute inflammation in COVID-19, however. Some companies have even taken it a step further and made it a "front and center," priority program. CytoDyn and Humanigen fall into this category.
CytoDyn is a company researching Leronlimab, a C-C chemokine receptor type 5 (CCR5) antagonist mAB. They have recently completed full enrollment and are awaiting the highly anticipated results of their CD12 trial, a phase 2/3 study administering Leronlimab in patients with severe or critical Coronavirus Disease. The study includes 390 hospitalized patients, and the company anticipates releasing results sometime in January, 2021. CytoDyn has conveyed to investors that their COVID-19 program is a priority for the company, with their last fivepublicly available investor conference calls in 2020 beginning with a status update on their COVID-19 initiatives. CytoDyn's stock price has increased over 400% since the beginning of 2020 amid hopes that their monoclonal antibody may be helpful for patients who have developed or are likely to develop COVID-19 acute inflammation.
Humanigen is researching Lenzilumab, an anti-granulocyte macrophage colony stimulating factor (GM-CSF) mAB. The company is nearing enrollment completion of their phase 3 study in hospitalized patients with severe and critical COVID-19 pneumonia, with results expected around the first quarter of 2021. Additionally, Lenzilumab is being evaluated in the National Institute of Health-sponsored ACTIV-5 study, a phase 2 study evaluating monoclonal antibody therapeutics for hospitalized patients with COVID-19. Humanigen's COVID-19 trials are currently their central focus, as evidenced by management's choice to discuss said studies as the leading topic on all four investor conference calls that they've held during the pandemic. Humanigen's stock price has increased over 700% since the beginning of 2020 amid hopeful claims that Lenzilumab, "may reduce or prevent cytokine storm resulting from COVID-19 infection," per this March 9th press release.
Unfortunately, the marketing efforts and investor optimism surrounding these companies' trials does not match the reality of this class of drug's performance in treating acute inflammation, as evidenced in the section below. This unjustified optimism has led to wildly-inflated valuations and expectations for both companies.
Monoclonal Antibodies as a Class of Drug: Status in Inflammatory Conditions
An extensive review of every publicly disclosed monoclonal antibody developed has led to the following findings:
There are 521 publicly disclosed monoclonal antibodies that have been developed (this information was primarily sourced from this link).
Of the 521 mABs, 432 of them are not FDA approved for any indications, and 89 of them are currently FDA approved for one or more indication.Of the 89 approved mABs, 33 of them are approved to target chronic inflammation and 2 are approved to target acute inflammation.
Those 33 approved mABs are approved for 88 specific chronic inflammatory indications.
Those 2 mABs are approved for 1 specific acute inflammatory indication each, amounting to 2 total approved acute inflammatory indications.
The remaining 54 mABs are approved for non-inflammatory targeted indications.
Therefore, of the 521 publicly disclosed monoclonal antibodies, there are 88 approved indications associated with chronic inflammation and only 2 approved indications associated with acute inflammation.
Interestingly, although there is medical need for therapies in both chronic inflammatory indications as well as acute inflammatory indications, approval documents show that chronic inflammatory indications currently hold 44 times more FDA approvals than acute inflammatory indications.
We took into consideration the possibility that monoclonal antibodies may not be heavily trialed in targeting acute inflammation but found this consideration to be false. There have been 223 completed trials of monoclonal antibodies targeting acute inflammation in humans. However, those 223 trials have only correlated with 2 current FDA approvals. Furthermore, a deeper look at these 2 approvals suggests that the data supporting their approval is weak and does not demonstrate compelling therapeutic benefit to patients experiencing acute inflammation (here is why).
The tables below summarize the trial landscape of monoclonal antibodies targeting acute inflammation in human trials, including a breakdown of trials for approved and unapproved monoclonal antibodies.
The comprehensive data-set, where we list every acute trial for every unapproved monoclonal antibody, can be viewed here [1]. The comprehensive data-set, where we list every acute trial for every approved monoclonal antibody as well as every FDA approved indication for each corresponding monoclonal antibody, can be viewed here [2].
Investment Implications
After performing this extensive review and recognizing the recurring theme of disappointing trial results, we consider investments in CytoDyn and Humanigen to have substantial downside risk in the short/mid-term for three primary reasons: 1) the likelihood of near-term trial failure for their prominent COVID-19 trials 2) perception of a diminishing target market 3) the financial positions of each company.
The unique necessity for therapeutics to treat COVID-19 has become widely known. Investors of CytoDyn and Humanigen have purchased shares in hopes that those companies have a product that can benefit COVID-19 patients. After reviewing prior ventures' inability to warrant FDA approval for similar programs, it becomes apparent that this hope is unsubstantiated. We believe that investors in these two companies are unaware of such prior endeavors. Once trial failure has been realized by the market it is likely to stifle forward-looking enthusiasm, affecting company valuations and therefore dropping share prices to levels approaching pre-COVID-19 interest or below.
Although the necessity for therapeutics to treat COVID-19 has become well-known, it's unclear how long this need will remain. Even if their therapeutic does warrant approval, it may be too late. The advent and distribution of several highly-effective vaccines and competing therapeutics may limit the potential market size of the company's therapeutic entering the market. Even worse, if their therapeutic fails to benefit patients in the context of COVID-19 acute inflammation, there are implications on the relevance of the therapeutic in other indications. These scenarios point towards muted future perceptions of the companies' target markets, and consequently place a lowering cap on their potential valuations.
CytoDyn and Humanigen are pre-commercial companies, with cash positions of $29.4m and $91.4m, respectively, according to their most recent quarterly reports. They do not have an approved product to sell and rely heavily upon selling shares to the capital markets for funding their operations. This means they will likely rely on dilutive financing going-forward. These companies are inclined to complete these financings before trial results are released as a capital risk mitigation strategy. Dilutive financings post-trial failure would likely yield suboptimal financings for investors.
We believe near-term trial disappointment, perception of a diminishing target market, and dilution is inevitable for both companies: a recipe for multifaceted downward pressure on both stocks. Taking a "short" position in these two stocks would allow market participants to place a diversified bet on future dilution and against events that have repeatedly proven fruitless, yet are currently being priced for success in the stock market.
Conclusion
By using FDA approvals as a proxy for improved patient outcomes, monoclonal antibodies as a class of drug have proven to be therapeutically beneficial in many chronic inflammatory indications, but not in acute inflammatory indications. Investors of companies with front and center programs targeting the acute inflammatory phase of COVID-19, like CytoDyn and Humanigen, should be mindful of the dim empirical context of how comparable drugs have performed in similar settings. This context shows that this story has already played out many times and continually points to the following message: investors are about to receive a dose of harsh reality.