The GLG Pharma STAT Blog

“Highlighting Chronic Lymphocytic Leukemia (CLL)”

The goal of every pharmaceutical and biotechnology scientist, physician and clinician is to save the patient’s life through an outright cure of the disease and if it can’t be saved then improve the quality of his/her life. Below are definitions of Rare Diseases, according to our friends at Evaluate Pharma[1]:

Evaluate Pharma Excerpt:

“The National Organization for Rare Disorders (NORD), which was instrumental in establishing the Act, currently estimates 30 million Americans suffer from 7,000 rare diseases. Prior to the 1983 Act, 38 orphan drugs were approved. To date, 468 indication designations covering 373 drugs have been approved. The success of the original Orphan Drug Act in the US led to it being adopted in other key markets, most notably in Japan in 1993 and in the European Union in 2000. Rare Disease Patient Populations are Defined in Law as:

• USA: <200,000 patients (<6.37 in 10,000, based on US population of 314m)
• EU: <5 in 10,000 (<250,000 patients, based on EU population of 506m)
• Japan: <50,000 patients (<4 in 10,000 based on Japan population of 128m)

Financial Incentives by Law Include: Market Exclusivity

• USA: 7 Years of marketing exclusivity from approval. Note: Majority of orphan drugs have a compound patent beyond 7 years. The market exclusivity blocks ‘same drug’ recombinant products, e.g. Fabrazyme (Genzyme, now Sanofi) vs. Replagal (Transkaryotic, now Shire). ‘Same drug’ exclusion can be overturned if clinically superior (mix of efficacy/ side effects), e.g. Rebif overturned Avonex’s orphan drug exclusivity (7 MAR 2002) 

• EU: 10 Years of marketing exclusivity from approval.

Reduced R&D Costs:  

• USA: 50% Tax Credit on R&D Cost
• USA: R&D Grants for Phase I to Phase III Clinical Trials ($30m for each of fiscal years 2008-12)
• USA: User fees waived (FFDCA Section 526: Company WW Revenues <$50m) 

Methodology on Classifying an Orphan Drug:  

"We, (Evaluate Pharma) have identified all products that have orphan drug designations filed in the US, EU or Japan. These are available as part of the core EvaluatePharma service. To further enhance analysis, we have defined a clean ‘Orphan’ sub-set of products following a number of criteria including:

• First indication approved is for an orphan condition.
• Products expected to generate more than 25% of sales from their orphan indications. 

This has led to the exclusion of drugs such as Avastin, Enbrel, Herceptin, Humira and Remicade, all of which have orphan designations for indications contributing less than 25% of sales.

• Trial sizes, with smaller Phase III trials suggesting orphan status.
• Drug pricing, higher prices were taken as an indicator of orphan status.
• All sales analysis in the report is based on this clean ‘Orphan’ sub-set of products.” End of Evaluate Pharma excerpt. 

Chronic Lymphocytic Leukemia (CLL) is considered a ‘rare disease’. A great source of information on CLL[2] is the Leukemia & Lymphoma Society[3] which has over the years poured over $1 billion into research for Leukemia.  The information found in the PDF download (see reference) is excellent and is a foundation for understanding this disease and other leukemia’s as well.  

Some rare diseases have identified mechanisms of action that lay across the biological human horizon of diseases but aren’t as highly expressed or manifest themselves as a chronic lethal disease. One of the mechanisms sometimes associated with proliferative diseases that includes rare forms of cancer, is an abnormality in a major signaling pathway located downstream where many other pathways convey extracellular signals into the nucleus.  This is the case of the Signal Transduction and Activators of Transcription (STAT) and in particular, STAT3.  

At GLG Pharma we have focused on the STAT3 signaling pathway and its uncontrolled hyperactivity. Activation of STAT3 can be blocked at three different sites: 

• Phosphorylation
• Dimerization
• DNA Binding

Three drugs are in the development pipeline. The first with the shortest path to the market is GLG-801. This is a repurposed drug and under US FDA rules for 505(b)(2) could be fast tracked for various indications and clinical trials might be initiated, as soon as funds become available, in patients with  rare diseases such as Chronic Lymphocytic Leukemia (CLL) and Gastro-intestinal Stromal Tumors (GIST). GLG-302, a new chemical entity (NCE) follows in the development cycle and is expected to be in the clinic in about 8 months from funding. GLG-202 is another NCE that will follow in the development cycle. GLG-801 inhibits DNA binding and both GLG-302 and GLG-202 inhibit dimerization of the STAT3 molecule, preventing its penetration of the nuclear membrane and the initiation of the transcription process and the continuation of the uncontrolled proliferation process.

Want to know more about GLG Pharma and Poliwogg? Raising awareness and helping us fight cancer! Then click on the Poliwogg picture and it will take you to the Poliwogg accredited investor site!

Want to find out more about what compounds are in the clinic for CLL? Then click the button. Once you have signed up, we will email you the PDF document that provides you with compound structures and data on the activity of the compounds as well as their site of action on the leukemia cells!

The Alpha-1 Question

Alpha-1 Antitrypsin Deficiency (Alpha-1) is an inherited genetic disorder and about 19 million people in the US are carriers of the gene. The problem is when genetic mixing creates the perfect Alpah-1 storm. Although there are many kinds of Alpha-1 Trypsin disease the most common amongst global populations is called the S and Z genes. 

For persons with both ZZ genes, which represent an estimated 100,000 persons in the USA and are likely to get liver and lung complications that will lead to transplant surgery. Persons with the SZ combination are not as likely but will be susceptible to chronic diseases such as emphysema, liver disorders and chronic pulmonary obstructive disease (COPD). About 3% of the COPD patient population test positive for the Alpha-1 disease according to the Alpha-1 Foundation. 

Why is GLG Pharma working and participating in raising money for Alpha-1 research? Simple, there is no cure for Alpha-1 and The Alpha-1 Foundation has invested more than $50 million to support research and programs to speed the commercialization of therapies for the elimination of Chronic Obstructive Pulmonary Disease (COPD) and liver disease caused by Alpha-1. Activated STAT3 mediates several diseases of the lung and liver and this may also be the case in Alpha-1 mediated liver and lung diseases. 

We want you to help the Alpha-1 Foundation by sponsoring Michael Lovell and Hector Gomez for a November 15^th walk. This money will help the foundation continue its work in looking for cures as well as helping new products reach the market sooner rather than later. Michael Lovell our Executive Vice President and Hector Gomez our CEO are walking so please support the Alpha-1 foundation by donating through their link. Just click on the photo of your choice and donate to the Alpha-1!

                                           Support Hector Gomez:                                      Support Michael Lovell:

STAT3 inhibitors are important agents for cancer therapy. STAT is an acronym for Signal Transducer and Activator of Transcription. STAT is a protein that is mostly found in the cell cytoplasm and is activated by upstream specific signals. It is first activated (phosphorylated by adding phosphorous to the protein to form p-STAT3), it then dimerizes (two p-STAT molecules bind together) and then it crosses the nuclear membrane, binds to the nuclear DNA and triggers a cascade of subsequent reactions that induces the cell to grow or die, a process called apoptosis. P-STAT3 is deactivated by the removal of phosphorous. In a normal cell this process turns on and off like a turn signal and lasts less than two hours. In cancer, the process remains on and cells don’t die, they continue to divide. 

There are seven STATs, each has a specific role in various cell functions. The one that interests GLG the most at this time is STAT3. As it turns out, measuring the p-STAT3 in a cancer cell tells the physician something really important, that this disease is in a run-away state of exponential growth rates. The molecule; p-STAT3, plays also a major role in acquired resistance to several anticancer therapies.   

In our normal tissues, STAT3 is what the scientists call a ‘highly conserved’ mechanism and is only produced and turned on when it is time for the cell to divide. In cancer, p-STAT3 is a non-stop mechanism. In diseases like esophageal cancer, multiple myeloma, pancreatic cancer, glioma blastoma, liver cancer, some lung cancers and triple negative breast cancer, p-STAT3 is present in approximately 65% of the tumors.

Not a pleasant thought for someone possibly with breast cancer.  

The good news is that this abnormal process can be stopped and GLG is in a race against the clock. GLG’s compounds (STAT3 inhibitors), inhibit p-STAT3 and stop cancer cell proliferation. GLG’s inhibitors target the abnormal proliferation process at any of three different points of attack:

 1. Phosphorylation

 2. Dimerization

 3. DNA Binding

 Here is a cartoon we borrowed to help explain how our inhibitors of p-STAT3 work:

The arrows show where our molecules stop the abnormal proliferation.

• Our phosphorylation (first two arrows) inhibitor is called GLG-101
• We have 2 dimerization inhibitors (second arrow from the top) GLG-202 and GLG-302. GLG-302 is currently in the NCI’s Prevent Cancer program.
• Our third inhibitor (third arrow from the top) is called GLG-801 and it is currently undergoing Phase 2 clinical trials in Chronic Lymphocytic Leukemia and has already demonstrated that in patients, it turns off p-STAT3. It is a repurposed drug, meaning that we can seek approval in cancer treatment under the FDA’s 505(b)(2) regulations (shorter and less costly to market approach sanctioned by the FDA). 

The 505(b)(2) application also means that the price of the new product, unless reformulated to deliver it to the patient in a more efficient delivery formulation, will have margins similar to the operating margins achieved by generic companies.  

What’s even more startling is that in the laboratory GLG-302 has been shown to reverse chemotherapy resistance in over 9 commercial anti-cancer drugs and across 10 different types of cancer!

9 Commercial Anti-Cancer Drugs Developing Resistance in Patients 

                                                                   Cancer types that have been found to develop acquired resistance to chemotherapy are:

1. Breast (Triple Negative)
2. Liver
3. Head & Neck
4. Melanoma
5. Multiple Myeloma
6. Ovary
7. Urinary Bladder
8. CTCL (cutaneous T cell lymphoma)
9. GIST (gastrointestinal stromal tumor)
10. Esophageal

By reversing the acquired resistance to chemotherapy, with our GLG-302 p-STAT3 inhibitor, the cancer cells once again become susceptible to chemotherapy treatment and are killed. We have seen this work reported in multiple independent laboratories across the world and across the listed cancers. If a cancer cell does not show p-STAT3 upregulation, then our compounds will not benefit the patient. If however the p-STAT3 is elevated, we could improve patient outcomes!

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Richard Gabriel, BS, MBA

COO

GLG Pharma, LLC

President

GLG Pharma, SAS