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3/17/09 - Ken Lewis in an interview with the Observer.
http://www.charlotteobserver.com/business/story/603855.html
Bank of America Corp. could pay back its $45 billion in government capital by late this year or early next year depending on the economy, chief executive Ken Lewis said in an interview Tuesday with the Observer.
Lewis also said he expects his Charlotte-based bank to be profitable this year “absent some unexpected meltdown” and to pass the government's stress test. He also said he'd like for the bank to make $30 billion in a year before he exits.
Lewis has previously said he is eager to return the money from the Troubled Asset Relief Program but that it would likely take two to three years to pay off the debt. The capital infusion has come with intense public scrutiny and restrictions on executive compensation and shareholder dividends.
He said he could see paying it back as the recession ends and maybe a portion of it before that. “In terms of paying it totally back then you're probably talking about sometime late this year or sometime early next year when we see the economy improving,” he said.
The bank could turn over the money now if it weren't maintaining higher-than-normal capital cushions because of the “fragile” state of the financial system, he said. He also noted that the money is not a “gift” from taxpayers. The bank has already made an initial $402 million dividend payment to taxpayers.
When the Treasury created TARP in October, it decreed that banks had to hold onto their funds for at least three years, or raise replacement capital. A last-minute provision inserted in the stimulus bill last month deleted the requirement about replacement capital, making it easier for banks to pay back the money more quickly. A number of smaller banks have already filed notice with the Treasury Department about plans to pay back the investment.
In the stress tests, federal regulators are reviewing the nation's biggest banks to see if they have enough capital to absorb losses in an extreme economic downturn.
“Given all that I know, I am confident that we will pass the stress test,” he said in the interview in his 58th floor office in the Bank of America Corporate Center.
As for a recent upturn in bank stocks, Lewis said investors are wondering whether the market has hit bottom. Bank of America shares have climbed 99 percent since March 6, closing up 1.5 percent on Tuesday to $6.27. The bank's shares are still down more than 50 percent this year.
The bank had been seen as one of the nation's strongest banks until problems surfaced with its Jan. 1 acquisition of Merrill Lynch. On Jan. 16, Bank of America disclosed a bigger-than-expected fourth quarter loss of more than $15 billion at Merrill, and the bank said it needed an extra $20 billion in government capital to stabilize the purchase.
Despite these issues, Lewis said he doesn't regret forging the deal, valued at $50 billion when it was announced in mid-September.
“I have to look out over a longer horizon than say the last three or four months,” he said. “If I look out over an intermediate timeframe such as the next three to five years or a longer time timeframe of five to 10 years I think Merrill will prove to be one of the best acquisitions we've ever made.”
In mid-December, Lewis met with regulators in Washington about possibly backing out of the acquisition, but the bank proceeded under the government's urging. “We got strong advice from the federal government we should do the deal,” Lewis said. “We listened to them, but at the end of the day we made our own decision.”
In the interview, Lewis also addressed whether he is concerned about keeping his job amid the bank's recent struggles. “I have not given it one single moment of thought,” he said. “I have been at this company almost 40 years, and what I want to do is see us get through this, and then start to realize our full potential and make $30 billion after tax, which is what we should make in a good time.”
At a January board meeting, he said his job status did not come up and that directors talked about what they “would normally would talk about at a time like this.” Asked whether he expects to retire when he turns 65 in 2012, he said: “I'm looking to pay back the TARP money and making $30 billion after tax and then I'll regroup.”
Lewis said the bank had a shot at hitting the $30 billion mark in 2011. The bank's biggest annual profit was $21.1 billion in 2006. Last year, it made $4 billion in net income, not counting $1.5 billion in dividends paid to preferred shareholders. The bank is scheduled to report first-quarter earnings on April 20.
As for his biggest regret in recent months, Lewis said he made a mistake in taking so much TARP money. The bank could have accepted $5 billion to $10 billion in January, instead of $20 billion, and kept its capital ratios in reasonable shape, he said.
“It put us too far away from the mainstream, and it did lump us together with Citigroup,” he said, referring to the institution regarded as the most damaged of the big U.S. banks. “We did it in an abundance of caution because you just don't know how bad things could get, but that was a mistake and that caused us to be painted with a broad brush in ways that we don't deserve.”
Asked whether the bank has been unfairly criticized for anything in recent months, he said: “I would need some time to compile a list.”
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"you people fail to understand that lomucin is a proof of principle on an entire pathway that genaera has the patents on called hclca1."
I agree on the potential long-term importance of the calcium activated chloride channel (hclca1) pathway, since this affects a wide variety of chronic obstructive pulmonary diseases (COPD) including asthma and chronic bronchitis, inflammatory lung diseases, cystic fibrosis and acute or chronic respiratory infectious diseases.
GENR IP in this area is not yet complete and still being prosecuted. They have obtained a patent (6,737,427) for lomucin, but their more general application (covering a much broader range of structures) was not approved. Based on a reading of the original application (20030236220), the claims appeared to be overly detailed and confusing. They resubmitted (Pat application 20040254096) this past May (in a simpler form) the same month the lomucin patent was issued.
The below link allows search of both uspto applications and patents on the right and left respectively. The database is updated Tuesday (patents) and Thursday (applications) weekly:
http://www.uspto.gov/patft/index.html
I would expect another mucin synthesis inhibitor patent to be issued in 2005 based upon this resubmission; this would provide GENR with much broader IP in the chloride channel arena and put them in a better negotiating position with potential partners.
The need to gain complete patent rights and the lack of capital have apparently put mucin inhibitor development work on the GENR backburner....
wc21
AMD Data update minus high/low readings.
Throwing out the high and low results for each of the AMD trials, here are the averages from the four remaining patients for the data that have been reported on GENR's site.
Date Mex 40mgst 40mg2nd 10mg
Wk3 6.5 6.9 4.3 0.8
EOT 8.8 7.8 7.1 2.7
2Mon 6.9 2.8 2.9 -1.9
4Mon 5.7 -1.5 3.9 -2.0
orep
RITA Stockholder Roth has recently sold ~2 million shares
"That holder had about 4 million shares and I think they may have been the sellers the last 3 days."
Good call. RITA's SEC filing published today lists Michael Roth with 2.5 Million shares. He had approximately 4.5 million shares in early December.
wc21
Claim on Lexapro Patent involves chemical intermediate labeling error
"How, exactly, where the isomers mislabeled"
The FRX IVAX lawsuit centers on Lundbeck's Lexapro patent 4,943,590 issued in 1990 and reissued (RE 34,712) in 1994 after a 1993 application.
Lexapro is a (+) enantiomer that is a more potent than the racemic mixture (+-). Both the original and the reissued patent clearly identified the + enantiomer as the key invention (Claims 1 and 2). (IMHO, since the "+" designation is linked to a distinguishing physical property (direction of rotating plane of polarized light) there was no need to necessarily include drawn structures of the two enantiomers).
Lexapro (the + enantiomer) is produced from a racemic mixture of starting material through chemical intermediates that form + and - enantiomers.
Interestingly, the (-) chemical intermediate enantiomer results in the production of the + enantiomer (Lexapro) product . This was discussed in the original and reissued patents (but not within the claims section).
The last claim (Claim 12) of the original patent laid claim to the chemical intermediate enantiomer. The chemical intermediate structure shown had a (+) notation. This was an error (should have been (-)); this was corrected in the reissued patent.
The chemical intermediate labeling error involved the last claim only and the error did not involve the primary claims of the patent. There still appears to be merit, since the + enantiomer (Lexapro) represents a new invention similar to other cases of racemic switches (e.g. allegra, nexium, clarinex).
After reading these two patents and better understanding the apparent errors made, I am less concerned about the probability that the patent will be ruled invalid. I also am not a patent attorney and would like to hear comments from someone with more a background in this field.
wc21
From the 1990 patent:
We claim:
1. A compound selected from substantially pure (+)-1-(3-Dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran -5-carbonitrile and non-toxic acid addition salts thereof.
2. A compound of claim 1 being pamoic acid salt of substantially pure (+)-1-(3-dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-dihydroisobenzofuran -5-carbonitrile.
.....
12. A compound of the formula ##STR6## wherein R is hydrogen or represents a group completing a labile ester.
Squalamine may not be effective as intravitreal injection.
"Sincerely, for such a small PR, I've never seen a company in the field insisting so much on local drug delivery, all of the players in the field (Oxigene, Eyetech, Alcon, Allergan, SiRNA...) have made the choice for local DD and pursue research in the field for an alternative to needlestick,...except Genaera..."
GENR's reluctance to puruse local delivery may be based on previous results...
There is a 2002 article in Retina that reported squalamine's effectiveness (when administered systemically) in monkeys as a prophylatic and to help regress blood vessel growth that had already occurred; this same study showed that intravitreal injections (at the highest nontoxic in-the-eye dose) had no effect:
"RETINA 22:772–778, 2002
EFFECT OF SQUALAMINE ON IRIS NEOVASCULARIZATION IN MONKEYS
MAHMOUD GENAIDY, MD,* ABDUL A. KAZI, MD,* GHOLAM A. PEYMAN, MD,* ELKE PASSOS–MACHADO, MD,* HASSAN G. FARAHAT, MD,* JON I. WILLIAMS, PHD,†‡ KENNETH J. HOLROYD, MD,† DIANE A. BLAKE, PHD*
Conclusions: Intravitreally injected squalamine did not affect the development of iris neovascularization; however, systemic squalamine injection inhibited the development of iris neovascularization and caused partial regression of new vessels in a primate model.
Intravitreal Dosing:
Group 1: Intravitreal squalamine injection.—In Group 1, 3 microgram/0.1 mL of squalamine in 5% dextrose (the highest nontoxic dose determined in parallel experiments in the rabbit eye) was injected intravitreally in four eyes. Similarly, 0.1 mL of balanced salt solution (BSS) was injected intravitreally in four control eyes. Injections were started immediately after vein occlusion (day 1) and repeated every 3 days for 3 weeks.
Results:
The results of this experiment showed that systemic squalamine could prevent iris neovascularization formation when given prophylactically after retinal vein occlusion and induction of hypotony with corneal suture placement. Systemic squalamine was also demonstrated to be effective in the regression of already established iris neovascularization. We were unable to demonstrate the benefit of intravitreal injection of squalamine in preventing iris neovascularization, possibly because of the low concentration of the drug, its bioavailability, and the repeated surgical trauma caused by intravitreal injections in these eyes."
wc21
Here is a comparison of mean results from middle four 207 patients (dropping the highest and lowest) vs Mexico trials in terms of changes in letters of visual acuity using data from the posted slides.
Date Mex 40mgs 40mgot 10mg
Wk3 6.5 6.9 4.3 0.8
EOT 8.8 7.8 7.1 2.7
2Mon 6.9 2.8 2.9 -1.9
4Mon 5.7
"Orphan Medical is a cheap stock just based on"
Drbio, what is you take on the April 2004 shelf registration for 4 million shares ORPH filed to meet potential cash requirements. Based on current market cap, there appears to be ~11 million shares outstanding.
This seems similar to the level GENR just filed.
TIA,
wc21
Updated Mucin Synthesis Inhibitors Patent Application Posted on USPTO
The USPTO site now shows that GENR filed a modified patent application in May 2004 for the remaining IP on chloride channel mucin inhibitors. That same month, they were awarded a patent for Lomucin--after originally applying in 2002 for a much broader range of molecular structures.
http://www.uspto.gov/patft/index.html
Patent Application 20040254096
"Abstract
The claimed invention relates to methods of modulating mucin synthesis and the therapeutic application of compounds in controlling mucin over-production associated with diseases such as chronic obstructive pulmonary diseases (COPD) including asthma and chronic bronchitis, inflammatory lung diseases, cystic fibrosis and acute or chronic respiratory infectious diseases."
It appears that GENR continues to aggressively pursue this.
wc21
Wonder if all the 10 mg work is based upon ongoing discussions with big pharma. Roy keeps emphasizing the safety of squalamine and its very short half-life outside of cells. If there were new safety issues, would he be doing this?
Are combo treatments, routes of delivery, or convenience to patients the driving force for the new interest in the 10mg doses. Levitt also keeps emphasizing the primary goal is a squalamine only treatment.
GENR's primary goal at this stage is to establish a partnership--one that will be needed before Phase III since they do not have the necessary capital for Phase III. Perhaps potential partners have specific ideas in mind and are interested in seeing certain types of data early.
All just speculation, but the focus on the 10 mg dosage is intriguing. Something is behind this interest.
wc21
AMD.org newletter article "Squalamine for Wet Macular Degeneration." GENR finally is getting some press from AMD.org, a source of information for patients.
wc21
http://www.amd.org/site/PageServer?pagename=Focus_100704&JServSessionIdr006=8ickbzxra1.app8b
"The FDA has just granted the Fast Track designation to this antiangiogenic drug, which is now in Phase II research. The Phase III clinical trial is expected to begin in early 2005.
Squalamine, like the other antiangiogenic drugs under development (Macugen, RETAANE, Lucentis), is designed to stop the growth of new blood vessels in the retina. These new blood vessels are the ones that leak and bleed, causing the damage from wet macular degeneration. Laser treatment can seal off the leaking, but the blood vessels will almost always eventually grow back. Using an antiangiogenic drug at some point in the process can reduce this risk and slow the progress of vision loss.
Unlike other antiangiogenic drugs, squalamine is not injected into the eye. Instead, it is administered intravenously. The current Phase II trials are looking at the safety and efficacy of the drug and are testing different dosage levels. Typically, Phase II trials are designed for that and only utilize a small number of patients.
The first trial for safety and efficacy involves 100 patients over a two year period. Two different dosages are being used.
The second trial will look at three different doses of squalamine, combined with treatment with Photodynamic Therapy (PDT) with Visudyne. The 45 patients will receive the squalamine before and after a Visudyne treatment. If the Visudyne stops the leaking and then the squalamine stops the vessels from growing back, patients will be able to avoid the multiple Visudyne treatments.
The third trial is a four month safety trial in 18 patients, using three different dosages of squalamine.
Further information on these trials and the larger Phase II Clinical Trial will be available soon. We’ll bring you that news when it’s released, plus details of the clinical trial recruitment."
Here are the two SBIR Abstracts from the NIH site. The AMD work started Sep 04, the MSI-1436 project started in Apr 04.
wc21
Grant Number: 1R43EY015971-01
PI Name: HUNG, HSIAO-LING L.
PI Email: hhung@genaera.com
PI Title:
Project Title: Aminosterols as Anti-angiogenic Therapeutics for AMD
Abstract: Age-related macular degeneration (AMD) is a public health problem resulting in the loss of independence in a significant number of the elderly population. The most severe form of AMD, wet AMD, is caused by the formation of new blood vessels in the choroidal region. Repeated blood leakage from these vessels damages the macula, thereby resulting in rapid irreversible vision loss. Several experimental therapeutics aimed at curtailing angiogenesis had been successful in treating wet AMD in clinical trials. However, these agents require intravitreal injections which present a significant risk of introducing infections and injuries to the eyes. Squalamine, a systemically delivered antiangiogenic aminosterol, had been shown to preserve/improve vision in 100% of patients 4 months following therapy in a phase 1/11clinical trial. Encouraged by these results, Genaera is seeking to explore squalamine analogs which may have higher potency, simpler synthesis scheme and better pharmacokinetic profile for their application in treating wet AMD. Two analogs that fit these criteria had been identified. The specific aims for this proposal are: 1. To evaluate the in vivo efficacy of squalamine and lead analogs in a rat model of choroidal neovascularization. CNV will be induced in rats by subretinal injection of Matrigel. Squalamine and analogs will be adminstered intraperitoneally daily followed by evaluation of CNV formation at the end of the studies. Studies will be carried out to evaluate squalamine and analogs' ability to prevent the formation of CNV and to regress pre-existing CNV. 2. To determine the effect of squalamine and analogs on VEGF signal transduction and integrin activity in endothelial cells. Coimmunoprecipitation and Western blotting with phosphospecific antibodies will be used to pinpoint squlamine and analogs' interference on these signaling events. The long term objective of this development program is to identify and refine safe and effective antiangiogenic aminosterols for the treatment of AMD.
Thesaurus Terms:
analog, angiogenesis inhibitor, cholestane compound, drug design /synthesis /production, eye disorder chemotherapy, macular degeneration, nonhuman therapy evaluation
aging, biological signal transduction, drug screening /evaluation, eye pharmacology, integrin, intraperitoneal injection, pharmacokinetics, protein structure function, vascular endothelial growth factor, vascular endothelium
human tissue, immunoprecipitation, laboratory rat, western blotting
Institution: GENAERA CORPORATION
5110 CAMPUS DRIVE
PLYMOUTH MEETING, PA 19462
Fiscal Year: 2004
Department:
Project Start: 01-SEP-2004
Project End: 31-AUG-2005
ICD: NATIONAL EYE INSTITUTE
IRG: ZRG1
--------------
Grant Number: 1R43DK066953-01
PI Name: MCLANE, MICHAEL
PI Email: mmclane@genaera.com
PI Title:
Project Title: Aminosterol MSI-1436 as a Therapeutic for Obesity
Abstract: DESCRIPTION (provided by applicant): Obesity is a disease that has increased at an alarming rate. Today, 64.5 percent of adult Americans (about 127 million) are categorized as being overweight (body mass index >25) or obese (body mass index >30). Obesity is strongly associated with type 2 diabetes, hypertension, coronary heart disease, respiratory conditions, increased incidence of certain forms of cancer, and many other diseases. Each year, obesity causes at least 300,000 excess deaths in the U.S. and healthcare costs of American adults with obesity amount to approximately $100 billion. Diet and exercise are stalwart anti-obesity therapies but success is variable. With the valvular heart disease associated with fenfluramine and phentermine in the late 1990's and subsequent withdrawal of fenfluramine and dexfenfluramine anti-obesity agents from the market, there has been a reduction in use of products that have similar pharmacological activities. Currently approved anti-obesity therapies (see Table 1) work by stimulating noradrenergic receptors, inhibiting serotonin and norepinephrine reuptake, or inhibiting absorption of fats via inhibition of Iipase but results are variable and there are some associated side effects. Major advances in understanding the homeostatic system and neural pathways that regulate body weight have led to potential therapeutic agents with novel activities, such as leptin, ghrelin antagonists, and ciliary neurotrophic factor (CNTF). We have discovered a natural occurring (in dogfish sharks), novel aminosterol, MS1-1436, that causes body weight reduction in genetically obese or diet-induced obese rodents when administered via various routes and in dogs. This compound, also re-established normoglycemia in diabetic obese animals and lowered serum cholesterol levels. Two steps are necessary to elevate this compound to clinical development and will be the aims of this grant: 1) the mechanism(s) of action(s) or neural pathways used by this compound need to be elucidated and 2) a minimal dose/frequency and formulation that allows subcutaneous implantable, intranasal or oral bio-availability needs to be developed.
Thesaurus Terms:
body weight, cholestane compound, dosage, drug design /synthesis /production, neuropharmacology, obesity, pharmacokinetics, weight control agent
animal extract, blood glucose, dosage forms, drug administration route, drug delivery system, neural transmission, neuropeptide
laboratory mouse, laboratory rat
Institution: GENAERA CORPORATION
5110 CAMPUS DRIVE
PLYMOUTH MEETING, PA 19462
Fiscal Year: 2004
Department:
Project Start: 01-APR-2004
Project End: 31-MAR-2005
ICD: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
IRG: ZRG1
This is a Phase I SBIR NIH Grant Program with a $100K limit for feasibility. There are follow-on Phase II grants that fund another $750K and are restricted to Phase I recipients. The SBIR is a setaside program that requires NIH and other funding agencies to allocate 2.5% of all externally funded research into this program.
Seems GENR is putting its cash into AMD and looking for outside help on some of its more longer-term R&D efforts. It is good to see further development in this area with significant potential payoffs down the road from GENR's IP on this.
wc21
>> Can anything about the progress of the other phase 2 clinical trials be deduced by virtue of the fact that GENR has started the last phase 2 trial? <<
The 10 mg dose was added based on initial results of the other phase 2 trials. One can reasonably infer some of the early phase II data indicate efficacy at the 10 mg level. Lower doses minimize systemic side effect concerns and also lessen the amount of squalamine needed for phase III trials...
wc21
Research Article Relating IL-9 promotion by Epstein-Barr Virus
It appears that Epstein-Barr Virus promotes growth of infected T cells through increased IL-9 expression. Of particular interest are the data that provide evidence of IL-9 anitbody inhibiting the growth of EBV-infected T cells.
GENR's IL-9 IP claims are for treating patients with asthmatic symptoms; not sure if it would cover this application???
wc21
"From Cancer Research 64, 5332-5337, August 1, 2004]
© 2004 American Association for Cancer Research
Epstein-Barr Virus (EBV)-Encoded RNA Promotes Growth of EBV-Infected T Cells through Interleukin-9 Induction
Lixin Yang1, Katsuyuki Aozasa2, Kazuo Oshimi3 and Kenzo Takada1
1 Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; 2 Department of Pathology, Osaka University Medical School, Suita, Japan; and 3 Division of Hematology, Department of Medicine, Juntendo University School of Medicine, Tokyo, Japan
EBV associates with various T-cell-proliferating diseases such as chronic active EBV infection and nasal lymphoma. In contrast to B cells, which are highly susceptible to EBV infection in vitro, T cells are refractory to EBV infection in vitro, and it has been difficult to examine the effects of EBV infection on T cells. We recently generated EBV recombinants with a selectable marker, which made it possible to select EBV-infected cells even when the efficiency of infection was low. Using the recombinant virus, we found that a human T-cell line, MT-2, was susceptible to EBV infection, and we succeeded in isolating EBV-infected cell clones with type II EBV latency, which was identical with those seen in EBV-infected T cells in vivo. EBV-infected MT-2 cell clones had shorter cell doubling times and higher saturation density than non-EBV-infected counterparts. We found that EBV-positive MT-2 cells expressed higher levels of interleukin (IL)-9 than EBV-negative MT-2 cells at the transcriptional level. It was also demonstrated that EBV-encoded small RNA was responsible for IL-9 expression. Addition of recombinant IL-9 accelerated the growth of MT-2 cells, whereas growth of the EBV-converted MT-2 cells was blocked by treatment with an anti-IL-9 antibody. These results suggest that IL-9 induced by EBV-encoded small RNA acts as an autocrine growth factor for EBV-infected T cells. Analysis of nasal lymphoma biopsies indicated that three of four specimens expressed IL-9. The present findings suggest that EBV directly affects the pathogenesis of EBV-associated T-cell diseases."
HCLCA1 Expression in CF lungs associated with mucus overproduction.
Recent research article highlights the role of IL-9 in upregulating the calcium activated chloride channel and mucus overproduction in patients with cystic fibrosis.
Eur Respir J. 2004 Jun;23(6):846-50
Hauber HP, Tsicopoulos A, Wallaert B, Griffin S, McElvaney NG, Daigneault P, Mueller Z, Olivenstein R, Holroyd KJ, Levitt RC, Hamid Q. Meakins-Christie Laboratories, McGill University, Montreal, Canada.
Abstract
"Mucus overproduction is typical in cystic fibrosis (CF) airway disease. The human calcium-activated chloride channel, hCLCA1, has been reported to be upregulated by interleukin (IL)-9 and to regulate the expression of mucins. Therefore, the expression of IL-9, IL-9 receptor (IL-9R) and hCLCA1 between the lungs of CF patients and healthy control subjects was compared. Endoscopic biopsy samples of bronchial mucosa from 10 CF patients and six control subjects were stained with periodic acid-Schiff. IL-9, IL-9R and hCLCA1 expression was determined by immunocytochemistry. Expression of hCLCA1 mRNA was also determined by in situ hybridisation. The present study found significant increases in IL-9, IL-9R and hCLCA1 immunoreactivity, hCLCA1 mRNA expression, and numbers of mucus-producing cells in the mucosa of CF patients compared to control subjects. Positive correlations were found between IL-9R-positive-cells with IL-9-positive cells and hCLCA1-positive cells, and between PAS-positive cells with hCLCA1-positive cells and IL-9R-positive cells. Expression of hCLCA1 mRNA was colocalised with IL-9R expression and PAS-positive staining in epithelial cells. Increased expression of interleukin-9 and interleukin-9 receptor, as well as an upregulation of the human calcium-activated chloride channel, hCLCA1, in mucus-producing epithelium of cystic fibrosis patients, support the hypothesis that interleukin-9 contributes to mucus overproduction in cystic fibrosis airway disease."
wc21
Recent research article on new roles of IL-9..
"Lymphomagenesis, Hydronephrosis, and Autoantibodies Result from Dysregulation of IL-9 and Are Differentially Dependent on Th2 Cytokines1"
http://www.jimmunol.org/cgi/content/abstract/173/1/113?ct
Angus J. Lauder*, Helen E. Jolin*, Philippa Smith*, José G. van den Berg, Alison Jones*, William Wisden2,*, Kenneth G. C. Smith, Ayan Dasvarma*, Padraic G. Fallon and Andrew N. J. McKenzie3,*
* Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom; Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands; Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom; and Immunomodulation Group, Department of Biochemistry, Trinity College, Dublin, Ireland
"Interleukin-9 is an immunoregulatory cytokine implicated in the development of asthma and allergy. To investigate the role of IL-9 in vivo, we have generated transgenic mice in which IL-9 is expressed from its own promoter. Strikingly, overexpression of IL-9 resulted in premature mortality associated with a complex phenotype characterized by the development of autoantibodies, hydronephrosis, and T cell lymphoma. By intercrossing IL-9 transgenic mice with a panel of Th2 cytokine-deficient mice, we demonstrate that these disorders represent distinct phenotypes that can be dissociated by their differential dependence on Th2 cytokines. Autoantibody production was ablated in IL-9 transgenic animals with a combined absence of IL-4, IL-5, and IL-13, coincident with a reduction in peritoneal B-1 cells. Hydronephrosis arose in 75% of IL-9 transgenic animals and was dependent on the presence of IL-4 and IL-13. In contrast, T cell lymphomas developed independently of the other Th2 cytokines, with the generation of rapidly proliferating CD8+ or CD4+CD8+ T cell clones that arose in the thymus before infiltrating both lymphoid and nonlymphoid tissues. Our data highlight potentially important new roles for IL-9, through its regulation of downstream Th2 effector cytokines, in autoantibody production and in hydronephrosis."
wc21
Combination Drugs Extending Patents for Big Pharma. Here is an interesting article in the current issue of Modern Drug Discovery (subscription freely available; MDD is well worth the time to read).
With the patent issued yesterday, perhaps there is a play for Lomucin to be tested and used as a combination partner.
wc21
http://pubs.acs.org/subscribe/journals/mdd/v07/i05/pdf/504news.pdf
"Two in one
Norvasc and Lipitor are both blockbuster drugs made by Pfizer, one for high blood pressure and the other for high cholesterol, respectively. They now have something else in common—namely, a home in each pill of Caduet, one of Pfizer’s newest products approved by the FDA.
Caduet—a combination of amlodipine besylate and atorvastatin calcium, the active ingredients of Norvasc and Lipitor—is being billed as “the first medicine to treat two different conditions in one pill.” “By treating both conditions at the same time, physicians can help patients reduce their risk of developing cardiovascular disease,” says Joe Feczko, Pfizer president of worldwide development. In clinical trials of 1600 subjects, about 57% reached both the blood pressure and cholesterol targets for their age. Pfizer points out that the same treatment goals are met by only 10% of the 30 million Americans with both of these conditions.
Caduet’s impact on preventing heart disease remains to be seen. However, the drug’s entrance into the market will certainly give Pfizer more economic mileage from its block-busters. Although patents on Norvasc are to expire in 2007, the new combination product will have patent protection until 2018. Eli Lilly recently made a similar move with Symbyax, which entered the U.S. market in January. The drug pairs Zyprexa and Prozac—the latter of which lost its patent protection several years ago. Lilly is promoting the drug as the first medicine to treat depression associated with bipolar disease. Another drug that may soon emerge on the U.S. market (it was recently approved in Mexico) brings together not only two medicines but also two companies. Merck and Schering-Plough have submitted a New Drug Application for Vytorin, which contains Zocor, Merck’s high-selling cholesterol-lowering statin that faces likely generic competition in 2006, and the newer intestinal cholesterol absorption inhibitor Zetia, developed by Schering-Plough and co-marketed with Merck. Zetia has been shown to substantially augment statins’ cholesterol-lowering activity.
Combination drugs are not a completely new concept. But according to a recent report from Cutting Edge Information, $80 billion in blockbuster medicines will face patent expiration and generic competition by 2007. Seeking opportune drug pairings may be a new weapon in the arsenal to combat this threat.
—DAVID FILMORE
MAY 2004 MODERN DRUG DISCOVERY
2004 AMERICAN CHEMICAL SOCIETY
Today's patent portends the use of Lomucin in combination with other treatments. While the patent issued today is more limited than the original application; it appears to primarily focus on IP rights for Lomucin and other 2-amino phenyl acetic acid compounds. The original application proposed a much broader range of molecular structures.
The "meat" of a patent lies in the claims section. What is interesting from today's patent are new claims that were not included in the original application that stake GENR rights for use of Lumucin and related structures to be used IN COMBINATION with other agents for a broad range of applications.
"52. A method of claim 1, wherein the composition is administered in combination with a second agent for the treatment of any of the diseases listed in claims 6 to 14.
{Note: Claims 6-14 include 6-asthma, 7-bronchitis, 8-chronic bronchitis, 9-cystic fibrosis, 10-emphysema, 11-gastrointestinal malabsorption syndrome, 12-steatorrhea, 13-diarrhea and 14-allergic inflammation]
53. A method of claim 52, wherein the second agent is selected from the group consisting of expectorants, mucolytics, antibiotics, antihistamines, steroids, anti-inflammatory agents, and decongestants.
54. A method of claim 52, wherein the second agent is a beta receptor agonist.
55. A method of claim 52, wherein the second agent is a steroid.
56. A method of claim 52, wherein the second agent is a leukotriene antagonist. "
I would not be surprised to see something soon on big pharma looking to test Lomucin in conjunction with other treatments. My guess is that GENR took steps with the USPTO to further solidify and broaden Lomucin rights now for this very reason and will continue working on gaining IP for other Mucin Inhibitor structures that were originally applied for. Given the safety profile of Lomucin, it appears that GENR is pressing forward on this front as well with their most mature products as Levitt as indicated.
The patent issued today appears to be a very positive development and further evidence of the behind-the-scenes actions that GENR has been taking to increase long-term shareholder value.
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GENR Issued Patent 6,737,427 Mucin synthesis inhibitors today.
This is the patent whose application has been on the USPTO website since December 2003. According to Levitt, a number of big pharma have been actively investigating this target.
Here are patent extracts:
"Abstract
The claimed invention relates to methods of modulating mucin synthesis and the therapeutic application of compounds in controlling mucin over-production associated with diseases such as chronic obstructive pulmonary diseases (COPD) including asthma and chronic bronchitis, inflammatory lung diseases, cystic fibrosis and acute or chronic respiratory infectious diseases.
"SUMMARY OF THE INVENTION
The current invention relates to the discovery of agents that inhibit the synthesis and over-production of mucin glycoproteins and methods of using these molecules to treat the pathologic over-production of mucus in chronic obstructive pulmonary disorders and other diseases.
In one aspect, the present invention provides a method of treating a subject with a respiratory disease characterized by the production of mucin, comprising administering to the subject an effective amount of a composition comprising at least one compound that decreases mucin synthesis or levels in the lungs or in the GI tract. In some embodiments, the mucin synthesis may be chloride channel dependent. In some embodiments, the compound decreases mucin synthesis in cells that express an ICACC chloride channel. In some embodiments, the compound is selected from a group consisting of analogues and derivatives of anthranilic acid, analogues and derivatives of 2-amino-nicotinic acid, analogues and derivatives of 2-amino-phenylacetic acid, bendroflumethiazide, salts thereof and prodrugs thereof. In some preferred embodiments, the compound is selected from the group consisting of talniflumate, flufenamic acid, niflumic acid, mefenamic acid, salts thereof, derivatives thereof and prodrugs thereof. In some preferred embodiments, the compositions of the present invention comprise talniflumate, a talniflumate derivative, a salt thereof or a prodrug thereof.
In some embodiments, the compositions of the present invention may comprise at least one compound that decreases mucin synthesis or levels in the lungs or in the GI tract wherein the compound is a quinoline or quinoline derivative. In some embodiments, the compound may be a quinoline modified with an amine group, preferably at the 2 or 3 position of the quinoline. In a preferred embodiment, the compound may be a 3-amino-quinoline in which the exocyclic nitrogen is modified with one or more moieties. In some embodiments, the exocyclic amine group may be modified with an aromatic moiety. The aromatic moiety may be modified or unmodified. In a preferred embodiment, the aromatic group is a benzyl group which may be modified with one or more substituents. Suitable substituents include, but are not limited to, halogens. In a preferred embodiment, the compound is an N-(fluorobenzyl)-3-amino-quinoline (FIG. 19), preferably the fluorine is in the meta position.
In another aspect of the present invention the compounds that decrease mucin synthesis are also inhibitors of the enzyme cyclooxygenase such as talniflumate. In a more preferred embodiment the compounds are specific inhibitors of the enzyme cyclooxygenase-2.
In another embodiment, the present invention provides a method of treating a subject with a respiratory disease characterized by the production of mucin by administering the compositions of the invention by inhalation. In some embodiments, the composition is in the form of a liquid or in the form of a powder. In some embodiments, the composition is aerosolized. In other embodiments, the composition further comprises at least one expectorant, antihistamine, mucolytic agent, antibiotic or decongestant agent. In some embodiments, the expectorant is guaifenesin. The compositions of the invention may further comprise at least one stabilizing agent, absorption-enhancing agent or flavoring agent. In some preferred embodiments, the stabilizing agent is cyclodextran and/or the absorption-enhancing agent is chitosan.
In some preferred embodiments, the compositions and methods of the present invention may be used to treat a respiratory disease selected from the group consisting of a chronic obstructive pulmonary disease (COPD), an inflammatory lung disease, cystic fibrosis and an acute or chronic infectious disease. The treatment of any one of these diseases may be by administering one or more of the compositions of the invention via inhalation. In some embodiments, the composition is administered via inhalation to the lungs. In preferred embodiments, the present invention provides methods and materials to treat a COPD selected from the group consisting of emphysema, chronic bronchitis and asthma.
In another preferred embodiment, the compositions and methods of the present invention may be used to treat the GI complications of cystic fibrosis such as malabsorption syndrome, steatorrhea and diarrhea. The treatment of this disease may be by administering one or more of the compositions of the invention orally.
In another embodiment, the present invention provides a therapeutic composition formulated for inhalation delivery comprising an amount effective to decrease mucin production or levels of at least one compound selected from the group consisting of talniflumate, flufenamic acid, niflumic acid, mefenamic acid, salts thereof, derivates thereof and prodrugs thereof. In some preferred embodiments, the composition comprises talniflumate, a talniflumate derivative, a salt thereof or a prodrug thereof. In some embodiments, the composition is in the form of a liquid or in the form of a powder. In some embodiments, the composition further comprises at least one expectorant, mucolytic agent, antibiotic, anti-histamine or decongestant agent. In some embodiments, the expectorant is guaifenesin.
In addition to the agents described above, the pharmaceutical compositions of the present invention formulated for inhalation may further comprise at least one stabilizing agent, absorption-enhancing agent or flavoring agent. In some embodiments, the stabilizing agent is a cyclodextran and/or the absorption-enhancing agent is chitosan.
The present invention also provides an inhalation device comprising a therapeutic composition as described above. "
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The GENR margin available today at $3.30 is 1/6 of what was recently available at the $4.80 share price for the many brokerage accounts serviced through National Financial Services (NFS) which allows margin borrowing against GENR for the portion of the share price over $3.
IMHO, part of the recent downward spiral is attributable to selling pressure from speculators who used margin to purchase a maximum number of GENR shares and now are having to sell.
The same thing appears to have happened in December.
wc21
Here is a link to Aciont's web site's pdf file that illustrates the Visulex system; the same figure is in the referenced DDT article. Apparently, the applicator is inserted under the lower eyelid during an office visit, electric current is run for 15-20 minutes, resulting in the drug being transferred from the applicator into the eye.
http://www.aciont.com/aboutvisulex.pdf
The drug being administered would need to be able to be administered in a charged state and be able to permeate outer eye membranes with electrical assistance.
The frequent of office visits would probably be similar to the frequency of eye injections required.
The Visulex drug delivery technology is a recent development for Aciont and they are targeting the need to eliminate eye injections in treating AMD and other BOTE diseases.
Visulex seems to be a technology that AMD competitors will "keep an eye on" and appears to be Aciont's major focus at the moment.
wc21
Iontophoretic Technology: Visulex(TM) for BOTE Noninvasive Therapeutics
The April 2004 issue of Drug Delivery Technology has an article about Aciont's Back of the Eye (BOTE) Noninvasive Drug Delivery Technology; the article was written by Aciont scientists.
Essentially Aciont has developed a drug applicator that easily slips into the lower cul-de-sac of the eye socket. This applicator is hooked via several electodes to a dosaging controller. A small electric current is applied to carry drugs, in the form of ions, through the tissue (iontophoretics). Administration appears to require 20 minutes at 3 mA for a surface contact area of 0.5 cm2. The article notes that human studies have shown that this electrical current and time did not adversely affect eye structure or function.
Data presented show the effectiveness of Visulex for delivering Dexamethasone disodium phosphate. Rabbits with experimentally induced uveitis (inflammation of the middle eye) were treated with both ocular injections and with the Visulex system. Both the Visulex and injections were effective treatments with the Visulex being slightly better.
The article highlights the risks associated with eye injections and the need for alternative delivery techniques.
Since squalamine has a charged site, I would expect that it could potentially be capable of being delivered via iontophoresis. The important question centers on the feasibility of Visulex for delivery of other antiangiogenics that are being developed to treat AMD.
Drug Delivery Technology apparently posts articles on their web site two months after issue. Subscriptions are free for many since this is a good way for companies to advertise what they are doing.
http://www.drugdeliverytech.com/cgi-bin/current_issue.cgi
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"Evidence-Based Medicine in Managed Care: A Survey of Current and Emerging Strategies"
Evidence-Based Medicine is a current hot topic in the field. Unfortunately, as noted below, most physicians practice "eminence-based medicine" instead of evidence-based medicine.
There is an excellent article on this just posted on Medscape.
http://www.medscape.com/viewarticle/470303
Some notable paragraphs:
"Evidence-based medicine is the "conscientious application of scientific best practice by clinicians in concert with patient understanding and values."[1] Recent studies by the Institute of Medicine, RAND, and others have called attention to the gap between scientifically supported approaches to care and day-to-day practice by clinicians."
"Large physician groups are using only one-third of recommended care-management processes for asthma, congestive heart failure, depression and diabetes. The four conditions account for about 140,000 deaths and more than $143 billion in costs each year in the U.S. Examining more than 1,000 physician groups with 20 or more doctors, researchers found that the groups on average employed 32% of 16 recommended care-management processes, including use of nurse care managers, development of disease registries and feedback to physicians on quality of care. Part of the problem is a lack of technology in doctors' offices and economic constraints limiting investments in electronic medical records. What's more, one in three physician groups reported having no incentives to improve quality. The results suggest that Americans are not receiving care that is as good as it could and should be."[7]
The late John Eisenberg,[8] former Executive Director of the Agency for Healthcare Research and Quality, concluded that physicians practice "eminence-based medicine" instead of evidence-based medicine. He noted that the root cause for widespread variation in practice patterns from community to community is physician reluctance to incorporate evidence-based guidelines in their practices.
"Indeed, there is sufficient evidence to suggest that most clinicians' practices do not reflect the principles of evidence-based medicine but rather are based upon tradition, their most recent experience, what they learned years ago in medical school or what they have heard from their friends. The average physician is said to read scientific journals approximately two hours a week and most are likely overwhelmed by the volume of material confronting them."[8]
There are 2 problems: the gap between knowledge and practice is significant, and physicians do not routinely adhere to evidence-based guidelines when known."
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"It’s disheartening to think of all the scientific discoveries that weren’t made on account of such groupthink."
I think groupthink leads to delay in making many discoveries rather than discoveries not being made at all; discovery is inevitable. The adverse consequences of these delays are indeed unfortunate, particularly for those in need of timely progress.
Stem cell research is a related area of concern where unnecessary delays in biomedical research progress in this country will undoubtedly occur as a result of current policies being implemented.
wc21
The Emperor of Scent is an Excellent Read on This Issue
"Whenever you have a field with limited funding, and a small number of people with big egos who have everything invested in one idea, you have the right chemistry for one theory to become so pervasive nothing else can flourish." Khachaturian added that the dominance of the amyloid hypothesis and the strangling of alternatives was "one of the most important issues in science today."
Over the last decade, Luca Turin has resurrected the vibrational theory of how we smell and presented overwhelming evidence of its validity. The recent book "Emperor of Scent" is a very well-written and fascinating summer beach read on Luca Turin's experiences. It points to the very same obstacle in science that people developing alternative treatments for AD are facing.
This clearly shows the frailty of human nature and how it so often hampers progress in science [and business]. Luca Turin has done work deserving of a Nobel, but unfortunately, won't be receiving an invitation to Stockholm.
wc21
Scirus Outstanding Find--Thanks Dew!! This is much better than Google and worth it while still free...
Elsevier journal prices are ridiculously high and way above industry norms. UC Berkeley has curtailed a lot of their business with Elsevier and just went through a major renegotiation with them in December.
Journal publishing is a multibillion $$ business. Universities provide intellectual content, peer reviews, and editorship for free and then have to pay big $$ to get back what they have collectively given. Journal prices are rising at 2-3 times the CPI. All of this is driving much-needed change toward more open literature access and more cost-effective uses of library resources that will be the inevitable result.
wc21
"Another view of Alzheimers treatment and other AD info
Dew, thanks for the post; another view I recently found highlighted the need to lengthen current AD treatments:
In the US, the average total duration of treatment with a ChE inhibitor [the standard treatment for AD]is less than 200 days,[1] which is of concern given the fact that the disease course of AD lasts for approximately 7-10 years.[2]"
[From "Strategies for Continued Successful Treatment of Alzheimer's Disease: Switching Cholinesterase Inhibitors," Curr Med Res Opin 19(8):707-714, 2003]
From another recent source,
"If we can delay the onset of AD by five years, we can cut the rate of incidence in half."
This link has good background info on AD:
http://www.lef.org/magazine/mag2001/sep2001_report_alzheimers_01.html
Here are two links that provide extensive recent data on various treatments. Rivastigmine has been shown to inhibit both AChe and Butylcholinesterase (BChe); the latter increases during AD progression and this is the only AChe inhibitor that works on both. The data show that rivastigmine delays AD symptoms by 12-18 months.
http://www.medscape.com/viewprogram/2914_pnt
http://www.medscape.com/viewprogram/2915_pnt
AD occurrence is associated with amyloid plaque formation; the jury still appears to be out on whether the protein plaques are causes or effects. To date there has been limited success with beta and game secretase inhibitors to slice Amyloid Precursor Protein (APP) to prevent plaque formation. Here is a excellent message link with an good description of active work in this area
http://www.siliconinvestor.com/stocktalk/msg.gsp?msgid=19666350
wc21
Mucin inhibitor patent has not yet been issued
"This is the mucin inhibitor patent that Dr. Levitt has been hoping to get, I believe."
Actually, the mucin inhibitor patent has not yet been issued; the patent application for the mucin inhibitor was posted on the USPTO site this past Christmas. (application 20030236220 Zhou, Yuhong ; et al. December 25, 2003).
Today's patent had Holroyd as the first author and appears to be related to Patent 6,576,434 "Methods for identification of agents which modulate chloride channel activity" issued last summer; Holroyd was also the first author on that one. The focus seems to be related to genetic predisposition to asthma.
Thanks for the info on Takeda and Merck's interest; in light of your comments on Cortex, what value would you place on the mucin inhibitor part of GENR?
TIA
wc21
Safety of an Intravitreal Injection of Triamcinolone
This abstract summary was included in the just released MEDSCAPE weekly newsletter and discusses the safety of performing intravitreal injections.
From the summary below:
-32 patients (out of 75) developed increased intraocular pressure (IOP) in the treatment arm vs 3 (out of 75) in the control group
-21 members of the treatment arm required medical treatment with glaucoma drops.
-there was an increased rate of cataract formation in the treatment arm (16 vs 2 patients) at 12 months.
Safety of an Intravitreal Injection of Triamcinolone: Results From a Randomized Clinical Trial
Gillies MC, Simpson JM, Billson FA, et al
Archives of Ophthalmology. 2004;122(3):336-340
The Intravitreal Triamcinolone Study was designed to evaluate the efficacy of a single, intravitreal dose of triamcinolone (4 mg) for reducing vision loss in classic neovascular age-related macular degeneration. This report discussed the safety of performing intravitreal injections. A total of 151 patients were randomized to receive either triamcinolone or placebo. There were no severe adverse events reported with the procedure. However, 32 patients developed increased intraocular pressure (IOP) in the treatment arm vs 3 in the control group; 21 members of the treatment arm required medical treatment with glaucoma drops. In addition, there was an increased rate of cataract formation in the treatment arm (16 vs 2 patients) at 12 months. Despite the risk of IOP rise and cataract formation, the authors were encouraged by the safety results of the trial. They noted that vigilant follow-up and treatment, as needed, were required. CRB
wc21
Assignees can decide whether a patent application is posted on the USPTO site prior to issuance of a patent. In the case of the Mucin inhibitors, they apparently wanted to advertise this target, since a number of big pharma are working in this area and GENR is interested in licensing to them.
The drawback in publicly posting an application before a patent is issued is that it makes potential competitors aware of new ideas and new developments earlier. There is also the risk of the patent application being turned down.
Since today's issued patent appears to be a subset of an earlier patent, my guess is that there was no incentive to have this application posted. Another possibility is that GENR does not plan on any near-term major initiatives in this area with currently available resources.
wc21
GENR Patent "Nucleic acids encoding a chloride channel protein," Patent number 6,716,603, April 6, 2004
GENR has been issued a new patent; note that Holroyd is the first author...the application for this patent was never posted on the USPTO site as others such as the Mucin Inhibitor patent application that GENR has been discussing recently.
The issued patent is apparently a "divisional application" of patent Number 6,576,434 "Methods for identification of agents which modulate chloride channel activity" that was issued June 10, 2003. The patent centers on a chloride channel gene that is apparently upregulated by IL-9.
Inventors: Holroyd; Kenneth J. (Plymouth Meeting, PA); Levitt; Roy C. (Plymouth Meeting, PA); Maloy; W. Lee (Plymouth Meeting, PA); Louahed; Jamila (Plymouth Meeting, PA); McLane; Mike (Plymouth Meeting, PA); Nicolaides; Nicholas C. (Boothwyn, PA); Zhou; Yuhong (Plymouth Meeting, PA); Dong; Qu (Dresher, PA)
Assignee: Genaera Corporation (Plymouth Meeting, PA)
Appl. No.: 270595
Filed: October 16, 2002
"Abstract
A new gene in the calcium-activated chloride channel family has been discovered that is induced by IL-9, thereby providing a therapeutic target in IL-9 mediated development of atopic allergy, asthma-related disorders and cystic fibrosis. A method for the identification and use of small molecule inhibitors of this gene and its products to treat these disorders has also been discovered. The invention also includes a method for diagnosing susceptibility to, and assessing treatment of atopic allergy, asthma-related disorders by measuring the level of gene expression in biologic samples using antibody specific for this protein. "
"This is a divisional application of U.S. Application 09/623,624 (filed Feb. 13, 2001) now U.S. Patent No. 6,576,434 which is a U.S. National Phase Application of International Application PCT/US99/04703 (filed Mar. 3, 1999), which claims the benefit of U.S. Provisional Application 60/076,815 (filed Mar. 3, 1998), all of which are herein incorporated by reference in their entirety."
wc21
Glad to see GENR bringing on board technical expertise in this area and significantly ramping up R&D expenditures during the fourth quarter to get things moving.
The "Acting Capacity" hints of a temporary arrangement, perhaps until the closing of a deal later this year.
While the IL9, MSI1436, and chloride channel IP have significant potential, all will require significant capital, time, and involve increased technical risk. The moves today appear to reflect these realities in light of available resources.
Funding gained from success with squalamine and AMD would result in GENR being in a position to retain a greater fraction of future revenues from success in any of these other areas.
Overall, today's developments appear to be positive for shareholders and provide evidence of management making necessary decisions to increase the value of the company.
wc21
Patent Application for Selective PDE-IV inhibitors for AMD was just published March 18, 2004 for an application (20040053939) that was filed in September 2003. The applicants are: Gamache, Daniel A.; (Arlington, TX) ; Bingaman, David P.; (Fort Worth, TX) ; Kapin, Michael A.; (Arlington, TX). [Gamache published an article in 1998 that showed he was working for Alcon at the time].
The main thrust of this application appears to be to treat AMD by using PDE-IV inhibitors to prevent neovascularization in posterior of the eye. Highlighted is the feasibility of administration of PDE-IV inhibitors either orally or via IV.
The application notes that:
"No strictly pharmacologic treatment has been approved for use against posterior segment NV, although several different compounds are being evaluated clinically, including, for example, anecortave acetate (Alcon Research, Ltd.), Macugen (Eyetech/Pfizer), Lucentis (Genentech/Novartis), squalamine (Genaera), and adPEDF (GenVec) for AMD and LY333531 (Lilly) and Fluocinolone (Bausch & Lomb) for diabetic macular edema."
Here is some other info from the application
SUMMARY OF THE INVENTION
[0011] The present invention is directed to the prevention and treatment of diseases and disorders of the eye involving angiogenesis and edema, using PDE-IV inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
[0012] Posterior segment neovascularization is the vision-threatening pathology responsible for the two most common causes of acquired blindness in developed countries: exudative age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR). Currently the only approved treatments for posterior segment NV that occurs in exudative AMD is laser photocoagulation or photodynamic therapy with Visudyne.RTM.; both therapies involve occlusion of affected vasculature which results in localized laser-induced damage to the retina. Surgical interventions with vitrectomy and membrane removal are the only options currently available for patients with proliferative diabetic retinopathy. No strictly pharmacologic treatment has been approved for use against posterior segment NV, although several different compounds are being evaluated clinically, including, for example, anecortave acetate (Alcon Research, Ltd.), Macugen (Eyetech/Pfizer), Lucentis (Genentech/Novartis), squalamine (Genaera), and adPEDF (GenVec) for AMD and LY333531 (Lilly) and Fluocinolone (Bausch & Lomb) for diabetic macular edema.
[0013] In addition to changes in the retinal microvasculature induced by hyperglycemia in diabetic patients leading to macular edema, proliferation of neovascular membranes is also associated with vascular leakage and edema of the retina. Where edema involves the macula, visual acuity worsens. In diabetic retinopathy, macular edema is the major cause of vision loss. Like angiogenic disorders laser photocoagulation is used to stabilize or resolve the edematous condition. Unfortunately, laser photocoagulation is a cytodestructive procedure, that while preventing further edema to develop, will alter the visual field of the affected eye.
[0014] An effective pharmacologic therapy for posterior segment NV and edema would likely provide substantial efficacy to the patient, thereby avoiding invasive surgical or damaging laser procedures. Effective treatment of the NV would improve the patient's quality of life and productivity within society. Also, societal costs associated with providing assistance and health care to the blind could be dramatically reduced.
[0015] This invention applies to inhibitors of the PDE type-IV enzyme with the primary biological effect being suppression of NV. Selective inhibitors of the PDE type-IV enzyme are preferred. As used herein, "selective PDE-IV inhibitor" means a non-steroid compound that selectively inhibits type IV phosphodiesterase enzyme activity (relative to activities of other types of phosphodiesterase enzymes). As used herein, a compound that selectively inhibits type IV phosphodiesterase enzyme activity is a compound that is at least ten times more potent at inhibiting type IV phosphodiesterase enzyme activity than any other type of phosphodiesterase enzyme activity. Preferred PDE-IV inhibitors for use in the present invention are at least one thousand times more potent at inhibiting type IV phosphodiesterase enzyme activity than any other type of phosphodiesterase enzyme activity.
[0016] Selective PDE-IV inhibitors are known. Examples of selective PDE-IV inhibitors useful in the methods of the present invention include, but are not limited to: 2-(4-ethoxycarbonylaminobenzyl)-6-(3,4-dimethoxypheny- l)-2,3,4,5-tetrahydro-pyridazin-3-one and the related compounds disclosed in EP 0 738 15; 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino)-8-i- sopropyl-3H-purine hydrochloride (also known as V-11294A) and the related compounds disclosed in WO 96/00218; 8-methoxyq\uinoline-5-[N-(2,5-dichloro- pyridin-3-yl)]carboxamide (also known as D-4418) and related compounds disclosed in WO 96/36595; the compounds disclosed in U.S. Pat. No. 5,605,914; cipamfylliine (also known as BRL-61063); ariflo (also known as SB-207499); and compounds disclosed in WO 99/50270.
[0017] According to the methods of the present invention, a composition comprising one or more selective PDE-IV inhibitors and a pharmaceutically acceptable carrier for systemic or local administration is administered to a mammal in need thereof. The compositions are formulated in accordance with methods known in the art for the particular route of administration desired.
[0018] The PDE-IV inhibitors of the present invention can be administered either systemically or locally. Systemic administration includes: oral, transdermal, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal. Preferred administration is oral. Local administration for ocular administration includes: topical, intravitreal, periocular, transcleral, retrobulbar, sub-tenon, or via an intraocular device.
wc21
Today's news seems to be a positive long-term development. I am glad to see GENR's continued partnership with Ludwig, since they have so much technical expertise in this area.
Ludwig also recently (Nov 11, 2003) was awarded a patent for IL-9 conjugates (6,645,486).
"The methods of this invention relate to immunizing animals with conjugates of cytokines and a carrier to induce a prolonged high titre antibody response specific for the cytokine."
It seems that GENR has been trying to obtain/license IP outside of the MEDI agreement for some time; my guess because of the greater long-term profit potential and interest.
There are also questions in the literature--that have not been answered in subsequent articles--on the effectiveness of treating asthma by targeting only IL-9. Success will likely require going after multiple targets simultaneously. It seems that Ludwig may be well suited for this.
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"When a company argues that a compound has a lot of potential but they aren’t willing to spend their own money to develop it, I have to wonder."
I agree, perhaps this is a case of financial resources and priorities, with AMD getting the initial focus. Same issue with trodulamine; no resources being dedicated in this area. Are there technical risks too great, or is the plan to use AMD development to generate funding for future work in these areas.
"If we are talking about a drug target as opposed to a compound, there may be some value along the lines you outlined. But targets by themselves do not generally command large sums of money in the licensing game. "
From the patent application, GENR is trying to obtain IP on the target and a fairly wide range of molecular structures that may be used for mucus inhibition. If any of these compounds end up in clinical use, the potential market is large. I don't have a good feel for other potential mucus inhibitors being developed. This area has been a particular interest of Levitt for over a decade.
wc21
Dew, question on value of chloride channel inhibitors
"In (#msg-1981262), I placed a value of only $5M on GENR’s Lomucin program in CF. I’m now inclined to revise that valuation downward to zero."
Dew, it seems that the chloride channel inhibitors would merit some value, particularly if the IP application is approved in '04 as Levitt seems to think. He has referred to a number of pharma developing candidate structures for this target and the possibility of licensing this target.
Since this is downstream of IL-9, perhaps mucus inhibition would be an alternative treatment for the medical conditions targeted by IL-9 antibodies, or a combination (IL-9 antibodies as antihistamine, chloride channel inhibitors as decongestants...)
Would be interested in your thoughts on potential value of this area. This seems a short term, very possible, realization.
Thanks,
wc21
NHE Inhibitors Patent Application Includes MSI 1436 United States Patent Application 20030149287
Here is another submitted GENR patent application that was published in August 2003 and originally filed in November 2001. It involves the use of aminosterols as sodium-proton exchange (NHE) inhibitors to include squalamine and MSI1436 (trodulamine). There are a series of NHE''s. Apparently squalamine acts to inhibit NHE3, while MSI-1436 uniquely affects NHE5.
The application provides some useful information on this mechanism of action for squalamine, the combined use of squalamine and trodulamine for antoangiogenesis, MSI-1436 for growth inhibition (weight gain), anti-viral therapy, treatment of diabetes, and lowering of blood pressure. While these patent applications try to cover as much as possible, MSI 1436 seems to show as much long-term promise as squalamine.
I have extracted some of the interesting paragraphs, there are many more worth reading. To access the application use this number: "20030149287" at this link:
http://appft1.uspto.gov/netahtml/PTO/srchnum.html
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{0225] Aminosterol compounds such as squalamine have been discovered to be effective inhibitors of NHE. In seeking to elucidate the antimicrobial mechanism of action for squalamine, squalamine has been found to advantageously inhibit a specific NHE isoform--the compound inhibits NHE3, but not NHE1. In addition, squalamine has been determined to inhibit the exchanger through a special mechanism. The special and advantageous effects and utilities of squalamine and other aminosterols are further evident from the results of the experimental tests discussed below.
[0276] As demonstrated by the experiments described above, squalamine provides a potent inhibitor of NHE3. Squalamine therefore should provide invaluable therapeutic intervention wherever new blood vessel formation in vivo is implicated.
[0277] Indeed, any pathological processes dependent on new blood vessel formation can be treated through inhibition of NHE3. As an agent that interferes with the process of neovascularization, squalamine has therapeutic utility in the treatment of diseases or disorders dependent on continued neovascularization where interruption of neovascularization diminishes the intensity of the pathological process. Thus, squalamine has utility for treating disorders including solid tumor growth and metastasis, rheumatoid arthritis, psoriasis, diabetic retinopathy, macular degeneration, neovascular glaucoma, papilloma, retrolental fibroplasia, and organ rejection.
[0311] Synergistic Inhibition of Tumor Growth
[0312] Based on the idea that tumor growth involves both the clonal expansion of a malignant cell along with the development of a supporting vascular supply, a combination of compound 1436 with squalamine was tested to determine whether it would achieve a synergistic effect on solid tumor growth. This concept was evaluated in the B16 melanoma model.
[0313] Animals were implanted with B16 melanoma followed by treatment with compound 1436 or 1256 administered in a combined schedule or separately. As apparent from FIG. 12, when squalamine was administered at 5 mg/kg/day or compound 1436 was administered at 10 mg/kg/every 3 days, no significant impact on tumor volume was observed. In contrast, when both agents were administered together, a significant reduction in tumor growth was noted. Neither administration of squalamine at 15 mg/kg/day nor compound 1436 alone in a tolerable schedule could achieve this effect. Thus, a combination of these two compounds achieves a therapeutic benefit in tumors dependent on neovascularization that may prevent metastatic spread.
[0314] Effect of Aminosterols on Lymphotropic Viruses
[0315] Since compound 1436 inhibits the PHA-stimulated proliferation of human T cells and controls the proliferation of a lymphoblastic leukemia in mice without unfavorable toxicity as shown above, it seemed a reasonable candidate for evaluation in vitro as an inhibitor of HIV. PHA-stimulated lymphocytes were inoculated with a clinical isolate of HIV at a multiplicity of infection of 10. Fresh lymphocytes were obtained and stimulated with PHA and IL-2. After 3 days, 1000 TCID of virus-(HIV clinical isolate) were applied for 1 hour and there was a M.O.I. of 1:10. The cells were washed and in a dose response fashion, and drug in media was applied. After 3 days, the supernatant was exchanged with 1/2 volume of fresh media and 1/2 the volume of fresh drug. After 7 days, detergent was added, and HIV P-24 Antigen was determined by Elisa. Viability of the lymphocytes was evaluated along with appearance of the viral gene product p24. [0316] As seen above, at 10 .mu.g/ml compound 1436 effectively inhibited antigen synthesis by 97%, while retaining lymphocyte viability to 95%.
[0317] The above experiments clearly support the utility of compound 1436 in the treatment of lymphotropic viral diseases. Based on these studies, the identification of the specific NHE inhibitors of specific cellular targets of specific virus should permit the rational development of an effective antiviral therapy for a given infectious agent. Thus, the NHE inhibitor from the aminosterols that acts on the respiratory epithelial cell should be effective in the treatment of respiratory viruses which propagate on these cells, such as Herpes, influenza and RSV. The concept can be generalized to viruses infecting the CNS (herpes) and liver (hepatitis). The approach prevents infection by the virus of the cellular target by preventing activation of the cellular NHE, required for cellular proliferation and effective intracellular
viral multiplication.
[0318] Effect on Insulin Secretion
[0322] As apparent from the data above, blood glucose levels were elevated between 2-3 fold normal after administration of these steroids. The fasting blood glucose of Group 2 was significantly elevated compared to Group 1 (p<0.05). The fasting blood glucose of Group 4 was significantly elevated compared to Group 1. Thus, it appears that the intravenous administration of compound 1436 in D5W (5% glucose) or compound 1437 in water caused hyperglycemia in mice. It is assumed that the observed hyperglycemic response results from inhibition of insulin secretion, as suggested from basic physiological principles. Thus, the long-term chronic administration of a compound such as compound 1436 may be of value in preventing or delaying the onset of both Type I and Type II diabetes.
[0326] Effect on Growth and Weight Gain
[0327] During evaluation of the physiological effects of compound 1436 in normal growing mice, it became evident that this steroid suppresses both linear growth and weight gain in growing mice in a dose-dependent fashion. Animals were dosed QTD (i.p.) starting on Day 1. FIG. 16 shows that C57B mice treated with 10 mg/kg, QTD i.p., 5 mg/kg QTD i.p., and 1 mg/kg QTD i.p. exhibited a dose dependent reduction in growth. After 6 doses, growth of the animals receiving 10 mg/kg QTD had been suppressed to a degree that growth was almost completely inhibited over about 1 month from the initiation of treatment. Animals receiving 5 mg/kg QTD experienced about a 50% reduction in growth, compared to untreated controls, while animals receiving 1 mg/kg QTD were affected by about 10%. Striking was the apparent health of the treated animals--all were active, normally proportioned, not-cachectic, and in excellent apparent clinical health. They appeared very much like hypophysectamized animals might appear.
[0328] Compound 1436 clearly inhibits the growth of many different types of cell and tissue and this, to some extent, explains the profound suppression of growth observed. However, the extraordinary good health of these animals suggests that an additional mechanism must be involved--one involving inhibition of pituitary function. Compound 1436 is believed to partially inhibit secretion of anterior pituitary hormones, resulting in the observed growth suppression.
[0329] This property of compound 1436, regardless of its precise mechanism, suggests that it can produce an unprecedented form of antiproliferative effect when administered to an animal. It will not only inhibit growth-factor induced cellular proliferation by acting on the proliferating cell, but also inhibit growth-promoting hormone secretion at a central, endocrine level. Thus, compound 1436 places the animal in a "growth-inhibited" state. In such a state, malignant cells will not receive optimal exogeneous hormonal stimulation from hormones such as growth hormone, and perhaps LH and FSH. Secretion of hormones such as estrogen and progesterone, as well as insulin, are likely to be dysregulated. Virally infected cells will be placed under physiologically unfavorable conditions, and the efficiency of viral infection should be dramatically reduced. Immunologically foreign cells, suppressed in growth, should be cleared by existing immune systems, now giving a chance to catch up kinetically to these "foreign" cells.
[0330] Effect on Arterial Resistance
[0331] Compound 1436 has also been found to reduce arterial resistance in the rat after intravenous(i.v.) administration. A 200-g rat was catheterized in the right carotid artery, and the compound was introduced over a ten-second period to a total dosage of 5 mg/kg. Within 30 seconds, the mean arterial pressure had fallen from about 100 mm Hg to about 70 mm Hg, with a marked reduction in pulse pressure from about 40 mm to about 10 mm. Despite the fall in blood pressure, no significant increase in heart rate was observed. If cardiac output was basically unaffected, reduction in blood pressure would have resulted principally from a reduction in system resistance.
[0332] The effect was followed for 30 minutes, without significant change. At that time, 40 .mu.g of noradrenaline was introduced. An almost immediate increase in blood pressure was observed, with an associated increase in pulse pressure. This data demonstrate that the effect of compound 1436 is readily reversible by standard pharmacological practice.
[0333] The ability of compound 1436 to reduce arterial resistance and arterial blood pressure indicates its application as an antihypertensive agent. Because it does not appear to induce a compensatory tachycardia, the net effect is to reduce cardiac afterload. A physiological consequence of this type of cardiovascular effect would be to slow the process of cardiac hypertroph and arteriolar smooth muscle proliferation. Because of these properties, compound 1436 should be an effective treatment of congestive heart failure, where reduction in afterload would be desired. Its rapidity of action and ready reversibility, along with minimal tachycardic effect, make the compound a valuable therapeutic agent.
MUCIN SYNTHESIS INHIBITORS Patent Application Pub Dec 25, 2003.
20030236220
This is the first info I have found on the chloride channel mucous inhibitors that Levitt has been discussing since the November WSJ interview. Apparently they initially filed this in Nov 2002 and the application was just posted on the USPTO.
Here is the abstract:
"The claimed invention relates to methods of modulating mucin synthesis and the therapeutic application of compounds in controlling mucin over-production associated with diseases such as chronic obstructive pulmonary diseases (COPD) including asthma and chronic bronchitis, inflammatory lung diseases, cystic fibrosis and acute or chronic respiratory infectious diseases."
Levitt has been predicting obtaining IP on this in '04 and licensing it to big pharma; apparently a number of companies are already investigating this target.
wc21