GSK+MNKD: PAH Flolan, Migrained Imitrex, Antiematic Zofran
Oct 9, 2015 20:43:08 GMT -5
zieg, mapotofu10, and 14 more like this
Post by lakers on Oct 9, 2015 20:43:08 GMT -5
GSK Likely partners w/ Mnkd for PAH Flolan, Migrained Imitrex, Antiematic Zofran, Hemorrhage Oxytoxin, Oebesity Oxyntomodulin
5 drugs GSK could license TS for to defend its blockbuster franchises. Great synergy between GSK and Mnkd!
Dr Shannon, GSK CMO joining Mnkd BoD, retired from GSK April 2015 possibly to avoid conflict of interest during negotiation.
1. Blood vessel dilators (vasodilators). Vasodilators open narrowed blood vessels. One of the most commonly prescribed vasodilators for pulmonary hypertension is epoprostenol (GSK's Flolan). The drawback to epoprostenol is that its effects last only a few minutes. This drug is continuously injected through an intravenous (IV) catheter via a small pump that you wear in a pack on your belt or shoulder. This means that you'll learn to prepare your own medication mixture, operate the pump and care for the IV catheter. You'll need comprehensive follow-up care. Potential side effects of epoprostenol include jaw pain, nausea, diarrhea, leg cramps, as well as pain and infection at the IV site.
Another form of the drug, iloprost (Ventavis), avoids many of these problems. Iloprost can be inhaled every three hours through a nebulizer, a machine that vaporizes your medication, making it far more convenient and less painful to use. And because it's inhaled, it goes directly to the lungs. Side effects associated with iloprost include chest pain — often accompanied by headache and nausea — and breathlessness.
2. Off-patent Immitrex (Sumatriptan) for Migraine.
Method and composition for treating migraines
US 8785396 B2
www.google.com/patents/US8785396
Abstract
A method for treating migraines is disclosed. The method utilizes a rapid drug delivery system which prevents deactivation or degradation of the active agent, including small molecules and peptides being administered to a patient in need of treatment. In particular, the drug delivery system is designed for inhalation for delivery of drugs to the pulmonary circulation in a rapid and therapeutically effective manner.
Stability of Novel Pain Therapy Tetrapeptide TPI-23 in Technosphere® Inhalation Powder and
Identification of Related-Compounds by Liquid Chromatography/Mass Spectrometry
Y. Livson, E. Harris, K. Fabio, J. Guarneri
MannKind Corporation
Purpose
To evaluate the stability of TPI23 tetrapeptide WsSF-NH2 under room temperature and accelerated conditions in a Technosphere inhalation powder using HPLC, and to identify the major related-compounds present using LC/MS.
abstracts.aapsDOTorg/Verify/aaps2013/postersubmissions/T3083.pdf
3. Off-patent Zofran for antiematic. It's hard to keep a Zofran pill down when you are nauseous.
4. GSK was working on Oxytoxin.
The Mintaka grant that powers MannKind’s effort for dosage form development was based on work performed at MannKind to develop a highly heat-resistant and noninvasive formula of oxytocin to reduce maternal death due to postpartum hemorrhage. The award recipients were selected from more than 750 submissions.
Many deaths by bleeding could be prevented by an immediate intravenous injection of the drug oxytocin. However, oxytocin is unstable in warm climates and trained staff are not always available to give injections. With MannKind Corporation (USA), we have formulated oxytocin in a dry, stabilized form which can be loaded into a robust, very inexpensive, disposable inhaler, eliminating at the same time the need for injection. Administration by inhalation at last makes treatment possible outside centres with trained medical staff.
Some 98% of our formulation of oxytocin survives 8 months at 40°C, and the inhaler has proved a highly efficient means of delivery. The next step is to design and then execute a clinical safety trial in a developed county (medicines should not be safety-tested on fragile populations). If our expectation that there will be no safety issues proves justified, the way will then be open to forming a product development partnership to take the product to market.
Anticipated Impact
A substantial decrease in the ~140,000 deaths per year and in the number of women (currently 1,600,000) who survive, but in a seriously weakened state. The return to their families of women in good health, ready to care for their children and assume once again their responsibilities in their community.
Heat-Stable Dry Powder Oxytocin Formulations for Delivery by Oral Inhalation.
Fabio K, et al. AAPS PharmSciTech. 2015.
Authors
Fabio K1, Curley K, Guarneri J, Adamo B, Laurenzi B, Grant M, Offord R, Kraft K, Leone-Bay A.
Author information
1Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA, kfabio@mannkindcorpDOTcom.
Citation
AAPS PharmSciTech. 2015 Mar 17. [Epub ahead of print]
Abstract
In this work, heat stable dry powders of oxytocin (OT) suitable for delivery by oral inhalation were prepared. The OT dry powders were prepared by spray drying using excipients chosen to promote OT stability including trehalose, isoleucine, polyvinylpyrrolidone, citrate (sodium citrate and citric acid), and zinc salts (zinc chloride and zinc citrate). Characterization by laser diffraction indicated that the OT dry powders had a median particle size of 2 μm, making them suitable for delivery by inhalation. Aerodynamic performance upon discharge from proprietary dry powder inhalers was evaluated by Andersen cascade impaction (ACI) and in an anatomically correct airway (ACA) model, and confirmed that the powders had excellent aerodynamic performance, with respirable fractions up to 77% (ACI, 30 L/min). Physicochemical characterization demonstrated that the powders were amorphous (X-ray diffraction) with high glass transition temperature (modulated differential scanning calorimetry, MDSC), suggesting the potential for stabilization of the OT in a glassy amorphous matrix. OT assay and impurity profile were conducted by reverse phase HPLC and liquid chromatography-mass spectrometry (LC-MS) after storage up to 32 weeks at 40°C/75%RH. Analysis demonstrated that OT dry powders containing a mixture of citrate and zinc salts retained more than 90% of initial assay after 32 weeks storage and showed significant reduction in dimers and trisulfide formation (up to threefold reduction compared to control).
PMID 25776985 [PubMed - as supplied by publisher]
Inhaler delivered peptide could prevent LDC deaths during childbirth, says GSK
Inhaled delivery of the labour inducing peptide oxytocin could help prevent millions of deaths in the lesser-developed countries (LDC), according to a GSK scientist.
The hormone oxytocin is given as standard during the third stage of labour to induce childbirth but the need for sterility and its reaction to temperature change means administration by injection in the developing world is an issue, according to GlaxoSmithKline Investigator and expert in inhalation delivery of biopharmaceuticals Richard Kaye.
He told a packed room at the annual AAPS meeting in San Diego yesterday an inhalable form of the peptide had the ability to prevent 41 million post-partum haemorrhages (PPHs) and over two million deaths in developing countries over a ten year period, and the Big Pharma company is working with Australia’s Monash University to achieve this.
“We are combining GSK’s infrastructure with Monash’s concept in order to expedite the development of this peptide,” he said. “The product will utilise our DPI [dry powder inhaler] manufacturing platforms to make a single-dose therapy, a throwaway device, which is essentially cheap as the governments and patients don’t have much to spend, and is stable at 30⁰C.”
The device which is being investigated is GSK’s Rotahaler which can be produced for under 10 pence (16 cents) per unit and can quickly deliver approximately 30mg of product.
Formulation Challenges
Using the lungs for systematic delivery of peptides and large molecule is not new exactly, as this has been achieved in the past with inhalable insulins - the US FDA recently approved Mannkind’s Afrezza for example. The technology challenge comes when formulating the drug to ensure a cost effective amount of the large molecule API is efficiently administered into the lungs, Kaye said.
“We procure the API as a freeze dried powder, dissolve it, add excipients with spray drying, and blend it with our carrier particle,” he said.
The role of the excipients helps to increase the solubility of the peptide and allows rapid clearance from the lungs. A carbohydrate is used as a water replacer and glassy stabiliser in spray-dried formulation, Kaye said, while an unnamed formulation additive helps improve stability.
Usually GSK uses lactose as the carrier in inhaled formulations but due to the nature of the oxytocin molecule the firm is using an alternative in this project.
5. Oxyntomodulin For Obesity and Type 2 Diabetes
Older slimming medicines made by companies like Sanofi and GlaxoSmithKline Plc stumbled because they were deemed too dangerous or came with unpleasant side effects
Dry Powder Formulations for the Inhalation of Oxyntomodulin
Andrea Leone-Bay
Vice President Scientific Research
MannKind
Obesity is a rapidly becoming a global epidemic and underlies many disease conditions including diabetes and cardiovascular disease. Current treatment options are limited and are challenged by undesirable side effects. Oxyntomodulin (OXY) is an endogenous peptide hormone that signals satiety in healthy individuals. High circulating OXY concentrations are associated with satiety and low OXY concentrations are associated with a feeling of hunger. This activity profile positions OXY as a potential treatment for obesity. To address this unmet medical need, this presentation will introduce an approach to developing an orally inhaled dry powder OXY product administered using a small, breath-powered inhaler for obesity therapy.
The audience will learn about oxyntomodulin, a potential new obesity therapy and about the administration of peptides by oral inhalation using a simple, patient-friendly approach.
www.gtcbio.com/conferences/diabetes-drug-discovery-development-agenda
Billionaire Frost Is Flab’s New Enemy With Diet Drug Bet
Bloomberg Business
by David Wainer
11:00 PM CST
February 3, 2015
(Bloomberg) — Phillip Frost at 78 isn’t your usual Florida retiree. Rather than spending his days playing golf and relaxing, the billionaire former chairman of Teva Pharmaceutical Industries Ltd. has embarked on his life’s most quixotic quest: a blockbuster cure for obesity.
Many before him have have tried and failed. Medicines currently on the market haven’t sold well. And investors are a little skeptical about Frost’s latest wager.
“It’s kind of like the unicorn of the pharma industry,” said David Munno, head of drug research at Sphera Global Healthcare, a hedge fund in Tel Aviv. “So many companies have tried and had their drugs pulled out of the market or fail miserably.”
Frost believes he can achieve what billions of pharma dollars and decades of research have failed to produce by using the blueprint that allowed him to amass a $4.9 billion fortune: re-engineering an existing product to stifle its flaws.
“The chances of success are extremely high,” he said in a telephone interview from his office in Miami.
A native of South Philadelphia, Frost turned a $50,000 investment in Key Pharmaceuticals Inc., a struggling drug developer, in 1972 into a $825 million sale to Schering-Plough Corp. 14 years later. His next company, the maker of generic drugs Ivax Corp., he sold to Teva, the industry leader, for $7.4 billion in 2006.
Not Hungry
“We have a lot of respect for Phil Frost and we definitely wouldn’t write him off,” Munno said. Still, he gives any drug that hasn’t entered human clinical tests — as is the case with Frost’s product — a chance of success that’s less than 5 percent.
Frost, who retired as Teva’s chairman last year, was freed up to focus on Opko Health Inc., the drug development company he started after selling Ivax. Valued at $5.2 billion on the New York Stock exchange and based in Miami, Opko has been working on tweaking a hormone called Oxyntomodulin, a powerful appetite suppressant whose mechanism of action isn’t well understood, and which alone lacks the staying power required for a diet medicine.
“We’re talking about a hormone that tells our brain that we’re no longer hungry,” said Gili Hart, the company’s vice president of clinical development.
Obesity Paradox
Opko has licensed technology from Israel’s Weizmann Institute of Science that could change that, according to Hart. It allows the hormone to act longer in the body, requiring one injection per week instead of one every few hours, she said. Opko tested the product on obese mice and rats, which shed more than 20 percent of their weight with no worrisome side effects. Human studies are slated to begin this year.
Frost figures the drug’s revenue potential could be about $100 billion, leapfrogging the pharmaceutical industry’s all-time bestseller, Pfizer Inc.’s cholesterol medicine Lipitor. The market for an obesity medicine is huge — even just in the U.S., where an estimated 79 million people are overweight or obese.
But so far no drugmaker has managed to convert that potential into a blockbuster, and it’s so early for the Opko drug that a lot could go wrong. Because obesity isn’t a disease, regulators have a low tolerance for worrisome side effects, and patients often give up treatment when they come to realize it’s no panacea.
No Blockbuster
“There have been many disappointments,” said Soeren Lontoft, an analyst at Sydbank A/S in Denmark. “Any company seeking to develop a blockbuster for this market will face major challenges.”
Opko shares have gained about 24 percent this year. They advanced 0.6 percent to $12.42 as of 10:05 a.m. in New York.
It takes 10 to 15 years on average for an experimental drug to make it from the lab to U.S. patients. Only one in 5,000 compounds that enter pre-clinical testing endure human trials and win permission to be sold, according to drugmaker Eli Lilly & Co.
In the last two years, four drugs have been approved to treat obesity in the U.S.: Novo Nordisk A/S’s Saxenda injection and Vivus Inc.’s Qsymia; a pill called Belviq from Eisai Co. and Arena Pharmaceuticals Inc.; and Contrave, a tablet developed by Orexigen Therapeutics Inc. and marketed by Takeda Pharmaceutical Co.
None of the products is forecast to reach anywhere near $1 billion in sales this year, the blockbuster threshold. Annual revenue for Qsymia and Belviq, both approved in 2012, have yet to surpass $100 million. Saxenda, cleared late last year, is only just going on sale. It’s expected to generate $470 million within two years, according to Bloomberg analyst estimates. Contrave, also approved last year, may be the exception: it’s too early to know if sales are taking off, but Simos Simeonidis, a senior analyst at RBC Capital Markets, estimates they could climb to $2.54 billion in 2027.
New With Old
“It’s not just finding the right drug,” said Munno, who warns he hasn’t studied Opko’s drug closely because it’s too early in the research process. “You need not only to produce enough weight loss but you need to get patients to change their lifestyles. No one has successfully done that yet.”
Older slimming medicines made by companies like Sanofi and GlaxoSmithKline Plc stumbled because they were deemed too dangerous or came with unpleasant side effects.
The Opko drug fits the profile of what Frost has been successful with in the past: not an entirely new product, but one that needed to be re-engineered to deliver.
Frost and partner Michael Jaharis built Key Pharmaceuticals in the 1970s by finding new ways to deliver familiar drugs that had already been tested in humans. In one case, they took an old asthma medicine called theophylline that was ineffective in small doses and unsafe in large doses and devised a time-released pill called Theo-Dur that went on to win regulatory approval and fuel sales growth.
Weekly Injection
At his next venture, Ivax, Frost was one of the early entrepreneurs to recognize the opportunity the 1984 Hatch-Waxman Act provided for generic companies that were first to present a file for approval. When Ivax developed a long-acting form of verapamil, a drug used to treat hypertension, sales shot up by more than 20 percent to over $600 million.
With the obesity challenge, Frost is taking a hormone known to the scientific community — Oxyntomodulin by itself has been tested in humans and found to be safe — and using new technology to prolong its action. Opko got the drug, known for now as MOD-6031, with the $480 million acquisition of drugmaker Prolor Biotech Inc. in 2013.
“We are taking a technology that extends the life of that hormone, which itself has already been proved in previous studies to reduce weight,” Frost said. “With a single injection a week, we think we can control obesity.”
6. Mnkd Leaks TS APIs in 7/16/15 Patent: PTH, sumatriptan pain, IRE1, BTK, Oxyntomodulin, GLP-1, peptide YY, Heparin
Dry powders comprising microparticles suitable for pulmonary delivery are well known in the art including, for example, those disclosed in U.S. Pat. Nos. 6,428,771 and 6,071,497, the disclosures of which are incorporated herein by reference in their entirety for all they disclose regarding microparticles. In respective exemplary embodiments, the dry powders, the active ingredient can be a protein, a peptide, or a polypeptide and combinations thereof, for example, and endocrine hormone such as insulin, glucagon-like peptide-1 (GLP-1), parathyroid hormone or analogs thereof.
In certain embodiments, a dry powder formulation for delivery to the pulmonary circulation comprises an active ingredient or agent, including a peptide, a protein, a hormone, analogs thereof or combinations thereof, wherein the active ingredient is insulin, calcitonin, growth hormone, erythropoietin, granulocyte macrophage colony stimulating factor (GM-CSF), chorionic gonadotropin releasing factor, luteinizing releasing hormone, follicle stimulating hormone (FSH), vasoactive intestinal peptide, parathyroid hormone (including black bear PTH), parathyroid hormone related protein, glucagon-like peptide-1 (GLP-1), exendin, oxyntomodulin, peptide YY, triptans such as sumatriptan, interleukin 2-inducible tyrosine kinase, Bruton's tyrosine kinase (BTK), inositol-requiring kinase 1 (IRE1), or analogs, active fragments, PC-DAC-modified derivatives, or O-glycosylated forms thereof. In particular embodiments, the pharmaceutical composition or dry powder formulation comprises fumaryl diketopiperazine and the active ingredient is one or more selected from insulin, parathyroid hormone 1-34, GLP-1, oxyntomodulin, peptide YY, heparin, PTHrP, analogs thereof and combinations thereof.
freshpatentsDOTcom/-dt20150716ptan20150196724.php
5 drugs GSK could license TS for to defend its blockbuster franchises. Great synergy between GSK and Mnkd!
Dr Shannon, GSK CMO joining Mnkd BoD, retired from GSK April 2015 possibly to avoid conflict of interest during negotiation.
1. Blood vessel dilators (vasodilators). Vasodilators open narrowed blood vessels. One of the most commonly prescribed vasodilators for pulmonary hypertension is epoprostenol (GSK's Flolan). The drawback to epoprostenol is that its effects last only a few minutes. This drug is continuously injected through an intravenous (IV) catheter via a small pump that you wear in a pack on your belt or shoulder. This means that you'll learn to prepare your own medication mixture, operate the pump and care for the IV catheter. You'll need comprehensive follow-up care. Potential side effects of epoprostenol include jaw pain, nausea, diarrhea, leg cramps, as well as pain and infection at the IV site.
Another form of the drug, iloprost (Ventavis), avoids many of these problems. Iloprost can be inhaled every three hours through a nebulizer, a machine that vaporizes your medication, making it far more convenient and less painful to use. And because it's inhaled, it goes directly to the lungs. Side effects associated with iloprost include chest pain — often accompanied by headache and nausea — and breathlessness.
2. Off-patent Immitrex (Sumatriptan) for Migraine.
Method and composition for treating migraines
US 8785396 B2
www.google.com/patents/US8785396
Abstract
A method for treating migraines is disclosed. The method utilizes a rapid drug delivery system which prevents deactivation or degradation of the active agent, including small molecules and peptides being administered to a patient in need of treatment. In particular, the drug delivery system is designed for inhalation for delivery of drugs to the pulmonary circulation in a rapid and therapeutically effective manner.
Stability of Novel Pain Therapy Tetrapeptide TPI-23 in Technosphere® Inhalation Powder and
Identification of Related-Compounds by Liquid Chromatography/Mass Spectrometry
Y. Livson, E. Harris, K. Fabio, J. Guarneri
MannKind Corporation
Purpose
To evaluate the stability of TPI23 tetrapeptide WsSF-NH2 under room temperature and accelerated conditions in a Technosphere inhalation powder using HPLC, and to identify the major related-compounds present using LC/MS.
abstracts.aapsDOTorg/Verify/aaps2013/postersubmissions/T3083.pdf
3. Off-patent Zofran for antiematic. It's hard to keep a Zofran pill down when you are nauseous.
4. GSK was working on Oxytoxin.
The Mintaka grant that powers MannKind’s effort for dosage form development was based on work performed at MannKind to develop a highly heat-resistant and noninvasive formula of oxytocin to reduce maternal death due to postpartum hemorrhage. The award recipients were selected from more than 750 submissions.
Many deaths by bleeding could be prevented by an immediate intravenous injection of the drug oxytocin. However, oxytocin is unstable in warm climates and trained staff are not always available to give injections. With MannKind Corporation (USA), we have formulated oxytocin in a dry, stabilized form which can be loaded into a robust, very inexpensive, disposable inhaler, eliminating at the same time the need for injection. Administration by inhalation at last makes treatment possible outside centres with trained medical staff.
Some 98% of our formulation of oxytocin survives 8 months at 40°C, and the inhaler has proved a highly efficient means of delivery. The next step is to design and then execute a clinical safety trial in a developed county (medicines should not be safety-tested on fragile populations). If our expectation that there will be no safety issues proves justified, the way will then be open to forming a product development partnership to take the product to market.
Anticipated Impact
A substantial decrease in the ~140,000 deaths per year and in the number of women (currently 1,600,000) who survive, but in a seriously weakened state. The return to their families of women in good health, ready to care for their children and assume once again their responsibilities in their community.
Heat-Stable Dry Powder Oxytocin Formulations for Delivery by Oral Inhalation.
Fabio K, et al. AAPS PharmSciTech. 2015.
Authors
Fabio K1, Curley K, Guarneri J, Adamo B, Laurenzi B, Grant M, Offord R, Kraft K, Leone-Bay A.
Author information
1Mannkind Corporation, One Casper Street, Danbury, Connecticut, 06810, USA, kfabio@mannkindcorpDOTcom.
Citation
AAPS PharmSciTech. 2015 Mar 17. [Epub ahead of print]
Abstract
In this work, heat stable dry powders of oxytocin (OT) suitable for delivery by oral inhalation were prepared. The OT dry powders were prepared by spray drying using excipients chosen to promote OT stability including trehalose, isoleucine, polyvinylpyrrolidone, citrate (sodium citrate and citric acid), and zinc salts (zinc chloride and zinc citrate). Characterization by laser diffraction indicated that the OT dry powders had a median particle size of 2 μm, making them suitable for delivery by inhalation. Aerodynamic performance upon discharge from proprietary dry powder inhalers was evaluated by Andersen cascade impaction (ACI) and in an anatomically correct airway (ACA) model, and confirmed that the powders had excellent aerodynamic performance, with respirable fractions up to 77% (ACI, 30 L/min). Physicochemical characterization demonstrated that the powders were amorphous (X-ray diffraction) with high glass transition temperature (modulated differential scanning calorimetry, MDSC), suggesting the potential for stabilization of the OT in a glassy amorphous matrix. OT assay and impurity profile were conducted by reverse phase HPLC and liquid chromatography-mass spectrometry (LC-MS) after storage up to 32 weeks at 40°C/75%RH. Analysis demonstrated that OT dry powders containing a mixture of citrate and zinc salts retained more than 90% of initial assay after 32 weeks storage and showed significant reduction in dimers and trisulfide formation (up to threefold reduction compared to control).
PMID 25776985 [PubMed - as supplied by publisher]
Inhaler delivered peptide could prevent LDC deaths during childbirth, says GSK
Inhaled delivery of the labour inducing peptide oxytocin could help prevent millions of deaths in the lesser-developed countries (LDC), according to a GSK scientist.
The hormone oxytocin is given as standard during the third stage of labour to induce childbirth but the need for sterility and its reaction to temperature change means administration by injection in the developing world is an issue, according to GlaxoSmithKline Investigator and expert in inhalation delivery of biopharmaceuticals Richard Kaye.
He told a packed room at the annual AAPS meeting in San Diego yesterday an inhalable form of the peptide had the ability to prevent 41 million post-partum haemorrhages (PPHs) and over two million deaths in developing countries over a ten year period, and the Big Pharma company is working with Australia’s Monash University to achieve this.
“We are combining GSK’s infrastructure with Monash’s concept in order to expedite the development of this peptide,” he said. “The product will utilise our DPI [dry powder inhaler] manufacturing platforms to make a single-dose therapy, a throwaway device, which is essentially cheap as the governments and patients don’t have much to spend, and is stable at 30⁰C.”
The device which is being investigated is GSK’s Rotahaler which can be produced for under 10 pence (16 cents) per unit and can quickly deliver approximately 30mg of product.
Formulation Challenges
Using the lungs for systematic delivery of peptides and large molecule is not new exactly, as this has been achieved in the past with inhalable insulins - the US FDA recently approved Mannkind’s Afrezza for example. The technology challenge comes when formulating the drug to ensure a cost effective amount of the large molecule API is efficiently administered into the lungs, Kaye said.
“We procure the API as a freeze dried powder, dissolve it, add excipients with spray drying, and blend it with our carrier particle,” he said.
The role of the excipients helps to increase the solubility of the peptide and allows rapid clearance from the lungs. A carbohydrate is used as a water replacer and glassy stabiliser in spray-dried formulation, Kaye said, while an unnamed formulation additive helps improve stability.
Usually GSK uses lactose as the carrier in inhaled formulations but due to the nature of the oxytocin molecule the firm is using an alternative in this project.
5. Oxyntomodulin For Obesity and Type 2 Diabetes
Older slimming medicines made by companies like Sanofi and GlaxoSmithKline Plc stumbled because they were deemed too dangerous or came with unpleasant side effects
Dry Powder Formulations for the Inhalation of Oxyntomodulin
Andrea Leone-Bay
Vice President Scientific Research
MannKind
Obesity is a rapidly becoming a global epidemic and underlies many disease conditions including diabetes and cardiovascular disease. Current treatment options are limited and are challenged by undesirable side effects. Oxyntomodulin (OXY) is an endogenous peptide hormone that signals satiety in healthy individuals. High circulating OXY concentrations are associated with satiety and low OXY concentrations are associated with a feeling of hunger. This activity profile positions OXY as a potential treatment for obesity. To address this unmet medical need, this presentation will introduce an approach to developing an orally inhaled dry powder OXY product administered using a small, breath-powered inhaler for obesity therapy.
The audience will learn about oxyntomodulin, a potential new obesity therapy and about the administration of peptides by oral inhalation using a simple, patient-friendly approach.
www.gtcbio.com/conferences/diabetes-drug-discovery-development-agenda
Billionaire Frost Is Flab’s New Enemy With Diet Drug Bet
Bloomberg Business
by David Wainer
11:00 PM CST
February 3, 2015
(Bloomberg) — Phillip Frost at 78 isn’t your usual Florida retiree. Rather than spending his days playing golf and relaxing, the billionaire former chairman of Teva Pharmaceutical Industries Ltd. has embarked on his life’s most quixotic quest: a blockbuster cure for obesity.
Many before him have have tried and failed. Medicines currently on the market haven’t sold well. And investors are a little skeptical about Frost’s latest wager.
“It’s kind of like the unicorn of the pharma industry,” said David Munno, head of drug research at Sphera Global Healthcare, a hedge fund in Tel Aviv. “So many companies have tried and had their drugs pulled out of the market or fail miserably.”
Frost believes he can achieve what billions of pharma dollars and decades of research have failed to produce by using the blueprint that allowed him to amass a $4.9 billion fortune: re-engineering an existing product to stifle its flaws.
“The chances of success are extremely high,” he said in a telephone interview from his office in Miami.
A native of South Philadelphia, Frost turned a $50,000 investment in Key Pharmaceuticals Inc., a struggling drug developer, in 1972 into a $825 million sale to Schering-Plough Corp. 14 years later. His next company, the maker of generic drugs Ivax Corp., he sold to Teva, the industry leader, for $7.4 billion in 2006.
Not Hungry
“We have a lot of respect for Phil Frost and we definitely wouldn’t write him off,” Munno said. Still, he gives any drug that hasn’t entered human clinical tests — as is the case with Frost’s product — a chance of success that’s less than 5 percent.
Frost, who retired as Teva’s chairman last year, was freed up to focus on Opko Health Inc., the drug development company he started after selling Ivax. Valued at $5.2 billion on the New York Stock exchange and based in Miami, Opko has been working on tweaking a hormone called Oxyntomodulin, a powerful appetite suppressant whose mechanism of action isn’t well understood, and which alone lacks the staying power required for a diet medicine.
“We’re talking about a hormone that tells our brain that we’re no longer hungry,” said Gili Hart, the company’s vice president of clinical development.
Obesity Paradox
Opko has licensed technology from Israel’s Weizmann Institute of Science that could change that, according to Hart. It allows the hormone to act longer in the body, requiring one injection per week instead of one every few hours, she said. Opko tested the product on obese mice and rats, which shed more than 20 percent of their weight with no worrisome side effects. Human studies are slated to begin this year.
Frost figures the drug’s revenue potential could be about $100 billion, leapfrogging the pharmaceutical industry’s all-time bestseller, Pfizer Inc.’s cholesterol medicine Lipitor. The market for an obesity medicine is huge — even just in the U.S., where an estimated 79 million people are overweight or obese.
But so far no drugmaker has managed to convert that potential into a blockbuster, and it’s so early for the Opko drug that a lot could go wrong. Because obesity isn’t a disease, regulators have a low tolerance for worrisome side effects, and patients often give up treatment when they come to realize it’s no panacea.
No Blockbuster
“There have been many disappointments,” said Soeren Lontoft, an analyst at Sydbank A/S in Denmark. “Any company seeking to develop a blockbuster for this market will face major challenges.”
Opko shares have gained about 24 percent this year. They advanced 0.6 percent to $12.42 as of 10:05 a.m. in New York.
It takes 10 to 15 years on average for an experimental drug to make it from the lab to U.S. patients. Only one in 5,000 compounds that enter pre-clinical testing endure human trials and win permission to be sold, according to drugmaker Eli Lilly & Co.
In the last two years, four drugs have been approved to treat obesity in the U.S.: Novo Nordisk A/S’s Saxenda injection and Vivus Inc.’s Qsymia; a pill called Belviq from Eisai Co. and Arena Pharmaceuticals Inc.; and Contrave, a tablet developed by Orexigen Therapeutics Inc. and marketed by Takeda Pharmaceutical Co.
None of the products is forecast to reach anywhere near $1 billion in sales this year, the blockbuster threshold. Annual revenue for Qsymia and Belviq, both approved in 2012, have yet to surpass $100 million. Saxenda, cleared late last year, is only just going on sale. It’s expected to generate $470 million within two years, according to Bloomberg analyst estimates. Contrave, also approved last year, may be the exception: it’s too early to know if sales are taking off, but Simos Simeonidis, a senior analyst at RBC Capital Markets, estimates they could climb to $2.54 billion in 2027.
New With Old
“It’s not just finding the right drug,” said Munno, who warns he hasn’t studied Opko’s drug closely because it’s too early in the research process. “You need not only to produce enough weight loss but you need to get patients to change their lifestyles. No one has successfully done that yet.”
Older slimming medicines made by companies like Sanofi and GlaxoSmithKline Plc stumbled because they were deemed too dangerous or came with unpleasant side effects.
The Opko drug fits the profile of what Frost has been successful with in the past: not an entirely new product, but one that needed to be re-engineered to deliver.
Frost and partner Michael Jaharis built Key Pharmaceuticals in the 1970s by finding new ways to deliver familiar drugs that had already been tested in humans. In one case, they took an old asthma medicine called theophylline that was ineffective in small doses and unsafe in large doses and devised a time-released pill called Theo-Dur that went on to win regulatory approval and fuel sales growth.
Weekly Injection
At his next venture, Ivax, Frost was one of the early entrepreneurs to recognize the opportunity the 1984 Hatch-Waxman Act provided for generic companies that were first to present a file for approval. When Ivax developed a long-acting form of verapamil, a drug used to treat hypertension, sales shot up by more than 20 percent to over $600 million.
With the obesity challenge, Frost is taking a hormone known to the scientific community — Oxyntomodulin by itself has been tested in humans and found to be safe — and using new technology to prolong its action. Opko got the drug, known for now as MOD-6031, with the $480 million acquisition of drugmaker Prolor Biotech Inc. in 2013.
“We are taking a technology that extends the life of that hormone, which itself has already been proved in previous studies to reduce weight,” Frost said. “With a single injection a week, we think we can control obesity.”
6. Mnkd Leaks TS APIs in 7/16/15 Patent: PTH, sumatriptan pain, IRE1, BTK, Oxyntomodulin, GLP-1, peptide YY, Heparin
Dry powders comprising microparticles suitable for pulmonary delivery are well known in the art including, for example, those disclosed in U.S. Pat. Nos. 6,428,771 and 6,071,497, the disclosures of which are incorporated herein by reference in their entirety for all they disclose regarding microparticles. In respective exemplary embodiments, the dry powders, the active ingredient can be a protein, a peptide, or a polypeptide and combinations thereof, for example, and endocrine hormone such as insulin, glucagon-like peptide-1 (GLP-1), parathyroid hormone or analogs thereof.
In certain embodiments, a dry powder formulation for delivery to the pulmonary circulation comprises an active ingredient or agent, including a peptide, a protein, a hormone, analogs thereof or combinations thereof, wherein the active ingredient is insulin, calcitonin, growth hormone, erythropoietin, granulocyte macrophage colony stimulating factor (GM-CSF), chorionic gonadotropin releasing factor, luteinizing releasing hormone, follicle stimulating hormone (FSH), vasoactive intestinal peptide, parathyroid hormone (including black bear PTH), parathyroid hormone related protein, glucagon-like peptide-1 (GLP-1), exendin, oxyntomodulin, peptide YY, triptans such as sumatriptan, interleukin 2-inducible tyrosine kinase, Bruton's tyrosine kinase (BTK), inositol-requiring kinase 1 (IRE1), or analogs, active fragments, PC-DAC-modified derivatives, or O-glycosylated forms thereof. In particular embodiments, the pharmaceutical composition or dry powder formulation comprises fumaryl diketopiperazine and the active ingredient is one or more selected from insulin, parathyroid hormone 1-34, GLP-1, oxyntomodulin, peptide YY, heparin, PTHrP, analogs thereof and combinations thereof.
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