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Item 1. Business

2022-03-31 compared with 2021-03-31 · 398 added, 480 removed, 121 unchanged (88% of the section changed)

We are a clinical stage biopharmaceutical company engaged in drug research and development to create new therapies for fibrotic disease, cancer and selected other diseases.

Our drug candidates are based on our method of targeting galectin proteins, which are key mediators of biologic and pathologic functions.

We use naturally occurring, readily-available plant products as starting material in manufacturing processes to create proprietary, patented complex carbohydrates with specific molecular weights and other pharmaceutical properties.

Our drug candidates are based on our

method of targeting galectin proteins, which are key mediators of biologic and pathologic functions.

We use naturally occurring, readily-available plant products as starting material in manufacturing processes to create proprietary, patented

complex carbohydrates with specific molecular weights and other pharmaceutical properties.

These complex carbohydrate molecules are appropriately formulated into acceptable pharmaceutical formulations.

Using these unique carbohydrate-based candidate compounds that largely bind and inhibit galectin proteins, particularly galectin-3,

we are undertaking the focused pursuit of therapies for indications where galectin proteins have a demonstrated role in the pathogenesis of a given disease.

We focus on diseases with serious, life-threatening consequences and those where current treatment options are limited specifically in NASH (non-alcoholic

steatohepatitis) with cirrhosis and certain cancer indications.

Our strategy is to establish and implement clinical development programs that add value to our business in the shortest period of time possible and to seek strategic partners when one of our programs becomes advanced and requires significant additional resources.

Our lead galectin-3

inhibitor is belapectin (GR-MD-02),

which has been demonstrated in preclinical models to reverse liver fibrosis and cirrhosis.

Belapectin has the potential to treat many diseases due to galectin-3’s

involvement in multiple key biological pathways such as fibrosis, immune cell function and immunity, cell differentiation, cell growth, and apoptosis (cell death).

The importance of galectin-3

in the fibrotic process is supported by experimental evidence.

Animals with the gene responsible for galectin-3

“knocked-out”

can no longer develop fibrosis in response to experimental stimuli compared to animals with an intact galectin-3

We are using our galectin-3

inhibitor to treat advanced liver fibrosis and liver cirrhosis in NASH patients.

We have completed two Phase 1 clinical studies, a Phase 2 clinical study in NASH patients with advanced fibrosis (NASH-FX)

and a second Phase 2b clinical trial in NASH patients with well compensated cirrhosis (NASH-CX)

meaning the liver is scarred but still able to perform most of its basic functions.

We are now engaged in a Phase 2b/3 clinical trial.

Our study protocol was filed with the FDA on April 30, 2020 for a seamless adaptively-designed Phase 2b/3 clinical study, the NAVIGATE trial (formerly called NASH-RX),

evaluating the safety and efficacy of its galectin-3

inhibitor, belapectin (GR-MD-02),

for the prevention of esophageal varices in patients with non-alcoholic

steatohepatitis (NASH) cirrhosis (Further details are available at www.clinicaltrials.gov

Using these unique carbohydrate-based

candidate compounds that largely bind and inhibit galectin proteins, particularly galectin-3, we are undertaking the focused pursuit of therapies for indications where galectin proteins have a demonstrated role in the pathogenesis of a given

We focus on diseases with serious, life-threatening consequences and those where current treatment options are limited specifically in NASH (non-alcoholic steatohepatitis) with cirrhosis and certain cancer indications.

Our strategy is to

establish and implement clinical development programs that add value to our business in the shortest period of time possible and to seek strategic partners when one of our programs becomes advanced and requires significant additional resources.

Our lead galectin-3 inhibitor is belapectin (GR-MD-02), which has been demonstrated in preclinical models to reverse liver fibrosis and cirrhosis and in clinical studies to decrease portal hypertension and prevent

its complication:

the development of esophageal varices.

Belapectin has the potential to treat many diseases due to galectin-3’s involvement in multiple key biological pathways such as fibrosis, immune cell function and immunity, cell

differentiation, cell growth, and apoptosis (cell death).

The importance of galectin-3 in the fibrotic process is supported by experimental evidence.

Animals with the galectin-3 gene “knocked-out” can no longer develop fibrosis in response to

experimental stimuli compared to animals with an intact galectin-3 gene.

We are using our galectin-3 inhibitor to treat advanced liver fibrosis and liver cirrhosis in NASH patients.

We have completed two Phase 1 clinical studies, a Phase 2

clinical study in NASH patients with advanced fibrosis (NASH-FX) and a second Phase 2b clinical trial in NASH patients with compensated cirrhosis and portal hypertension (NASH-CX).

We are now engaged in a large, global Phase 2b/3 clinical trial.

Our study protocol was filed with the FDA on April 30, 2020, for a seamless adaptively-designed Phase 2b/3 clinical study, the NAVIGATE trial

(formerly called NASH-RX), evaluating the safety and efficacy of our galectin-3 inhibitor, belapectin, for the prevention of esophageal varices in patients with non-alcoholic steatohepatitis (NASH) cirrhosis (Further details are available at www.clinicaltrials.gov

under study NCT04365868);

this study began enrolling patients in Q2-2020.

Recently the Company received a letter from the FDA providing comments, asking questions and providing guidance on various aspects of the ongoing NAVIGATE trial.

Additionally, a study protocol entitled “A Single-dose, Open-label, Pharmacokinetic Study of Belapectin

in Subjects With Normal Hepatic Function and Subjects With Varying Degrees of Hepatic Impairment” has been filed with the FDA to examine the effects of the drug in subjects with normal hepatic function and subjects with varying degrees of hepatic impairment (study details are listed under study NCT04332432 on www.clinicaltrials.gov

this study is enrolling patients.

In September 2020, the Company received a letter from the FDA providing comments, asking questions and providing guidance on various aspects of the ongoing NAVIGATE trial.

These comments were addressed, and the study proceeded accordingly.

Additionally, a study protocol entitled “A Single-dose, Open-label, Pharmacokinetic Study of Belapectin (GR-MD-02) in Subjects With Normal Hepatic Function and Subjects With Varying Degrees of Hepatic Impairment”

has been filed with the FDA to examine the effects of the drug in subjects with normal hepatic function and subjects with varying degrees of hepatic impairment (study details are listed under study NCT04332432 on www.clinicaltrials.gov );

this study became fully enrolled in February 2022.

We endeavor to leverage our scientific and product development expertise as well as established relationships with outside sources to achieve cost-effective and efficient drug development.

These outside sources, amongst others, provide us with expertise in preclinical models, pharmaceutical development, toxicology, clinical trial operations, pharmaceutical manufacturing, sophisticated physical and chemical characterization, and commercial development.

We also have established through our majority-owned joint venture subsidiary, Galectin Sciences LLC, a discovery program aimed at the targeted development of small molecules (generally, non-carbohydrate)

that bind galectin proteins and may afford options for alternative means of drug delivery (e.g., oral) and as a result expand the potential uses of our galectin-3

inhibitor compounds.

Three series of composition of matter patents covering discoveries at Galectin Sciences have been filed.

We are also pursuing a development pathway to clinical enhancement and commercialization for our lead compounds in immuno-oncology for cancer therapy in collaboration with Providence Portland Cancer Center.

However, our clinical development efforts are primarily focused on liver fibrosis and NASH.

All of our proposed products are presently in development, including pre-clinical

and clinical trials.

We were founded in July 2000 as Pro-Pharmaceuticals,

Inc., a Massachusetts corporation.

On April 25, 2001, DTR-Med

(“DTR”), which was incorporated in Nevada on January 26, 2001, entered into a stock exchange agreement with Pro-Pharmaceuticals,

Inc., whereby DTR acquired all of the outstanding shares of common stock of Pro-Pharmaceuticals,

On May 10, 2001, DTR changed its name to “Pro-Pharmaceuticals,

Inc.” and on June 7, 2001, the Massachusetts corporation was merged into the Nevada corporation.

On May 26, 2011, Pro-Pharmaceuticals,

changed its name to “Galectin Therapeutics Inc.” In October, 2012, we moved our headquarters to a suburb of Atlanta, GA to be closer to a center of discovery collaboration while maintaining a laboratory operation in the Boston area.

These outside sources,

amongst others, provide us with expertise in preclinical models, pharmaceutical development, toxicology, clinical trial operations, pharmaceutical manufacturing, including physical and chemical drug characterization, and commercial development.

We also have established through our majority-owned joint venture subsidiary, Galectin Sciences LLC, a discovery program developing small molecules that inhibit galectin-3 and may afford alternative drug delivery (e.g., oral) and as a result

expand the potential uses of galectin-3 inhibitor beyond belapectin.

Three chemical series of composition of matter patents have been filed.

We are also pursuing a development pathway to clinical enhancement and commercialization for our lead compounds in immuno-oncology following our previous successful collaboration with Providence Portland Cancer

We are now planning a phase 2 trial in advanced or metastatic head and neck cancer using belapectin in combination with a checkpoint (PD-1) inhibitor.

All of our proposed products are presently in development, including pre-clinical and

clinical trials.

We were founded in July 2000 as Pro-Pharmaceuticals, Inc., a Massachusetts corporation.

On April 25, 2001, DTR-Med Pharma Corp.

(“DTR”), which was incorporated in Nevada on January 26, 2001, entered into a stock

exchange agreement with Pro-Pharmaceuticals, Inc., whereby DTR acquired all of the outstanding shares of common stock of Pro-Pharmaceuticals, Inc.

On May 10, 2001, DTR changed its name to “Pro-Pharmaceuticals, Inc.” and on June 7, 2001, the

Massachusetts corporation was merged into the Nevada corporation.

On May 26, 2011, Pro-Pharmaceuticals, Inc.

changed its name to “Galectin Therapeutics Inc.” In October 2012, we moved our headquarters to a suburb of Atlanta, GA to be closer to a

center of discovery collaboration while maintaining a laboratory operation in the Boston area.

Our Drug Development Programs

Galectins are a class of proteins that are made by many cells in the body, but predominantly in cells of the immune system.

As a group, these proteins are able to bind to sugar molecules that are part of other proteins, glycoproteins, in and on the cells of our body.

Galectin proteins act as a kind of molecular glue, bringing together molecules that have sugars on them.

Galectin proteins, in particular galectin-3,

are known to be markedly increased in a number of important diseases including inflammatory diseases, scarring of organs (e.g.

liver, lung, kidney, and heart) and cancers of many kinds.

The increase in galectin protein promotes the disease and is detrimental to the patient.

Published data substantiating the importance of galectin-3

in the fibrotic process arises from gene knockout experiments in animal studies.

Mice genetically altered to eliminate the galectin-3

gene, and thus unable to produce galectin-3,

are incapable of developing liver fibrosis in response to toxic insult to the liver and in fatty liver disease as well as development of fibrosis in other tissues.

We have one new proprietary chemical entity (NCE) in development, belapectin, which has shown promise in preclinical and early clinical studies in treatment of fibrosis, severe skin disease, and in cancer therapy.

Currently we are focusing on development of belapectin intended to be used in the treatment of liver fibrosis associated with fatty liver disease (NASH) and more specifically in NASH cirrhosis.

We have also leveraged our relationships with well-known investigators to demonstrate clinical effects of belapectin in treating moderate to severe plaque psoriasis, severe atopic dermatitis, and in cancer therapy in combination with immune-system modifying agent(s).

Belapectin is a proprietary, patented compound derived from natural, readily available, plant-based starting materials, which, following chemical processing, exhibits the properties of binding to and inhibiting galectin-3

A second NCE, GM-CT-01

is a proprietary, patented compound that is made from a completely different starting source plant material and also binds and inhibits galectin proteins.

Previously in clinical development for cancer indications, GM-CT-01

compound has been explored in limited other preclinical studies.

As a group, these proteins are able to bind to sugar molecules that are attached to other

proteins, called glycoproteins that are responsible for various functions within the body, most notably inflammation and fibrosis.

Galectins, in particular galectin-3,act as a molecular glue, bringing together molecules that have sugars on them.

Galectin-3, is known to be markedly increased in a number of important diseases including inflammatory diseases leading to organs scarring (e.g.

liver, lung, kidney, and heart) and cancers.

The increase in galectin-3 , by creating the so-called

galectin-3 fibrosome, promotes the progression of multiple diseases.

Published data substantiating the importance of galectin-3 in the fibrotic process arises from gene knockout experiments in animal studies.

For instance, mice genetically

altered to eliminate the galectin-3 gene, and thus unable to produce galectin-3, do not develop liver fibrosis in response to toxic insult to the liver.

We have one new proprietary chemical entity (NCE) in development, belapectin, which has shown promise in preclinical and clinical studies for the treatment of liver fibrosis, severe skin disease, and cancer (melanoma

and head and neck squamous cell carcinoma).

Currently we are focusing on development of belapectin for the treatment of NASH cirrhosis and Head and neck cancer.

Belapectin is a proprietary, patented compound derived from natural, plant-based,

starting materials, which, following chemical processing, exhibits the properties of binding to and inhibiting galectin-3.

Our product pipeline is shown below:

NASH with Advanced Fibrosis:

Prevention of esophageal varices in NASH cirrhosis

Phase 1 interaction trial:

NASH-CX trial and

NASH-FX trial

IND submitted January 2013.

Results from the Phase 1 clinical trial were reported in 2014, with final results reported in January 2015.

The Phase 2 NASH FX trial was designed for patients with advanced fibrosis but not cirrhosis.

Results from the Phase 1 interaction trial were reported in 2014, with final results reported in January 2015.

The Phase 2 NASH FX trial was conducted in patients with advanced fibrosis but not cirrhosis.

Its principal purpose was to evaluate various imaging modalities.

The NASH FX trial top line data was reported in September 2016

The Phase 2 NASH CX trial, was designed for patients with well compensated cirrhosis.

The NASH FX trial top line data was reported in September 2016 and

published in Alimentary Pharmacology and Therapeutics in 2016.

The Phase 2 NASH CX trial was conducted in patients with compensated cirrhosis and portal hypertension.

The NASH CX trial top line data was reported in December 2017 and was published in Gastroenterology

NASH NAVIGATE

Based on FDA feedback, the NAVIGATE trial is an adaptive Phase 2b/3 trial for the prevention of esophageal varices in NASH patients with compensated cirrhosis.

A Phase 2b interim efficacy analysis will be incorporated to confirm previous Phase 2 data, select an optimal dose and reaffirm the risk/benefit of belapectin.

The Phase 3 end of study analysis will evaluate the development of esophageal varices as the primary outcome of efficacy and a composite clinical endpoint including progression to varices requiring treatment as a key secondary outcome of efficacy.

See www.clinicaltrials.gov NCT04365868.

The first patient was randomized in the third quarter of 2020.

A hepatic impairment is being conducted in subjects with normal hepatic function and subjects with varying degrees of hepatic impairment (CF:

www.clinicaltrials.gov NCT04332432) and began enrolling patients in the second quarter of 2020.

Lung Fibrosis

In pre-clinical

Kidney Fibrosis

In pre-clinical

Cardiac and Vascular Fibrosis

belapectin and GM-CT-01

In pre-clinical

Following FDA feedback, the NAVIGATE trial is an adaptive Phase 2b/3 trial for the prevention of esophageal varices in NASH patients with compensated cirrhosis and clinical signs of portal hypertension.

A Phase 2b interim efficacy

analysis will be incorporated to confirm previous Phase 2 data, select an optimal dose and reaffirm the risk/benefit of belapectin.

The Phase 3 end of study analysis will evaluate the development of esophageal varices as the same primary

outcome of efficacy and a composite clinical endpoint including progression to varices requiring treatment as a key secondary outcome of efficacy ( www.clinicaltrials.gov NCT04365868).

The first patient was randomized in the third quarter

Phase 1 study:

hepatic insufficiency

A hepatic impairment study is being conducted in subjects with normal hepatic function and subjects with varying degrees of hepatic impairment (www.clinicaltrials.gov NCT04332432) and began

enrolling patients in the second quarter of 2020.

The study completed enrollment in February 2022.

Cancer Immunotherapy

4 unchanged sentences

Early data was reported in February 2017 and additional data were reported in September 2018.

The trial is ongoing to expand the dataset of melanoma and HNSCC patients and determine if a Phase 2 trial is warranted.

Moderate to Severe Plaque Psoriasis

Severe Atopic Dermatitis

IND submitted March 2015.

A Phase 2a trial in moderate to severe plaque psoriasis patients began in January 2016.

Interim data on the first four patients were positive and were reported in May 2016.

Further positive data was reported in September 2016.

Investigator initiated IND submitted for treatment of three patients with severe atopic dermatitis, with positive preliminary data presented in February 2017.

Further studies are dependent on finding a suitable strategic partner which is unlikely.

Belapectin is our lead product candidate for treatment of fibrotic disease.

Data from an extension trial was reported in July 2021 for additional

melanoma and HNSCC patients which provided a rational basis for additional trials which the Company is exploring.

Liver cirrhosis.

Belapectin is our lead product

candidate for treatment of compensated NASH cirrhosis in patients with portal hypertension.

Our preclinical data show that belapectin has a significant therapeutic effect on liver fibrosis as shown in several relevant animal models.

In addition, in NASH animal models, belapectin has been shown to reduce liver fat, inflammation, and ballooning degeneration (death of liver cells).

Therefore, we chose belapectin as the lead candidate in a development program targeted initially at fibrotic liver disease associated with non-alcoholic

steatohepatitis (NASH).

In January 2013, an Investigational New Drug (“IND”) was submitted to the FDA with the goal of initiating a Phase 1 study in patients with NASH and advanced liver fibrosis to evaluate the human safety of belapectin and pharmacodynamics biomarkers of disease.

On March 1, 2013, the FDA indicated we could proceed with a US Phase 1 clinical trial for belapectin with a development program aimed at obtaining support for a proposed indication of belapectin for treatment of NASH with advanced fibrosis.

addition, in NASH animal models, belapectin has been shown to reduce liver fat, inflammation, portal pressure, and ballooning degeneration (death of liver cells).

Therefore, we chose belapectin as the lead candidate in a development program

targeted initially at fibrotic liver disease associated with non-alcoholic steatohepatitis (NASH).

In January 2013, an Investigational New Drug (“IND”) was submitted to the FDA with the goal of initiating a Phase 1 study in patients with NASH

and advanced liver fibrosis to evaluate the safety of belapectin and pharmacodynamics biomarkers of disease.

On March 1, 2013, the FDA indicated we could proceed with a US Phase 1 clinical trial for belapectin with a development program aimed

at obtaining support for a proposed indication of belapectin for treatment of NASH with advanced fibrosis.

The Phase 1 trial was completed and demonstrated that belapectin up to 8 mg/kg Lean Body Mass (LBM), i.v.

was safe and well tolerated.

Additionally, an open label drug-drug interaction study was completed in healthy volunteers during the second quarter of 2015 with belapectin and it showed that with 8 mg/kg LBM dose of belapectin and 2 mg/kg LBM dose of midazolam there was no drug-drug interaction and no serious adverse events or drug-related adverse events were observed.

The secondary objective was to assess the safety and tolerability of belapectin when administered concomitantly with midazolam.

Additionally, an open label drug-drug phase 1 interaction study was completed in healthy volunteers during the second quarter of 2015 with belapectin and it showed that with 8 mg/kg LBM dose of belapectin and 2

mg/kg LBM dose of midazolam there was no drug-drug interaction, and no serious adverse events or drug-related adverse events were observed.

The secondary objective was to assess the safety and tolerability of belapectin when administered

concomitantly with midazolam.

Our Phase 2 program in fibrotic disease consisted of two separate human clinical trials.

The primary clinical trial was the Phase 2b NASH-CX

study for one year for patients with NASH with compensated cirrhosis, which began enrolling in June 2015.

This study was the primary focus of our program and was a randomized, placebo-controlled, double-blind, parallel-group Phase 2b trial to evaluate the safety and efficacy of belapectin for treatment of liver fibrosis and resultant portal hypertension in NASH patients with compensated cirrhosis.

A smaller, exploratory NASH-FX

trial was conducted to explore potential use of various non-invasive

imaging techniques in NASH patients with advanced fibrosis but not cirrhosis.

trial was a Phase 2a pilot trial for patients with NASH and advanced fibrosis that explored use of three non-invasive

imaging technologies.

It was a short, single site, four-month trial in 30 NASH patients with advanced fibrosis (F3), but not cirrhosis (F4), randomized 1:1 to either 9 bi-weekly

doses of 8 mg/kg LBM of belapectin or placebo.

The trial did not meet its primary biomarker endpoint as measured using multi-parametric magnetic resonance imaging (LiverMultiScan (R)

, Perspectum Diagnostics).

The trial also did not meet secondary endpoints that measure liver stiffness as a surrogate for fibrosis using, magnetic resonance-elastography and FibroScan ®

We, and many experts in the field, now believe that a four-month treatment period was not sufficient to show efficacy results in established advanced liver fibrosis.

This small study was also not adequately powered for the secondary endpoints.

In the trial, belapectin was found to be safe and well tolerated with no serious adverse events and evidence of a pharmacodynamic effect.

The main clinical trial was the Phase 2b NASH-CX study for one year for patients with NASH with compensated cirrhosis and

portal hypertension, which began enrolling patients in June 2015.

This study was a randomized, placebo-controlled, double-blind, parallel-group Phase 2b trial to evaluate the safety and efficacy of belapectin for treatment of liver fibrosis and

resultant portal hypertension in NASH patients with compensated cirrhosis.

A smaller, exploratory NASH-FX trial was conducted to explore potential use of various non-invasive imaging techniques in NASH patients with advanced fibrosis but not

NASH-FX Trial:

The NASH-FX trial was a Phase 2a

pilot trial for patients with NASH and advanced fibrosis that explored use of three non-invasive imaging technologies.

It was a short, single site, four-month trial in 30 NASH patients with advanced fibrosis (F3) randomized 1:1 to either 9

bi-weekly doses of 8 mg/kg LBM of belapectin or placebo.

The trial did not meet its primary endpoint as measured using multi-parametric magnetic resonance imaging (LiverMultiScan (R) , Perspectum Diagnostics).

The trial also did not meet secondary endpoints that measure liver stiffness as a surrogate for fibrosis using, magnetic resonance-elastography and FibroScan ® score.

With a four-month treatment period and a small number of patients per arm the study was not powered to demonstrate efficacy results in established advanced liver fibrosis.

however, belapectin was found to be safe and well tolerated with no serious adverse events and showing evidence of a pharmacodynamic effect.

These results provided support for further development in NASH.

trial was a larger multi-center clinical trial that explored the use of belapectin for the treatment of liver fibrosis and resultant portal hypertension in patients with well-compensated NASH cirrhosis.

Enrollment in this trial was completed in September 2016, and a total of 162 patients at 36 sites in the United States were randomized to receive either 2 mg/kg LBM of belapectin, 8 mg/kg LBM of belapectin or placebo, with 54 patients in each group.

NASH-CX Trial:

The NASH-CX trial was a larger

multi-center clinical trial that explored the use of belapectin for the treatment of patients with well-compensated NASH cirrhosis and portal hypertension.

Enrollment was completed in September 2016, and a total of 162 patients at 36 sites in

the United States were randomized to receive either 2 mg/kg LBM of belapectin, 8 mg/kg LBM of belapectin or placebo.

Approximately 50% of patients at baseline had esophageal varices (a complication of portal hypertension).

The primary endpoint was a reduction in hepatic venous pressure gradient (HVPG).

Patients received an infusion of belapectin or placebo every other week for one year, a total of 26 infusions, and were evaluated to determine the change in HVPG as compared with placebo.

Secondary or exploratory endpoints included fibrosis on liver biopsy, measurement of liver stiffness (FibroScan (R)

) and assessment of liver metabolism ( 13

breath test, Exalenz).

The primary endpoint

was a reduction in hepatic venous pressure gradient (HVPG), a hemodynamic measure that estimates portal hypertension.

Patients received an infusion of belapectin or placebo every other week for one year and were evaluated to determine the

change in HVPG as compared with placebo.

Secondary or exploratory endpoints included evaluation of fibrosis on liver biopsy, measurement of liver stiffness (FibroScan (R) )

and assessment of liver metabolism ( 13 C-methacetin breath test).

Top line data readout was reported in December 2017.

The study demonstrated a favorable safety profile and clinically meaningful efficacy results in patients without esophageal varices at baseline demonstrated by a prevention of development of varices when compared to placebo.

The study demonstrated a favorable safety

profile and clinically meaningful efficacy results in patients without esophageal varices at baseline as demonstrated by a decrease in portal pressure associated with the prevention of development of varices when compared to placebo.

In the total patient population, the primary endpoint HVPG showed a trend toward benefit with belapectin treatment, but the difference from placebo was not statistically significant.

The mean change in HVPG of placebo from baseline to week 54 was 0.3 mm Hg.

The mean change in HVPG from baseline was -0.37

for the 2 mg/kg LBM dose and 8 mg/kg LBM dose of belapectin, respectively.

In those NASH cirrhosis patients without varices at baseline (about 50% of the total population), there was a statistically significant effect of the 2 mg/kg LBM dose of belapectin on the absolute change in HVPG (-1.08

mm Hg, p<0.01).

The mean change in HVPG of

placebo from baseline to week 54 was 0.3 mm Hg.

The mean change in HVPG from baseline was -0.37 and -0.42 for the 2 mg/kg LBM dose and 8 mg/kg LBM dose of belapectin, respectively.

In those NASH cirrhosis patients with portal hypertension who have not yet developed esophageal varices at baseline (about 50% of the total population), there was a statistically significant effect of the 2 mg/kg

LBM dose of belapectin on the absolute change in HVPG (-1.08 mm Hg, p<0.01).

The effect of the 8 mg/Kg LBM dose of belapectin on absolute or percent change in HVPG from baseline to week 54 was not significant.

Also because of the clinical relevance of this population, a responder analysis was performed on those patients without varices at baseline.

Also because of the clinical relevance of this population, a responder analysis was performed on those patients without esophageal varices at baseline.

Analysis was performed looking at two groups:

those with an equal to or greater than 2 mm Hg decrease in HVPG from baseline or those with an equal to or greater than 2 mm Hg and a greater than or equal to 20% decrease in HVPG from baseline.

In both cases, the change observed in the belapectin 2 mg/kg LBM group was statistically significant (p<0.01) while that of the 8 mg/kg LBM group was not.

Over the 54-week

treatment period, in patients without varices there were statistically significantly fewer new varices that developed in the belapectin treatment groups (0% and 4% in the 2 mg/kg LBM and the 8 mg/kg LBM, respectively) vs placebo (18%).

As esophageal varices can lead to hemorrhagic complication, which can be fatal, we believe the prevention of esophageal varices may represent a clinically relevant measure of clinical efficacy in patients with NASH cirrhosis.

The major conclusions from the NASH-CX

trial results were that:

i) belapectin had a statistically significant and clinically meaningful effect in improving HVPG vs placebo in patients with NASH cirrhosis who did not have esophageal varices at baseline.

This effect was seen regardless of the patient’s baseline portal hypertension.

ii) There was an important drug effect of belapectin in the total patient population on liver biopsy with a statistically significant improvement in hepatocyte ballooning (ie cell death), (iii) There was a statistically significant reduction (p=0.02) in the development of new esophageal varices in drug-treated patients compared to placebo.

We believe that this is a clinically relevant endpoint related to patient outcomes, (iv) While there was a drug effect in both the 2 mg/kg LBM and 8 mg/kg LBM groups on the development of varices and liver biopsy there was a consistently greater and statistically significant effect of the 2 mg/kg LBM dose of belapectin, (v) belapectin appears to be safe and well tolerated in this one year clinical trial, a feature that is of prime importance for a cirrhotic population and (vi) We believe this is the first large, randomized clinical trial to demonstrate a clinically meaningful improvement in portal hypertension or liver biopsy in patients with compensated NASH cirrhosis who have not yet developed esophageal varices.

Further information and details on the NASH-CX

results summarized above is available in public presentations posted to our website and filed with the SEC and in a peer reviewed publication in Gastroenterology

(Gastroenterology 2020;158:1334–1345).

those with an

equal to or greater than 2 mm Hg decrease in HVPG from baseline or those with an equal to or greater than 2 mm Hg and a greater than or equal to 20% decrease in HVPG from baseline.

In both cases, the change observed in the belapectin 2 mg/kg LBM

group was statistically significant (p<0.01) while that of the 8 mg/kg LBM group was not.

Over the 54-week treatment period, in patients without varices at baseline there were also a statistically significantly fewer new varices that developed in the belapectin treatment groups (0% and 4% in the 2 mg/kg

LBM and the 8 mg/kg LBM, respectively) vs placebo (18%).

This meant that the decrease seen in portal pressure was associated with a decreased incidence of esophageal varices.

The results were noticeable in the belapectin 2 mg/Kg LBM group as

statistical significance against placebo was achieved for both parameters.

As esophageal varices can lead to hemorrhagic complication, which can be fatal, and are a severe complication of liver cirrhosis, we believe the prevention of esophageal

varices may represent a clinically relevant measure of clinical efficacy in patients with NASH cirrhosis.

The major conclusions from the NASH-CX trial results were that:

(i) belapectin had a statistically significant and clinically meaningful effect in improving HVPG vs placebo in patients with NASH cirrhosis who did

not have esophageal varices at baseline, (ii) Belapectin in the total patient population was associated with a statistically significant improvement in hepatocyte ballooning (ie cell death), (iii) There was a statistically significant reduction

(p=0.02) in the development of new esophageal varices in drug-treated patients compared to placebo.

We believe that the prevention of esophageal varices is a clinically relevant endpoint related to patient outcomes, (iv) While there was a drug

effect in both the 2 mg/kg LBM and 8 mg/kg LBM groups on the development of varices and liver biopsy there was a consistently greater and statistically significant effect of the 2 mg/kg LBM dose of belapectin, (v) belapectin appears to be safe

and well tolerated in this one year clinical trial, a feature that is of prime importance for a cirrhotic population and (vi) This is the first large, randomized clinical trial to demonstrate a clinically meaningful improvement in portal

hypertension in patients with compensated NASH cirrhosis who have not yet developed esophageal varices.

Further information and details on the NASH-CX results is available in public presentations posted to our website and filed with the SEC and in a peer reviewed publication in Gastroenterology

2020;158:1334–1345.

NASH NAVIGATE Trial:

Building on the experience of the NASH-CX

trial, the NAVIGATE Trial is a seamless adaptively-designed Phase 2b/3 clinical study evaluating the safety and efficacy of our galectin-3

inhibitor, belapectin (GR-MD-02),

for the prevention of esophageal varices in patient with non-alcoholic

Building on the experience of

the NASH-CX trial, the NAVIGATE Trial is a seamless adaptively-designed Phase 2b/3 clinical study evaluating the safety and efficacy of our galectin-3 inhibitor, belapectin, for the prevention of esophageal varices in patient with non-alcoholic

steatohepatitis (NASH) cirrhosis.

The major features of this innovative Phase 2b/3 study design are:

i) In patients with NASH cirrhosis and clinical signs of portal hypertension but without esophageal varices at baseline, this trial will assess the effect of belapectin on the incidence of new varices (the primary endpoint) – as well as assessing effect on the incidence of long-term, clinically significant cirrhosis-related outcomes (a key secondary efficacy endpoint), (ii) The study targets NASH patients with a clearly identified unmet medical need:

patients with compensated cirrhosis who are at risk of developing esophageal varices, a potentially life-threatening complication of cirrhosis (bleeding varices are a cause of death in about one-third

of cirrhotic patients).

There is no approved treatment for preventing varices in these patients.

In addition, the development of esophageal varices reflects the progression of hepatic cirrhosis and thus portends the development of other cirrhosis complications such as ascites, hepatic encephalopathy, and liver failure, and (iii) During the first 18 months, two belapectin dose levels (2 mg/kg LBM and 4 mg/kg LBM) will be compared to placebo (phase 2b).

Then, at the interim analysis (IA), one belapectin dose will be selected based on efficacy and safety, for continued evaluation (Phase 3).

The belapectin dose selected for the phase 2b/3 are based on the analysis of the NASH-CX

trial, including a dose response pharmacokinetic analysis of the hepatic venous gradient pressure (HVPG, a reflection of portal hypertension).

Prior belapectin clinical studies have also indicated the good tolerance and safety profile of belapectin with doses of up to 8 mg/kg LBM for 52 weeks (Phase 2b Study NASH-CX),

an important feature of the future risk benefit analysis in patients with NASH cirrhosis.

The study design provides for a pre-specified

interim analysis (IA).

The IA of efficacy and safety data will be conducted after all planned subjects in Phase 2b component have completed at least 78 weeks (18 months) of treatment and an esophago-gastro-duodeno endoscopic assessment.

i) In patients with NASH cirrhosis and clinical signs of portal hypertension but without esophageal varices at baseline, this trial will assess

the effect of belapectin on the incidence of new varices (the primary endpoint) – as well as assessing the effect of belapectin on the incidence of additional clinically significant cirrhosis-related outcomes (a key secondary efficacy

endpoint), (ii) The study targets NASH patients with a clearly identified unmet medical need:

patients with compensated cirrhosis who have clinical signs of portal hypertension and, thus, are at risk of developing esophageal varices, a

potentially life-threatening complication of cirrhosis (bleeding varices are a cause of death in about one-third of cirrhotic patients).

There is currently no approved treatment for preventing varices in these patients.

In addition, the

development of esophageal varices reflects the progression of hepatic cirrhosis and thus portends the development of other cirrhosis complications such as ascites, hepatic encephalopathy, and liver failure, and (iii) During the first 18 months,

two belapectin dose levels (2 mg/kg LBM and 4 mg/kg LBM) will be compared to placebo (phase 2b).

Then, at the interim analysis (IA), the best belapectin dose will be selected, based on efficacy and safety, for continued evaluation (Phase 3).

The belapectin dose selected for the phase 2b/3 were based on the analysis of the NASH-CX trial.

Prior belapectin clinical studies have also indicated the good tolerance and safety profile of belapectin with doses of up to 8 mg/kg LBM for up to

52 weeks, an important feature to inform the future risk benefit analysis in patients with NASH cirrhosis.

The study design provides for a pre-specified interim analysis (IA).

The IA of efficacy and safety data will be conducted after all planned subjects in Phase 2b component have completed at least 78 weeks (18

months) of treatment and a second esophago-gastro-duodeno endoscopic assessment.

The purpose of the IA is to allow potential seamless adaptive modifications of the study, including:

(1) the selection of the optimal dose of belapectin for Phase 3, (2) the re-estimation

of the study sample size for Phase 3 portion of the trial, (3) the re-evaluation

of the randomization ratio for the Phase 3 portion of the trial, (4) the refinement of the inclusion and exclusion criteria for the Phase 3 portion of the trial, including the cirrhosis status, (5) and/or termination of the study for overwhelming efficacy or for futility.

The trial design also includes a blinded sample size re-estimation

(“SSR”) during the Phase 2b, prior to the IA, to allow for potential sample size readjustment.

The SSR will be conducted when 50% of the patients have completed 18 months of therapy.

(1) the selection of the optimal dose of belapectin for Phase 3,

(2) the re-estimation of the study sample size for Phase 3 portion of the trial, (3) the re-evaluation of the randomization ratio for the Phase 3 portion of the trial, (4) the refinement of the inclusion and exclusion criteria for the Phase 3

portion of the trial, including the cirrhosis status, (5) and/or termination of the study for overwhelming efficacy or for futility.

The trial design also includes a blinded sample size re-estimation (“SSR”) during the Phase 2b, prior to the IA, to allow for potential sample size readjustment.

The SSR will be conducted when 50% of the patients

have completed 18 months of therapy.

This will allow us to confirm the underlying assumption regarding the rate of varices development, currently estimated from our prior Phase 2b trial (NASH-CX).

The study design also minimizes invasive testing requirements, such as the measurement of HVPG or repeated liver biopsies, which we believe will facilitate enrollment and retention of patients.

It also provides for a seamless transition of patients from the Phase 2b component into the phase 3 stage, including the potential addition of new patients.

The trial design preserves the surrogate end-point

concepts (development of new varices versus variceal hemorrhage) previously discussed with FDA.

We believe that these adaptations taken together are innovative and optimize conduct of the NAVIGATE trial with a clinically relevant primary outcome giving belapectin the best opportunity to show a positive therapeutic effect to address an unmet medical need.

The study design also minimizes invasive testing

requirements, such as the measurement of HVPG or repeated liver biopsies, which we believe are particularly risky in patients with portal hypertension and will facilitate enrollment and retention of patients.

It also provides for a seamless

transition of patients from the Phase 2b component into the phase 3 stage, including the potential addition of new patients.

The trial design preserves the surrogate end-point concepts (development of new varices versus variceal hemorrhage)

previously discussed with FDA.

therapeutic effect to address an unmet medical need.

As a testimony of this innovation, the NAVIGATE trial design was presented to the hepatology community and featured during the last meeting of the American Association for the Study of Liver

Diseases, in November 2021.

If the IA results of the NAVIGATE trial are compelling, there could be the potential for accelerated FDA approval and/or partnership opportunity with a pharmaceutical company.

In the Phase 3 component of this trial, as proposed in the protocol, the primary endpoint remain the development of varices.

Secondary endpoints include a composite clinical outcomes endpoint, including varices requiring treatment (development of large varices or varices with a red wale), decompensating events, all-cause

mortality, MELD score increase, liver transplant.

Also, NASH non-invasive

biomarkers will be evaluated.

To target a population at risk of developing esophageal varices, patient selection will be based on clinical signs of portal hypertension, including, a low platelet count, an increased spleen size and/or evidence of collaterals circulation.

The focus and goal of the therapeutic program is to stop the progression of and/or reverse portal hypertension and thereby prevent the development of varices, potentially one of the most immediately life-threatening complication of cirrhosis.

Based on the results of the NASH-CX

trial and subject to confirmation in later stage clinical trials, we believe that this goal is achievable in a significant portion of the NASH cirrhosis patient population i.e.

those NASH cirrhosis patients with clinical signs of portal hypertension.

pandemic has delayed and may continue to delay our recruitment of sites and enrollment of patients for our Phase 2b/3 NAVIGATE trial despite a recent uptick in screening activities.

Many cities in the United States and Europe have experienced shut-downs, and while some cities have begun to loosen restrictions, they are at risk of experiencing new shut-downs and restrictions.

In some countries, shutdown orders have also affected the regulatory process to authorize study starts.

Governments and medical facilities are focusing their resources for battling the COVID-19

For several reasons, the pandemic makes enrolling patients for the NAVIGATE trial more challenging, including because patients eligible for the NAVIDGATE trial have liver cirrhosis and, as such, are at a greater health risk of complications from COVID-19

until vaccinations are more readily available and completed.

We believe that as more people get vaccinated for COVID-19,

site recruitment and patient enrollment will accelerate.

At this time, we estimate that enrollment completion will occur by the end of 2022.

We have identified more than 130 clinical trial sites in 11 countries for the NAVIGATE trial.

Further details on the NAVIGATE trial can be found on www.clinicaltrials.gov

under study NCT04365868.

Secondary endpoints include a composite clinical outcomes endpoint, including varices

requiring treatment (development of large varices or varices with a red wale), decompensating events, all-cause mortality, MELD score increase, liver transplant.

Also, NASH non-invasive biomarkers will be evaluated.

To target a population at risk

of developing esophageal varices, patient selection will be based on clinical signs of portal hypertension, including, but not limited to, a low platelet count, an increased spleen size and/or evidence of abdominal collaterals circulation.

The focus and goal of the therapeutic program is to stop the progression of and/or reverse portal hypertension and thereby prevent the development of varices, potentially one of the most immediately

life-threatening complication of cirrhosis.

Based on the results of the NASH-CX trial and subject to confirmation in later stage clinical trials, we believe that this goal is achievable in a significant portion of the NASH cirrhosis patient

population i.e.

those NASH cirrhosis patients with clinical signs of portal hypertension for whom, currently no specific, liver targeted, treatment are available.

The COVID-19 pandemic has delayed and may continue to delay our regulatory and ethics approvals, recruitment of sites, and enrollment of patients for our Phase 2b/3 NAVIGATE trial despite a recent uptick in

screening activities.

Many investigational centers in the United States and Europe have experienced shut-downs, and while some have loosened or removed restrictions, there may be a risk of experiencing new shut-downs and restrictions.

countries, shutdown orders have also affected the regulatory process to authorize study starts.

Governments and medical facilities have focused their resources for battling the COVID-19 pandemic.

For several reasons, the pandemic makes enrolling

patients for the NAVIGATE trial more challenging, including because patients eligible for the NAVIGATE trial have liver cirrhosis and, as such, are at a greater health risk of complications from COVID-19.

It is also important to consider the

safety of our candidate participants first, as cirrhotic patients with portal hypertension are immune compromised.

We believe that as we continue to emerge from the COVID-19 pandemic, site recruitment and patient enrollment will accelerate and we

have experienced increases in enrollment, particularly in the U.S.

However, we have not seen the enrollment in Europe that we anticipated, and conditions there remain uncertain.

Consequently, we have activated multiple sites in Latin America.

At this time, although enrollment completion is targeted for June 30, 2022, it may require an additional quarter to complete.

We have identified and activated approximately 138 clinical trial sites in 14 countries for the NAVIGATE trial.

Further details on the NAVIGATE trial can be found on www.clinicaltrials.gov under study NCT04365868 and on our NAVIGATE website (navigatenash.com).

The Company also has commenced a Hepatic Impairment Study, which will run in parallel with the phase 2b/3 trial as part of the development program.

The Hepatic Impairment Study is being conducted at three sites and will involve approximately 40 patients (divided amongst normal healthy volunteers, and patients with hepatic impairment categorized as Child-Turcotte-Pugh (CTP) classes A (mild), B (moderate), and C (severe)).

Each subject will receive a single infusion of belapectin (4 mg/kg LBM) and their serum belapectin levels will be monitored for up to approximately two weeks to define the effects of various stages of cirrhosis on serum belapectin levels.

The tolerance and safety of belapectin will be evaluated.

Based on the results from this hepatic impairment study, the Company may consider including patients with more advanced cirrhosis in the Phase 3 portion of its NAVIGATE trial.

The Hepatic Impairment Study is being conducted at three sites and

involves approximately 40 patients (divided amongst normal healthy volunteers, and patients with hepatic impairment categorized as Child-Turcotte-Pugh (CTP) classes A (mild), B (moderate), and C (severe).

Each subject will receive a single

infusion of belapectin (4 mg/kg LBM) and their serum belapectin levels will be monitored for up to approximately two weeks to define the effects of various stages of cirrhosis on serum belapectin levels.

The tolerance and safety of belapectin

will be evaluated.

Enrollment in this study was completed in February 2022, and the results will be announced when available.

Based on the results from this hepatic impairment study, the Company may consider including patients with more

advanced cirrhosis in the Phase 3 portion of its NAVIGATE trial.

Until dosing and safety profile is further informed in CTP Class B and/or Class C patients, the NAVIGATE trial will enroll only CTP Class A patients.

Further details on this hepatic impairment study can be found on www.clinicaltrials.gov

study NCT04332432.

Further details on this hepatic

impairment study can be found on www.clinicaltrials.gov study NCT04332432.

Cancer Immunotherapy.

We believe there is potential for galectin inhibition to play a key role in the burgeoning area of cancer immunotherapy.

We believe there is

potential for galectin inhibition to play a key role in the innovative area of cancer immunotherapy.

For example, there have been several recent approvals of drugs that enhance a patient’s immune system to fight cancer.

It is our goal to use a galectin inhibitor to further enhance the immune system function to fight cancer in a way that complements other approaches to this type of therapy.

This hypothesis is supported by the fact that galectin-3

is expressed at high levels in multiple types of tumors, adds to the malignant nature of the tumors, and protects the tumors from immune system attack.

Our drug candidates provide a promising new therapeutic approach to enhance the activity of the immune system against cancer cells.

Preclinical studies have indicated that belapectin enhances the immune response to cancer cells, increased tumor shrinkage and enhanced survival in immune competent mice with prostate, breast, melanoma and sarcoma cancers when combined with one of the immune checkpoint inhibitors, anti-CTLA-4

or anti-PD-1,

or with the immune cell activator anti-OX40.

These preclinical data led to the filing of two Investigator-sponsored INDs and the initiation of studies of belapectin in combination with Yervoy ®

(ipilimumab) and KEYTRUDA (pembrolizumab) in Phase 1B studies of patients with metastatic melanoma.

The KEYTRUDA trial has also been expanded to include patients with non-small

cell lung cancer and head and neck squamous cell carcinoma.

These studies are being conducted under the sponsorship of Providence Portland Medical Center’s Earle A.

It is our goal to use

ourgalectin-3 inhibitor to further enhance the immune system function to help the body to fight cancer in a way that complements other approaches to this type of therapy.

This hypothesis is supported by the fact that galectin-3 is expressed at

high levels in multiple types of tumors and their micro-environment, where it fosters the malignant nature of the tumors, and protects the tumors from immune attack by the patient’s own defense mechanism.

Our drug candidates provide a promising

new therapeutic approach to enhance the activity of the immune system against cancer cells.

Preclinical studies have indicated that belapectin enhances the immune response to cancer cells, increased tumor shrinkage and enhanced survival in

immune competent mice with prostate, breast, melanoma and sarcoma cancers when combined with one of the immune checkpoint inhibitors, anti-CTLA-4 or anti-PD-1, or with the immune cell activator anti-OX40.

These preclinical data led to the

filing of two Investigator-sponsored INDs and the initiation of Phase 1B studies of belapectin in combination with Yervoy ® (ipilimumab) in metastatic melanoma and

another phase 1B study in combination with KEYTRUDA (pembrolizumab) in patients with metastatic melanoma and head and neck squamous cell carcinoma.

These studies were conducted under the sponsorship of Providence Portland Medical Center’s Earle

Chiles Research Institute (EACRI).

The phase IB study in combination with Yervoy was rapidly discontinued after the first patients were recruited because of the availability on new treatment in the selected population.

Promising results were reported in the Phase 1b trial combining belapectin with pembrolizumab (KEYTRUDA ® ).

Cohort 1 was completed (n=6, 5 with melanoma, one with head and neck cancer) with one partial response and one mixed response in the melanoma patients.

There was a rapid and marked tumor response after 3 doses of combined belapectin and pembrolizumab in the one partial response patient who had failed high-dose IL-2

and oncolytic virus + ipilimumab.

The study is ongoing and progression to further development will be based on response rate as compared to historical response rates to pembrolizumab alone.

In September 2018 we announced additional preliminary clinical data from cohort 3 of this investigator-initiated trial.

When aggregated with cohorts previously reported, the data shows a 50% objective response rate in advanced melanoma with belapectin in combination with KEYTRUDA, and a significant decrease in the frequency of suppressive myeloid-derived suppressor cells following treatment in the responding patients (on day 85 post-treatment).

Fourteen advanced melanoma patients across three dose cohorts now have Objective Response Rate (ORR) and Disease Control Rate (DCR) data.

Six patients completed in cohort 3 (8 mg/kg LBM) have now been added to the three patients completed in cohort 2 (4 mg/kg LBM) and five patients completed in cohort 1 (2 mg/kg LBM).

Cohorts 1 and 3 each had two patients with an objective response.

All three patients in cohort 2 had an objective response.

In addition to the fourteen advanced melanoma patients, six patients with head and neck cancer were enrolled in this trial with a 33% ORR and 67% DCR.

These data, taken together with the observed favorable safety and tolerability of the combination, in the view of the principal investigator, provide compelling rationale to move forward.

Given that all three melanoma patients were responders at the 4 mg/kg dose, the investigators plan to continue the trial with the expansion of the 4 mg/Kg cohort to include additional advanced melanoma patients and additional head and neck cancer patients.

The expansion cohort includes 14 patients and is planned to have continued belapectin dosing to match the recommended duration of pembrolizumab administration.

The expansion cohort has been enrolled and further information will be reported as it becomes available.

Discussions are ongoing about the planning and feasibility of a multicenter Phase 2 study, assuming the additional expansion cohort data are positive.

Severe skin diseases.

During our Phase 1 NASH fibrosis trial with belapectin, a clinical effect on plaque psoriasis was observed in a NASH patient who also suffered from psoriasis.

This patient had marked improvement in her psoriasis, with improvement beginning after the third infusion.

She reported that her psoriasis was “completely gone” and her skin was “normal” after the fourth infusion.

Her skin remained normal for 17 months after the final infusion of study drug.

The patient is convinced that the improvement in her psoriasis is related to the study drug.

This serendipitous finding, combined with galectin-3

protein being markedly upregulated in the capillary epithelia (small blood vessels) of the psoriatic dermis (plaque lesions), led to a phase 2a trial in patients with moderate to severe plaque psoriasis.

belapectin inhibition of galectin-3

may attenuate capillary changes in the psoriatic dermis and inflammatory recruitment, perhaps explaining the improvements observed in the NASH fibrosis trial patient.

In this open-label, unblinded trial (no placebo, all patients knowingly receive active drug), 5 patients with moderate to severe plaque psoriasis were administered belapectin every two weeks for 24 weeks.

In May 2016, we reported positive results on the first four patients after 12 weeks of therapy.

Based on these results, we modified the trial to include 24 weeks of therapy.

In August 2016, we reported on four patients after 24 weeks of therapy and one patient after 12 weeks of therapy.

The four patients who received 24 weeks of therapy experienced an average of 48% improvement in their plaque psoriasis.

At the end of that study, the average response in all five patients was at 50% with one patient having an 82% improvement.

However, there are existing drugs on the market in this disease that produce 75% and higher improvements in 60-90%

While we are encouraged that this study has demonstrated clinically meaningful results in a human disease with belapectin, the next steps would entail a controlled, does-ranging clinical trial, which we do not expect to conduct absent a strategic partnership which is unlikely.

We believe the mechanism of action for belapectin is based upon interaction with, and inhibition of, galectin proteins, particularly galectin-3,

which are expressed at high levels in certain pathological states including inflammation, fibrosis and cancer.

While belapectin is capable of binding to multiple galectin proteins, we believe that it has the greatest affinity for galectin-3,

the most prominent galectin implicated in pathological processes.

Blocking galectin in cancer and liver fibrosis has specific salutary effects on the disease process, as discussed below.

Liver Fibrosis:

New Approach for a Significant Unmet Medical Need

When an internal organ is exposed to chronic disease one of the responses is that scar tissue is laid down in the organ (this process is called fibrosis).

The longer the disease affects the organ, the more fibrous tissue is deposited, and this ultimately results in the failure of the organ.

This chronic fibrosis of organs may occur in the liver, lung, kidney, and heart, as well as others and, as a result, fibrosis of organs has been estimated to account for as much as 45% of all mortality in the United States.

Scientific findings during the last few years indicate that the galectin-3

protein is critically important in this fibrotic process in multiple organs.

In the liver, fibrosis is the end result of multiple inflammatory conditions and infections.

Progressive liver fibrosis leads to cirrhosis, which results in reduction of liver function, multiple medical complications and ultimately death.

It is estimated that one to two million patients have cirrhosis in the United States with close to 50,000 losing their lives yearly.

Only a fraction of patients’ lives, approximately 6,200 per year, are saved by liver transplantation at a cost of at least $350,000 per transplantation with significant additional costs of care and medications after the transplant.

One condition in particular that frequently leads to cirrhosis is non-alcoholic

steatohepatitis, or NASH, a liver disease characterized by the accumulation of fat in the liver with associated inflammation and fibrosis, which can lead to end-stage

cirrhosis requiring liver transplantation.

The National Institutes of Health estimates that 9 to 15 million Americans are affected by NASH, and other sources suggest it may be as many as 30 million people have NASH, and forecasts that the number of Americans affected by this disease is growing due to obesity and diabetes, with the potential to become the leading cause of liver cirrhosis and liver transplantation in the future.

Liver transplantation is currently the only therapeutic approach to NASH or other forms of liver fibrosis because, to the best of our knowledge, there are no drug therapies on the market.

Organ transplantation is a difficult, risky and costly procedure, and organ availability is scarce.

There is also the risk of developing cirrhosis in the transplanted liver from the same disease that damaged the patient’s original liver.

Therefore, there is a great need for other therapeutic options.

All diseases that affect the liver (viral hepatitis, alcoholic liver disease, and fatty liver as examples) lead to the development of scarring of the liver.

The primary focus of the Company is to use galectin inhibitors to block galectin-3

and treat organ scarring or fibrosis in the liver.

There are no approved therapies for treatment of liver fibrosis.

We believe that our drug candidates have the potential to treat NASH and other forms of liver fibrosis.

Scientific evidence suggests that galectin-3

is essential for the development of liver fibrosis in animals.

Published data show that mice lacking the galectin-3

gene, and thus unable to produce galectin-3,

are essentially incapable of developing liver fibrosis in response to toxic insult to the liver and in fatty liver disease.

Moreover, mice that do not have the galectin-3

gene are resistant to lung and kidney fibrosis.

These published data show that galectin-3

is a critical protein for the development of organ fibrosis.

Our drugs, based on experiments in well characterized animal models, are also potentially useful in scarring or fibrosis of other organs such as lung and kidney which expands the possibilities for future therapeutic indications.

We have evaluated the ability of belapectin to block galectin-3

in animal models of liver fibrosis, the conclusions of which yielded positive results.

Our pre-clinical

data show that belapectin may have a therapeutic effect on liver fibrosis as shown in several relevant animal models.

Therefore, we chose belapectin as the lead candidate in a development program targeted initially at fibrotic liver disease associated with NASH.

We evaluated belapectin in pre-clinical

toxicology and pharmacology studies during 2013, and filed an IND with the FDA in January 2013, for initiating human studies in patients with NASH.

In February 2013, we entered into an agreement with CTI Clinical Trial Services to assist with the design, development and conduct of one or more clinical research studies, specifically for services with respect to our Phase 1 clinical trials to evaluate safety of belapectin in patients with NASH.

The FDA notified us in March 2013 that we may proceed with a Phase 1 clinical trial for patients with NASH, and we began enrolling patients in the Phase 1 clinical trial in the third quarter of 2013.

In August 2013, belapectin was granted Fast Track designation by the FDA for NASH with hepatic fibrosis, commonly known as fatty liver disease with advanced fibrosis.

In January 2014, we completed the enrollment of the first cohort of patients in the Phase 1 trial with no serious adverse events being reported.

We reported initial safety and tolerability results from the first cohort of patients on June 30, 2014.

The second cohort of this Phase 1 trial began, and enrollment was completed in April 2014.

In July 2014, we reported the results from the second cohort of patients.

Enrollment of the third cohort of Phase 1 began in July 2014, with interim results presented in November 2014 with the final report on cohort 3 presented in January 2015.

The results of the Phase 1 study demonstrate that (i) belapectin was safe and well tolerated by patients with advanced NASH liver fibrosis after IV administration of four doses of 2 mg/kg, 4 mg/kg and 8mg/kg lean body weight, (ii) Pharmacokinetics in patients with advanced fibrosis, but not cirrhosis, revealed drug exposure in humans at the 8 mg/kg dose that was equivalent to the upper range of the targeted therapeutic dose determined from effective doses in NASH animal models, (iii) Disease Serum Marker Effect showed there was a statistically significant, dose-dependent reduction in FibroTest ®

scores due to a statistically significant reduction in alpha-2

macroglobulin (A2M) serum levels, and (iv) Liver Stiffness Effect, as measured by FibroScan ®

showed that there was a signal of reduced liver stiffness in patients receiving belapectin.

The reduction seen in A2M does not

necessarily mean fibrosis got better in this short study but does suggest changes in the fibrogenic process that might lead to an improvement in fibrosis with longer-term therapy.

These Phase 1 results in NASH patients with advanced fibrosis, in addition to completion of further toxicology and drug-drug interaction studies provided a firm foundation for entry into a Phase 2 development program (described above).

Top line results of our Phase 2b in compensated NASH cirrhosis patients was reported in December 2017 and is more fully described above as well in our SEC filings;

the Phase 2b study results provide the foundation for our NAVIGATE trial which is underway.

Belapectin is a proprietary, patented galactoarabino-rhamnogalacturonan polysaccharide polymer that is comprised predominantly of galacturonic acid, galactose, arabinose, rhamnose, and smaller amounts of other sugars.

Structural studies have shown that belapectin binds to galectin-1

and to galectin-3

with binding affinity to galectin-3

being significantly greater than binding to galectin-1.

With respect to belapectin, we currently have, as of December 31, 2020, 24 granted U.S.

patents, and 81 foreign granted patents.

These patents, which are more fully described below, include a composition of matter patent, and methods of use including manufacture, use patient in patients with NASH, in patients with liver fibrosis, and in patients with diabetic kidney disease.

Additional patent applications are pending with respect to, amongst other uses, cancer immunotherapy, lung fibrotic disease, and inflammatory disease associated with increase in inducible nitric oxide synthase.

Patents have also been granted with respect to liver fibrosis, NASH, and liver fibrosis in combination with other therapeutic agents.

Galectin Inhibition in Cancer Therapy

We believe the potential exists for galectin inhibition to play an important role in cancer therapy.

Galectin proteins, particularly galectin-1

and galectin-3,

have been shown to be highly expressed in the majority of cancers and have multiple roles in promoting cancer progression, including tumor cell invasion, metastasis, angiogenesis, and tumor evasion of the immune system.

The role of galectins in cancer immunotherapy can be understood through the “Galectin Effect”, a recent discovery of how tumors avoid the body’s own immune system, i.e., the tumors secrete galectin proteins that block the body’s efforts to fight tumors.

Our current program to block the “Galectin Effect” is based on the research of Dr.

Pierre van der Bruggen (of the Ludwig Institute of Cancer Research in Brussels, Belgium), demonstrating that galectin-3,

which is produced by the vast majority of human cancers, binds to and blocks the actions of tumor-infiltrating T-lymphocytes,

the major immune cell in the body’s defense against cancers.

In addition, Dr.

Redmond of Providence Portland Medical Center’s Earl A.

Chiles Research Institute (EACRI) has shown that our galectin inhibitors can enhance the anti-tumor immunogenic effect of other immunotherapies based on targeting lymphocyte checkpoints such as CTLA4.

Based on these results, we believe that the body’s immune cells may be unable to attack and kill tumor cells in the presence of galectins.

Using this approach, the mechanism of action for our drugs seeks to block galectins and, in turn, restore the ability of the T-lymphocytes

to kill tumor cells.

The preclinical study found that belapectin increased tumor shrinkage and enhanced survival in immune competent mice with prostate or breast cancers when combined with one of the immune checkpoint inhibitors, anti-CTLA-4

or anti-PD-1.

These findings suggest a role for belapectin in cancer immunotherapy.

These preclinical observations by Dr Redmond provided scientific rationale for proceeding and lead to the filing by Providence Portland Medical Center of an Investigator-sponsored IND to conduct a Phase 1B study to determine if belapectin enhances the probability of melanoma response with ipilimumab by inducing proliferation, activation and memory function of CD8+ T cells in human patients.

The company has licensed the underlying invention from Providence Portland Medical Center.

This study represents a novel approach for patients with metastatic melanoma.

The IND was approved by FDA in February 2014.

This study is being conducted under the sponsorship of Providence Portland Medical Center’s Earle A.

Chiles Research Institute (EACRI) and is being supported by the Company.

The study employs a dose escalation of belapectin in conjunction with the standard therapeutic dose of ipilimumab in patients with advanced melanoma for whom ipilimumab would be considered standard of care.

In addition to monitoring for toxicity and clinical response by irRECIST criteria on imaging tests, blood samples will be obtained to assess immunologic measures relevant to galectin biology and ipilimumab T-cell

check-point inhibition.

Galectin Therapeutics is providing its proprietary compound belapectin to EACRI researchers, as well as supplying researchers with supporting analysis of the pharmacokinetics of belapectin and the right to reference the Company’s open IND on belapectin.

To date the first two dosing groups have been completed without serious adverse events that were determined to be related to belapectin.

The third dosing group is no longer enrolling due to the availability of newer agents such as the anti-PD1

Similar to the agreement set forth for the ipilimumab (Yervoy ®

) Phase 1B study, Providence Portland Medical Center submitted an IND in September 2015 to conduct a Phase 1B study of belapectin and pembrolizumab (Keytruda ®

) in patients with metastatic melanoma.

The combination of belapectin and an anti-PD1

(pembrolizumab) has been shown to enhance T-cell

activation, memory, and effector function, and promote better antitumor responses in multiple mouse studies.

The study will test the hypothesis that galectin-3

antagonism using belapectin with enhance the probability of melanoma response using pembrolizumab in patients by inducing proliferation, activation and memory function of CD8+ T cells that recognize melanoma antigens.

Similar to the ipilimumab study, the study employs a dose escalation of belapectin in conjunction with the standard therapeutic dose of pembrolizumab in patients with metastatic melanoma who have had progression of their melanoma after ipilimumab and/or BRAF targeted therapy when a BRAF mutation is present.

In addition to monitoring for toxicity and clinical response, blood and tumor samples will be obtained to assess immunologic measures relevant to galectin biology and pembrolizumab T-cell

checkpoint inhibition.

Top line results of the combination of the 3 dosing cohorts was reported in September 2018 and is more fully described above as well in our SEC filings and press releases.

These data, taken together with the observed favorable safety and tolerability of the combination, in the view of the principal investigator, provide compelling rationale to move forward.

Given that all three melanoma patients were responders at the 4 mg/kg LBM dose, the investigators continued the trial with the expansion of the 4 mg/kg LBM cohort to include additional advanced melanoma patients and additional head and neck cancer patients.

The expansion cohort has been enrolled and further information will be reported as it becomes available.

Assuming these additional data are positive, the feasibility of a multicenter Phase 2 study will be evaluated.

Further details on the study is available at www.clinicaltrials.gov

(NCT02575404)

When aggregated cohorts are combined, in

advanced melanoma, a 50% objective response rate with belapectin in combination with KEYTRUDA, was documented.

In addition, a 33% response rate was documented in patients with head and neck cancer The results have been published in 2021 in a

highly rated peer reviewed journal (Curti et al.

Journal of Immunotherapy of cancer 2021;9:e002371) .

There was also a suggestion that the combination of belapectin with pembrolizumab could decrease the

auto-immune side-effect induced by pembrolizumab.

These side-effects, which are directly linked to the mechanism of action of pembrolizumab, can be poorly tolerated and even severe enough to lead to treatment interruption, even if the effect on

the cancer was encouraging.

This is of course, a very frustrating situation for patients who have to discontinue an active treatment but have no other options available to them.

We believe these data, taken together with the observed favorable

safety and tolerability of the combination, provide a rationale to move the belapectin program in oncology forward.

Late in 2021, we engaged three noted physicians – Dr.

Chetan Bettegowda, from Johns Hopkins, and Dr.

Nishant Agrawal and Dr.

Ari Rosenberg, both from University of Chicago Medical Center – as consultants to help

define the path forward in oncology.

In consultation with our oncology experts, we have now selected the treatment of recurrent or metastatic head and neck cancer as the lead indication to pursue for belapectin in combination with an immune

checkpoint inhibitor.

The decision is notably based on the lack of available treatments for these patients, the limited number of therapies in development, and the resulting very high medical need.

We are currently working to compile an IND

package with the objective for Galectin Therapeutics to file an IND and are planning a phase 2 trial to be filed with the FDA oncology division.

Patents and Proprietary Rights

Our development and commercial viability, and ultimately our competitiveness, depend on our ability to develop and maintain the proprietary aspects of our technology and operate without infringing on the proprietary rights of others.

proprietary rights of others.

We rely on a combination of patent, trademark, trade secret and copyright law and contract restrictions to protect the proprietary aspects of our technologies.

We seek to limit disclosure of our intellectual property by requiring employees, consultants, and any third parties with access to our proprietary information to execute confidentiality agreements and by restricting access to that information.

We seek to limit disclosure of our intellectual property

by requiring employees, consultants, and any third parties with access to our proprietary information to execute confidentiality agreements and by restricting access to that information.

In August 2015, we received a notice of allowance from the U.S.

Patent and Trademark Office for patent application number 13/726,900, titled “Galactose-pronged polysaccharides in a formulation for antifibrotic therapies.” This patent extends coverage of the Company’s pectin-derived compounds (including broad molecular weight ranges and other sources of pectin) to include treatment of chronic kidney disease associated with the development of fibrosis, established kidney fibrosis, chronic lung disease associated with the development of fibrosis and established lung fibrosis.

Claims in this patent include administering pectin-derived compound parenterally to a patient having at least one of the four aforementioned diseases where the established fibrosis or progression of the fibrosis or cirrhosis is inhibited or slowed down.

Additional specific claims encompass deriving the compound from citrus pectin, apple pectin, soybean hull pectin or sugar beet pectin with a molecular weight between 2 kDa and 400kDa.

Also covered is the step of administering the modified galacto-rhamnogalacturonan compound in an admixture with a therapeutic agent, where the agent is an antifibrotic compound.

Patent and Trademark Office for patent application number 13/726,900, titled “Galactose-pronged polysaccharides in a formulation for antifibrotic

therapies.” This patent extends coverage of the Company’s pectin-derived compounds (including broad molecular weight ranges and other sources of pectin) to include treatment of chronic kidney disease associated with the development of fibrosis,

established kidney fibrosis, chronic lung disease associated with the development of fibrosis and established lung fibrosis.

Claims in this patent include administering pectin-derived compound parenterally to a patient having at least one of the

four aforementioned diseases where the established fibrosis or progression of the fibrosis or cirrhosis is inhibited or slowed down.

Additional specific claims encompass deriving the compound from citrus pectin, apple pectin, soybean hull pectin

or sugar beet pectin with a molecular weight between 2 kDa and 400kDa.

Also covered is the step of administering the modified galacto-rhamnogalacturonan compound in an admixture with a therapeutic agent, where the agent is an antifibrotic

In August 2014, we received a notice of allowance from the U.S.

Patent and Trademark Office for patent application number 13/573,442 titled “Composition of Novel Carbohydrate Drug for Treatment of Human Diseases.” The patent covers composition and chemical structural claims for compounds that includes the Company’s lead galectin inhibitor compound belapectin and will expire in December 2031.

Claims include multiple routes of administration, including intravenous, subcutaneous and oral.

The application also covers therapeutic formulations for use in the treatment of NASH (fatty liver disease), cancer and fibrotic, inflammatory and autoimmune disorders in which galectin proteins are involved, at least in part, in the pathogenesis.

Patent and Trademark Office for patent application number 13/573,442 titled “Composition of Novel Carbohydrate Drug for Treatment of Human Diseases.”

The patent covers composition and chemical structural claims for compounds that includes the Company’s lead galectin inhibitor compound belapectin and will expire in December 2031.

Claims include multiple routes of administration, including

intravenous, subcutaneous and oral.

at least in part, in the pathogenesis.

Additional specific claims encompass liver fibrosis, kidney fibrosis, lung fibrosis or heart fibrosis.

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In May 2014, we received notice of allowance from the U.S.

Patent and Trademark Office for patent application number 13/998,197 titled “Galactose-Pronged Carbohydrate Compounds for the Treatment of Diabetic Nephropathy and Associated Disorders.” The patent covers both composition claim for and uses of the Company’s carbohydrate-based galectin inhibitor compound belapectin in patients with diabetic nephropathy, a type of progressive kidney disease that occurs in individuals with diabetes.

Patent and Trademark Office for patent application number 13/998,197 titled “Galactose-Pronged Carbohydrate Compounds for the Treatment of Diabetic

Nephropathy and Associated Disorders.” The patent covers both composition claim for and uses of the Company’s carbohydrate-based galectin inhibitor compound belapectin in patients with diabetic nephropathy, a type of progressive kidney disease

that occurs in individuals with diabetes.

Diabetic nephropathy is the major cause for chronic renal failure in the United States.

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In February 2014, we received notice of issuance that the U.S.

Patent and Trademark Office issued patent number 8,658,787 to the Company for its application titled “Galacto-rhamnogalacturonate compositions for the treatment of non-alcoholic

steatohepatitis and non-alcoholic

fatty liver disease.” The patent covers the Company’s carbohydrate-based galectin inhibitor compound belapectin for use in patients with fatty liver disease with or without fibrosis or cirrhosis, providing patent protection through 2031.

The major claims are for methods of obtaining galectin inhibitor compounds, obtaining a composition for parenteral or enteral administration in an acceptable pharmaceutical carrier and administering to a subject having at least one of the following:

fatty liver, non-alcoholic

fatty liver disease, non-alcoholic

steatohepatitis, non-alcoholic

hepatitis with liver fibrosis, non-alcoholic

steatohepatitis with cirrhosis, or non-alcoholic

steatohepatitis with cirrhosis and hepatocellular carcinoma.

Patent and Trademark Office issued patent number 8,658,787 to the Company for its application titled “Galacto-rhamnogalacturonate compositions for the

treatment of non-alcoholic steatohepatitis and non-alcoholic fatty liver disease.” The patent covers the Company’s carbohydrate-based galectin inhibitor compound belapectin for use in patients with fatty liver disease with or without fibrosis or

cirrhosis, providing patent protection through 2031.

The major claims are for methods of obtaining galectin inhibitor compounds, obtaining a composition for parenteral or enteral administration in an acceptable pharmaceutical carrier and

administering to a subject having at least one of the following:

fatty liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic hepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, or

non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma.

The use covers reversing or slowing the progression of disease activity or medical consequences of the disease.

Applications are pending in multiple countries to extend patent protection globally.

Applications are pending in multiple countries to extend

patent protection globally.

In January 2014, we received a notice of allowance from the U.S.

Patent and Trademark Office for Patent Application Number 13/550,962 titled “Galactose-Pronged Polysaccharides in a Formulation for Anti-fibrotic Therapies.” The patent covers both composition claim for and uses of the Company’s carbohydrate-based galectin inhibitor compound belapectin for use in patients with liver fibrosis in combination with other potential therapeutic agents.

The patent covers use of belapectin with agents directed at multiple targets, some of which are currently in clinical development for fibrotic disorders including monoclonal antibodies to connective tissue growth factor, integrins, and TGF-ß1.

The patent, assigned U.S.

Patent and Trademark Office for Patent Application Number 13/550,962 titled “Galactose-Pronged Polysaccharides in a Formulation for Anti-fibrotic

Therapies.” The patent covers both composition claim for and uses of the Company’s carbohydrate-based galectin inhibitor compound belapectin for use in patients with liver fibrosis in combination with other potential therapeutic agents.

patent covers use of belapectin with agents directed at multiple targets, some of which are currently in clinical development for fibrotic disorders including monoclonal antibodies to connective tissue growth factor, integrins, and TGF-ß1.

patent, assigned U.S.

8,722,645, was issued May 13, 2014.

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Patent and Trademark Office for the U.S.

Patent number 8,236,780 issued on August 7, 2013 titled “Galactose-prolonged polysaccharides in a formulation for antifibrotic therapies”.

This methods patent covers key methods of derivation and use for our carbohydrate-based galectin inhibitor compound for use in patients with chronic liver disease associated with the development of fibrosis, established liver fibrosis or end-stage

scarring, or cirrhosis.

The major claim is for a method of obtaining a galacto-rhamnogalacturan compound from an apple pectin, obtaining a composition for parenteral administration the galacto-rhamnogalacturonan compound in an acceptable pharmaceutical carrier and administering to a subject having at least one of the following:

chronic liver disease associated with the development of fibrosis, established liver fibrosis or cirrhosis.

Patent number 8,236,780 issued on August 7, 2013 titled “Galactose-prolonged polysaccharides in a formulation

for antifibrotic therapies”.

established liver fibrosis or end-stage scarring, or cirrhosis.

The major claim is for a method of obtaining a galacto-rhamnogalacturan compound from an apple pectin, obtaining a composition for parenteral administration the

galacto-rhamnogalacturonan compound in an acceptable pharmaceutical carrier and administering to a subject having at least one of the following:

chronic liver disease associated with the development of fibrosis, established liver fibrosis or

The use covers inhibiting or slowing the progression of fibrosis.

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held 23 granted U.S.

patents, 81 foreign granted, 6 Foreign patent applications allowed, 7 Foreign patent applications pending, and 2 U.S.

patents, 100 foreign granted, 3 foreign patent applications pending, and 2 U.S.

patent applications pending.

Many of our patents and patent applications cover composition of matter for complex carbohydrate drugs and/or methods of use for reducing toxicity and enhancing chemotherapeutic drugs by co-administering

a polysaccharide with a chemotherapeutic agent or for use in treatment of fibrosis.

Many of our patents and patent

applications cover composition of matter for complex carbohydrate drugs and/or methods of use for reducing toxicity and enhancing chemotherapeutic drugs by co-administering a polysaccharide with a chemotherapeutic agent or for use in treatment of

The scheduled expiration dates of our United States patents span out to 2034 before considering any potential extensions.

We have corresponding patent applications pending in various territories where we see potential for commercial interest.

We have corresponding patent applications pending in various territories where we see potential for commercial

Additionally, we have patent applications in other areas to utilize our carbohydrate-based compounds to treat disease other than cancer.

See “Risk Factors — Risks Related to Our Intellectual Property”.

Our competitive position, in part, is contingent upon protection of our intellectual property.

Our competitive position, in part,

is contingent upon protection of our intellectual property.

Galectin Sciences LLC has 3 granted international patent, 1 international patent allowed, 3 US patent application pending, and 27 foreign applications pending.

Our primary focus is on the design and testing of agents that target galectins in various in vitro

systems and that demonstrate efficacy in treatment of experimentally induced fibrosis or enhance immune system responsiveness in various tissues and in live animal models.

We contract with independent laboratories and other facilities to conduct our research, which is designed, evaluated and managed by our scientists.

While we conduct in house research related to our compounds at SBH laboratories in Massachusetts, we do not anticipate building additional in-house

research or development facilities or hiring significantly additional staff other than for purposes of designing and managing our out-sourced

research and development activities.

As we develop products eligible for clinical trials, we contract with independent parties to assist in the design of the clinical trial protocols, arrange for and monitor the clinical trials, collect data and analyze data.

Our primary focus is on the design and testing of agents that target galectins in various in vitro and in vivo systems and that

demonstrate efficacy in treatment of experimentally induced fibrosis or enhance immune system responsiveness in various tissues and in live animal models.

We contract with independent laboratories and other facilities to conduct our research,

which is designed, evaluated and managed by our scientists.

We do not anticipate building additional in-house research or development facilities or hiring significantly additional staff other than for purposes of designing and managing our

out-sourced research and development activities.

analyze data.

In addition, certain clinical trials for our products may be conducted by government-sponsored agencies and will be dependent on governmental participation and funding.

Our dependence on independent parties and clinical sites involves risks including reduced control over the timing and other aspects of our clinical trials.

In September 2014, the Company established a collaborative research program with Dr.

William Redmond’s laboratory located at the Providence Portland Medical Center, Portland, Oregon.

This program focuses on combination immunotherapy plus galectin inhibition to augment tumor immunogenicity.

Our dependence on independent parties and clinical sites

involves risks including reduced control over the timing and other aspects of our clinical trials.

During the years ended December 31, 2021 and 2020, our expenditures for research and development were $24.0 million and $18.0 million, respectively.

We expense all research and development costs as they are incurred.

We expense all research and development costs as they are

In January 2014 we created, with SBH Sciences, Inc.

(Natick, Ma), Galectin Sciences, LLC, a collaborative joint venture to research and develop small organic molecule inhibitors of galectin-3

for oral administration.

Using computer molecular modeling techniques coupled with in vitro

screening of a variety of compound libraries, SBH Sciences had identified several small organic molecules with promising galectin-3

inhibitory activity in vitro

Galectin Sciences LLC will further develop these unique organic molecule inhibitors of galectin-3

as drug candidates as well as develop additional candidates.

Subject to availability of funding, Galectin Sciences LLC will build on the scientific body of knowledge amassed by SBH Sciences, coupled with Galectin Therapeutics’ knowledge and expertise of galectins’ pathological role and mechanism of action in inflammation, fibrosis and many cancers.

(Natick, Ma), Galectin Sciences, LLC, a collaborative joint venture to research and develop small organic molecule inhibitors of galectin-3 for oral

administration.

Using computer molecular modeling techniques coupled with in vitro screening of a variety of compound libraries, SBH Sciences had identified several small organic molecules

with promising galectin-3 inhibitory activity in vitro .

Galectin Sciences LLC will further develop these unique organic molecule inhibitors of galectin-3 as drug candidates as well as develop additional

mechanism of action in inflammation, fibrosis and many cancers.

The long-term goal of this effort is to identify and develop drug candidates that are highly specific galectin inhibitors which may be formulated for oral administration.

The intermediate term goal is the development of small molecule inhibitors of galectin-3

which exhibit activity in in vivo

preclinical disease models of fibrosis and cancer in which galectins play a key role.

intermediate term goal is the development of small molecule inhibitors of galectin-3 which exhibit activity in in vivo preclinical disease models of fibrosis and cancer in which galectins play a key role.

Several patent applications have been filed to protect the various series of compounds discovered by these efforts.

Because increased levels of galectin proteins have been implicated in a very large number of inflammatory, fibrotic and neoplastic diseases;

the discovery and development of orally active galectin inhibitors would be a major step towards expanded treatment approaches for these disorders.

This early drug discovery effort may lead to drugs that would expand our pipeline as follow-on

compounds to our first in class galectin inhibitors, belapectin and GM-CT-01.

the discovery and development of orally active galectin inhibitors would

be a major step towards expanded treatment approaches for these disorders.

This early drug discovery effort may lead to drugs that would expand our pipeline as follow-on compounds to our first in class galectin inhibitors, belapectin and

These efforts have identified several potential compounds which are continuing to be explored to identify lead molecules that may be identified for clinical development.

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We are a development stage Company at this time and do not intend to establish internal facilities for the manufacture of our products for clinical or commercial production.

To have our products manufactured, we have developed and will continue to develop relationships with third-parties that have established pharmaceutical manufacturing capabilities and expertise.

We are not a party to any long-term agreement with any of our suppliers and, accordingly, we have our products manufactured on a purchase-order basis from one of two primary well-known and established pharmaceutical suppliers that meet FDA requirements.

To have our products manufactured, we

have developed and will continue to develop relationships with third-parties that have established pharmaceutical manufacturing capabilities and expertise.

We are not a party to any long-term agreement with any of our suppliers and, accordingly,

we have our products manufactured on a purchase-order basis from one of two primary well-known and established pharmaceutical suppliers that meet FDA requirements.

Additionally, belapectin is manufactured as a sterile liquid formulation.

We have experienced, and may experience in the future, certain delays related to COVID-19

related supply issues with certain components necessary to manufacture belapectin.

experienced, and may experience in the future, certain delays related to COVID-19 related supply issues with certain components necessary to manufacture belapectin.

Because our products are in the development stage, we have not created a sales and marketing staff to commercialize pharmaceutical products.

If we develop products eligible for commercial sale, we will need to develop a sales and marketing capability or rely on third parties such as licensees, collaborators, joint venture partners or independent distributors to market and sell those products.

Our dependence on third-party manufacturers, analytical testing and other laboratories and marketers will involve risks relating to our reduced control, and other risks including those discussed in “Risk Factors — Risks Related to our Company — There are risks associated with reliance on our third parties for manufacturing, marketing, sales, managed care and distribution infrastructure channels.”

If we develop products eligible for commercial sale, we will need to

develop a sales and marketing capability or rely on third parties such as licensees, collaborators, joint venture partners or independent distributors to market and sell those products.

Our dependence on third-party manufacturers, analytical

testing and other laboratories and marketers will involve risks relating to our reduced control, and other risks including those discussed in “Risk Factors — Risks Related to our Company — There are risks associated with reliance on our third

parties for manufacturing, marketing, sales, managed care and distribution infrastructure channels.”

Many biotechnology and pharmaceutical companies are developing new technologies for the treatment of cancer, fibrotic diseases and other diseases.

Technologies such as monoclonal antibodies could be competitive with our galectin therapeutic platforms.

Technologies such as monoclonal antibodies could be competitive

with our galectin therapeutic platforms.

Other companies are trying to improve the therapeutic profile of widely used protein-based drugs.

While these companies may broaden the market for our products they may also provide competitive alternatives to our products.

While these companies may broaden the market for our products they may also provide competitive

alternatives to our products.

We expect increased competition in the area of galectins will be fueled by a nearly exponential increase in the publication rate of research papers on galectins.

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Government Regulation

The research, development, testing, manufacture, labeling, promotion, advertising, distribution, and marketing, among other things, of our products are extensively regulated by governmental authorities in the United States and other countries.

United States and other countries.

The FDA regulates drugs under the federal Food, Drug, and Cosmetic Act and its implementing regulations.

Failure to comply with the applicable U.S.

requirements may subject us to administrative or judicial sanctions, such as FDA refusal to approve pending New Drug Applications (“NDAs”), warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, and/or criminal prosecution.

requirements may subject us to administrative or judicial

sanctions, such as FDA refusal to approve pending New Drug Applications (“NDAs”), warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, and/or criminal prosecution.

Drug Approval Process

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The steps required before a drug may be marketed in the U.S.

laboratory tests, animal studies, and formulation studies,

Pre-clinical laboratory tests, animal studies, and formulation studies,

Submission to the FDA of an IND for human clinical testing, which must become effective before human clinical trials may begin,

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FDA review and approval of a trademark used in connection with a pharmaceutical.

tests include laboratory evaluation of product chemistry, toxicity, and formulation, as well as numerous in vitro and in vivo animal studies.

The results of the pre-clinical

tests, together with manufacturing information and analytical data, are submitted to the FDA as part of an IND, which must become effective before human clinical trials may begin and the Company must resolve any outstanding FDA concerns or questions before clinical trials can proceed.

Pre-clinical tests include laboratory evaluation of product chemistry, toxicity, and formulation, as well as numerous in vitro and in vivo animal studies.

The results of the pre-clinical tests, together with

manufacturing information and analytical data, are submitted to the FDA as part of an IND, which must become effective before human clinical trials may begin and the Company must resolve any outstanding FDA concerns or questions before clinical

trials can proceed.

There is no certainty that submission of an IND will result in the FDA allowing clinical trials to begin.

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Clinical trials typically are conducted in three sequential phases, but the phases may overlap or be combined.

Each trial must be reviewed and approved by an independent Institutional Review Board (“IRB”), before it can begin.

Each trial must be reviewed and approved by an independent Institutional Review Board (“IRB”), before

it can begin.

Study subjects must sign an informed consent form before participating in a clinical trial.

Phase 1 usually involves the initial introduction of the investigational drug into patients to evaluate its safety, dosage tolerance, pharmacodynamics, and, if possible, to gain an early indication of its effectiveness.

Phase 1 usually involves the initial introduction of the investigational drug into patients to evaluate its safety, dosage tolerance,

pharmacodynamics, and, if possible, to gain an early indication of its effectiveness.

Phase 2 usually involves trials in a limited patient population to (i) evaluate dosage tolerance and appropriate dosage;

(ii) identify possible adverse effects and safety risks;

(ii) identify possible adverse effects

and safety risks;

and (iii) evaluate preliminarily the efficacy of the drug for specific indications.

Phase 3 trials usually further evaluate clinical efficacy and test further for safety by using the drug in its final form in an expanded patient population.

Phase 3 trials usually further evaluate clinical efficacy and test further for safety by using the drug in its final form in an expanded patient

There is no assurance that these trials will be completed within a specified period of time, if at all.

Assuming successful completion of the required clinical testing, the results of the pre-clinical

studies and of the clinical studies, together with other detailed information, including information on the manufacture and composition of the drug, are submitted to the FDA in an NDA requesting approval to market the product for one or more indications.

Before approving an NDA, the FDA usually will inspect the facilities at which the drug is manufactured and will not approve the product unless compliance with cGMP is satisfactory.

Assuming successful completion of the required clinical testing, the results of the pre-clinical studies and of the clinical studies, together with other detailed information, including information on the

manufacture and composition of the drug, are submitted to the FDA in an NDA requesting approval to market the product for one or more indications.

Before approving an NDA, the FDA usually will inspect the facilities at which the drug is

manufactured and will not approve the product unless compliance with cGMP is satisfactory.

If the FDA evaluates the NDA and the manufacturing facilities as acceptable, the FDA will generally issue an approval letter.

If the FDA evaluates the NDA submission or the manufacturing facilities as not acceptable, the FDA will generally outline the deficiencies in the submission and often will request additional testing or information.

Even if an applicant submits the requested additional information, the FDA ultimately may decide that the NDA does not satisfy the regulatory criteria for approval.

The testing and approval process require substantial time, effort, and financial resources, and there is no assurance that any approval will be granted on a timely basis, if at all.

If the FDA evaluates the NDA

submission or the manufacturing facilities as not acceptable, the FDA will generally outline the deficiencies in the submission and often will request additional testing or information.

Even if an applicant submits the requested additional

information, the FDA ultimately may decide that the NDA does not satisfy the regulatory criteria for approval.

The testing and approval process require substantial time, effort, and financial resources, and there is no assurance that any approval

will be granted on a timely basis, if at all.

After approval, certain changes to the approved product, such as adding new indications, manufacturing changes, or additional labeling claims are subject to further FDA review and approval.

See “Risk Factors — Risks Related to the Regulation of Our Products — We will need regulatory approvals to commercialize our products” for additional discussion of regulatory risks related to our drug development program.

FDA Priority Review

FDA procedures provide for priority review of an NDA submitted for drugs that, compared to currently marketed products, offer a significant improvement in the treatment, diagnosis, or prevention of a disease.

NDAs that are granted priority review are acted upon more quickly than NDAs given standard review.

If we were to seek priority review, there can be no guarantee that the FDA will grant priority review status, that priority review status will affect the time of review, or that the FDA will approve the NDA submitted for any of our product candidates, whether or not priority review status is granted.

that are granted priority review are acted upon more quickly than NDAs given standard review.

If we were to seek priority review, there can be no guarantee that the FDA will grant priority review status, that priority review status will affect

the time of review, or that the FDA will approve the NDA submitted for any of our product candidates, whether or not priority review status is granted.

Post-Approval Requirements

If FDA approval of one or more of our products is obtained, we will be required to comply with a number of post-approval requirements.

For example, holders of an approved NDA are required to report certain adverse reactions to the FDA and to comply with certain requirements concerning advertising and promotional labeling for their products.

Also, quality control and manufacturing procedures must continue to conform to current Good Manufacturing Practices (“cGMP”) after approval, and the FDA periodically inspects manufacturing facilities to assess compliance with cGMP.

Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

For example, holders of an approved NDA are required to report certain adverse

reactions to the FDA and to comply with certain requirements concerning advertising and promotional labeling for their products.

Also, quality control and manufacturing procedures must continue to conform to current Good Manufacturing Practices

(“cGMP”) after approval, and the FDA periodically inspects manufacturing facilities to assess compliance with cGMP.

Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to

maintain cGMP compliance.

In addition, discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved NDA, including withdrawal of the product from the market.

Also, new government requirements may be established that could delay or prevent regulatory approval of our products under development.

government requirements may be established that could delay or prevent regulatory approval of our products under development.

Regulation Outside the United States

Before our products can be marketed outside of the United States, they are subject to regulatory approval similar to that required in the United States, although the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary widely from country to country.

trials, product licensing, pricing and reimbursement vary widely from country to country.

No action can be taken to market any product in a country until an appropriate application has been approved by the regulatory authorities in that country.

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In certain countries, the sales price of a product must also be approved.

The pricing review period often begins after market approval is granted.

The pricing review period

often begins after market approval is granted.

No assurance can be given that even if a product is approved by a regulatory authority, satisfactory prices will be approved for such product.

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Pharmaceutical research and development involves the controlled use of hazardous materials.

Biotechnology and pharmaceutical companies must comply with laws and regulations governing the use, generation, manufacture, storage, air emission, effluent discharge, handling and disposal of certain materials, biological specimens and wastes.

We do not anticipate building in-house

research, development or manufacturing facilities, and, accordingly, do not expect to have to comply directly with environmental regulation.

However, our contractors and others conducting research, development or manufacturing activities for us may be required to incur significant compliance cost, and this could in turn could increase our expense or delay our completion of research or manufacturing programs.

As of February 28, 2021, we currently have six full-time employees, three of whom are involved primarily in management of our pre-clinical

research and development and clinical trials and three who were involved primarily in management and administration of our Company.

As previously announced, Dr.

Boudes, MD joined us as Chief Medical Officer on March 2, 2020.

Biotechnology and pharmaceutical companies must comply with laws and regulations governing the use, generation,

manufacture, storage, air emission, effluent discharge, handling and disposal of certain materials, biological specimens and wastes.

We do not anticipate building in-house research, development or manufacturing facilities, and, accordingly, do

not expect to have to comply directly with environmental regulation.

However, our contractors and others conducting research, development or manufacturing activities for us may be required to incur significant compliance cost, and this could in

turn could increase our expense or delay our completion of research or manufacturing programs.

Human Capital Resources

As of February 28, 2022, we currently have nine full-time employees, six of whom are involved primarily in management of our pre-clinical research and development and clinical trials and three who were involved

primarily in management and administration of our Company.

We also utilize several contractors and consultants who provide product development, manufacture, analytical testing, clinical trial expertise, and clinical trial support.

Available Information

The Company is required to file annual, quarterly and current reports, proxy statements and other information with the Securities and Exchange Commission (“SEC”), including Annual Reports on Form 10-K,

Quarterly Reports on Form 10-Q,

Current Reports on Form 8-K

and amendments to reports filed pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934.

The SEC maintains an Internet site that contains reports, proxy and information statements, and other information regarding issuers that file electronically with the SEC at http://www.sec.gov.

Reports on Form 10-Q, Current Reports on Form 8-K and amendments to reports filed pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934.

The SEC maintains an Internet site that contains reports, proxy and information

statements, and other information regarding issuers that file electronically with the SEC at http://www.sec.gov.

The Company’s website is www.galectintherapeutics.com.

The information contained on, or hyperlinked from, our website or any other websites is not a part of, nor is it incorporated by reference into, this Annual Report on Form 10-K.

The information contained on, or hyperlinked from, our website or any other

websites is not a part of, nor is it incorporated by reference into, this Annual Report on Form 10-K.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business