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Archive for the ‘Patient-centered Medicine’ Category


PEER-REVIEWED MEDICAL JOURNAL PUBLISHES LANDMARK STUDY ON EFFICACY AND SAFETY OF FDgard® (COLM-SST), DEMONSTRATING RAPID REDUCTION OF FUNCTIONAL DYSPEPSIA (FD OR RECURRING, MEAL-TRIGGERED INDIGESTION) SYMPTOMS WITHIN 24 HOURS

  • FDgard® (COLM-SST), a solid-state microsphere formulation of caraway oil and l-Menthol, taken daily and proactively 30-60 minutes before meals, showed statistically significant, rapid reduction of Functional Dyspepsia (FD) symptoms within 24 hours and, additionally, relief of severe FD symptoms.
  • FDREST clinical trial with FDgard represents an important medical advance, as no previous trials have shown rapid relief of FD symptoms. There are no approved products for this highly prevalent condition.
  • In FDREST, patients received greater and more durable benefits with the addition of FDgard taken daily and proactively to their typical medical regimen.
  • FDREST is the first clinical trial in FD to use patented, Site Specific Targeting (SST®) technology to deliver the FDgard formulation to the upper belly (duodenum), the primary site of disturbance in FD.
  • FDgard represents an effective, safe and well-tolerated option to address the unmet medical needs of millions of adults with FD.

Reporter: Gail S. Thornton

Boca Raton Fl., – (April 30, 2019) – IM HealthScience today announced that Clinical and Translational Gastroenterology (CTG), a peer-reviewed medical journal, has published the U.S. results of a landmark, double-blind, placebo-controlled study, FDREST™ (Functional Dyspepsia Reduction Evaluation and Safety Trial), which showed statistically significant, rapid reduction of Functional Dyspepsia (FD or recurring, meal-triggered indigestion) symptoms within 24 hours and, additionally, relief of severe FD symptoms.

The study, entitled “A Novel, Duodenal-Release Formulation of a Combination of Caraway Oil and L-Menthol for the Treatment of Functional Dyspepsia: A Randomized Controlled Trial,” is now available to the public via open access on the Clinical and Translational Gastroenterology website. Clinical and Translational Gastroenterology, published on behalf of the American College of Gastroenterology (ACG), is dedicated to innovative clinical work in the field of gastroenterology and hepatology.

The FDREST study demonstrated that patients who took COLM-SST (FDgard®) on a daily and proactive basis, 30 to 60 minutes before meals, along with commonly used off-label FD medications versus patients who took placebo along with commonly used off-label FD medications, experienced a statistically significant, rapid reduction of FD symptoms within 24 hours across the FD study population.

This study had a higher hurdle than previous studies on a similar combination of ingredients. Firstly, concomitant medications for FD symptoms were allowed in order to assess FDgard in a real-world setting. Second, only a subgroup of patients in FDREST was categorized into the high-symptom burden, while they constituted the entire groups in previous studies. Among this subgroup of patients with the high-symptom burden, FDgard showed efficacy at 24 hours. In spite of the polypharmacy and use of rescue medications for FD, after 48 hours of first dose, FDgard helped further improve symptoms at 4 weeks, especially in those high-symptom burden patients. In all cases, FDgard was safe and well-tolerated.  

The study results of FDREST were first presented at Digestive Disease Week (DDW), the largest gathering of gastroenterologists, in May 2017.

Study Commentary

Commenting on the study, lead author William Chey, M.D., FACG, Director in the Division of Gastroenterology, Michigan Medicine Gastroenterology Clinic, Ann Arbor, said, “This landmark study was designed to answer a very important scientific question about the effectiveness, safety, and tolerability of a novel and innovative formulation of caraway oil and l-Menthol designed as solid state, enteric coated microspheres for targeted duodenal release for FD. In patients taking their usual medications for FD, FDgard was found to be effective, safe and well tolerated in rapidly reducing symptoms and in relieving severe symptoms.” Chey continued, “The positive finding at 24 hours is clinically important as symptoms are often triggered by a meal and patients are looking for rapid relief of those symptoms.”

The study authors also cited the importance of utilizing the microsphere-based site-specific targeting of FDgard (caraway oil and l-Menthol, the active ingredient in peppermint oil) to the duodenum. They wrote, “This site (duodenum) was targeted primarily due to mounting evidence that gastroduodenal mucosal integrity and low-grade inflammation play a role in FD. Furthermore, studies have shown that caraway oil and peppermint oil act on the duodenum to induce smooth muscle relaxation, and that l-Menthol has anti-inflammatory effects.” This may help normalize motility effects.

About FDREST™

FDREST™ (Functional Dyspepsia Reduction and Evaluation Safety Trial) was a multi-centered, post-marketing, parallel group, U.S-based study conducted at seven university-based or gastroenterology research-based centers (study period July 1, 2015, to September 14, 2016). The study was designed to compare the efficacy, safety and tolerability of FDgard plus commonly used, off-label medications for FD vs. a control group of placebo plus commonly used, off-label medications prescribed for FD.

Ninety-five patients were enrolled (mean age = 43.4 years; 75.8 percent women). At 24 hours, the active arm reported a statistically significant reduction in Postprandial Distress Syndrome (PDS) symptoms (P = 0.039), and a nonsignificant trend toward benefit of Epigastric Pain Syndrome (EPS) symptoms (P = 0.074). In patients with more severe symptoms, approximately three-quarters showed substantial global improvement (i.e., clinical global impressions) after 4 weeks of treatment vs. half in the control arm. These differences were statistically significant for patients with EPS symptoms (epigastric pain or discomfort and burning) (P = 0.046), and trending toward significance for patients with PDS symptoms (early satiety, abdominal heaviness, pressure and fullness) (P = 0.091). There were no statistically significant differences between groups for Global Overall Symptom scores for the overall population at 2 and 4 weeks.

Dr. Chey said, “The results of this high-quality study highlight an advance in the management of FD, as current off-label medications such as PPIs, H2RAs and antidepressants offer only a modest level of therapeutic gain over placebo and may be associated with adverse events, especially with continued use. FDgard addresses a significant unmet medical need for a product to help manage symptoms in the 1 in 6 adults suffering from this common disorder.”

About Functional Dyspepsia (FD)

Functional dyspepsia is a very common disorder affecting 11 percent – 29.2 percent of the world’s population1, making it comparable in prevalence to IBS. However, unlike IBS, there is no FDA approved product to treat FD. Sufferers are often treated off-label with prescribed proton pump inhibitors (PPIs), histamine type-2 receptor antagonists (H2RAs), antidepressants, and prokinetics. While offering relief to a portion of FD patients, some of these have been associated with adverse events. Functional dyspepsia can have a negative effect on workplace attendance and productivity, with associated costs estimated in excess of $18 billion annually.2

In FD, which is typically recurring, meal-triggered indigestion with no known organic cause, the normal digestive processes are disrupted along with digestion and absorption of food nutrients. FD is accompanied by symptoms such as epigastric pain or discomfort, epigastric burning, postprandial fullness, inability to finish a normal sized meal, heaviness, pressure, bloating in the upper abdomen, nausea, and belching. When doctors diagnose FD, they often identify patients as those who have these symptoms for at least three months, with symptom onset six months previously.

About FDgard®

FDgard® is a nonprescription medical food designed to address the unmet medical need for products to help manage Functional Dyspepsia (FD or recurring, meal-triggered indigestion) and its accompanying symptoms.  FDgard capsules contain caraway oil and l-Menthol, the primary component in peppermint oil, for the dietary management of FD. These two main ingredients are specially formulated to be available in a solid state.  With patented Site Specific Targeting (SST®) technology pioneered by IM HealthScience, FDgard capsules release individually triple-coated, solid-state microspheres of caraway oil and l-Menthol quickly and reliably where they are needed most in FD — the duodenum or upper belly. The l-Menthol helps with smooth muscle relaxation and provides analgesic and anti-inflammatory activities.3–5 Caraway oil helps mitigate the effect of gastric acid on the stomach wall and also helps to normalize gallbladder function and may help to normalize motility in the small intestine (primarily the duodenum) and in the stomach.6,7 In addition to caraway oil and l-Menthol, FDgard also provides fiber and amino acids (from gelatin protein). These ingredients have additional positive effects on the gut wall and thus help toward normalizing digestion and absorption.            

Caraway oil and peppermint oil have a history of working in FD. In multiple clinical studies, the combination of caraway oil and peppermint oil has been shown to manage FD and its accompanying symptoms, such as reducing the intensity of epigastric pain, pain frequency, dyspeptic discomfort, and the intensity of sensations of pressure, abdominal heaviness and fullness significantly better than control.8,9 Cisapride, no longer an FDA-approved pro-motility drug after its removal from the market in 2000 due to cardiovascular side effects, was shown to have efficacy similar to a caraway oil/peppermint oil formulation10.

Complete and final results from a real-world, observational study of 600 patients who took FDgard, called FDACT™ (Functional Dyspepsia Adherence and Compliance Trial), were selected after peer review and presented by William D. Chey, M.D., FACG, at the World Congress of Gastroenterology at ACG 2017 in Orlando, Florida. The data showed there was a consistently high level of patient satisfaction and rapid improvement of FD symptoms with the product. A majority of patients (95 percent) reported major or moderate improvement in their overall FD symptoms, while many patients (86.4 percent) indicated experiencing relief from symptoms within 2 hours after taking FDgard. The findings from FDACT substantiate the data reported in FDREST.

The usual adult dose of FDgard is 2 capsules, as needed, up to two times a day, not to exceed six capsules per day. Many physicians are now recommending taking FDgard daily and proactively 30-60 minutes before a meal, as this enables the supportive effect of FDgard to start as early as possible. While FDgard does not require a prescription and is available in retail outlets and online, it is a medical food that should be used under medical supervision.

About IM HealthScience®

IM HealthScience® (IMH) is the innovator of IBgard®and FDgard®for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD or recurring, meal-triggered indigestion), respectively. In 2017, IMH added Fiber Choice®, a line of prebiotic fibers, to its product line via an acquisition. The sister subsidiary of IMH, Physician’s Seal®, also provides REMfresh®,

a well-known continuous release and absorption melatonin (CRA-melatonin™) supplement for sleep.

IMH is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. The company is dedicated to developing products to address overall health and wellness, especially in digestive health conditions with a high unmet medical need. The IM HealthScience advantage comes from developing products based on its patented, targeted-delivery technologies called Site Specific Targeting (SST). For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com,

 www.FDgard.com, www.FiberChoice.com, and www.Remfresh.com.

References

1.        Mahadeva S, Goh KL. Epidemiology of functional dyspepsia. A global perspective. World J Gastroenterol. 2006. doi:10.3748/wjg.v12.i17.2661.

2.        Lacy BE, Weiser KT, Kennedy AT, Crowell MD, Talley NJ. Functional dyspepsia: the economic impact to patients. Aliment Pharmacol Ther. 2013;38(May):170-177. doi:10.1111/apt.12355.

3.        Amato A, Liotta R, Mulè F. Effects of menthol on circular smooth muscle of human colon: Analysis of the mechanism of action. Eur J Pharmacol. 2014. doi:10.1016/j.ejphar.2014.07.018.

4.        Liu B, Fan L, Balakrishna S, Sui A, Moris JB, Jordt S-E. TRPM8 is the Principal Mediator of Menthol-induced Analgesia of Acute and Inflammatory Pain. Pain. 2013;154(10):2169-2177. doi:10.1016/j.pain.2013.06.043.TRPM8.

5.        Juergens U, Stober M, Vetter H. The anti-inflammatory activity of L-menthol compared to mint oil in human monocytes in vitro: a novel perspective for its therapeutic use in inflammatory diseases. Eur J Med Res. 1998;3(12):539-545.

6.        Alhaider A, Al-Mofleh I, Mossa J, Al-Sohaibani M, Rafatullah S, Qureshi S. Effect of Carum carvi on experimentally induced gastric mucosal damage in Wistar albino rats. Int J Pharmacol. 2006;2(3):309-315.

7.        Micklefield G, Jung O, Greving I, May B. Effects of intraduodenal application of peppermint oil (WS 1340) and caraway oil (WS 1520) on gastroduodenal motility in healthy volunteers. Phyther Res. 2003;17:135-140. doi:10.1002/ptr.1089.

8.        May B, Köhler S, Schneider B. Efficacy and tolerability of a fixed combination of peppermint oil and caraway oil in patients suffering from functional dyspepsia. Aliment Pharmacol Ther. 2000;14:1671-1677. doi:10.1046/j.1365-2036.2000.00873.x.

9.        Rich G, Shah A, Koloski N, et al. A randomized placebo-controlled trial on the effects of Menthacarin, a proprietary peppermint- and caraway-oil-preparation, on symptoms and quality of life in patients with functional dyspepsia. Neurogastroenterol Motil. 2017;29(May):e13132. doi:10.1111/nmo.13132.

10.      Madisch A, Heydenreich C, Wieland V, Hufnagel R, Hotz J. Treatment of Functional Dyspepsia with a Fixed Peppermint Oil and Caraway Oil Combination Preparation as Compared to Cisapride – A multicenter, reference-controlled double-blind equivalence study. Arzneimittelforsch Drug Res. 1999;49(II):925-932.

This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. This information should not be used for diagnosing a health problem or disease. While medical foods do not require prior approval by the FDA for marketing, they must comply with regulations. It should not be assumed that medical foods are alternatives for FDA-approved drugs. Only doctors can definitively diagnose functional dyspepsia. Use under medical supervision. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.fdgard.com. Individual results may vary.

Other related articles were published in this Open Access Online Scientific Journal include the following:

2017

Series D: BioMedicine & Immunology https://pharmaceuticalintelligence.com/biomed-e-books/series-d-e-books-on-biomedicine/

2015

The relationship of stress hypermetabolism to essential protein need

https://pharmaceuticalintelligence.com/2015/10/25/the-relationship-of-stress-hypermetabolism-to-essential-protein-needs/

Liposomes, Lipidomics and Metabolism

https://pharmaceuticalintelligence.com/2015/11/02/liposomes-lipidomics-and-metabolism/

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

RNA plays various roles in determining how the information in our genes drives cell behavior. One of its roles is to carry information encoded by our genes from the cell nucleus to the rest of the cell where it can be acted on by other cell components. Rresearchers have now defined how RNA also participates in transmitting information outside cells, known as extracellular RNA or exRNA. This new role of RNA in cell-to-cell communication has led to new discoveries of potential disease biomarkers and therapeutic targets. Cells using RNA to talk to each other is a significant shift in the general thought process about RNA biology.

 

Researchers explored basic exRNA biology, including how exRNA molecules and their transport packages (or carriers) were made, how they were expelled by producer cells and taken up by target cells, and what the exRNA molecules did when they got to their destination. They encountered surprising complexity both in the types of carriers that transport exRNA molecules between cells and in the different types of exRNA molecules associated with the carriers. The researchers had to be exceptionally creative in developing molecular and data-centric tools to begin making sense of the complexity, and found that the type of carrier affected how exRNA messages were sent and received.

 

As couriers of information between cells, exRNA molecules and their carriers give researchers an opportunity to intercept exRNA messages to see if they are associated with disease. If scientists could change or engineer designer exRNA messages, it may be a new way to treat disease. The researchers identified potential exRNA biomarkers for nearly 30 diseases including cardiovascular disease, diseases of the brain and central nervous system, pregnancy complications, glaucoma, diabetes, autoimmune diseases and multiple types of cancer.

 

As for example some researchers found that exRNA in urine showed promise as a biomarker of muscular dystrophy where current studies rely on markers obtained through painful muscle biopsies. Some other researchers laid the groundwork for exRNA as therapeutics with preliminary studies demonstrating how researchers might load exRNA molecules into suitable carriers and target carriers to intended recipient cells, and determining whether engineered carriers could have adverse side effects. Scientists engineered carriers with designer RNA messages to target lab-grown breast cancer cells displaying a certain protein on their surface. In an animal model of breast cancer with the cell surface protein, the researchers showed a reduction in tumor growth after engineered carriers deposited their RNA cargo.

 

Other than the above research work the scientists also created a catalog of exRNA molecules found in human biofluids like plasma, saliva and urine. They analyzed over 50,000 samples from over 2000 donors, generating exRNA profiles for 13 biofluids. This included over 1000 exRNA profiles from healthy volunteers. The researchers found that exRNA profiles varied greatly among healthy individuals depending on characteristics like age and environmental factors like exercise. This means that exRNA profiles can give important and detailed information about health and disease, but careful comparisons need to be made with exRNA data generated from people with similar characteristics.

 

Next the researchers will develop tools to efficiently and reproducibly isolate, identify and analyze different carrier types and their exRNA cargos and allow analysis of one carrier and its cargo at a time. These tools will be shared with the research community to fill gaps in knowledge generated till now and to continue to move this field forward.

 

References:

 

https://www.nih.gov/news-events/news-releases/scientists-explore-new-roles-rna

 

https://www.cell.com/consortium/exRNA

 

https://www.sciencedaily.com/releases/2016/06/160606120230.htm

 

https://www.pasteur.fr/en/multiple-roles-rnas

 

https://www.nature.com/scitable/topicpage/rna-functions-352

 

https://www.umassmed.edu/rti/biology/role-of-rna-in-biology/

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Leigh syndrome is one of the hundreds of so-called mitochondrial diseases, which are caused by defects in the mitochondria that produce 90 percent of the body’s energy. These disorders are rare; about 1,000 to 4,000 babies in the United States are born with one every year. But they are devastating and can result in grave impairment of nearly any bodily system. They are largely untreatable, uniformly incurable and very difficult to screen.

 

Leigh syndrome is a terrible disease. It emerges shortly after birth and claims one major organ after another. Movement becomes difficult, and then impossible. A tracheotomy and feeding tube are often necessary by toddlerhood, and as the disease progresses, lungs frequently have to be suctioned manually. Most children with the condition die by the age of 5 or 6.

 

Scientists have devised a procedure called mitochondrial replacement therapy (M.R.T.) that involves transplanting the nucleus of an affected egg (mitochondrial diseases are passed down from the mother’s side) into an unaffected one whose nucleus has been removed. The procedure is sometimes called “three-parent in vitro fertilization”. Mitochondria contain a minuscule amount of DNA, any resulting embryo would have mitochondrial DNA from the donor egg and nuclear DNA from each of its parents.

 

After decades of careful study in cell and animal research M.R.T. is now finally being tested in human clinical trials by doctors in Britain (no births confirmed yet officially). In the United States, however, this procedure is effectively illegal. M.R.T. does not involve altering any genetic code. Defective mitochondria are swapped out for healthy ones.

 

Mitochondrial DNA governs only a handful of basic cellular functions. It is separate from nuclear DNA, which helps determine individual traits like physical appearance, intelligence and personality. That means M.R.T. cannot be used to produce the genetically enhanced “designer babies” and thus should be allowed in humans. But, there is no way to know how safe or effective M.R.T. is until doctors and scientists test it in humans.

 

References:

 

 

https://pharmaceuticalintelligence.com/2016/10/07/the-three-parent-technique-to-avoid-mitochondrial-disease-in-embryo/

 

 

 

 

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Celgene Triumphs in Legal Battle over Revlimid Patent: Curation of Patents, Litigations, and Impact on Drug Pricing

Curator: Stephen J. Williams, PhD

From Celgene

REVLIMID® (lenalidomide) in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM). as maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT). and indicated for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

REVLIMID is also indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

REVLIMID® sales for the fourth quarter 2018 increased 16 percent to $2,549 million. Fourth quarter U.S. sales of $1,729 million and international sales of $820 million increased 17 percent and 15 percent, respectively. REVLIMID® sales growth was driven by increases in treatment duration and market share. Full year REVLIMID® sales were $9,685 million, an increase of 18 percent year-over-year. (from Celgene press release)

However, Celgene’s Revlimid basically has no competition in the multiple myeloma market and there are no generics of Revlimid, even though Revlimid is a conger of thalidomide, the 1950 era drug developed for depression and resulted in the infamous thalidomide baby cases.

The problem is highlighted in two reports:

As seen in Fortune: Celgene Boosted Price of Top Cancer Drug on Day of Mega Deal

By BLOOMBERG

January 4, 2019

On the same day Celgene Corp. was announcing that it would be acquired by Bristol-Myers Squibb Co. in the biggest pharma deal ever, the company was also raising the price of its blockbuster cancer drug. The Summit, New Jersey-based biotechnology company, which has routinely increased the prices of its top-selling drugs, boosted the price of a 10-milligram dose of Revlimid by 3.5 percent to $719.82 effective Jan. 3, according to price data compiled by Bloomberg Intelligence and First Databank. Cancer patients need many doses of Revlimid a year, and the overall cost can approach $200,000. The same dose cost $247.28 at the end of 2007.

As reported on NPR by Alison Kodjak: Celgene’s Patent Fortress Protects Revlimid, Thalidomide: How A DrugMaker Gamed the Patent System to Keep Generic Competition Away

When Celgene Corp. first started marketing the drug Revlimid to treat multiple myeloma in 2006, the price was $6,195 for 21 capsules, a month’s supply.By the time David Mitchell started taking Revlimid in November 2010, Celgene had bumped the price up to about $8,000 a month. When he took his last month’s worth of pills in April 2016, the sticker price had reached $10,691. By last March, the list price had reached $16,691. Revlimid appears to have caught the attention of Health and Human Services Secretary Alex Azar, who used it as an example Wednesday — without naming it outright — of how some drug’s prices rise with impunity. He said the copay for the average senior taking the drug rose from $115 to about $690 per month in the last year. Celgene can keep raising the price of Revlimid because the drug has no competition. It’s been around for more than a decade and its original patent expires next year. But today it looks like another four years could pass with no generic competitor to Revlimid.

 

Therefore, when the European company Alvogen tired to produce a generic version of this drug and took Celgene to court, Celgene quickly shored up its patent fight as outlined below.

As reported in Biopharmadive.com:

 

Celgene dodges Alvogen bid to overturn Revlimid patent

Here is Celgene’s patent on Revlimid (thalidomide).

Some notes:

  • notice the multiple congeners, chemical derivatives
  • notice the multiple drug combination claims especially with using other antibodies with thalidomide (second active ingredient)
  • note multiple dosage forms

Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione

Abstract
Methods of treating, preventing and/or managing cancer as well as and diseases and disorders associated with, or characterized by, undesired angiogenesis are disclosed. Specific methods encompass the administration of an immunomodulatory compound alone or in combination with a second active ingredient. The invention further relates to methods of reducing or avoiding adverse side effects associated with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy which comprise the administration of an immunomodulatory compound. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.

Images (1)

Classifications
A61K31/454 Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
View 21 more classifications

US7968569B2

United States

Inventor
Jerome B. Zeldis
Current Assignee
Celgene Corp

Worldwide applications

Application US10/438,213 events
2002-05-17
Priority to US38084202P
2011-06-28
Application granted
Application status is Active
Adjusted expiration
Show all events

Description

This application claims the benefit of U.S. provisional application No. 60/380,842, filed May 17, 2002, and No. 60/424,600, filed Nov. 6, 2002, the entireties of which are incorporated herein by reference.

1. FIELD OF THE INVENTION

This invention relates to methods of treating, preventing and/or managing specific cancers, and other diseases including, but not limited to, those associated with, or characterized by, undesired angiogenesis, by the administration of one or more immunomodulatory compounds alone or in combination with other therapeutics. In particular, the invention encompasses the use of specific combinations, or “cocktails,” of drugs and other therapy, e.g., radiation to treat these specific cancers, including those refractory to conventional therapy. The invention also relates to pharmaceutical compositions and dosing regimens.

2. BACKGROUND OF THE INVENTION

2.1 Pathobiology of Cancer and Other Diseases

Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host’s immune surveillance. Roitt, I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

There is an enormous variety of cancers which are described in detail in the medical literature. Examples includes cancer of the lung, colon, rectum, prostate, breast, brain, and intestine. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer.

Many types of cancers are associated with new blood vessel formation, a process known as angiogenesis. Several of the mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines with angiogenic properties. Examples of these cytokines include acidic and basic fibroblastic growth factor (a,b-FGF), angiogenin, vascular endothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cells can release angiogenic peptides through the production of proteases and the subsequent breakdown of the extracellular matrix where some cytokines are stored (e.g., b-FGF). Angiogenesis can also be induced indirectly through the recruitment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (e.g., TNF-α, bFGF).

A variety of other diseases and disorders are also associated with, or characterized by, undesired angiogenesis. For example, enhanced or unregulated angiogenesis has been implicated in a number of diseases and medical conditions including, but not limited to, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, rubeosis (neovascularization of the angle), viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to: diabetic retinopathy; retinopathy of prematurity; corneal graft rejection; neovascular glaucoma; retrolental fibroplasia; and proliferative vitreoretinopathy.

Accordingly, compounds that can control angiogenesis or inhibit the production of certain cytokines, including TNF-α, may be useful in the treatment and prevention of various diseases and conditions.

2.2 Methods of Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonal therapy and/or radiation treatment to eradicate neoplastic cells in a patient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). Recently, cancer therapy could also involve biological therapy or immunotherapy. All of these approaches pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to the health of a patient or may be unacceptable to the patient. Additionally, surgery may not completely remove neoplastic tissue. Radiation therapy is only effective when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy can also often elicit serious side effects. Hormonal therapy is rarely given as a single agent. Although hormonal therapy can be effective, it is often used to prevent or delay recurrence of cancer after other treatments have removed the majority of cancer cells. Biological therapies and immunotherapies are limited in number and may produce side effects such as rashes or swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeutic agents available for treatment of cancer. A majority of cancer chemotherapeutics act by inhibiting DNA synthesis, either directly, or indirectly by inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors, to prevent DNA replication and concomitant cell division. Gilman et al., Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York).

Despite availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous side effects including severe nausea, bone marrow depression, and immunosuppression. Additionally, even with administration of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. In fact, those cells resistant to the particular chemotherapeutic agents used in the treatment protocol often prove to be resistant to other drugs, even if those agents act by different mechanism from those of the drugs used in the specific treatment. This phenomenon is referred to as pleiotropic drug or multidrug resistance. Because of the drug resistance, many cancers prove refractory to standard chemotherapeutic treatment protocols.

Other diseases or conditions associated with, or characterized by, undesired angiogenesis are also difficult to treat. However, some compounds such as protamine, hepain and steroids have been proposed to be useful in the treatment of certain specific diseases. Taylor et al., Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos. 5,001,116 and 4,994,443. Thalidomide and certain derivatives of it have also been proposed for the treatment of such diseases and conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, 5,712,291, 6,071,948 and 6,114,355 to D’Amato.

Still, there is a significant need for safe and effective methods of treating, preventing and managing cancer and other diseases and conditions, particularly for diseases that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies.

2.3 IMIDS™

A number of studies have been conducted with the aim of providing compounds that can safely and effectively be used to treat diseases associated with abnormal production of TNF-α See, e.g., Marriott, J. B., et al., Expert Opin. Biol. Ther. 1(4):1-8 (2001); G. W. Muller, et al., Journal of Medicinal Chemistry 39(17): 3238-3240 (1996); and G. W. Muller, et al, Bioorganic & Medicinal Chemistry Letters 8: 2669-2674 (1998). Some studies have focused on a group of compounds selected for their capacity to potently inhibit TNF-α production by LPS stimulated PBMC. L. G. Corral, et al., Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999). These compounds, which are referred to as IMiDS™ (Celgene Corporation) or Immunomodulatory Drugs, show not only potent inhibition of TNF-α but also marked inhibition of LPS induced monocyte IL1β and IL12 production. LPS induced IL6 is also inhibited by immunomodulatory compounds, albeit partially. These compounds are potent stimulators of LPS induced IL10. Id. Particular examples of IMiD™s include, but are not limited to, the substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described in U.S. Pat. Nos. 6,281,230 and 6,316,471, both to G. W. Muller, et al.

3. SUMMARY OF THE INVENTION

This invention encompasses methods of treating and preventing certain types of cancer, including primary and metastatic cancer, as well as cancers that are refractory or resistant to conventional chemotherapy. The methods comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention also encompasses methods of managing certain cancers (e.g., preventing or prolonging their recurrence, or lengthening the time of remission) which comprise administering to a patient in need of such management a prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In particular methods of the invention, an immunomodulatory compound is administered in combination with a therapy conventionally used to treat, prevent or manage cancer. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.

This invention also encompasses methods of treating, managing or preventing diseases and disorders other than cancer that are associated with, or characterized by, undesired angiogenesis, which comprise administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In other methods of the invention, an immunomodulatory compound is administered in combination with a therapy conventionally used to treat, prevent or manage diseases or disorders associated with, or characterized by, undesired angiogenesis. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.

This invention encompasses pharmaceutical compositions, single unit dosage forms, dosing regimens and kits which comprise an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second, or additional, active agent. Second active agents include specific combinations, or “cocktails,” of drugs.

4. BRIEF DESCRIPTION OF FIGURE

FIG. 1 shows a comparison of the effects of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Revimid™) and thalidomide in inhibiting the proliferation of multiple myeloma (MM) cell lines in an in vitro study. The uptake of [3H]-thymidine by different MM cell lines (MM. 1S, Hs Sultan, U266 and RPMI-8226) was measured as an indicator of the cell proliferation.

5. DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention encompasses methods of treating, managing, or preventing cancer which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In particular methods encompassed by this embodiment, the immunomodulatory compound is administered in combination with another drug (“second active agent”) or method of treating, managing, or preventing cancer. Second active agents include small molecules and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods, or therapies, that can be used in combination with the administration of the immunomodulatory compound include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies presently used to treat, prevent or manage cancer.

Another embodiment of the invention encompasses methods of treating, managing or preventing diseases and disorders other than cancer that are characterized by undesired angiogenesis. These methods comprise the administration of a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Examples of diseases and disorders associated with, or characterized by, undesired angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, and rubeosis (neovascularization of the angle).

In particular methods encompassed by this embodiment, the immunomodulatory compound is administer in combination with a second active agent or method of treating, managing, or preventing the disease or condition. Second active agents include small molecules and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods, or therapies, that can be used in combination with the administration of the immunomodulatory compound include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies presently used to treat, prevent or manage disease and conditions associated with, or characterized by, undesired angiogenesis.

The invention also encompasses pharmaceutical compositions (e.g., single unit dosage forms) that can be used in methods disclosed herein. Particular pharmaceutical compositions comprise an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent.

5.1 Immunomodulatory Compounds

Compounds used in the invention include immunomodulatory compounds that are racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof. Preferred compounds used in the invention are small organic molecules having a molecular weight less than about 1,000 g/mol, and are not proteins, peptides, oligonucleotides, oligosaccharides or other macromolecules.

As used herein and unless otherwise indicated, the terms “immunomodulatory compounds” and “IMiDs™” (Celgene Corporation) encompasses small organic molecules that markedly inhibit TNF-α, LPS induced monocyte IL1β and IL12, and partially inhibit IL6 production. Specific immunomodulatory compounds are discussed below.

TNF-α is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF-α is responsible for a diverse range of signaling events within cells. TNF-α may play a pathological role in cancer. Without being limited by theory, one of the biological effects exerted by the immunomodulatory compounds of the invention is the reduction of synthesis of TNF-α. Immunomodulatory compounds of the invention enhance the degradation of TNF-αmRNA.

Further, without being limited by theory, immunomodulatory compounds used in the invention may also be potent co-stimulators of T cells and increase cell proliferation dramatically in a dose dependent manner. Immunomodulatory compounds of the invention may also have a greater co-stimulatory effect on the CD8+ T cell subset than on the CD4+ T cell subset. In addition, the compounds preferably have anti-inflammatory properties, and efficiently co-stimulate T cells.

Specific examples of immunomodulatory compounds of the invention, include, but are not limited to, cyano and carboxy derivatives of substituted styrenes such as those disclosed in U.S. Pat. No. 5,929,117; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as those described in U.S. Pat. No. 5,874,448; the tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines described in U.S. Pat. No. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of thalidomide and EM-12), including, but not limited to, those disclosed in U.S. Pat. No. 5,635,517; and a class of non-polypeptide cyclic amides disclosed in U.S. Pat. Nos. 5,698,579 and 5,877,200; analogs and derivatives of thalidomide, including hydrolysis products, metabolites, derivatives and precursors of thalidomide, such as those described in U.S. Pat. Nos. 5,593,990, 5,629,327, and 6,071,948 to D’Amato; aminothalidomide, as well as analogs, hydrolysis products, metabolites, derivatives and precursors of aminothalidomide, and substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles such as those described in U.S. Pat. Nos. 6,281,230 and 6,316,471; isoindole-imide compounds such as those described in U.S. patent application Ser. No. 09/972,487 filed on Oct. 5, 2001, U.S. patent application Ser. No. 10/032,286 filed on Dec. 21, 2001, and International Application No. PCT/US01/50401 (International Publication No. WO 02/059106). The entireties of each of the patents and patent applications identified herein are incorporated herein by reference. Immunomodulatory compounds of the invention do not include thalidomide.

Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo- and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring as described in U.S. Pat. No. 5,635,517 which is incorporated herein by reference. These compounds have the structure I:

Figure US07968569-20110628-C00001


in which one of X and Y is C═O, the other of X and Y is C═O or CH2, and Ris hydrogen or lower alkyl, in particular methyl. Specific immunomodulatory compounds include, but are not limited to:

  • 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;
  • 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline;
  • 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline;
  • 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline;
  • 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and
  • 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.

Other specific immunomodulatory compounds of the invention belong to a class of substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles, such as those described in U.S. Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, and International Patent Application No. PCT/US97/13375 (International Publication No. WO 98/03502), each of which is incorporated herein by reference. Compounds representative of this class are of the formulas:

Figure US07968569-20110628-C00002


wherein Ris hydrogen or methyl. In a separate embodiment, the invention encompasses the use of enantiomerically pure forms (e.g. optically pure (R) or (S) enantiomers) of these compounds.

Still other specific immunomodulatory compounds of the invention belong to a class of isoindole-imides disclosed in U.S. patent application Ser. Nos. 10/032,286 and 09/972,487, and International Application No. PCT/US01/50401 (International Publication No. WO 02/059106), each of which are incorporated herein by reference. Representative compounds are of formula II:

Figure US07968569-20110628-C00003

and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:

one of X and Y is C═O and the other is CHor C═O;

Ris H, (C1-C8)alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, C(O)R3, C(S)R3, C(O)OR4, (C1-C8)alkyl-N(R6)2, (C1-C8)alkyl-OR5, (C1-C8)alkyl-C(O)OR5, C(O)NHR3, C(S)NHR3, C(O)NR3R3′, C(S)NR3R3′ or (C1-C8)alkyl-O(CO)R5;

Ris H, F, benzyl, (C1-C8)alkyl, (C2-C8)alkenyl, or (C2-C8)alkynyl;

Rand R3′ are independently (C1-C8)alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, (C0-C8)alkyl-N(R6)2, (C1-C8)alkyl-OR5, (C1-C8)alkyl-C(O)OR5, (C1-C8)alkyl-O(CO)R5, or C(O)OR5;

Ris (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkyl-OR5, benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, or (C0-C4)alkyl-(C2-C5)heteroaryl;

Ris (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, or (C2-C5)heteroaryl;

each occurrence of Ris independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C2-C5)heteroaryl, or (C0-C8)alkyl-C(O)O—Ror the R6groups can join to form a heterocycloalkyl group;

n is 0 or 1; and

* represents a chiral-carbon center.

In specific compounds of formula II, when n is 0 then Ris (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, C(O)R3, C(O)OR4, (C1-C8)alkyl-N(R6)2, (C1-C8)alkyl-OR5, (C1-C8)alkyl-C(O)OR5, C(S)NHR3, or (C1-C8)alkyl O(CO)R5;

Ris H or (C1-C8)alkyl; and

Ris (C1-C8)alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, (C5-C8)alkyl-N(R6)2; (C0-C8)alkyl-NH—C(O)O—R5; (C1-C8)alkyl-OR5, (C1-C8)alkyl-C(O)OR5, (C1-C8)alkyl-O(CO)R5, or C(O)OR5; and the other variables have the same definitions.

In other specific compounds of formula II, Ris H or (C1-C4)alkyl.

In other specific compounds of formula II, Ris (C1-C8)alkyl or benzyl.

In other specific compounds of formula II, Ris H, (C1-C8)alkyl, benzyl, CH2OCH3, CH2CH2OCH3, or

Figure US07968569-20110628-C00004

In another embodiment of the compounds of formula II, Ris

Figure US07968569-20110628-C00005


wherein Q is O or S, and each occurrence of Ris independently H, (C1-C8)alkyl, benzyl, CH2OCH3, or CH2CH2OCH3.

In other specific compounds of formula II, Ris C(O)R3.

In other specific compounds of formula II, Ris (C0-C4)alkyl-(C2-C5)heteroaryl, (C1-C5)alkyl, aryl, or (C0-C4)alkyl-OR5.

In other specific compounds of formula II, heteroaryl is pyridyl, furyl, or thienyl.

In other specific compounds of formula II, Ris C(O)OR4.

In other specific compounds of formula II, the H of C(O)NHC(O) can be replaced with (C1-C4)alkyl, aryl, or benzyl.

Still other specific immunomodulatory compounds of the invention belong to a class of isoindole-imides disclosed in U.S. patent application Ser. No. 09/781,179, International Publication No. WO 98/54170, and U.S. Pat. No. 6,395,754, each of which are incorporated herein by reference. Representative compounds are of formula III:

Figure US07968569-20110628-C00006


and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:

one of X and Y is C═O and the other is CHor C═O;

R is H or CH2OCOR′;

(i) each of R1, R2, R3, or R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3, or Ris nitro or —NHRand the remaining of R1, R2, R3, or Rare hydrogen;

Ris hydrogen or alkyl of 1 to 8 carbons

Rhydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro;

R′ is R7—CHR10—N(R8R9);

Ris m-phenylene or p-phenylene or —(CnH2n)— in which n has a value of 0 to 4;

each of Rand Rtaken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or Rand Rtaken together are tetramethylene, pentamethylene, hexamethylene, or —CH2CH2[X]X1CH2CH2— in which [X]Xis —O—, —S—, or —NH—;

R10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl; and

* represents a chiral-carbon center.

The most preferred immunomodulatory compounds of the invention are 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione and 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. The compounds can be obtained via standard, synthetic methods (see e.g., U.S. Pat. No. 5,635,517, incorporated herein by reference). The compounds are available from Celgene Corporation, Warren, N.J. 4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (ACTIMID™) has the following chemical structure:

Figure US07968569-20110628-C00007


The compound 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (REVIMID™) has the following chemical structure:

Figure US07968569-20110628-C00008

Compounds of the invention can either be commercially purchased or prepared according to the methods described in the patents or patent publications disclosed herein. Further, optically pure compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral columns as well as other standard synthetic organic chemistry techniques.

As used herein and unless otherwise indicated, the term “pharmaceutically acceptable salt” encompasses non-toxic acid and base addition salts of the compound to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases know in the art, which include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, and the like.

Compounds that are acidic in nature are capable of forming salts with various pharmaceutically acceptable bases. The bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations such as, but not limited to, alkali metal or alkaline earth metal salts and the calcium, magnesium, sodium or potassium salts in particular. Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine.

As used herein and unless otherwise indicated, the term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of immunomodulatory compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of immunomodulatory compounds of the invention that comprise —NO, —NO2, —ONO, or —ONOmoieties. Prodrugs can typically be prepared using well-known methods, such as those described in 1 Burger’s Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, N.Y. 1985).

As used herein and unless otherwise indicated, the terms “biohydrolyzable amide,” “biohydrolyzable ester,” “biohydrolyzable carbamate,” “biohydrolyzable carbonate,” “biohydrolyzable ureide,” “biohydrolyzable phosphate” mean an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyl-oxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

Various immunomodulatory compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular immunomodulatory compounds of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions(Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, N.Y., 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

As used herein and unless otherwise indicated, the term “stereomerically pure” means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. As used herein and unless otherwise indicated, the term “stereomerically enriched” means a composition that comprises greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, more preferably greater than about 80% by weight of one stereoisomer of a compound. As used herein and unless otherwise indicated, the term “enantiomerically pure” means a stereomerically pure composition of a compound having one chiral center. Similarly, the term “stereomerically enriched” means a stereomerically enriched composition of a compound having one chiral center.

It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

5.2 Second Active Agents

Immunomodulatory compounds can be combined with other pharmacologically active compounds (“second active agents”) in methods and compositions of the invention. It is believed that certain combinations work synergistically in the treatment of particular types of cancer and certain diseases and conditions associated with, or characterized by, undesired angiogenesis. Immunomodulatory compounds can also work to alleviate adverse effects associated with certain second active agents, and some second active agents can be used to alleviate adverse effects associated with immunomodulatory compounds.

One or more second active ingredients or agents can be used in the methods and compositions of the invention together with an immunomodulatory compound. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Typical large molecule active agents are biological molecules, such as naturally occurring or artificially made proteins. Proteins that are particularly useful in this invention include proteins that stimulate the survival and/or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vitro or in vivo. Others stimulate the division and differentiation of committed erythroid progenitors in cells in vitro or in vivo. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.

Particular proteins that can be used in the methods and compositions of the invention include, but are not limited to: filgrastim, which is sold in the United States under the trade name Neupogen® (Amgen, Thousand Oaks, Calif.); sargramostim, which is sold in the United States under the trade name Leukine® (Immunex, Seattle, Wash.); and recombinant EPO, which is sold in the United States under the trade name Epogen® (Amgen, Thousand Oaks, Calif.).

Recombinant and mutated forms of GM-CSF can be prepared as described in U.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which are incorporated herein by reference. Recombinant and mutated forms of G-CSF can be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; all of which are incorporated herein by reference.

This invention encompasses the use of native, naturally occurring, and recombinant proteins. The invention further encompasses mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in vivo, at least some of the pharmacological activity of the proteins upon which they are based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins. Also encompassed by the term “mutants” are proteins that lack carbohydrate moieties normally present in their naturally occurring forms (e.g., nonglycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).

Antibodies that can be used in combination with compounds of the invention include monoclonal and polyclonal antibodies. Examples of antibodies include, but are not limited to, trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin™), pertuzumab (Omnitarg™), tositumomab (Bexxar®), edrecolomab (Panorex®), and G250. Compounds of the invention can also be combined with, or used in combination with, anti-TNF-α antibodies.

Other posts on Revlimid, Celgene, and other such Patent Litigation on this Open Access Journal Include:

From Thalidomide to Revlimid: Celgene to Bristol Myers to possibly Pfizer; A Curation of Deals, Discovery and the State of Pharma

REVLIMID® (Lenalidomide) Approved by the European Commission for the Treatment of Adult Patients with Previously Untreated Multiple Myeloma who are Not Eligible for Transplant

FDA: Rejects NDA filing: “clinical and non-clinical pharmacology sections of the application were not sufficient to complete a review”: Celgene’s Relapsing Multiple Sclerosis Drug – Ozanimod

The top 15 best-selling cancer drugs in 2022 & Projected Sales in 2020 of World’s Top Ten Oncology Drugs

Monoclonal antibody treatment of Multiple Myeloma

At California Central District Court Juno Therapeutics, Inc. et al v. Kite Pharma, Inc. – Multi-party Patent Infringement

 

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Immunoediting can be a constant defense in the cancer landscape


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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Stem Cells Differentiated into Insulin-Producing Cells in Mice

Reported: Irina Robu, PhD

Dr. Douglas Melton team from Harvard University funded in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases set out to transform stem cells into beta cells that have the potential to replace damaged beta cells. While scientists have been able to change stem cells into insulin-producing cells, these cells don’t have markers that indicate they are beta cells, and they aren’t responsive to glucose.

Since diabetes is a disorder of elevated blood sugars where the body does not harvest enough insulin to meet where the body does not harvest enough insulin to respond properly to the insulin being made. When blood glucose levels rise, beta cells in the pancreas normally make the hormone insulin. Insulin triggers cells throughout the body to take up sugar from the blood. In type 2 diabetes, the most common form, tissues in the body lose their sensitivity to insulin, and pancreatic beta cells can’t make enough insulin to keep glucose levels in check. In type 1 diabetes, the body’s own immune system attacks and destroys beta cells. High blood glucose levels can lead to heart disease, blindness, and other health problems over time.

One approach to treat diabetes is to replace destroyed beta cells. Transplanted human pancreatic cells from deceased donors have been successfully used to treat people with type 1 diabetes. But this method is restricted by the accessibility of donor cells and the side effects of immunosuppression. The other approach is to develop functioning beta cells from stem cells which have the potential to transform into many different cell types. These cells can grow indefinitely in the laboratory and can differentiate, into any cell type found in the body.
In this experiment, the researchers grew a human embryonic stem cell line and 2 human-induced pluripotent stem cell lines in a culture system that allowed them to produce large numbers of cells. The researchers tested more than 150 combinations of over 70 compounds to figure out a method to produce functional human beta cells from the cultured stem cells which when added in exact combinations over a period of several weeks, they transformed human pluripotent stem cells into beta cells that functioned similarly to normal adult beta cells.

The cultured beta cells had specific markers that were found on normal beta cells which displayed changes in calcium levels when exposed to glucose and packaged insulin into granules. However, when transplanted into mice these cells secreted insulin in response to glucose. However, when the cells were transplanted into diabetic mice, abnormally high blood glucose levels lowered. More work is needed to develop these cells for clinical use. However, at this point they can serve as a useful screening tool for diabetes drugs.

SOURCE
http://www.frontlinegenomics.com/news/26168/stem-cells-turned-into-insulin-producing-cells-in-mice/

 

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Stroke is a leading cause of death worldwide and the most common cause of long-term disability amongst adults, more particularly in patients with diabetes mellitus and arterial hypertension. Increasing evidence suggests that disordered physiological variables following acute ischaemic stroke, especially hyperglycaemia, adversely affect outcomes.

 

Post-stroke hyperglycaemia is common (up to 50% of patients) and may be rather prolonged, regardless of diabetes status. A substantial body of evidence has demonstrated that hyperglycaemia has a deleterious effect upon clinical and morphological stroke outcomes. Therefore, hyperglycaemia represents an attractive physiological target for acute stroke therapies.

 

However, whether intensive glycaemic manipulation positively influences the fate of ischaemic tissue remains unknown. One major adverse event of management of hyperglycaemia with insulin (either glucose-potassium-insulin infusions or intensive insulin therapy) is the occurrence of hypoglycaemia, which can also induce cerebral damage.

 

Doctors all over the world have debated whether intensive glucose management, which requires the use of IV insulin to bring blood sugar levels down to 80-130 mg/dL, or standard glucose control using insulin shots, which aims to get glucose below 180 mg/dL, lead to better outcomes after stroke.

 

A period of hyperglycemia is common, with elevated blood glucose in the periinfarct period consistently linked with poor outcome in patients with and without diabetes. The mechanisms that underlie this deleterious effect of dysglycemia on ischemic neuronal tissue remain to be established, although in vitro research, functional imaging, and animal work have provided clues.

 

While prompt correction of hyperglycemia can be achieved, trials of acute insulin administration in stroke and other critical care populations have been equivocal. Diabetes mellitus and hyperglycemia per se are associated with poor cerebrovascular health, both in terms of stroke risk and outcome thereafter.

 

Interventions to control blood sugar are available but evidence of cerebrovascular efficacy are lacking. In diabetes, glycemic control should be part of a global approach to vascular risk while in acute stroke, theoretical data suggest intervention to lower markedly elevated blood glucose may be of benefit, especially if thrombolysis is administered.

 

Both hypoglycaemia and hyperglycaemia may lead to further brain injury and clinical deterioration; that is the reason these conditions should be avoided after stroke. Yet, when correcting hyperglycaemia, great care should be taken not to switch the patient into hypoglycaemia, and subsequently aggressive insulin administration treatment should be avoided.

 

Early identification and prompt management of hyperglycaemia, especially in acute ischaemic stroke, is recommended. Although the appropriate level of blood glucose during acute stroke is still debated, a reasonable approach is to keep the patient in a mildly hyperglycaemic state, rather than risking hypoglycaemia, using continuous glucose monitoring.

 

The primary results from the Stroke Hyperglycemia Insulin Network Effort (SHINE) study, a large, multisite clinical study showed that intensive glucose management did not improve functional outcomes at 90 days after stroke compared to standard glucose therapy. In addition, intense glucose therapy increased the risk of very low blood glucose (hypoglycemia) and required a higher level of care such as increased supervision from nursing staff, compared to standard treatment.

 

References:

 

https://www.nih.gov/news-events/news-releases/nih-study-provides-answer-long-held-debate-blood-sugar-control-after-stroke

 

https://www.ncbi.nlm.nih.gov/pubmed/27873213

 

https://www.ncbi.nlm.nih.gov/pubmed/19342845

 

https://www.ncbi.nlm.nih.gov/pubmed/20491782

 

https://www.ncbi.nlm.nih.gov/pubmed/21211743

 

https://www.ncbi.nlm.nih.gov/pubmed/18690907

 

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