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Tuesday, September 27, 2022

Navigating through the Galectin Therapeutics (NASDAQ: GALT) Triangle In Search of Therapies

Galectin Therapeutics (NASDAQ: GALT), Galecto Biotech (NASDAQ: GLTO), and BioXyTran Inc. (OTCMKTS: BIXT)—these three companies all currently have market capitalizations under $100 million in the field of galectin research, one of the most promising fields of science which is suffering from the biotech beatdown where over 80+ biotechs are trading below cash value. GALT would be considered a microcap, whereas GLTO and BIXT would be considered nanocap stocks, with market capitalizations near or under $50 million. These tiny valuations are in contrast to the companies’ developmental pipelines, each with therapies in mid-to-late stage development—phase 2 or phase 3 clinical studies. The market is simply ignoring galectin-focused biotechs in what could become a field of research worth tens of billions in the next few years.

There are just a handful of companies in this emerging field of galectin research. These three biotechs are developing galectin inhibitors for some of humanity’s most significant unmet medical needs, ranging from liver disease to cancer to COVID-19. Galectins, particularly galectin-3, are implicated in a wide range of diseases and hold significant therapeutic promise. A quick browse through Google will reveal that a search of virtually any chronic disease plus galectin-3 will get multiple hits of medical journal articles recommending galectin-3 as a biomarker of disease severity or as a potential treatment.

Galectin Science Getting the Cold Shoulder

It is hard to fathom that something with so much potential is being utterly ignored. This is precisely why buying a basket of these stocks could result in an exceptional return. Investors may want to get in on the ground floor of this up-and-coming technology, but which company should they pick or should they pick all three and weigh them differently?  Each of these three companies has its strong points and weaknesses.  There is, however, one that remains the best of the breed.

Galecto Biotech (GLTO): Cash King

Many investors in this market are looking for biotechs with lots of cash such that they are not subject to volatile markets and in need of cash—usually via equity raises. The company is trading well below its liquid assets, valued at $97 million (cash and marketable securities), and has multiple synthetic galectin inhibitor formulations in its pipeline. Their lead candidate, GB0139, is a promising inhaled galectin-3 inhibitor for idiopathic pulmonary fibrosis (IPF)

Galecto Biotech Pipeline

Galecto was also testing its galectin-3 inhibitor in COVID-19 acute respiratory distress syndrome, but they appear to have discontinued the program in light of effective early-stage therapies (antivirals) being developed and in some cases approved, like Pfizer’s (NYSE: PFE) Paxlovid, and Merck’s (NYSE: MRK) molnupiravir. It is also possible they saw what BioXyTran was accomplishing with its galectin inhibitor Prolectin-M in mild-moderate COVID-19 and decided they could not compete.

Galecto is also advancing another oral galectin-3 inhibitor, GB1211, in liver cirrhosis and cancer. The company is measuring outcomes for NASH cirrhosis, a projected $54 billion market with no current approved therapies and hardly any candidates for late-stage NASH (cirrhosis), which accounts for over 40% of the cost burden of NASH. However, their phase 2 trial is only 12 weeks long and will almost certainly not detect any significant efficacy signals with a small sample size and short duration, as many NASH trials need to be 12-18 months or longer, especially in cirrhosis, to detect outcomes as liver scarring can take a while to reverse and patients whose livers decompensate on placebo may only do so at a slow pace. Additionally, it is not known whether the drug is very tolerable yet (though it may be) as cirrhosis patients have delicate livers and need an extremely well-tolerated drug.

The company’s oncology indication is promising as the company is in a phase 2 trial and recently published some research showing GB0139 reverses galectin-3 induced resistance of PD-1 inhibitors like Keytruda, which occurs due to galectin blockade. Galectin’s and BioXyTran’s galectin inhibitors are also known to synergize with cancer treatments to enhance outcomes.

Galectin-3 is a key player in the tumor microenvironment and therefore oncology remains a very promising indication for Galecto.

Galectin Therapeutics (GALT): Leader In Development and Clinical Testing

Galectin Therapeutics’ key differentiator from Galecto is its use of a naturally derived, refined complex carbohydrate as a galectin inhibitor. These compounds are known to be well-tolerated and have much better half-lives than the small synthetic compounds developed by Galecto; for instance, Galectin’s lead drug, belapectin, has a 20-hour half-life in NASH cirrhosis patients, whereas Galecto’s GB0139 (formerly TD139) has an 8hr half-life (IPF patients). Additionally, belapectin may be uptaken by macrophages rather than purely metabolized, meaning its therapeutic effect can persist inside the main source of galectin-3, the macrophage. For this reason, the therapy is very targeted and well-tolerated, reportedly reducing side effects (rather than adding side effects) when used in combination with Keytruda (pembrolizumab) in cancer therapy. Keytruda is projected to be the best-selling drug on the planet.

Galectin Therapeutics is pursuing belapectin treatment for NASH cirrhosis, primarily, with a 3-year, robust global phase 2b/3 trial assessing the progression of cirrhosis patients developing esophageal varices, which occur due to significant liver pressure buildup from fibrosis. Their phase 2 study showed that patients on belapectin developed fewer varices than those on placebo, the only NASH cirrhosis clinical trial to show signs of clinical efficacy.

The company has also conducted preliminary studies in cancer—advanced melanoma and head and neck squamous cell carcinoma—and has demonstrated likely synergy with PD-1 inhibitors like Keytruda with its phase 1 study and some preclinical studies. Notably, the therapy is expected to improve clinical outcomes and also potentially the side effect profile of PD-1 inhibitors. Checkpoint inhibitors are known to unfortunately induce autoimmune or inflammatory side effects in patients, causing them to have to pause or terminate therapy, which can further have a detrimental effect on their underlying condition. A therapy that can ameliorate the side effects and improve the efficacy of, for instance, Merck’s Keytruda, could be worth a lot to patients and Big Pharma. Galectin-3 expression predicts response to checkpoint inhibitor response in various tumors, notably non small cell lung cancer (NSCLC).

Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy: The Galectin-3 Signature in NSCLCs

The spider plot above shows how much of a clear difference galectin-3 may make for the patient’s response to therapy and the enormous potential galectin inhibitors have in improving immunotherapy, and this is a key piece of evidence for all three of the galectin companies. Galectin’s belapectin is extremely promising in oncology, making the entire company very attractive given its financial support from Chairman of the Board and billionaire Richard Uihlein, but the main drawback with the company is that it is slow, having taken about 2 years to design a phase 3 trial and about 5 years so far to move from phase 1 in oncology to a planned phase 2.

BioXyTran Inc. (BIXT): Best Indications and Formulations, Dark Horse

BioXyTran may not have the cash on hand that Galecto does, nor the number of patients dosed that Galectin has, but it may have potentially the best galectin inhibitor formulations and clinical indications to bring to market. The Company’s pipeline slide makes it difficult to ascertain where exactly they are in the clinical trial process, but their statistically significant finding in their pilot study was without a doubt an international breakthrough that was largely ignored or drowned out but the overwhelming focus on the vaccination effort.

In this peer-reviewed study, an oral chewable tablet called Prolectin-M eliminated viral load to undetectable levels in symptomatic COVID-19 patients within 3 days.  In their upcoming PROTECT study, they are expected to enroll 408 patients “regardless of vaccine status, viral variant, or underlying medical conditions.” This enrollment criterion is noticeably different than every other clinical trial in COVID-19 which seeks to exclude healthy subjects that can get better on their own.  They are choosing to go after the hardest-to-treat group which is for the most part healthy subjects that show symptoms of infection. On the surface, this type of trial design is risky, but there is a very subtle inclusion criterion that highlights the skill of BioXyTran’s regulatory team. Their strategy revolves around cherrypicking (selecting) patients that are symptomatic with high viral loads defined by a Ct value <25.  Even a healthy patient with this high viral load is going to take well over a week to recover.  If their statistical significance holds, then viral elimination should occur in 3 days versus a week or more.  The BIXT team has to be extremely confident in their mechanism of action (MOA) to pursue what many pundits would call a risky trial design. Prolectin-M is shaping up to be potentially the most effective COVID-19 antiviral in existence.

The approval of Paxlovid and molnupiravir was based on reduction of the risk of hospitalization or death.  Prolectin-M would likely need to demonstrate efficacy in the same endpoint. The rationale for Prolectin-M meeting its endpoints so quickly is based on an MOA that doesn’t need a competent immune system to eliminate the virus.  The galectin antagonist binds to the spike protein and prevents viral entry and then eventually gets filtered out of the liver with the virus in tow.

Recently, a real-world study was conducted with the approved Merck and Pfizer antivirals (Paxlovid and Molnupiravir), and the time to undetectable COVID-19 was measured. Paxlovid outperformed molnupiravir, but when Prolectin-M is plotted against Paxlovid and control, the night and day difference in efficacy can be observed.  In 20 days of using Paxlovid, approximately 30% of the patient population reached an undetectable level of Ct value. In theory, 100% of the patient population would reach undetectable levels in 3 days using Prolectin-M (depicted with the black line).

Adapted from Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir among COVID-19 inpatients during Hong Kong’s Omicron BA.2 wave: an observational study

Paxlovid is expected to do $22 billion in sales this year. The largest order of pharmaceuticals in history was the $5.3 billion order for 10 million doses of Paxlovid.  If BIXT can show better safety and efficacy over Paxlovid, a new record could be set. One thing that Prolectin-M clearly outperforms on is safety. There are no safety signals and galectin inhibitors as a class of drugs are quite safe. On the other hand, Pfizer’s Paxlovid is paired with an HIV medicine called ritonavir in order to slow the metabolism of the actual antiviral compound (nirmatrelvir) in order to use less to get the same effect avoiding any safety signals, and to improve the pharmacokinetic profile of nirmatrelvir.

Though BioXyTran’s primary pipeline candidate for COVID-19 is promising, the company shows a number of additional indications in its pipeline, including cancer and NASH using galectin inhibitors. Finally, the company has an oxygenation platform that is highly promising for stroke and organ transplantation which acts as an oxygen transport molecule that can perform the same functions as hemoglobin on red blood cells without blood type matching, degradation, or getting stuck in clots.

Galectin Comparison

When it comes to drug design and the best science, BIXT has the newest galectin inhibitor that was developed within the last 2 years.  Looking at their presentations, BIXT carefully stayed away from specifically calling their molecules galectin-3 inhibitors as their competitors do; instead, they called them galectin antagonists. BioXyTran’s galectin antagonists clearly target galectin-3, so there has to be more to the story or perhaps a trade secret. Galectins 1, 3, and 9 are modulators of viral infection. It is reasonable to think their antagonist is targeting multiple galectins as multiple galectins mediate different processes in disease pathology (specifically galectin-1, galectin-3, and galectin-9 in multiple viral infections).  Belapectin has shown in structural studies that it inhibits galectin-1 and galectin-3, and Galecto’s drugs are only really galectin-3 inhibitors. Obviously, galectin-3 is the most important, but there could be benefits to antagonizing multiple galectins.

In terms of clinical trials, GALT seems to hold the lead. They have done clinical trials in liver fibrosis, NASH cirrhosis, atopic dermatitis, psoriasis, melanoma, and head and neck squamous cell carcinoma. They also have dosed many patients. GLTO is doing clinical trials in idiopathic pulmonary fibrosis (IPF), NSCLC, liver cirrhosis, and myelofibrosis. BIXT currently only has an active indication in acute COVID-19 but from their recent patent approvals, it seems they are about to announce something new. While GALT has a commanding lead, they could easily lose the race to commercialization once BIXT starts a phase 2 or phase 3 trial in COVID-19. The trials in COVID-19 represent a much shorter pathway to approval than a NASH cirrhosis study which can take a number of years.

In terms of cash, GLTO is the strongest of the bunch with $3.7/share in cash. GALT comes in second with $0.53/share in cash. However, GALT does have the support of its Chairman of the Board, Richard Uihlein, who has consistently supported the company with lines of credit as well as above-the-market priced convertible notes. BIXT comes in last with approximately $700,000 and it simply needs money to move forward; this is the company’s primary problem, which should be surmountable given its clinical trial results and assets.

Investment Summary

With close to 4,000 journal articles on galectins suggesting their use as a prognostic biomarker of disease or as a therapeutic target, it’s imperative that a galectin inhibitor reaches approval.  The top 3 companies in the space each have their strengths but none has the complete package.  GALT has been the undisputed leader for years, but their slow management and one-molecule development has left them vulnerable to being overtaken by their rivals. GLTO has the weakest technology platform with its small molecule architecture, but it was able to boost its pipeline to 4 drug candidates. Their cash horde is significant but management has little skin in the game and has only retained 9.6% cumulative ownership of the company. BIXT seemingly came out of nowhere and has one if not two molecules in the clinic and is zipping through clinical trials. They have massive insider ownership and the most robust technology platforms, but they have little-to-no cash to develop their product. Their management team is led by Dr. Platt, who is arguably the grandfather of galectin science and has invented the greatest number of carbohydrate drugs and commands the greatest clinical trial experience.

The most impressive molecule award goes to Prolectin-M, developed by BIXT. It eliminated the SARS-CoV-2 virus to undetectable levels in 3 days (p=.029). It has the quickest and cleanest pathway to approval and is simply waiting for a larger, short-duration confirmatory trial before commercialization which means there is very little execution and regulatory risk.  There is a very real possibility that this drug could end the pandemic by dramatically slowing the transmission of the disease and stopping virtually all hospitalizations in treated patients. BIXT appears best in breed followed by GALT.

Disclosure: MicroCapDaily and its owners do not have a position in any of the stocks mentioned and have posted this article for free without editorial input. This article was written by a guest contributor and solely reflects his opinions.

Image by Michal Jarmoluk from Pixabay

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