Patients treated with GR-MD-02 experienced significant clinical improvement

As described in the press release, each of the four patients who received six doses of GR-MD-02 over 12 weeks of therapy reported improvement in their psoriasis symptoms. Moreover, three patients had significant, and one had modest, improvement in the Psoriasis Area Severity Index (PASI), which is an objective and standardized means of evaluating disease response (see table below). 

In addition to these quantitative results, photographs provide vivid evidence of response to therapy (below). Each patient had over 70 pictures taken at each photography session, so this represents only a small sample and not a full representation of their whole body disease. These photographs provide evidence of disease improvement in areas of significant improvement.

Patient 1 had complete clearing of multiple chest lesions. Patient 2 had near complete resolution of arm and elbow lesions. Patient 4, the one with the greatest reduction in PASI score, had nearly complete resolution of an abdominal lesion and remarkable improvement of very severe leg lesions. Most of the disease on Patient 4’s leg is actually completely resolved with only some skin hyperpigmentation, which generally takes months to slowly fade.

What does this mean for our drug GR-MD-02?

It is uncommon for patients with moderate-to-severe plaque psoriasis to spontaneously improve without treatment, so the improvements we have seen in this trial are due to GR-MD-02. Furthermore, these improvements are clinically significant for these patients, as all of them suffered from moderate-to-severe psoriasis for years (between 6 and 40 years) prior to entering the trial. Therefore, it is our belief that GR-MD-02 had a positive effect on psoriasis in these patients.

We believe this is the first definitive clinical effect of GR-MD-02 to be shown in patients. While all diseases are not the same in terms of etiology, these results support our optimism for GR-MD-02 to affect other disease processes that the company is investigating.

How do our results with GR-MD-02 compare with other available psoriasis therapies?

Beyond the fact that GR-MD-02 has a biological effect on psoriasis in patients, we need to consider the possibility that GR-MD-02 could be additive to the medical armamentarium for treating psoriasis. There are multiple commercial and development-stage drugs for the treatment of moderate-to-severe plaque psoriasis, including biological agents that would constitute the direct competition for GR-MD-02.

There is an established FDA regulatory pathway for drug approval in moderate-to-severe plaque psoriasis that all the recent marketed biological drugs have followed. PASI is universally used in registration clinical trials (also referred to as phase 3 or pivotal clinical trials) as an objective measurement of drug response. All registration clinical trials assess the number of patients who achieve a 75% improvement in PASI (called PASI-75) at various times following initiation of therapy. For currently approved drugs, the percentage of patients who achieve PASI-75 at between 12 and 24 weeks of therapy ranges from 54% to as high as 90% in some studies.

At the time of this interim analysis of our trial, none of the four patients had reached a PASI-75, which is why we have taken the next steps described below.

What are the next steps?

We have extended therapy in the study with the current dose of GR-MD-02 for a full 24 weeks, or 13 infusions, to determine whether improvement at this dose continues and reaches PASI-75. Extension beyond 24 weeks of therapy to reach PASI-75 would not be competitive from an efficacy standpoint among the currently marketed biological agents for moderate-to-severe plaque psoriasis. However, in general, approval of drugs is a balance between efficacy and safety and most of the drugs on the market have serious side effect profiles. We are now attempting to enroll the full cohort of 10 patients in this trial, with all receiving 24 weeks of therapy. We will continue to report interim data from this trial.

This interim analysis of four patients has given us great encouragement on the biological effect of GR-MD-02 in a human disease and we look forward to reporting results later this year on this trial and our trial with GR-MD-02 in patients with NASH and advanced (stage 3) fibrosis (the NASH-FX trial).

These “CEO Perspectives” are a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including whether GR-MD-02 may be effective in the treatment of psoriasis.  These statements relate to future events and use words such as “may,” “might,” “could,” “expect” and others. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2015, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements.

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Galectin Therapeutics is collaborating with a number of academic groups to evaluate cardiovascular diseases that might be amenable to treatment with our galectin inhibitor drugs. In this article, I discuss the results obtained by the outstanding investigators at the Vascular Biology Center and the Department of Pharmacology and Toxicology at Augusta University (formerly known as Georgia Regents University), which were recently presented at the 2016 American Thoracic Society International Conference and highlighted in a recent press article.

What is pulmonary arterial hypertension (PAH)?

Pulmonary hypertension (PH) is high blood pressure in the main arteries that supply blood to the lungs, caused by the narrowing and constriction of blood vessels in the lungs themselves. This elevated blood pressure increases the work required of the heart’s right ventricle to pump blood into the lung, which eventually culminates in failure of the right ventricle, circulatory collapse and death. The causes of PH have been categorized into five groups. Group 1, also called pulmonary arterial hypertension (PAH), includes idiopathic and hereditary PAH, as well as multiple disorders that affect the small arterioles (blood vessels) in the lung. The remaining four groups are secondary to other disease including left heart failure (Group 2), chronic lung disease (Group 3), chronic pulmonary embolism (Group 4) or multifactorial mechanisms (Group 5).

The figure below on the left shows a normal pulmonary artery with the various layers of cells in the wall, including the external elastic lamina on the outside of the artery, the smooth muscle cell layer, the internal elastic lamina and the endothelial cell lining on the inside. As depicted in the figure below on the right, in PAH there is a marked increase in the thickness of the smooth muscle cell layer as well as fibrosis. This narrows the lumen of the artery and restricts blood flow.

One of the more pressing needs is for new PH therapies in Group 1 disorders, particularly idiopathic PAH. Although there are a number of vasodilator drugs that are approved for the treatment of PAH, additional therapies are needed to address the structural narrowing of pulmonary arteries..

Galectin-3 protein is markedly elevated in human and experimental pulmonary arterial hypertension

The investigators at Augusta University experimented with three animal models of PAH using chemical treatments and/or low oxygen environments. These models are well established to cause narrowing of the pulmonary blood vessels leading to stress and failure of the right ventricle, meaning they mimic what happens in human PAH. The investigators found that the galectin-3 protein was markedly higher in the pulmonary arteries of diseased animals and the degree of increased blood pressure correlated with the level of galectin-3 elevation. 

Since a picture is worth a thousand words, I have reproduced below images of the microscopic assessment of galectin-3 in pulmonary arteries in one rat model with monocrotaline treatment (MCT), as compared with the human disease.

The red stain is for the protein alpha smooth muscle actin (α-SMA), which stains smooth muscle cells in the artery, and the green stain is for the galectin-3 protein; the overlay combines the two images and shows that galectin-3 is predominantly in smooth muscle cells. In both the normal rat and the human pulmonary arteries, a thin layer of smooth muscle cells that contain galectin-3 is visible. In the rats and humans with PAH there is a marked increase in thickness of the muscle cells that surround the artery associated with a marked increase in galectin-3. 

GR-MD-02 is effective in experimental pulmonary hypertension

The investigators next tested whether our galectin-3 inhibitors were able to change the course of experimental PAH using the model in which the rats were given a single injection of MCT to induce pulmonary hypertension. Two of our galectin inhibitors were used as treatments: GR-MD-02, which is currently in clinical trials for NASH, psoriasis, and cancer, and GM-CT-01.

As shown in the figure below, the control (normal) rat pulmonary artery has a thin layer of smooth muscle cells surrounding it, whereas the animals treated with MCT have a markedly thickened smooth muscle layer that nearly blocks the lumen of the artery. Treatment of MCT animals with either GR-MD-02 or GM-CT-01 resulted in significantly fewer smooth muscle cells and a much larger artery lumen.

Below are images of pulmonary arteries stained to show fibrosis, mostly the protein collagen, which is identified by the light blue material. In the MCT treated animals, there is a significant amount of fibrosis associated with the smooth muscle cells in the pulmonary artery. This fibrosis is virtually eliminated in the artery wall following treatment with GR-MD-02, which provides a link to data showing improvement in fibrosis in other models of disease in liver, lung and kidney.

Treatment with either GR-MD-02 or GM-CT-01 also resulted in functional improvement in the PAH rats as indicated by reduced right ventricular systolic pressure (RVSP), as shown below. This improvement was seen whether the treatment was started immediately after the MCT injection (Prevention) or three weeks after the MCT injection (Reversal).

Prospects for human therapy

The results from these animal studies suggest that exploration of anti-galectin therapies, and specifically with GR-MD-02, might be a new therapeutic approach for these seriously ill patients. Currently there are approved therapies that help dilate constricted pulmonary arteries, but there are no therapies that effectively change the structure of the arteries or reverse the long-term course of the disease. A drug able to reverse the arterial smooth muscle and fibrosis findings in PAH might play an important role in treating these patients.

These “CEO Perspectives” are a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including whether GR-MD-02 and GM-CT-01 may be effective in the treatment of pulmonary arterial hypertension.  These statements relate to future events and use words such as “may,” “might,” “could,” “expect” and others. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2015, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements.

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Last September, Galectin Therapeutics began a Phase 2a open-label clinical trial with GR-MD-02, our galectin-3 inhibitor drug, in patients with moderate-to-severe plaque psoriasis. We initiated this trial because a patient in our Phase 1 trial with GR-MD-02 in NASH had a remarkable and sustained remission of her psoriasis following treatment, as described in a previous CEO Perspective (here). Since then, I have been asked on numerous occasions how we will interpret the results of this trial.

What are the psoriasis trial endpoints?

Multiple drugs have been approved for the treatment of psoriasis, so there is an established FDA regulatory pathway to approval. It is well accepted that assessment of drug efficacy in psoriasis clinical trials is best performed using the Psoriasis Area and Severity Index, or PASI. PASI is used both to measure the severity of psoriasis as well as to measure the effect of treatment.  While this index score is not generally used in the clinical practices of dermatology, it is universally used in clinical trials as an objective measurement of drug response. 

PASI is an objective set of measurements that are conducted by a physician to assess the area of skin involvement and the severity of skin lesions in patients with psoriasis. The figure below, taken from a review article written by experts in the field, outlines the approach to the measurement (1).

Therefore, the primary endpoint in our psoriasis trial will focus on improvement in PASI following treatment with GR-MD-02.  We will evaluate the number of patients who have various percentage improvements in PASI. We will also record the durability of response to treatment for up to one year, should there be a beneficial effect. Finally, we are monitoring the incidence of adverse events and vital sign and laboratory abnormalities, if any, during study treatment.

What constitutes a meaningful effect?

Moderate psoriasis is generally defined as a PASI of ≥10.  In our trial, as is typical for clinical trials in moderate-to-severe psoriasis, patients who enroll in the trial are required to have at least 10% of their body area affected by psoriasis and a PASI of ≥12, parameters which were agreed to with the FDA. Moreover, the patients will have the diagnosis of psoriasis confirmed by a skin biopsy. Therefore, patients in the trial will have significant disease and are similar to those who have been enrolled in the trials of approved drugs for psoriasis.

Once an individual has established psoriasis, it generally does not spontaneously dissipate or improve. As published in the medical literature, it has been suggested that clinically significant improvements in psoriasis are clearly obtained when PASI is lowered by 50% of baseline values, i.e., a PASI 50 response (2). However, the accepted clinical trial endpoint for drug registration is PASI 75, meaning a 75% reduction in psoriasis versus baseline. However, since this is an exploratory trial in which we do not have any information on optimal dosing, we will be looking for any objective response. 

What will this trial tell us and what might be the next steps?

First and most important, our exploratory psoriasis clinical trial will either confirm the effect on psoriasis seen in the one Phase 1 patient, or show that her remission was unrelated to our drug. Should a significant proportion of patients in the trial respond to GR-MD-02 with an improvement in their psoriasis, such a finding would represent the first human disease response to GR-MD-02. That would be an important finding with potential implications for activity in our main therapeutic program for NASH, a disease where there is a higher incidence of psoriasis.

Second, this trial may indicate whether GR-MD-02 is a viable candidate to advance as a therapy for psoriasis. There are a number of biologic agents that have been approved in recent years for moderate-to-severe psoriasis, and GR-MD-02 would need to be competitive with those drugs. In my view, based on the efficacy of approved drugs, GR-MD-02 would need to demonstrate a PASI 75 in at least 50% of treated patients to consider full clinical development. If it does have such a degree of efficacy, it might be considered as a potential drug therapy on the basis of its lower cost to manufacture than existing drugs, a potentially better safety profile or the duration of effect after stopping treatment.

While each of these potential benefits would need to be studied in detail, the first step is to determine whether the drug has an effect on the disease, which is the primary goal of this study. 

These “CEO Perspectives” are a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including whether GR-MD-02 may be effective in the treatment of psoriasis.  These statements relate to future events and use words such as “may,” “might,” “could,” “expect” and others. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2015, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements.

Reference List

1. Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis 2005 Mar;64 Suppl 2:ii65-ii68.

2. Carlin CS, Feldman SR, Krueger JG, Menter A, Krueger GG. A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis. J Am Acad Dermatol 2004 Jun;50(6):859-866.

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The post How Will We Interpret Results from the GR-MD- 02 Psoriasis Trial? appeared first on NASH & Liver Fibrosis | Galectin Therapeutics.

We often talk about how Galectin Therapeutics’ proprietary compound, GR-MD-02, is protected by a strong intellectual property portfolio. I thought it might be useful to drill a little more deeply into that statement.

Our patent portfolio is an important asset for Galectin Therapeutics, and it took hard and careful work to put it in place. Each patent/patent application is a strategic building block which reflects present and future business objectives and protects current core technology. The Galectin Therapeutics’ patent portfolio covers the products or composition of matter (i.e. active pharmaceutical ingredient or API), formulations of the products, use of the products and methods of manufacturing.

The most valuable patent in the Galectin Therapeutics’ portfolio is a composition of matter patent which covers the active pharmaceutical ingredient. Composition patents exclude others from making, using, selling or offering for sale the API. 

Patenting complex carbohydrates can be more challenging than for a small molecule

Galectin Therapeutics’ proprietary compound, GR-MD-02, is derived from the modification of a natural pectin. Pectins are widely used in the food industry as a thickening agent for making things such as jellies and jams. There are a substantial number of patents on using pectin in pharmaceutical applications. Galectin Therapeutics had to show that GR-MD-02 was novel and non-obvious, in view of the prior pectin art.

GR-MD-02 is a complex carbohydrate molecule. A small molecule with a small molecular weight (e.g. 300 Da) in comparison can have a very specific structure and the U.S. Patent and Trademark Office (USPTO) can then compare the molecule to a chemical database to assess if the compound is different than publically available compounds.

GR-MD-02 on the other hand, is a mixture of complex carbohydrates having an average molecular weight between 20,000 to 70,000 Da. These are big molecules. This means that Galectin Therapeutics had to take a slightly different approach to characterizing the molecule in its patent applications. GR-MD-02 can be defined by its physical and chemical properties such as the average molecular weight, the carbohydrate composition, the ratio of critical carbohydrates from one to the other, and a two-dimensional NMR to establish a “fingerprint” of the molecule. One of the most critical carbohydrates in GR-MD-02 is galactose, and GR-MD-02 can be characterized by the ratio between galactose and arabinose. GR-MD-02 can be characterized by its degree of methoxylation — or the amount of methyl groups on the backbone of the molecule. Galectin Therapeutics was awarded a composition of matter patent in the U.S. on GR-MD-02 (U.S. patent 8,871,925 entitled “Compositions of Novel Carbohydrate Drug for Treatment of Human Diseases.” The U.S. patent issued on October 28, 2014 and will expire in 2032.

Protecting not just the molecule but also its manufacture and its use

Beyond the composition of matter patent for GR-MD-02 stands a portfolio of other patents that strengthen Galectin Therapeutics’ patent portfolio. Galectin Therapeutics holds a process patent that covers the manufacture GR-MD-02 from the pectin (U.S. patent No. 8,962,824). Presumably, a similar process has to be used to manufacture a drug similar to GR-MD-02, and having the process patented adds a second layer of protection to the compound as well.

Galectin Therapeutics also has 5 different patent families that cover the methods of use. These support the various indications for GR-MD-02 that Galectin Therapeutics plans to test. Method of use patents exclude others for using the API in specific indications. Galectin Therapeutics has a method of use U.S. patent for NASH (U.S. patent No. 8,658,787). Galectin Therapeutics has a method of use patent for kidney disease, specifically diabetic nephropathy as well as other similar types of glomerulopathy that patients develop, not necessarily related to diabetes (U.S. patent No. 8,828,971). We also have a method of use patent application allowed for pulmonary fibrosis, as well as method of use U.S. patents covering liver fibrosis, kidney fibrosis and heart fibrosis.

Patents pending

Galectin Therapeutics has more than 50 patent applications pending. There are a number of method of use patents pending, in both cancer immunotherapy and other disease states. The method of use patents and applications strengthen the patent portfolio and protect Galectin Therapeutics for future business objectives.

Foreign patents

Galectin Therapeutics has filed for patent protection in 10 foreign countries which are viewed are significant market for the API or the manufacture of the API (Australia, Brazil, Canada, China, Europe, Israel, Japan, Korea, Mexico and South Africa).  The U.S. patent process generally moves more quickly than the rest of the world and issuance of patents in the U.S. can be helpful to expedite prosecution in foreign countries.

These “CEO Perspectives” are a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.  These statements relate to future events and use words such as “may,” “might,” “could,” “expect” and others. These statements include those regarding the hope that Galectin Therapeutic’ s development program for GR-MD-02 will show that it can be both safe and effective when used in combination with other drugs for the treatment of patients with cancer. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements.

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The many accomplishments at Galectin Therapeutics during 2015 ranged from incremental progress touching every aspect of our business to significant advancements with GR-MD-02.  Importantly, this progress forms the basis for numerous milestones expected in the coming years including clinical progress, intellectual property fortification, further engagement with the investment community and ongoing outreach to educate our shareholders about our work to develop new therapies, the regulatory environment in which we operate and our target markets.

CEO Perspectives, Dr. Traber’s blog introduced last year, is designed to provide scientific and technical information largely regarding our work with GR-MD-02 in layman’s language.  Much of our progress and accomplishments during 2015 were chronicled in the 14 blog postings, which can be found here.

We were delighted that in the final days of 2015 a U.S. District Court dismissed both the federal securities class-action lawsuit and the shareholder derivative actions lawsuit filed in the Summer of 2014 against Galectin and certain officers, directors and a shareholder, which had cast an inappropriate cloud over our many achievements in 2015. The Court entered final judgments of dismissals in both actions based on the Court’s finding that any further amendment of the complaints would be futile (i.e., dismissed with prejudice).  Plaintiffs have the right to appeal the Court’s dismissals within 30 days.  Based on the Federal Court’s rulings, Galectin is seeking dismissal of a duplicative shareholder derivative action in Nevada which was filed after the federal actions.

Our Clinical Programs

NASH with advanced liver fibrosis

Development of GR-MD-02 for the treatment of non-alcoholic steatohepatitis (NASH) with advanced fibrosis and cirrhosis continues to be the primary focus of our company.  We completed a successful Phase 1 clinical trial and announced final data in January 2015.  The Phase 1 trial demonstrated that GR-MD-02 is safe, with potential for therapeutic effect on fibrosis in NASH patients with advanced fibrosis.  We found no serious adverse events and no treatment-emergent adverse events related to our drug.  Furthermore, GR-MD-02 was found to be safe and well tolerated in each of the three dose-escalating cohorts of patients, who were suffering from NASH with advanced fibrosis.

This finding alone defines the study as a success, but we gained additional valuable information.  We found that the FibroTest^® score, a composite biomarker of five different blood tests that has been correlated with the extent of liver fibrosis, was significantly reduced by GR-MD-02 treatment in the third dosing cohort of 8 mg/kg. In addition, we found that some patients in this cohort also showed a decrease in liver stiffness, which has a direct correlation with fibrosis.  We published a comprehensive piece on the results of the Phase 1 study in a CEO Perspectives blog post, which can be found here.

In addition to the phase 1 trial in NASH patients with advanced fibrosis, we reported the results of a drug-drug interaction study with GR-MD-02 and midazolam, a common sedative, which showed that in healthy volunteers there was no unfavorable interaction between the two compounds.  Because many patients with chronic diseases are on multiple medications over long periods of time and may take other medications on an intermittent basis, this finding is important to the commercial potential of GR-MD-02 and to the patient population that is eligible to participate in our Phase 2 program.  We published a CEO Perspectives piece on this topic, which is available here.

The information gleaned from the Phase 1 studies formed the basis for our Phase 2 program, which consists of two studies, one in NASH patients with advanced fibrosis and the other in NASH patients with cirrhosis. We submitted our protocol to the U.S. Food and Drug Administration (FDA) for the cirrhosis study in the first quarter, engaged our contract research organization and began screening patients at the end of June.

This study, the NASH-CX trial, is a multicenter, randomized, placebo-controlled, double-blind, parallel-group Phase 2 trial to evaluate the safety and efficacy of GR-MD-02 for the treatment of liver fibrosis and resultant portal hypertension (HVPG) in patients with NASH cirrhosis.  A total of 156 patients at approximately 50 sites in the U.S. will be randomized to receive either 2 mg/kg of GR-MD-02, 8 mg/kg of GR-MD-02 or placebo, with 52 patients in each arm. The primary endpoint is a reduction in HVPG. Patients will receive a total of 26 infusions every other week for one year, at which time they will be evaluated for change in HVPG compared with placebo.  HVPG will be correlated with secondary endpoints of fibrosis on liver biopsy as well as with measurement of liver stiffness via FibroScan^® and assessment of liver metabolism (¹³C-methacetin breath test, Exalenz), which are non-invasive measures of the liver that may be used in future studies.  More information can be found at www.clinicaltrials.gov and in a CEO Perspectives blog post, which can be found here.

We are pleased with the pace of the NASH-CX study and we remain on track to provide data readout in at the end of 2017, as we have previously indicated.

In September we initiated a 30-patient study with GR-MD-02 in NASH patients with advanced fibrosis, our NASH-FX study, with 15 patients receiving 8 mg/kg of GR-MD-02 and 15 patients receiving placebo every other week for 16 weeks. This study will evaluate the safety and efficacy of GR-MD-02 on liver fibrosis using multi-parametric magnetic resonance imaging (LiverMultiScan^®, Perspectum Diagnostics) as the primary endpoint and liver stiffness as assessed by magnetic resonance-elastography and FibroScan as secondary endpoints. This study is also proceeding as planned, with top-line data expected around the end of the third quarter of 2016. We published a CEO Perspectives piece on this trial, which is available here.

Psoriasis

As we have previously reported, one of the patients participating in our Phase 1 NASH study was a long-term psoriasis sufferer, and this patient’s psoriasis cleared as the study progressed, and remained cleared for many months following the conclusion of the study.  With an established theoretical pathway for how inhibition of galectin-3 might affect psoriasis, in September we began an open label 10-patient Phase 2a pilot study in patients with moderate-to-severe plaque psoriasis.  We expect data readout from this study late in the third quarter of 2016.  More information and background on this study can be found here.

Melanoma

We continued to support independent research with GR-MD-02 in combination with two commercial melanoma drugs, as preclinical research has shown our compound enhances the efficacy of immune checkpoint blockade therapies, or so-called checkpoint inhibitors, a new class of drugs. GR-MD-02 is progressing through a Phase 1b study in combination with Yervoy®, and a Phase 1b study in combination with Keytruda® was initiated in the fourth quarter of 2015 with enrollment to begin early in 2016. Preclinical work in mouse cancer models with GR-MD-02 added to checkpoint inhibitors shows a boost in anti-tumor immunity, a reduction in tumor size and increased survival. Both of these studies are being conducted at the Providence Cancer Center in Portland, Oregon. Galectin is providing GR-MD-02 to the investigators, who are funding the costs of these studies. We published a CEO Perspectives on these trials, which is available here.

In the trial combining Yervoy and GR-MD-02, two dosing cohorts have been completed and the third cohort delivering 4 mg/kg of GR-MD-02 is enrolling now.  Of the seven patients that have received the combination therapy, there has been no dose limiting toxicity. Following completion of the 4 mg/kg dose cohort, a total of 10 patients will be dosed at 8 mg/kg. Immune markers as well as tumor response are being monitored in this study.

Significant Presentations and Publications

Galectin’s researchers presented at several important industry meetings during the year. Dr. Traber delivered an invited presentation of the company’s research with GR-MD-02 in NASH at the American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in March.  He participated in the session entitled “NASH: Clinical Endpoints and Drug Development” and discussed the role of galectin-3 in organ fibrosis generally and liver fibrosis in particular, and GR-MD-02 as a galectin-3 inhibitor.  He reviewed the published preclinical data showing that GR-MD-02 is effective in reversing inflammation and fibrosis in a mouse model of NASH and also in reversing cirrhosis and improving portal hypertension in a rat model of cirrhosis. He also reviewed the company’s Phase 1 study results and its Phase 2 clinical program design. The abstract of Dr. Traber’s presentation can be found here.

In addition, preclinical research from a study led by Stefanie Linch, Ph.D. in the laboratory of tumor immunology expert William L. Redmond, Ph.D. of the Providence Cancer Center’s Earle A. Chiles Research Institute was presented in November at the Society for Immunotherapy of Cancer’s (SITC) 30^th Anniversary Annual Meeting. The studies presented were conducted by the Institute in collaboration with Galectin Therapeutics.  The poster presentation “Galectin-3 inhibition using novel inhibitor GR-MD-02 improves survival and immune function while reducing tumor vasculature” and an abstract was published in the Journal for ImmunoTherapy of Cancer.  The poster presentation is available for review here.

Interviews with Dr. Traber appeared in a number of publications throughout 2015, including R&D Magazine in a piece entitled “Finding the Holy Grail Treatment for Fatty Livers,” available here, Obesity News Today published its Q&A article entitled, “Exclusive: Dr. Peter Traber Discusses Non-alcoholic Fatty Liver Disease”, available here, and MD Magazine, which conducted an online interview with Dr. Traber at the AASLD meeting.  That interview can be found here.

Galectin management also participated in a number of investment conferences throughout the year, including programs for institutional investors, retail investors and family offices.

Foundational Support for our Business 

During 2015 we considerably strengthened our intellectual property portfolio and received a U.S. patent Notice of Allowance for the use of pectin compounds to reduce fibrosis in multiple diseases.  This patent is particularly important because it not only permits GR-MD-02 use for NASH with fibrosis, but it covers other compounds in our pipeline and a multitude of diseases with a fibrotic etiology. We also continued to build our international patent portfolio with patents issued or allowed in Israel and Australia.

We also made excellent progress with our Chemistry, Manufacturing and Controls (CMC), all of which are vital to the proper conduct of our clinical trials with GR-MD-02 and are essential components of the final application to the FDA for a drug’s approval.  We discussed this progress during the year in the CEO Perspective post found here. We also reached a very significant milestone in our preclinical toxicology program, having completed chronic administration of GR-MD-02 in two animal species, allowing chronic administration in human subjects.

Lastly, we were very pleased to have completed a $9.8 million financing during the fourth quarter.  This capital is expected to fund currently planned operations through the first quarter of 2017, and will be used mainly for clinical trial expenses and other research and development expenses, as well as for general corporate purposes.

Looking Ahead to 2016

We are looking forward to executing on several important milestones in 2016, with highlights including the following:

• We will continue enrollment in the NASH-CX study and work with our investigators and contract research organization to keep on our stated timelines for data readout in late 2017
• We will continue enrollment in the NASH-FX study, and continue to expect data readout around the end of the third quarter of 2016
• We will continue enrollment in the psoriasis Phase 2a study, with data readout also expected at the end of the third quarter of 2016
• While we do not control the rate of enrollment of the trial, we expect data from the Providence Cancer Center’s study with Yervoy in combination with GR-MD-02 in advanced metastatic melanoma by the end of 2016.
• We expect that Providence Cancer Center will be enrolling patients in the study with GR-MD-02 in combination with Keytruda during 2016.

We are fully aware that yesterday’s accomplishments set tomorrow’s expectations, and we look forward to creating shareholder value by executing on numerous milestones during 2016. We are grateful to our long-standing, loyal shareholders for their continued support and to the hard-working staff at Galectin Therapeutics who share a unifying commitment to addressing significant unmet clinical needs in NASH, as well as in oncology and psoriasis.

These “CEO Perspectives” are a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.  These statements relate to future events and use words such as “may,” “might,” “could,” “expect” and others. These statements include those regarding the hope that Galectin Therapeutic’ s development program for GR-MD-02 will show that it can be both safe and effective when used in combination with other drugs for the treatment of patients with cancer. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements

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The galectin-3 protein appears to play an important role in the progression of many cancers, especially with respect to the ability of cancer cells to hide from the body’s immune response. With combination immunotherapies becoming increasingly important in the treatment of cancer, inhibiting galectin-3 could provide another way to boost the body’s ability to fight cancer.

While liver fibrosis remains the primary focus of Galectin Therapeutics, we are pleased to support the Providence Cancer Center in Portland, Oregon, in exploring the use of our GR-MD-02 galectin-3 inhibitor in combination with the commercial immunotherapeutic agents Keytruda® (pembrolizumab) and Yervoy® (ipilimumab) in patients with advanced melanoma. Should using GR-MD-02 prove effective against melanoma, it could be a component of therapy in the quest for cancer cures.

We recently announced that Providence Cancer Center filed an Investigational New Drug (IND) application with the FDA to study GR-MD-02 in combination with Keytruda in a Phase 1b study of patients with advanced refractory metastatic melanoma. This study joins an ongoing Phase 1b study of GR-MD-02 in combination with Yervoy in patients with malignant melanoma, which is also being conducted by researchers at Providence Cancer Center.

The IND filing was prompted by findings from preclinical studies led by William L. Redmond, Ph.D., of the Providence Cancer Center’s Earle A. Chiles Research Institute. Those studies found that GR-MD-02 increased tumor shrinkage and enhanced survival in immune-competent mice with multiple types of cancers when combined with checkpoint inhibitors such as Yervoy or Keytruda.

We could not have a better partner than the Providence Cancer Center and the group undertaking this research. This is a prominent team of investigators led by Walter J. Urba, M.D., Ph.D., who established the Center in 1993 after working at the National Cancer Institute. They have access to a very strong, large and innovative group of scientists and clinicians who are experts in immunotherapy. Not only were they one of the sites involved with Bristol-Myers Squibb’s (BMS) first trials with Yervoy, they’ve also developed one of their own monoclonal antibodies (anti-Ox40) that was out licensed to MedImmune via a spin-off company called AgonOx, and which is now in clinical trials.

The Providence Cancer Center performed the preclinical work with GR-MD-02 that supports the clinical work now underway. Based on the preclinical results, it was decided that the data showed a sufficiently robust effect to undertake these combination clinical trials. The Providence Cancer Center is paying for the studies, and we are providing them with GR-MD-02. More than anything, I believe the fact that one of the top research groups in the country is funding this research using GR-MD-02 reinforces the potential importance of our drug in cancer immunotherapy.

A Bit of Background on the Trials

The first patient in the combination GR-MD-02/Yervoy trial was dosed in July, 2014, when Yervoy was the only cancer immunotherapy drug on the market. This first trial was in melanoma because that’s the indication for which Yervoy is approved. While Yervoy, a CTLA-4 inhibitor, is truly a revolution in the treatment of melanoma, the long-term survival in patients with advanced melanoma is only about 10 to 15 percent. With upwards of 85 percent of patients dying of their disease while being treated with Yervoy monotherapy, there was clearly a big opportunity for improvement.

The Yervoy trial has enrolled two cohorts at two dose levels. This is a dose-escalation trial, so we started with a low dose of 1 mg/kg of GR-MD-02, progressing to 2 mg/kg, and so on. We just finished dosing the 2 mg/kg group and observed no adverse events related to GR-MD-02, so now the next dosing cohort is underway, which is 4 mg/kg. Once we have three patients at that level, we will then proceed to 8 mg/kg and enroll 10 patients in that high-dose group.

Results in the Yervoy trial are being evaluated by looking at the size of the tumor – meaning does it shrink or grow – and also by measuring multiple types of immune cells in circulation. This last approach may give us an early indication of whether GR-MD-02 is providing some effect. One of the benefits of working with the Providence Cancer Center is that they’re one of the leading groups working in this area.

We could dose higher than 8 mg/kg, but we’ll have to assess the results we see at that dosage to determine whether we go higher. For instance, if we see immune markers that increase a small amount at 2 mg/kg, even more at 4 and then they level off at 8, we might well think we’re getting the maximum effect. If we see that the markers are continuing to increase at 8, we might then move on to higher doses.

The Keytruda trial, which has been cleared by the FDA, will would follow much the same approach.

Keytruda, a PD-1 inhibitor, works on an entirely different biological pathway than Yervoy. Keytruda was approved by the FDA last year for use in melanoma, and it shows an even greater effect than Yervoy with a 20 to 25 percent long-term survival rate. My last CEO Perspective touched on how powerful it can be to use two immunotherapy agents in combination, in particular Yervoy and Opdivo, which is also a PD-1 inhibitor. I would expect Yervoy and Keytruda to yield similar results if they were ever to be used in combination.

For our part, we are excited that GR-MD-02 is entering a trial for use in combination with Keytruda. The preclinical science looks promising. Why are we using Keytruda rather than Opdivo? Frankly, Providence Cancer Center and Galectin Therapeutics chose Keytruda because it was approved and on the market at the time we started to develop these studies. Now that we are set to begin the studies, I would expect enrollment to be even faster than the Yervoy study, as Keytruda is a more efficacious drug and it’s indicated for people who have failed Yervoy.

These “CEO Perspectives” are a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.  These statements relate to future events and use words such as “may,” “might,” “could,” “expect” and others. These statements include those regarding the hope that Galectin Therapeutic’ s development program for GR-MD-02 will show that it can be both safe and effective when used in combination with other drugs for the treatment of patients with cancer. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements

Please look for future editions in which multiple aspects of our development programs for unmet medical needs will be addressed.

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Bristol-Myers Squibb ($BMS) recently paid $150 million for the exclusive right to acquire Promedior, a clinical-stage biotechnology company in the midst of a Phase 2 trial on the treatment of idiopathic pulmonary fibrosis (IPF) and myelofibrosis (MF). If clinical trials are successful, the deal could be worth as much as $1.25 billion. This is just one of a number of fibrosis-related acquisitions for BMS over the past few years, and BMS is not the only company active in this market. Fibrosis is a hot area right now. But why so?

The scientific community has known for a long time that fibrosis is a common final pathway for many different diseases. An investigator at the NIH suggested in 2004 that as many as 45 percent of the deaths in the United States are related to fibrosis (1). That would include, in addition to liver fibrosis, heart, kidney, lung, skin, and arterial fibrosis – all organs that can be scarred as the result of a chronic disease, which then leads to organ failure and death.

While we can certainly work on curing each individual chronic disease that causes fibrosis, another approach would be to inhibit the fibrotic process. This approach could potentially be applied to a lot of other diseases as well — it’s been something of a Holy Grail in medicine for decades.

It’s a great idea. Unfortunately, there hasn’t been very much progress in the development of anti-fibrotic agents, until now.

Recently, there has been promising work in agents that appear to inhibit fibrosis — for example, our own GR-MD-02, which in our preclinical studies has shown to not only prevent fibrotic damage, but even reverse it. I think these breakthroughs are happening now because the medical community is coming to understand that fibrotic diseases, such as NASH, are complex conditions that require agents that affect multiple pathways in the fibrogenic process.

Let me give an example. There are many important cytokines in the inflammatory process, so it might make sense to inhibit one of them and see how that changes the inflammatory or the fibrotic process. However, by doing that, you are ignoring dozens of other cytokines that are also involved in the inflammatory process. Even if you inhibit the one, you’re not having any impact on the other cytokines involved.

Therefore, agents that address a number of different cell types in the liver that express a wide range of cytokines and fibrotic mediators may be more effective than a pinpoint attack on a particular cytokine or mediator. GR-MD-02 appears to affect macrophages as well as activated myofibroblasts in the liver, which inhibits a wide range of different fibrotic processes. It may be that affecting master regulatory cells involved in inflammation and fibrosis is going to be more effective than affecting any individual mediators.

But as I pointed out, fibrosis is a problem in many other organs than the liver. My sense of it is, if you’re going to have a drug that is robust for a particular organ fibrosis, it’s more than likely going to work for other fibrotic diseases. That’s one of the reasons why we have done pre-clinical studies of GR-MD-02 in lung, kidney and heart, and it’s shown an effect in those as well. That is also, I suspect, part of BMS’ calculations in acquiring Promedior. IPF and lung fibrosis is an indication that creates a large enough market on its own, but the potential to address a disease process involved in 45 percent of the deaths in the U.S. can be found in the background of any fibrosis drug.

That is one of the things that makes GR-MD-02 different than many of the other drugs being developed to address NASH and fatty liver disease. Most of the dozen or so compounds don’t address the core fibrotic process, so even if they work in NASH, they’re not likely to work elsewhere in the body. Only the truly anti-fibrotic drugs like GR-MD-02 have the potential to address fibrosis in other organs.

These “CEO Perspectives” will be a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.  These statements relate to future events and use words such as “may”, “could”, “expect” and others. These statements include those regarding the hope that Galectin’s development program for GR-MD-02 will lead to the first therapy for the treatment of fatty liver disease with advanced fibrosis and cirrhosis. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements

Please look for future editions in which multiple aspects of our development programs for unmet medical needs will be addressed.

Reference List

1. Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 2004 Aug;4(8):583-594.

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When thinking about the development of a drug, one naturally tends to think of performing animal and human studies to demonstrate the safety and effectiveness of the drug in the intended disease indication. However, a drug development program not only includes these safety and efficacy studies, but importantly it also must provide the chemistry, manufacturing and controls (CMC) information to demonstrate the quality and stability of the drug product. This CMC information includes the physical and chemical properties of the drug, the processes by which the drug is made, the formulations for administration of the drug to patients, quality control specifications and stability data to ensure the quality of the drug product over time.

The CMC information is a critical part of regulatory submissions for approval. In 2008, Booz Allen Hamilton, an independent consulting firm hired by the U.S. Food and Drug Administration (FDA) found that approximately 20% of all deficiencies delaying first cycle reviews of drug applications were related to CMC issues1. A more recent study by the FDA, published in 2014 by the Journal of the American Medical Association, confirmed that CMC information remains critical to the FDA’s review and approval of new drugs, indicating that CMC deficiencies were the cause of 12.6% of first cycle review failures and 21.1% of delays following application resubmissions2.

The CMC development program for GR-MD-02

What follows is a general overview of the CMC development program for GR-MD-02, Galectin Therapeutics’ leading drug under development, which targets and inhibits the expression of galectin-3 protein. Galectin-3 is important in the promotion of multiple types of diseases, including inflammation, fibrosis, and cancer. We have focused the use of this drug in a development program for potential treatment of patients with liver fibrosis, and specifically in those patients with NASH (non-alcoholic steatohepatitis) with advanced fibrosis or the most severe form of fibrosis, cirrhosis, and in moderate-to-severe plaque psoriasis. Currently, Phase 2 clinical trials are being conducted with GR-MD-02 in patients with advanced liver fibrosis due to NASH, which at present has no available therapies approved, and an exploratory Phase 2a study has commenced for the psoriasis indication.

Please be patient with me through this discussion, because the technical details really matter here. It is important to note that GR-MD-02 is a polysaccharide (polymeric carbohydrate) with defined chemical and physical characteristics. Several polysaccharide drugs have been approved by the FDA. One example is heparin, an anticoagulant which is a composite of poly-sulfated glycosaminoglycan. (For those who want to get very technical, GR-MD-02 is a patented galactoarabino-rhamnogalacturonate polysaccharide derived through proprietary chemical processing and modification from pharmaceutical grade apple pectin.)

Understanding the physical properties of GR-MD-02

From the beginning of the program, we performed studies to characterize the physical, chemical and biological properties of GR-MD-02 utilizing state-of-the-art analytical techniques and methodologies, some of which were developed in collaboration with leading scientists in the academic field of carbohydrate research.

As a composite polysaccharide, characterization of GR-MD-02 required the development of some very sophisticated new analytical techniques and technologies to adequately assess GR-MD-02’s building blocks and integrity. A variety of high pressure liquid chromatography (HPLC) methods and detection systems were optimized to measure the polymeric molecular weight and molecular weight distribution, carbohydrate composition, degradation products and impurities. In addition, two-dimensional nuclear magnetic resonance (NMR) were successfully validated to detect the infrastructure of GR-MD-02. Advanced mass spectrometry methods and technologies developed in cooperation with the University of Georgia were implemented to characterize the internal linkages of the carbohydrates within the polymeric structure, creating a “fingerprint” mapping of GR-MD-02.

Determining the most effective formulation

Initially, several formulations of GR-MD-02 were evaluated to determine the best method of delivering an intended dose to patients, including oral, subcutaneous (SC) and intravenous (IV) routes of administration. The proof of concept and efficacy of GR-MD-02 formulations were verified in multiple animal models of liver inflammation and fibrosis3, 4. The IV formulation of GR-MD-02 was determined to be optimal for further development based on the intended patient population and the bioavailability of the drug. Considering the dosages established in the animal fibrosis NASH models and preclinical safety studies, a sterile IV solution of 30 mg/mL of GR-MD-02 in 10 mL vials was then designed for the current drug product formulation being used in our clinical trials.

Ensuring consistency, stability, and shelf life

Specifications for GR-MD-02 were established to ensure the safety, identity, strength, quality and purity of the active drug substance and final drug product. These specifications include analytical methods to control all stages of manufacturing from raw material to drug substance to final drug product formulations. Each GR-MD-02 batch produced is tested for conformance to the specifications to ensure the consistency and quality of batches used throughout the development program. The batches are also tested periodically to ensure that GR-MD-02 is stable and will meet product specifications over time. The data from these stability studies provide the basis for the established shelf life of the product.

Optimizing the production process

Current production processes for GR-MD-02 were designed considering the physical and chemical properties of the drug, yield, cost, quality raw material availability, safety and environmental factors, among other quality considerations. Experiments were performed to define the optimal process for the synthesis and production of the bulk drug substance (the API, or active pharmaceutical ingredient) and the final drug product (30mg/mL sterile solution).

Procedures and tests were implemented throughout the production process to control the quality of the starting materials, intermediates and final drug product. Initially, the synthesis of the drug was developed and optimized in the laboratory and then transferred to scaled-up manufacturing facilities for production of batches for preclinical and clinical studies. Eventually, the processes will be further optimized and scaled-up for larger batch sizes to meet commercial and market needs.

Commitment to the Highest Quality and Regulatory Standards

The FDA requires that all production and testing of human drug products meet a high standard for quality of pharmaceuticals, referred to as the good manufacturing practices (GMPs). Galectin maintains a continued communication with the FDA to make sure that GR-MD-02 and all aspects of its production meet regulatory-established GMP standards and requirements. Further, all contracted laboratories and manufacturing sites used in the production of GR-MD-02 are certified GMP facilities, audited by both Galectin and the FDA to meet these standards.

Galectin Therapeutics continues to seek out new and innovative technologies and strategies to improve our products, and we are committed to maintaining the highest quality standards and principles in the development of anti-galectin drugs for fibrotic disease and cancer.

These “CEO Perspectives” will be a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.  These statements relate to future events and use words such as “may”, “could”, “expect” and others. These statements include those regarding the hope that Galectin’s development program for GR-MD-02 will lead to the first therapy for the treatment of fatty liver disease with advanced fibrosis and cirrhosis. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements

Please look for future editions in which multiple aspects of our development programs for unmet medical needs will be addressed.

Reference List

1. Booz Allen Hamilton, “Independent Evaluation of FDA’s First Cycle Review Performance – Final Report”, July 16, 2008, http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm127117.htm
2. Leonard V. Sacks, Hala H. Shamsuddin, Yuliya I. Yasinskaya, Khaled Bouri, Michael L. Lanthier, Rachel E. Sherman. Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012. JAMA, 2014; 311 (4): 378 DOI: 10.1001/jama.2013.282542
3. Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel MI, et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One 2013;8(10):e75361.
4. Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One 2013;8(12):e83481.

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Serendipity, or fortunate happenstance, has always been an important part of the search for medicines. As pointed out by Thomas A. Ban (1), serendipity in drug discovery is more than just luck, but rather is best described by Pasteur’s famous quote that “Chance favors the prepared mind”. Serendipity may have entered our development program with our anti-galectin drug, GR-MD-02, and today we kick off another Phase 2 clinical trial to test whether an unexpected effect observed in our Phase 1 trial is truly something of significance.

Our surprising clinical trial observation

 In the course of our Phase 1 clinical trial of GR-MD-02 in patients with fatty liver disease (NASH) and advanced fibrosis, we encountered a patient with plaque psoriasis, who happened to be one of the patients treated with four infusions of 4 mg/kg of GR-MD-02. Psoriasis is a relatively common, chronic skin disorder that causes a red, thickened and scaling rash that can cover many parts of the body.

Upon the patient’s follow-up visit to her physician, she reported resolution of her long-standing psoriasis. In an interview with a dermatologist and myself, the patient confirmed that she had severe psoriasis involving much of both arms continuously for six years. Following treatment with GR-MD-02, the psoriasis resolved and has not recurred for over a year! There was another patient in the study with mild psoriasis who was able to reduce use of topical steroids and another with severe psoriasis who had just been withdrawn from therapy with Stelara (ustekinumab), a powerful injection therapy for psoriasis, who did not improve.

Observation prompts exploratory clinical trial

On the strength of the marked effect in the one patient, both a dermatologist investigator and we felt it was worth investigating whether this was a real effect of GR-MD-02. In addition to the clinical finding, research publications suggest the potential importance of galectin-3 in psoriasis (2, 3).  Therefore, we initiated a phase 2a, open label clinical trial in patients with moderate to severe plaque psoriasis (press release September 22, 2015). In this trial, 10 psoriasis patients with ≥ 10% of their skin affected and a PASI (psoriasis activity and severity index) of ≥ 12 points will be treated with 7 every other week infusions of 8 mg/kg GR-MD-02. The severity of psoriasis was agreed upon with the FDA as warranting experimental therapy. More information on the trial can be found at: https://clinicaltrials.gov/ct2/show/NCT02407041?term=GR-MD-02&rank=5

The primary endpoint for evaluation of these patients will be the PASI-75, which means that they have had a 75% improvement in the severity of the disease 30 days following the final infusion. This is a standard endpoint used in studies of drugs that have been approved for marketing. The PASI system assesses each affected body area as to the extent of skin redness, thickness, and scaling.  We intend on reporting data 30 days following treatment of the last patient treated.   Additional results would then be reported following 6 month and 1 year follow up periods to assess for durability of response.

What is next following exploratory trial?

Our current trial is based on an observation with one patient. It is promising enough to investigate in an exploratory trial, but single-patient observations are notoriously unreliable. Therefore, while we anticipate results, we are cautious in our optimism.

We will consider this clinical trial successful if ≥ 50% of patients treated meet the primary efficacy endpoint. Positive results from this trial would be significant, since we would have demonstrated a potentially important clinical effect of our galectin-3 inhibiting drug, GR-MD-02. Moreover, it is of interest that there is a relatively high incidence of NASH in patients with psoriasis (4, 5), which is our other major indication for GR-MD-02.

With positive results, we will then consider entering into a development program aimed at marketing approval for psoriasis. There are already multiple excellent drugs on the market for this indication, some of which have been approved in the last few years. Potential areas that GR-MD-02 may be differentiated from other drugs include safety, prolonged response (if the one patient results are confirmed), and lower cost manufacture.

These “CEO Perspectives” will be a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.  These statements relate to future events and use words such as “may,” “could,” “expect” and others. These statements include those regarding the hope that Galectin’s development program for GR-MD-02 will lead to the first therapy for the treatment of fatty liver disease with advanced fibrosis and cirrhosis. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements

Please look for future editions in which multiple aspects of our development programs for unmet medical needs will be addressed.

Reference List

1. Ban TA. The role of serendipity in drug discovery. Dialogues Clin Neurosci 2006;8(3):335-344.

2. Chen HY, Lo C-H, Li C-S, Hsu DK, Liu FT. Galectins and cutaneous immunity. Dermatologica Sinica 2012;30:121-127.

3. Lacina L, Plzakova Z, Smetana K, Jr., Stork J, Kaltner H, Andre S. Glycophenotype of psoriatic skin. Folia Biol (Praha) 2006;52(1-2):10-15.

4. Roberts KK, Cochet AE, Lamb PB, Brown PJ, Battafarano DF, Brunt EM, et al. The prevalence of NAFLD and NASH among patients with psoriasis in a tertiary care dermatology and rheumatology clinic. Aliment Pharmacol Ther 2015 Feb;41(3):293-300.

5. Wenk KS, Arrington KC, Ehrlich A. Psoriasis and non-alcoholic fatty liver disease. J Eur Acad Dermatol Venereol 2011 Apr;25(4):383-391.

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An important question in drug development, and the subject of U.S. Food and Drug Administration (FDA) regulations, is whether a drug candidate interacts with other medications the target patient population may also be taking. This is a critical issue, because many patients with chronic diseases are on multiple medications over long periods of time and may take other medications on an intermittent basis.

The basis of many drug-drug interactions is that the experimental new drug may use some of the same metabolic pathways that other drugs use. If this is the case, the new drug may inadvertently increase the levels of other drugs in the system, and thus alter their effect and increase their side effects. Prescribing physicians need to know about potential unfavorable interactions, if any, between an experimental new drug like GR-MD-02 and other drugs their patients may require.

In evaluating potential drug interactions, the first experiments with GR-MD-02 were done in test tubes and with cell cultures. Many metabolic pathways were evaluated in this way to determine whether there were potential interactions with GR-MD-02. Generally, the results of these experiments showed there was little to no risk of drug metabolism interactions with GR-MD-02, but the analysis of one particular metabolic enzyme, called CYP3A4, suggested there was small risk for interaction with other drugs. Therefore, the company agreed with the FDA to evaluate the possible interaction in humans of GR-MD-02 with a model drug for the CYP3A4 enzyme.  The model drug used was midazolam, which is known as Versed® and is widely used for mild, conscious sedation.

We designed, conducted, completed, disclosed publicly (see our press release dated May 14, 2015) and reported to the FDA results of a Phase 1 study in normal healthy volunteer subjects.  This study first tested drug levels of midazolam after a single intravenous (IV) dose, which served as a control. Midazolam was then administered again and drug levels were monitored following a single IV dose of GR-MD-02 (8 mg/kg) and following three weekly IV doses of GR-MD-02 (also 8 mg/kg). A total of 17 subjects completed the study, and all met the primary endpoint of no difference between midazolam levels when administered alone and in combination with single and multiple doses of GR-MD-02. Of note, 8 mg/kg of body weight of GR-MD-02 is the same dose we are testing in our current Phase 2 program in nonalcoholic steatohepatitis (NASH) patients with cirrhosis and with advanced fibrosis.

These Phase 1 results show that GR-MD-02 has no effect on the metabolism and serum levels of midazolam, and these results can be imputed to other drugs metabolized by CYP3A4 that are in common use. In fact, the CYP3A4 enzyme metabolizes about half of all the drugs currently on the market, according to published estimates. (Click here for more information on CYP3A4.)  With the successful completion of this study, the company does not anticipate further drug-drug interaction studies will be required.

So, what does this science mean for the development of GR-MD-02?  First, another 17 healthy individuals received up to three doses of GR-MD-02 without any significant adverse events, confirming the safety of the drug as seen in the first Phase 1 trial. Second, these findings allow patients on concomitant medications to be enrolled in our Phase 2 clinical trials with minimal concern for drug interactions, thus increasing the pool of potential patients that can be included in the trials. Finally, should GR-MD-02 receive marketing approval, patients and physicians will be less concerned our drug will interfere with other drugs they may be taking and we will not be faced with restrictive labeling regarding concomitant drug therapy. Therefore, successful completion of this drug interaction study in people checks another box in describing the underlying properties to support approval of GR-MD-02.

These “CEO Perspectives” will be a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995.  These statements relate to future events and use words such as “may,” “could,” “expect” and others. These statements include those regarding the hope that Galectin’s development program for GR-MD-02 will lead to the first therapy for the treatment of fatty liver disease with advanced fibrosis and cirrhosis. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements

Please look for future editions in which multiple aspects of our development programs for unmet medical needs will be addressed. 

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