$NVLX bio- Nuvilex, Inc. About Nuvilex, Inc. (OTC
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Posted On: 10/01/2013 6:16:08 PM
$NVLX bio- Nuvilex, Inc.
About Nuvilex, Inc. (OTCQB: NVLX): Nuvilex, Inc. is an international biotechnology firm focused on developing and preparing to commercialize treatments for cancer, diabetes and other diseases based on the live, therapeutically valuable, encapsulated cells platform. The Company is leveraging its cancer biology and clinical oncology research experience and expertise, particularly for use in oncology treatments, in addition to initiating oncology applications of medical marijuana.
For more information visit: http://www.nuvilex.com
RESEARCH & DEVELOPMENT of NVLX
NVLX LIVE-CELL ENCAPSULATION RESEARCH & DEVELOPMENT
The live-cell encapsulation technology employed by Nuvilex is a way to enclose living cells in protective “cocoons” about the size of the head of a pin - we do not encapsulate drugs, but living cells. Each capsule can enclose approximately 10,000 cells; this number can differ depending upon the size of the cells encapsulated. The cell encapsulation technology used by Nuvilex can be classified as a “platform” upon which treatments for different indications may be built.
Depending on the type of cells used, the encapsulated cells can be employed in developing treatments for serious, debilitating and even deadly diseases. Nuvilex’s primary interests in the use of the live-cell encapsulation technology are for the development of treatments for various cancers and for diabetes.
Our live-cell encapsulation differs from that done by others in that the capsules that enclose the cells are made primarily of cellulose whereas others use substances such as alginate (a seaweed derivative), agarose, or chitosan, to name three. Because of this, the capsules are very robust and can withstand various external forces and this allows them to be implanted using needles or catheters without damage. Also, because they are made principally of cellulose, the capsules are essentially bio-inert in humans, so they do not degrade even after being present in the body for over two years.
The capsules contain pores that allow essential nutrients to enter and waste products and beneficial substances produced by the encapsulated cells to leave. Therefore, the cells inside the capsules can live and function for long periods of time after implantation. However, the pores are not large enough to permit the cells to leave the capsules or large enough to allow any cells of the body’s immune system to enter the capsules and destroy the encapsulated cells.
Even after more than two years in the body, no immune or inflammatory response is caused by the capsules themselves or by the cells within the capsules. In addition, the presence of the capsules does not cause fibrous overgrowth from, or other damage to, tissues nearby or surrounding the capsules.
Cells encapsulated using our technology can be stored frozen at -80°C or lower for long periods of time and then successfully thawed for use; this also allows for shipment of encapsulated cells to distant locations. Large-scale manufacturing of encapsulated cells using our technology has already been carried out according to GMP (Good Manufacturing Practice) conditions – a necessity for ultimately attaining marketing approval from drug regulatory authorities such as the U.S. FDA and the EMEA in Europe.
Nuvilex has recently acquired worldwide exclusive rights to the live cell-encapsulation technology described above from SG Austria Pte. Ltd. for the development of treatments for any and all types of cancer. The rights to use the cancer drug-activating cells (22P1G cells) that will be part of Nuvilex’s treatment for advanced pancreatic cancer (see Pancreatic Cancer section of this website) were also acquired. The acquisition of rights to use this live-cell encapsulation technology for the development of treatments for insulin-dependent diabetes is being finalized.
NVLX PANCREATIC CANCER RESEARCH & DEVELOPMENT
According to the American cancer Society, in the US alone, approximately 45,000 new cases of pancreatic cancer are expected to be diagnosed this year and about 38,000 people are predicted to die from the disease; it is the leading cause of cancer deaths in the US and worldwide. Often pancreatic cancer is not diagnosed until it has reached an advanced stage. By this time, the cancer cannot be removed surgically, is often resistant to radiation therapy or chemotherapy, and has spread (metastasized) to other organs in the body. Because of this, the average survival of patients with advanced, inoperable pancreatic cancer is given in terms of weeks or months, not years.
To date, there has only been one anticancer drug approved (in 1997) for use by the US FDA as a single agent for the treatment of advanced pancreatic cancer, namely GEMZAR®, also known as gemcitabine. Since 2000, more than 30 pivotal (for drug marketing approval) late-phase clinical trials have been carried out in an attempt to improve upon the effectiveness of gemcitabine against advanced pancreatic cancer by adding other drugs to it. Only a very few of these trials have even been moderately successful.
One of the success stories was the combination of gemcitabine with TARCEVA® (erlotinib). In the Phase III pivotal trial of that combination, the one-year survival rate for the gemcitabine/TARCEVA® combination was 24% as compared to 17% for a gemcitabine/placebo combination. In 2005, the FDA approved the gemcitabine/TARCEVA® combination as first-line therapy for advanced, metastatic pancreatic cancer.
The results of the second successful Phase III trial of a gemcitabine-containing combination were reported in January 2013. Here, the combination of ABRAXANE® plus gemcitabine was compared to gemcitabine alone in patients with advanced pancreatic cancer. ABRAXANE® is a formulation of nanoparticle-albumin-bound paclitaxel (TAXOL®). In this trial, when compared to gemcitabine alone, the ABRAXANE®/gemcitabine combination improved both median survival and one-year survival rate by about 30% and 59%, respectively. On September 6 2013, the combination of ABRAXANE® plus gemcitabine was approved by the FDA as first-line treatment for advanced, metastatic pancreatic cancer and replaced the gemcitabine/TARCEVA® combination as the “gold standard” for the treatment of the disease
A four-drug combination known as FOLFIRINOX (5-fluorouracil, leucovorin [WELLCOVORIN®], ironotecan [CAMPTOSAR®], and oxaliplatin [ELOXATIN®] is also fairly widely used to treat advanced pancreatic cancer. But, as for gemcitabine itself, and the gemcitabine/TARCEVA® and ABRAXANE®/gemcitabine combinations, FOLFIRINOX use carries with it severe drug-related side effects.
Nuvilex’s pancreatic cancer treatment consists of the use of a proprietary cellulose-based live-cell encapsulation technology together with the long-known and widely used anticancer drug ifosfamide (IFEX®). Ifosfamide is a prodrug that must be activated to its cancer-killing form for it to be effective; this usually occurs in the liver. Ifosfamide is administered intravenously (systemically), and like all anticancer drugs given this way, can cause drug-related toxicities in organs of the body unrelated to the tumor itself. The 22P1G cells encapsulated are capable of converting ifosfamide into its cancer killing form. The cells contain high levels of activity of one of the components of the cytochrome P450 enzyme system known as CYP2B1. The cytochrome P450 enzyme system is found in the liver and is responsible for the metabolism of lipids, steroid hormones, drugs, and other toxic substances. In actual practice, the pancreatic cancer treatment consists of first implanting the capsules containing the ifosfamide-activating cells through the use of radiography and then giving ifosfamide by its usual route of administration.
In a Phase I/II open-label, prospective, single-arm clinical trial, the live-cell encapsulation/ifosfamide combination was used to treat patients with advanced, inoperable pancreatic cancer. Fifty-one patients were originally “screened” for the trial; of these, 17 were enrolled in the study. Other patients were excluded from enrollment for therapy because of previous chemotherapy, previous pancreatic surgery, poor overall health, unwillingness to participate, or death prior to the start of the trial. Of the 17 patients initially enrolled in the study, 14 were ultimately treated.
Each patient in the trial received a single implantation of approximately 300 capsules (each capsule contained approximately 10,000 ifosfamide-activating cells), except for one patient who received 250 capsules, in the blood supply to the pancreas near that organ and thus the tumor itself; this was followed by two courses of therapy with ifosfamide at one-third of the dose normally used. Capsules were implanted on day 0 of treatment. After monitoring the patients on day 1, ifosfamide administration at a dose of 1 g/m2 of body surface area occurred on day 2 as a one-hour intravenous administration for three consecutive days; this was accompanied by the administration of the uroprotectant MESNA (also known as UROMITEXAN® or MESNEX®), as is normally the case when ifosfamide is used (the dose-limiting toxicity with ifosfamide is known to be damage to the urinary tract). Administration of ifosfamide was repeated on days 25-27; except for two patients who only received the initial course of treatment with ifosfamide. In addition a “quality-of-life” questionnaire was used for all 14 patients to document the clinical benefit of the treatment.
NVLX Results obtained in the clinical trial were compared with historical data for gemcitabine and included:
-median survival time of 44 weeks (after diagnosis) with the cell encapsulation/ifosfamide treatment as compared to 28 weeks with gemcitabine;
-doubling of the one-year survival rate – 36% with our treatment vs. 18% with gemcitabine;
-tumor volume was reduced 25-50% in 4 of the 14 treated patients and remained stable in the remaining patients;
-no serious drug-related side effects with the encapsulated cell/ifosfamide treatment whereas serious and very serious side effects were reported with gemcitabine; the lack of serious side effects using our treatment is probably related to the use of “lower than normal” doses of ifosfamide;
-limited side effects and reduced cancer pain intensity led to a generally increased ‘quality of life” for the majority of patients.
In a “worst case” scenario, some clinical benefit was seen in 50% of patients and in a “best case” scenario, this number increased to 71%; none of the patients who experienced a clinical benefit required and increase in their pain medication. In addition, no deleterious effects were seen that could be attributed to the presence of the capsules or the encapsulated cells; this observation testifies to the ability of the capsules to protect the cells inside them from attack and rejection by the body’s immune system for significant periods of time.
Reports of the Phase I/II trial of the cellulose-based live-cell encapsulation/ifosfamide combination in patients with advanced, inoperable pancreatic cancer have been published in reputable, peer-reviewed, scientific journals. The journal citations for the published articles are:
1. Löhr M., Hoffmeyer A., Kröger J-C., Freund M., Hain J., Holle A., Karle P., Knöfel W.T., Liebe S., Müller P., Nizze H., Renner M., Saller R.M., Wagner T., Hauenstein K., Günzburg W.H., and Salmons B. Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma. THE LANCET, Vol. 357, p. 1591 (2001).
To view the above-cited trial report click here. http://www.thelancet.com/journals/lancet/arti...8/abstract . The website in this link requires that readers register before the article can be viewed – the process is simple and free.
2. Löhr M., Kröger J-C., Hoffmeyer A., Freund M., Hain J., Holle A., Knöfel W.T., Liebe S., Nizze H., Renner M., Saller R., Müller P., Wagner T., Hauenstein K., Salmons B., and Günzburg W.H. Safety, feasibility and clinical benefit of localized chemotherapy using microencapsulated cells for inoperable pancreatic cancer in a phase I/II trial. Cancer Therapy, Vol. 1, p. 121 (2003).
To view the above-cited trial report click here. http://www.cancer-therapy.org/CT/v1/A/13%20%2...%20cop.pdf
To summarize, local implantation of encapsulated cancer prodrug-activating cells near the tumor increases the locally available amount of the activated anticancer drug directly in the pancreatic tumor. This ensures high efficacy of the anticancer drug with lower doses of that drug and thus also reduces the unpleasant and often serious side effects of the chemotherapy.
On the basis of the above positive clinical trial results, Nuvilex is making preparations for conducting a late-phase, randomized, multi-site, multinational clinical trial in which our treatment will be compared “head-to-head” with gemcitabine in patients with advanced, inoperable pancreatic cancer. Initial activities underway include the “scaling-up” of the production of ifosfamide-activating cells to ensure that sufficient numbers will be available for encapsulation to complete the trial, and the establishment of a GMP-compliant facility in which to conduct the encapsulation of the cells, as well as having the requisite equipment manufactured with which to do so. In addition, Contract Research Organizations (CROs) are being evaluated to assist in all aspects of the clinical trial.
NVLX BREAST CANCER RESEARCH & DEVELOPMENT
For 2013, the American Cancer Society estimates that more than 230,000 cases of breast cancer will be diagnosed in the US alone and more than 40,000 individuals are predicted to die from this disease; about 99% of these are females. Worldwide, breast cancer is the fifth most common cause of cancer deaths, and is second only to lung cancer in overall prevalence; more than one million new cases are diagnosed each year. After skin cancer, breast cancer is the most common of all cancers among women both in the US and worldwide. The breast cancer market (in major markets) has been predicted to be almost $ 11 billion by 2018.
From 5-10% of all breast cancers have a hereditary link, with women who have a first-degree relative with breast cancer being most at risk for developing the disease. Between 20 and 25% of hereditary breast cancers and 5-10% of all breast cancers result from mutations of the breast cancer suppressor genes BRCA1 and/or BRCA2. A particularly well-known form of breast cancer, accounting for about 20-25% of non-hereditary forms of the disease, is one in which the HER2 (human epidermal growth factor) gene is overexpressed; it is known as HER2-positive, or HER2+, breast cancer. Normally, breast cells contain two copies of the HER2 gene, but in HER2+ breast cancer cells, many more copies of the gene are present; this results in a greatly increased amount of HER2 receptors on the outside of HER2+ breast cancer cells than is normally the case. This overexpression of HER2 receptors has been exploited in the development of two blockbuster monoclonal antibody drugs, HERCEPTIN® (trastuzumab) and PERJETA® (pertuzumab); these are used in various combinations against only HER2+ breast cancer..
According to the American Cancer Society, 10 different chemotherapeutic drug combinations have been widely used for years to treat various forms of breast cancer – particularly non-HER2+ breast cancer. Of these, three can be classified as two-drug combinations, six as three-drug combinations, and one is a four-drug combination. Nine of these 10 combination chemotherapies use the anticancer drug cyclophosphamide (CYTOXAN®) as one of the components of the combination.
Cyclophosphamide is a “sister” drug to ifosfamide, the anticancer agent used in the mid-phase clinical trials in patients with advanced, inoperable pancreatic cancer that employed the Company’s cell encapsulation-based treatment. Both drugs are classified as “prodrugs” and must be activated (converted to their cancer-killing form) for them to be effective; this usually takes place in the liver. The same enzyme system in the liver activates both cyclophosphamide and ifosfamide.
Given the effectiveness of Nuvilex’s pancreatic cancer treatment in which cells capable of activating ifosfamide were encapsulated in cellulose-based microcapsules. The same ifosfamide-activating enzyme as that found normally found in the liver was genetically increased in activity in the encapsulated cells. Because ifosfamide and cyclophosphamide are activated in the same way, the same type of encapsulated cells was used in a veterinary early/mid-phase clinical trial in which dogs with spontaneously-occurring mammary tumors were treated with either cyclophosphamide alone or with the combination of encapsulated cells plus cyclophosphamide.
Spontaneously-occurring mammary tumors in dogs represent a good animal model system for the testing of anticancer drugs designed to be used against breast cancer in humans. Cyclophosphamide was chosen for the study rather than ifosfamide because it is often used to treat mammary tumors in dogs and because it is a component of most combination chemotherapy regimens used against breast cancer in humans.
In the study itself, encapsulated cyclophosphamide-activating cells were implanted into the tumors and then cyclophosphamide was administered intravenously, at its usual dose, in four treatments 2,9,22, and 29 days later. As in the pancreatic cancer clinical trials in humans, the capsules and the cells within them were well tolerated – no “safety” issues were seen. Dogs that received the cell encapsulation/cyclophosphamide combination exhibited a greater degree of tumor shrinkage than dogs that received cyclophosphamide alone.
One dog had two spontaneously-occurring mammary tumors. In that animal, encapsulated cells were implanted in only one of the tumors. The tumor that did not receive the encapsulated cells, and thus was treated with cyclophosphamide alone, shrank in size by 14% as compared to the 70% shrinkage seen with the tumor that was treated with the combination of cell encapsulation plus cyclophosphamide.
The results of this study indicate that the combination of cellulose-based live-cell encapsulation and cyclophosphamide may prove to be of significant benefit for the treatment of breast cancer in humans, by optimizing the cancer-killing activity of cyclophosphamide, when that drug is used in various combination chemotherapy regimens for the disease.
NVLX DIABETES RESEARCH & DEVELOPMENT
The International Diabetes Federation estimates that more than 370 million people worldwide have diabetes and that about 190 million remain undiagnosed. Therefore, many millions of people are subject to the debilitating, and even deadly, complications of this disease; these include heart disease, vision loss, kidney disease, and nerve damage, particularly to the feet and legs, which may ultimately necessitate amputation. The worldwide market for diabetes treatments has been projected to reach $65 billion by 2020.
Diabetes is characterized by sustained high levels of sugar (glucose) in the blood. Glucose is a source of energy for all cells in the body. Normally, the levels of glucose are regulated by insulin produced by ?-cells of the Islets of Langerhans (islet cells or islets)within the pancreas.
There are two “types” of diabetes:
Type 1 Diabetes - About 5-10% of diabetics have Type 1 disease,formerly called juvenile onset diabetes because it mainly occurs in those 20 of age or younger. Here, the pancreas, having been damaged by autoantibodies, is incapable of producing insulin. As a consequence, these individuals require insulin daily given either by injection or by an insulin “pump.”
Type 2 Diabetes - The majority of diabetics have Type 2 diabetes, also known as adult onset diabetes because it is not usually diagnosed until individuals are 35 years of age or older. In Type 2 diabetes, either the pancreas produces too little insulin or the insulin produced cannot be used efficiently by the body - a phenomenon known as “insulin resistance.” Insulin resistance develops because of many factors, including genetics, obesity, increasing age, and the presence of high blood sugar for a long time. Type 2 diabetes, at least in its early stages, can be “treated” by such things as increased exercise, weight loss, and by anti-diabetic drugs, but over time, many of these individuals may also require insulin administration either with or without anti-diabetic medications.
One way to reduce diabetics’ dependence on insulin administration is through the use of pancreatic islet cell transplantation. In a ground-breaking study known as the “Edmonton Protocol,” islet cells from human cadavers were transplanted into insulin-dependent diabetics. However, cadaveric islet cell transplantations are problematic because (a) the supply of islet cells is limited and (b) potent and expensive immunosuppressive drugs must be administered for the remainder of diabetic patients’ lives or for as long as islet cell transplantations are used.
In an effort to avoid the use of islet cells from human cadavers, islet cells from pigs have been employed instead. This approach, known as xenotransplantation, has been used with alginate-encapsulated pig islets and has shown some success. However, the integrity of capsules composed of alginate have been shown to degrade with time; this allows for immune system attack on the transplanted pig islets and necessitates additional transplantations. Furthermore, drug regulatory authorities have been resistant to such interspecies transplantations of tissues in the past. Finally, the use of pig islets requires that a population of “germ-free” pigs be maintained – an expensive and problematic situation.
In a “proof-of-principle” study, cellulose-based capsules (produced in the same way as the capsules used in the pancreatic cancer clinical trials) containing live pancreatic islet cells from pigs were implanted into diabetic rats. Within a very short time, the blood glucose levels of the rats became normalized and remained that way for the 6-month duration of the study. Because of the robustness and longevity (over two years in humans in the pancreatic cancer trials done to date) of the cellulose-based capsules, no immunosuppressive drugs were necessary. Finally, when the capsules were removed from the rats at the end of the study, the cells that had been encapsulated were found to be fully viable and capable of responding to changes in glucose levels in their surroundings. This study illustrates the true platform nature of the cellulose-based live-cell encapsulation technology in developing a type of artificial pancreas.
Because of the positive results from the above proof-of-principle study, the Company plans additional expanded animal studies (longer duration, more animals) in which insulin-producing cells are encapsulated in its cellulose-based capsules. If the results from the proof-of-principle study are confirmed, this would ultimately lead to human clinical trials in diabetic individuals.
dd part 1
About Nuvilex, Inc. (OTCQB: NVLX): Nuvilex, Inc. is an international biotechnology firm focused on developing and preparing to commercialize treatments for cancer, diabetes and other diseases based on the live, therapeutically valuable, encapsulated cells platform. The Company is leveraging its cancer biology and clinical oncology research experience and expertise, particularly for use in oncology treatments, in addition to initiating oncology applications of medical marijuana.
For more information visit: http://www.nuvilex.com
RESEARCH & DEVELOPMENT of NVLX
NVLX LIVE-CELL ENCAPSULATION RESEARCH & DEVELOPMENT
The live-cell encapsulation technology employed by Nuvilex is a way to enclose living cells in protective “cocoons” about the size of the head of a pin - we do not encapsulate drugs, but living cells. Each capsule can enclose approximately 10,000 cells; this number can differ depending upon the size of the cells encapsulated. The cell encapsulation technology used by Nuvilex can be classified as a “platform” upon which treatments for different indications may be built.
Depending on the type of cells used, the encapsulated cells can be employed in developing treatments for serious, debilitating and even deadly diseases. Nuvilex’s primary interests in the use of the live-cell encapsulation technology are for the development of treatments for various cancers and for diabetes.
Our live-cell encapsulation differs from that done by others in that the capsules that enclose the cells are made primarily of cellulose whereas others use substances such as alginate (a seaweed derivative), agarose, or chitosan, to name three. Because of this, the capsules are very robust and can withstand various external forces and this allows them to be implanted using needles or catheters without damage. Also, because they are made principally of cellulose, the capsules are essentially bio-inert in humans, so they do not degrade even after being present in the body for over two years.
The capsules contain pores that allow essential nutrients to enter and waste products and beneficial substances produced by the encapsulated cells to leave. Therefore, the cells inside the capsules can live and function for long periods of time after implantation. However, the pores are not large enough to permit the cells to leave the capsules or large enough to allow any cells of the body’s immune system to enter the capsules and destroy the encapsulated cells.
Even after more than two years in the body, no immune or inflammatory response is caused by the capsules themselves or by the cells within the capsules. In addition, the presence of the capsules does not cause fibrous overgrowth from, or other damage to, tissues nearby or surrounding the capsules.
Cells encapsulated using our technology can be stored frozen at -80°C or lower for long periods of time and then successfully thawed for use; this also allows for shipment of encapsulated cells to distant locations. Large-scale manufacturing of encapsulated cells using our technology has already been carried out according to GMP (Good Manufacturing Practice) conditions – a necessity for ultimately attaining marketing approval from drug regulatory authorities such as the U.S. FDA and the EMEA in Europe.
Nuvilex has recently acquired worldwide exclusive rights to the live cell-encapsulation technology described above from SG Austria Pte. Ltd. for the development of treatments for any and all types of cancer. The rights to use the cancer drug-activating cells (22P1G cells) that will be part of Nuvilex’s treatment for advanced pancreatic cancer (see Pancreatic Cancer section of this website) were also acquired. The acquisition of rights to use this live-cell encapsulation technology for the development of treatments for insulin-dependent diabetes is being finalized.
NVLX PANCREATIC CANCER RESEARCH & DEVELOPMENT
According to the American cancer Society, in the US alone, approximately 45,000 new cases of pancreatic cancer are expected to be diagnosed this year and about 38,000 people are predicted to die from the disease; it is the leading cause of cancer deaths in the US and worldwide. Often pancreatic cancer is not diagnosed until it has reached an advanced stage. By this time, the cancer cannot be removed surgically, is often resistant to radiation therapy or chemotherapy, and has spread (metastasized) to other organs in the body. Because of this, the average survival of patients with advanced, inoperable pancreatic cancer is given in terms of weeks or months, not years.
To date, there has only been one anticancer drug approved (in 1997) for use by the US FDA as a single agent for the treatment of advanced pancreatic cancer, namely GEMZAR®, also known as gemcitabine. Since 2000, more than 30 pivotal (for drug marketing approval) late-phase clinical trials have been carried out in an attempt to improve upon the effectiveness of gemcitabine against advanced pancreatic cancer by adding other drugs to it. Only a very few of these trials have even been moderately successful.
One of the success stories was the combination of gemcitabine with TARCEVA® (erlotinib). In the Phase III pivotal trial of that combination, the one-year survival rate for the gemcitabine/TARCEVA® combination was 24% as compared to 17% for a gemcitabine/placebo combination. In 2005, the FDA approved the gemcitabine/TARCEVA® combination as first-line therapy for advanced, metastatic pancreatic cancer.
The results of the second successful Phase III trial of a gemcitabine-containing combination were reported in January 2013. Here, the combination of ABRAXANE® plus gemcitabine was compared to gemcitabine alone in patients with advanced pancreatic cancer. ABRAXANE® is a formulation of nanoparticle-albumin-bound paclitaxel (TAXOL®). In this trial, when compared to gemcitabine alone, the ABRAXANE®/gemcitabine combination improved both median survival and one-year survival rate by about 30% and 59%, respectively. On September 6 2013, the combination of ABRAXANE® plus gemcitabine was approved by the FDA as first-line treatment for advanced, metastatic pancreatic cancer and replaced the gemcitabine/TARCEVA® combination as the “gold standard” for the treatment of the disease
A four-drug combination known as FOLFIRINOX (5-fluorouracil, leucovorin [WELLCOVORIN®], ironotecan [CAMPTOSAR®], and oxaliplatin [ELOXATIN®] is also fairly widely used to treat advanced pancreatic cancer. But, as for gemcitabine itself, and the gemcitabine/TARCEVA® and ABRAXANE®/gemcitabine combinations, FOLFIRINOX use carries with it severe drug-related side effects.
Nuvilex’s pancreatic cancer treatment consists of the use of a proprietary cellulose-based live-cell encapsulation technology together with the long-known and widely used anticancer drug ifosfamide (IFEX®). Ifosfamide is a prodrug that must be activated to its cancer-killing form for it to be effective; this usually occurs in the liver. Ifosfamide is administered intravenously (systemically), and like all anticancer drugs given this way, can cause drug-related toxicities in organs of the body unrelated to the tumor itself. The 22P1G cells encapsulated are capable of converting ifosfamide into its cancer killing form. The cells contain high levels of activity of one of the components of the cytochrome P450 enzyme system known as CYP2B1. The cytochrome P450 enzyme system is found in the liver and is responsible for the metabolism of lipids, steroid hormones, drugs, and other toxic substances. In actual practice, the pancreatic cancer treatment consists of first implanting the capsules containing the ifosfamide-activating cells through the use of radiography and then giving ifosfamide by its usual route of administration.
In a Phase I/II open-label, prospective, single-arm clinical trial, the live-cell encapsulation/ifosfamide combination was used to treat patients with advanced, inoperable pancreatic cancer. Fifty-one patients were originally “screened” for the trial; of these, 17 were enrolled in the study. Other patients were excluded from enrollment for therapy because of previous chemotherapy, previous pancreatic surgery, poor overall health, unwillingness to participate, or death prior to the start of the trial. Of the 17 patients initially enrolled in the study, 14 were ultimately treated.
Each patient in the trial received a single implantation of approximately 300 capsules (each capsule contained approximately 10,000 ifosfamide-activating cells), except for one patient who received 250 capsules, in the blood supply to the pancreas near that organ and thus the tumor itself; this was followed by two courses of therapy with ifosfamide at one-third of the dose normally used. Capsules were implanted on day 0 of treatment. After monitoring the patients on day 1, ifosfamide administration at a dose of 1 g/m2 of body surface area occurred on day 2 as a one-hour intravenous administration for three consecutive days; this was accompanied by the administration of the uroprotectant MESNA (also known as UROMITEXAN® or MESNEX®), as is normally the case when ifosfamide is used (the dose-limiting toxicity with ifosfamide is known to be damage to the urinary tract). Administration of ifosfamide was repeated on days 25-27; except for two patients who only received the initial course of treatment with ifosfamide. In addition a “quality-of-life” questionnaire was used for all 14 patients to document the clinical benefit of the treatment.
NVLX Results obtained in the clinical trial were compared with historical data for gemcitabine and included:
-median survival time of 44 weeks (after diagnosis) with the cell encapsulation/ifosfamide treatment as compared to 28 weeks with gemcitabine;
-doubling of the one-year survival rate – 36% with our treatment vs. 18% with gemcitabine;
-tumor volume was reduced 25-50% in 4 of the 14 treated patients and remained stable in the remaining patients;
-no serious drug-related side effects with the encapsulated cell/ifosfamide treatment whereas serious and very serious side effects were reported with gemcitabine; the lack of serious side effects using our treatment is probably related to the use of “lower than normal” doses of ifosfamide;
-limited side effects and reduced cancer pain intensity led to a generally increased ‘quality of life” for the majority of patients.
In a “worst case” scenario, some clinical benefit was seen in 50% of patients and in a “best case” scenario, this number increased to 71%; none of the patients who experienced a clinical benefit required and increase in their pain medication. In addition, no deleterious effects were seen that could be attributed to the presence of the capsules or the encapsulated cells; this observation testifies to the ability of the capsules to protect the cells inside them from attack and rejection by the body’s immune system for significant periods of time.
Reports of the Phase I/II trial of the cellulose-based live-cell encapsulation/ifosfamide combination in patients with advanced, inoperable pancreatic cancer have been published in reputable, peer-reviewed, scientific journals. The journal citations for the published articles are:
1. Löhr M., Hoffmeyer A., Kröger J-C., Freund M., Hain J., Holle A., Karle P., Knöfel W.T., Liebe S., Müller P., Nizze H., Renner M., Saller R.M., Wagner T., Hauenstein K., Günzburg W.H., and Salmons B. Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma. THE LANCET, Vol. 357, p. 1591 (2001).
To view the above-cited trial report click here. http://www.thelancet.com/journals/lancet/arti...8/abstract . The website in this link requires that readers register before the article can be viewed – the process is simple and free.
2. Löhr M., Kröger J-C., Hoffmeyer A., Freund M., Hain J., Holle A., Knöfel W.T., Liebe S., Nizze H., Renner M., Saller R., Müller P., Wagner T., Hauenstein K., Salmons B., and Günzburg W.H. Safety, feasibility and clinical benefit of localized chemotherapy using microencapsulated cells for inoperable pancreatic cancer in a phase I/II trial. Cancer Therapy, Vol. 1, p. 121 (2003).
To view the above-cited trial report click here. http://www.cancer-therapy.org/CT/v1/A/13%20%2...%20cop.pdf
To summarize, local implantation of encapsulated cancer prodrug-activating cells near the tumor increases the locally available amount of the activated anticancer drug directly in the pancreatic tumor. This ensures high efficacy of the anticancer drug with lower doses of that drug and thus also reduces the unpleasant and often serious side effects of the chemotherapy.
On the basis of the above positive clinical trial results, Nuvilex is making preparations for conducting a late-phase, randomized, multi-site, multinational clinical trial in which our treatment will be compared “head-to-head” with gemcitabine in patients with advanced, inoperable pancreatic cancer. Initial activities underway include the “scaling-up” of the production of ifosfamide-activating cells to ensure that sufficient numbers will be available for encapsulation to complete the trial, and the establishment of a GMP-compliant facility in which to conduct the encapsulation of the cells, as well as having the requisite equipment manufactured with which to do so. In addition, Contract Research Organizations (CROs) are being evaluated to assist in all aspects of the clinical trial.
NVLX BREAST CANCER RESEARCH & DEVELOPMENT
For 2013, the American Cancer Society estimates that more than 230,000 cases of breast cancer will be diagnosed in the US alone and more than 40,000 individuals are predicted to die from this disease; about 99% of these are females. Worldwide, breast cancer is the fifth most common cause of cancer deaths, and is second only to lung cancer in overall prevalence; more than one million new cases are diagnosed each year. After skin cancer, breast cancer is the most common of all cancers among women both in the US and worldwide. The breast cancer market (in major markets) has been predicted to be almost $ 11 billion by 2018.
From 5-10% of all breast cancers have a hereditary link, with women who have a first-degree relative with breast cancer being most at risk for developing the disease. Between 20 and 25% of hereditary breast cancers and 5-10% of all breast cancers result from mutations of the breast cancer suppressor genes BRCA1 and/or BRCA2. A particularly well-known form of breast cancer, accounting for about 20-25% of non-hereditary forms of the disease, is one in which the HER2 (human epidermal growth factor) gene is overexpressed; it is known as HER2-positive, or HER2+, breast cancer. Normally, breast cells contain two copies of the HER2 gene, but in HER2+ breast cancer cells, many more copies of the gene are present; this results in a greatly increased amount of HER2 receptors on the outside of HER2+ breast cancer cells than is normally the case. This overexpression of HER2 receptors has been exploited in the development of two blockbuster monoclonal antibody drugs, HERCEPTIN® (trastuzumab) and PERJETA® (pertuzumab); these are used in various combinations against only HER2+ breast cancer..
According to the American Cancer Society, 10 different chemotherapeutic drug combinations have been widely used for years to treat various forms of breast cancer – particularly non-HER2+ breast cancer. Of these, three can be classified as two-drug combinations, six as three-drug combinations, and one is a four-drug combination. Nine of these 10 combination chemotherapies use the anticancer drug cyclophosphamide (CYTOXAN®) as one of the components of the combination.
Cyclophosphamide is a “sister” drug to ifosfamide, the anticancer agent used in the mid-phase clinical trials in patients with advanced, inoperable pancreatic cancer that employed the Company’s cell encapsulation-based treatment. Both drugs are classified as “prodrugs” and must be activated (converted to their cancer-killing form) for them to be effective; this usually takes place in the liver. The same enzyme system in the liver activates both cyclophosphamide and ifosfamide.
Given the effectiveness of Nuvilex’s pancreatic cancer treatment in which cells capable of activating ifosfamide were encapsulated in cellulose-based microcapsules. The same ifosfamide-activating enzyme as that found normally found in the liver was genetically increased in activity in the encapsulated cells. Because ifosfamide and cyclophosphamide are activated in the same way, the same type of encapsulated cells was used in a veterinary early/mid-phase clinical trial in which dogs with spontaneously-occurring mammary tumors were treated with either cyclophosphamide alone or with the combination of encapsulated cells plus cyclophosphamide.
Spontaneously-occurring mammary tumors in dogs represent a good animal model system for the testing of anticancer drugs designed to be used against breast cancer in humans. Cyclophosphamide was chosen for the study rather than ifosfamide because it is often used to treat mammary tumors in dogs and because it is a component of most combination chemotherapy regimens used against breast cancer in humans.
In the study itself, encapsulated cyclophosphamide-activating cells were implanted into the tumors and then cyclophosphamide was administered intravenously, at its usual dose, in four treatments 2,9,22, and 29 days later. As in the pancreatic cancer clinical trials in humans, the capsules and the cells within them were well tolerated – no “safety” issues were seen. Dogs that received the cell encapsulation/cyclophosphamide combination exhibited a greater degree of tumor shrinkage than dogs that received cyclophosphamide alone.
One dog had two spontaneously-occurring mammary tumors. In that animal, encapsulated cells were implanted in only one of the tumors. The tumor that did not receive the encapsulated cells, and thus was treated with cyclophosphamide alone, shrank in size by 14% as compared to the 70% shrinkage seen with the tumor that was treated with the combination of cell encapsulation plus cyclophosphamide.
The results of this study indicate that the combination of cellulose-based live-cell encapsulation and cyclophosphamide may prove to be of significant benefit for the treatment of breast cancer in humans, by optimizing the cancer-killing activity of cyclophosphamide, when that drug is used in various combination chemotherapy regimens for the disease.
NVLX DIABETES RESEARCH & DEVELOPMENT
The International Diabetes Federation estimates that more than 370 million people worldwide have diabetes and that about 190 million remain undiagnosed. Therefore, many millions of people are subject to the debilitating, and even deadly, complications of this disease; these include heart disease, vision loss, kidney disease, and nerve damage, particularly to the feet and legs, which may ultimately necessitate amputation. The worldwide market for diabetes treatments has been projected to reach $65 billion by 2020.
Diabetes is characterized by sustained high levels of sugar (glucose) in the blood. Glucose is a source of energy for all cells in the body. Normally, the levels of glucose are regulated by insulin produced by ?-cells of the Islets of Langerhans (islet cells or islets)within the pancreas.
There are two “types” of diabetes:
Type 1 Diabetes - About 5-10% of diabetics have Type 1 disease,formerly called juvenile onset diabetes because it mainly occurs in those 20 of age or younger. Here, the pancreas, having been damaged by autoantibodies, is incapable of producing insulin. As a consequence, these individuals require insulin daily given either by injection or by an insulin “pump.”
Type 2 Diabetes - The majority of diabetics have Type 2 diabetes, also known as adult onset diabetes because it is not usually diagnosed until individuals are 35 years of age or older. In Type 2 diabetes, either the pancreas produces too little insulin or the insulin produced cannot be used efficiently by the body - a phenomenon known as “insulin resistance.” Insulin resistance develops because of many factors, including genetics, obesity, increasing age, and the presence of high blood sugar for a long time. Type 2 diabetes, at least in its early stages, can be “treated” by such things as increased exercise, weight loss, and by anti-diabetic drugs, but over time, many of these individuals may also require insulin administration either with or without anti-diabetic medications.
One way to reduce diabetics’ dependence on insulin administration is through the use of pancreatic islet cell transplantation. In a ground-breaking study known as the “Edmonton Protocol,” islet cells from human cadavers were transplanted into insulin-dependent diabetics. However, cadaveric islet cell transplantations are problematic because (a) the supply of islet cells is limited and (b) potent and expensive immunosuppressive drugs must be administered for the remainder of diabetic patients’ lives or for as long as islet cell transplantations are used.
In an effort to avoid the use of islet cells from human cadavers, islet cells from pigs have been employed instead. This approach, known as xenotransplantation, has been used with alginate-encapsulated pig islets and has shown some success. However, the integrity of capsules composed of alginate have been shown to degrade with time; this allows for immune system attack on the transplanted pig islets and necessitates additional transplantations. Furthermore, drug regulatory authorities have been resistant to such interspecies transplantations of tissues in the past. Finally, the use of pig islets requires that a population of “germ-free” pigs be maintained – an expensive and problematic situation.
In a “proof-of-principle” study, cellulose-based capsules (produced in the same way as the capsules used in the pancreatic cancer clinical trials) containing live pancreatic islet cells from pigs were implanted into diabetic rats. Within a very short time, the blood glucose levels of the rats became normalized and remained that way for the 6-month duration of the study. Because of the robustness and longevity (over two years in humans in the pancreatic cancer trials done to date) of the cellulose-based capsules, no immunosuppressive drugs were necessary. Finally, when the capsules were removed from the rats at the end of the study, the cells that had been encapsulated were found to be fully viable and capable of responding to changes in glucose levels in their surroundings. This study illustrates the true platform nature of the cellulose-based live-cell encapsulation technology in developing a type of artificial pancreas.
Because of the positive results from the above proof-of-principle study, the Company plans additional expanded animal studies (longer duration, more animals) in which insulin-producing cells are encapsulated in its cellulose-based capsules. If the results from the proof-of-principle study are confirmed, this would ultimately lead to human clinical trials in diabetic individuals.
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