Post by lakers on Nov 19, 2015 2:26:09 GMT -5
www.fool.com/investing/general/2015/04/29/mannkinds-future-more-than-just-afrezza.aspx
MannKind has also hinted in the past that another opportunity may exist in the diabetes space: GLP-1 agonists. This drug class, which is designed to stimulate the pancreas to produce more insulin when blood sugar levels are high, is already on the market and is used to treat patients with type 2 diabetes. When asked about the opportunity here, CEO Edstrom confirmed that they are discussing the opportunity with their partner Sanofi, and hinted that there many be a development project in the works.
We do not have a lot to go on about the clinical status of the GLP-1 opportunity, as the company hasn't put out a follow up press release since posting positive phase 1a results way back in November 2007. However, with CEO Edstrom calling it out as a potential development project with Sanofi, it could be an interesting opportunity for the company.
www.mannkindcorp.com/Collateral/Documents/English-US/MKC-253-001%20PKPD_ADA_June8v6.pdf
Pulmonary Administration of GLP-1 Technosphere® Powder Elicits Dose-dependent Insulin Response
Robert Baughman, PhD, PharmD
Vice President, Experimental Pharmacology
MannKind Corporation MannKind Corporation
screencast.com/t/lfvJnQwPlF5H
Lyxumia® (lixisenatide), a once-daily prandial GLP-1 receptor agonist was approved for treatment of T2 in Europe in Feb 2013. U.S. regulatory decision expected in 3Q16.
www.mannkindcorp.com/Collateral/Documents/English-US/marino%202010%20pk%20pd%20inhaled%20GLP-1%20MKC%20253%20POC%20T2.pdf
Pharmacokinetics and Pharmacodynamics
of Inhaled GLP-1 (MKC253): Proof-of-Concept
Studies in Healthy Normal Volunteers
and in Patients With Type 2 Diabetes
MT Marino1, D Costello1, R Baughman1, A Boss1, J Cassidy1, C Damico1, S van Marle2,
A van Vliet2 and PC Richardson1
MKC253 is glucagon-like peptide 1 (GLP-1, 7–36 amide) adsorbed onto Technosphere microparticles for oral inhalation.
The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic–pharmacodynamic (PK–PD) relationship between
inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with
type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5min, and levels
returned to baseline within 30min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those
of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose
excursions in subjects with type 2 diabetes. An Emax (maximum effect) model described the relationship between
GLP-1 concentration and insulin release. The variability in the Emax may be due to differences in baseline glucose levels,
differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.
www.mannkindcorp.com/Collateral/Documents/English-US/DOM%20GLP-1%20CMC%20PK%20PD%20paper.pdf
Evaluation of novel particles as an inhalation system for GLP-1
A. Leone-Bay, M. Grant, S. Greene, G. Stowell, S. Daniels, A. Smithson, S. Villanueva,
S. Cope, K. Carrera, S. Reyes and P. Richardson
MannKind Corporation, Valencia, CA, USA
professional.diabetes.org/Abstracts_Display.aspx?TYP=1&CID=74463
Inhaled GLP-1 and Exenatide: Different Effects on Pancreatic and Gastric Activity
Year: 2009
Abstract Number: 160-OR
Authors: ROBERT A. BAUGHMAN, DONALD J. COSTELLO, MARK T. MARINO, JAMES P. CASSIDY, ANDERS H. BOSS, CHRISTINE A. DAMICO, PAMELA C. HAWORTH, PETER C. RICHARDSON, JEROEN VAN DE WETERING DE ROOIJ, ANDRE A. VAN VLIET
Institutions: Valencia, CA, Zuidlaren, The Netherlands
Results: MKC253 is GLP-1 adsorbed onto Technosphere® microparticles for oral inhalation. This double-blind, double-dummy, placebo and active control crossover trial compared the effects of MKC253 (1.5 mg) and subcutaneous injection of exenatide (EXE; 10 µg) on postprandial glucose (PPG) excursions, postprandial insulin, gastric emptying, and GLP-1 pharmacokinetics. Included were 20 nonsmoking subjects with type 2 diabetes (A1C 6.2%-8.5%) on a stable oral antidiabetic regimen. Subjects received 5 treatments 2 days apart. All received MKC253 or inhaled placebo (InhP) while fasting. EXE or placebo sc (SCP) was given 15 min premeal, and MKC253 or InhP was given premeal (Pre) or 30 min postmeal (Post). Subjects received in randomized order: SCP + MKC253 Pre + InhP Post; SCP + MKC253 Pre + MKC253 Post; EXE + InhP Pre+InhP Post; or SCP + InhP Pre + InhP Post. Gastric emptying was measured by absorption of 13C-octanoate from a 575 Kcal standardized meal. MKC253 produced a rapid spike in insulin. Mean insulin Cmax occurred <10 min after dosing and fell sharply thereafter. Mean peak insulin was 60 µU/mL. Mean PK of insulin release closely tracked mean GLP-1 kinetics. The insulin response following EXE was slower and less pronounced. In fasting subjects with baseline glucose <9 mmol/L, MKC253 produced a mean maximal decrease in glucose of 0.75 mmol/L about 30 min after inhalation. Subjects with baseline glucose >9 mmol/L had a 1.2 mmol/L decrease in glucose approx. 45 min after inhalation. MKC253 reduced PPG excursions. Compared with InhP, MKC253 Pre decreased PPG by ≥1 mM/L for >1 hr and MKC253 Pre + Post decreased PPG for >3 hr. Reductions were longer than that predicted by a GLP-1 t1/2 of <2 min. MKC253 had little or no effect on gastric emptying. In contrast, EXE also reduced PPG but acted by delaying gastric emptying. More than 90% of 13C ingested was unabsorbed 4 hr after the meal compared with <60% with MKC253. After EXE injection, insulin response to meal challenge was much smaller than with MKC253. Only 1 of 20 subjects reported nausea with MKC253 vs rates >66% from literature with injected GLP-1. Both MKC253 and EXE reduce PPG excursions, but appear to do so by different mechanisms.
books.google.com/books?id=nN9sBgAAQBAJ&pg=PA35&lpg=PA35&dq=inhaled+glp-1&source=bl&ots=TPNLjCxtDB&sig=0qXUe4f2dry_IcmWsKD9YnKunSo&hl=en&sa=X&ved=0CE0Q6AEwBWoVChMItuGomfybyQIVRjeICh2MAw06#v=onepage&q=inhaled%20glp-1&f=false
Environmental Biomedicine - Page 35 - Google Books Result
books.google.com/books?isbn=3319146904
Mieczyslaw Pokorski - 2015 - Science
In the treatment period, patients received five different treatments (I: 1.5 mg GLP-1 as MKC253 inhalation powder or Technosphere® inhalation powder with..
www.biotechduediligence.com/mnkd.html
In consideration for the rights granted to Sanofi by us under the Sanofi License Agreement, upon effectiveness of the Sanofi License Agreement, we will receive an upfront payment of $150.0 million. If certain manufacturing, regulatory and sales milestones are achieved, we will also eligible to receive up to $775.0 million in milestone payments, of which $75.0 million in milestone payments relate to certain development and manufacturing milestone events, $50.0 million in milestone payments relate to the filing and completion of regulatory approvals and $650.0 million in milestone payments relate to the achievement of certain product sales milestones. In addition, worldwide profits and losses be shared 65% by Sanofi and 35% by us.
[$25M remained for Qualifying Sny's insulin for Afrezza. $30M for EU, $20M for Japan approval. $250M for annual Afrezza sale of first $250M probably, dollar bonus for dollar rev.]
Under the terms of the Sanofi License Agreement, we granted to Sanofi a right of first negotiation in the event we propose to grant to any third party a license to develop or exploit an inhaled glucagon-like peptide-1 agonist. In addition, if our board of directors determines to pursue a change of control of MannKind, we will be required notify Sanofi of such determination within a certain period of time so that Sanofi may, at is discretion, negotiate with us for a potential acquisition of MannKind by Sanofi.
In addition, we received a commitment letter from an affiliate of Sanofi to provide the Sanofi Loan Facility. The commitment letter provides for a $175.0 million secured revolving loan facility to fund our share of net losses under the Sanofi License Agreement. Pursuant to the commitment letter, loans under the Sanofi Loan Facility would bear interest at a rate of 8.5% per annum, paid-in-kind on a quarterly basis (2.06% per quarter compounded) and would become due and payable in full on the tenth anniversary of the effective date of the Sanofi License Agreement. We would be required to prepay any loans with net profits received under the Sanofi License Agreement. The commitment letter provides that our obligations under the Sanofi Loan Facility would be secured by a first priority mortgage on our facility in Valencia, California, a first priority security interest in certain insulin inventory located at our facility in Danbury, Connecticut and any contractual rights and obligations pursuant to which we purchase or have purchased such insulin, and a second priority security interest in our assets that secure our obligations under the Facility Agreement. The commitment is subject to customary conditions, including the effectiveness of the Sanofi License Agreement, the finalization of loan documentation and the entry into satisfactory intercreditor agreement with Deerfield.
The effectiveness of the Sanofi License Agreement and the Supply Agreement is contingent upon satisfaction of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended, and the entry into the definitive loan documents relating to the Sanofi Loan Facility (unless we terminate the commitment letter for the Sanofi Loan Facility).
The Sanofi License Agreement will remain in effect unless either party terminates the Sanofi License Agreement in accordance with its terms. Either party may terminate the Sanofi License Agreement for a material breach the other party if such breach remains uncured for 90 days, or 45 days in the case of a non-payment breach; provided that if Sanofi breaches the Sanofi License Agreement for failure to comply with its obligation to use commercially reasonable efforts to file for, obtain and maintain regulatory approval for AFREZZA in certain major markets and countries and to market, promote and commercialize AFREZZA in countries where regulatory approval has been received, as set forth in the Sanofi License Agreement, with respect to (i) the United States, we may terminate the Sanofi License Agreement in its entirety, and (ii) certain major markets or countries, we may terminate the Sanofi License Agreement only with respect to such markets or countries and not in its entirety. Either party may also terminate the Sanofi License Agreement upon written notice to the other party in the event of the other party’s insolvency. Sanofi may terminate the Sanofi License Agreement at any time on or after January 1, 2016 (a) upon 90 days’ written notice if Sanofi determines in good faith that the commercialization of AFREZZA is no longer economically viable in the United States, and (b) without cause upon six months’ written notice in its entirety or on a country-by-country basis other than with respect to the United States, subject to certain exceptions. In addition, Sanofi may terminate the Sanofi License Agreement on a country-by-country basis upon 30 days’ written notice for certain safety or regulatory reasons.
MannKind has also hinted in the past that another opportunity may exist in the diabetes space: GLP-1 agonists. This drug class, which is designed to stimulate the pancreas to produce more insulin when blood sugar levels are high, is already on the market and is used to treat patients with type 2 diabetes. When asked about the opportunity here, CEO Edstrom confirmed that they are discussing the opportunity with their partner Sanofi, and hinted that there many be a development project in the works.
We do not have a lot to go on about the clinical status of the GLP-1 opportunity, as the company hasn't put out a follow up press release since posting positive phase 1a results way back in November 2007. However, with CEO Edstrom calling it out as a potential development project with Sanofi, it could be an interesting opportunity for the company.
www.mannkindcorp.com/Collateral/Documents/English-US/MKC-253-001%20PKPD_ADA_June8v6.pdf
Pulmonary Administration of GLP-1 Technosphere® Powder Elicits Dose-dependent Insulin Response
Robert Baughman, PhD, PharmD
Vice President, Experimental Pharmacology
MannKind Corporation MannKind Corporation
screencast.com/t/lfvJnQwPlF5H
Lyxumia® (lixisenatide), a once-daily prandial GLP-1 receptor agonist was approved for treatment of T2 in Europe in Feb 2013. U.S. regulatory decision expected in 3Q16.
www.mannkindcorp.com/Collateral/Documents/English-US/marino%202010%20pk%20pd%20inhaled%20GLP-1%20MKC%20253%20POC%20T2.pdf
Pharmacokinetics and Pharmacodynamics
of Inhaled GLP-1 (MKC253): Proof-of-Concept
Studies in Healthy Normal Volunteers
and in Patients With Type 2 Diabetes
MT Marino1, D Costello1, R Baughman1, A Boss1, J Cassidy1, C Damico1, S van Marle2,
A van Vliet2 and PC Richardson1
MKC253 is glucagon-like peptide 1 (GLP-1, 7–36 amide) adsorbed onto Technosphere microparticles for oral inhalation.
The pharmacokinetics of inhaled GLP-1 and the pharmacokinetic–pharmacodynamic (PK–PD) relationship between
inhaled GLP-1 and insulin were analyzed in two trials, one in healthy normal volunteers and the other in patients with
type 2 diabetes. Inhaled GLP-1 was absorbed quickly, with peak concentrations occurring within 5min, and levels
returned to baseline within 30min. Inhaled GLP-1 appeared to produce plasma levels of GLP-1 comparable to those
of parenteral administration and sufficient to induce insulin secretion resulting in attenuation of postmeal glucose
excursions in subjects with type 2 diabetes. An Emax (maximum effect) model described the relationship between
GLP-1 concentration and insulin release. The variability in the Emax may be due to differences in baseline glucose levels,
differences resulting from genetic polymorphisms in GLP-1 receptors (GLP-1Rs), or the stage of diabetes of the patient.
www.mannkindcorp.com/Collateral/Documents/English-US/DOM%20GLP-1%20CMC%20PK%20PD%20paper.pdf
Evaluation of novel particles as an inhalation system for GLP-1
A. Leone-Bay, M. Grant, S. Greene, G. Stowell, S. Daniels, A. Smithson, S. Villanueva,
S. Cope, K. Carrera, S. Reyes and P. Richardson
MannKind Corporation, Valencia, CA, USA
professional.diabetes.org/Abstracts_Display.aspx?TYP=1&CID=74463
Inhaled GLP-1 and Exenatide: Different Effects on Pancreatic and Gastric Activity
Year: 2009
Abstract Number: 160-OR
Authors: ROBERT A. BAUGHMAN, DONALD J. COSTELLO, MARK T. MARINO, JAMES P. CASSIDY, ANDERS H. BOSS, CHRISTINE A. DAMICO, PAMELA C. HAWORTH, PETER C. RICHARDSON, JEROEN VAN DE WETERING DE ROOIJ, ANDRE A. VAN VLIET
Institutions: Valencia, CA, Zuidlaren, The Netherlands
Results: MKC253 is GLP-1 adsorbed onto Technosphere® microparticles for oral inhalation. This double-blind, double-dummy, placebo and active control crossover trial compared the effects of MKC253 (1.5 mg) and subcutaneous injection of exenatide (EXE; 10 µg) on postprandial glucose (PPG) excursions, postprandial insulin, gastric emptying, and GLP-1 pharmacokinetics. Included were 20 nonsmoking subjects with type 2 diabetes (A1C 6.2%-8.5%) on a stable oral antidiabetic regimen. Subjects received 5 treatments 2 days apart. All received MKC253 or inhaled placebo (InhP) while fasting. EXE or placebo sc (SCP) was given 15 min premeal, and MKC253 or InhP was given premeal (Pre) or 30 min postmeal (Post). Subjects received in randomized order: SCP + MKC253 Pre + InhP Post; SCP + MKC253 Pre + MKC253 Post; EXE + InhP Pre+InhP Post; or SCP + InhP Pre + InhP Post. Gastric emptying was measured by absorption of 13C-octanoate from a 575 Kcal standardized meal. MKC253 produced a rapid spike in insulin. Mean insulin Cmax occurred <10 min after dosing and fell sharply thereafter. Mean peak insulin was 60 µU/mL. Mean PK of insulin release closely tracked mean GLP-1 kinetics. The insulin response following EXE was slower and less pronounced. In fasting subjects with baseline glucose <9 mmol/L, MKC253 produced a mean maximal decrease in glucose of 0.75 mmol/L about 30 min after inhalation. Subjects with baseline glucose >9 mmol/L had a 1.2 mmol/L decrease in glucose approx. 45 min after inhalation. MKC253 reduced PPG excursions. Compared with InhP, MKC253 Pre decreased PPG by ≥1 mM/L for >1 hr and MKC253 Pre + Post decreased PPG for >3 hr. Reductions were longer than that predicted by a GLP-1 t1/2 of <2 min. MKC253 had little or no effect on gastric emptying. In contrast, EXE also reduced PPG but acted by delaying gastric emptying. More than 90% of 13C ingested was unabsorbed 4 hr after the meal compared with <60% with MKC253. After EXE injection, insulin response to meal challenge was much smaller than with MKC253. Only 1 of 20 subjects reported nausea with MKC253 vs rates >66% from literature with injected GLP-1. Both MKC253 and EXE reduce PPG excursions, but appear to do so by different mechanisms.
books.google.com/books?id=nN9sBgAAQBAJ&pg=PA35&lpg=PA35&dq=inhaled+glp-1&source=bl&ots=TPNLjCxtDB&sig=0qXUe4f2dry_IcmWsKD9YnKunSo&hl=en&sa=X&ved=0CE0Q6AEwBWoVChMItuGomfybyQIVRjeICh2MAw06#v=onepage&q=inhaled%20glp-1&f=false
Environmental Biomedicine - Page 35 - Google Books Result
books.google.com/books?isbn=3319146904
Mieczyslaw Pokorski - 2015 - Science
In the treatment period, patients received five different treatments (I: 1.5 mg GLP-1 as MKC253 inhalation powder or Technosphere® inhalation powder with..
www.biotechduediligence.com/mnkd.html
In consideration for the rights granted to Sanofi by us under the Sanofi License Agreement, upon effectiveness of the Sanofi License Agreement, we will receive an upfront payment of $150.0 million. If certain manufacturing, regulatory and sales milestones are achieved, we will also eligible to receive up to $775.0 million in milestone payments, of which $75.0 million in milestone payments relate to certain development and manufacturing milestone events, $50.0 million in milestone payments relate to the filing and completion of regulatory approvals and $650.0 million in milestone payments relate to the achievement of certain product sales milestones. In addition, worldwide profits and losses be shared 65% by Sanofi and 35% by us.
[$25M remained for Qualifying Sny's insulin for Afrezza. $30M for EU, $20M for Japan approval. $250M for annual Afrezza sale of first $250M probably, dollar bonus for dollar rev.]
Under the terms of the Sanofi License Agreement, we granted to Sanofi a right of first negotiation in the event we propose to grant to any third party a license to develop or exploit an inhaled glucagon-like peptide-1 agonist. In addition, if our board of directors determines to pursue a change of control of MannKind, we will be required notify Sanofi of such determination within a certain period of time so that Sanofi may, at is discretion, negotiate with us for a potential acquisition of MannKind by Sanofi.
In addition, we received a commitment letter from an affiliate of Sanofi to provide the Sanofi Loan Facility. The commitment letter provides for a $175.0 million secured revolving loan facility to fund our share of net losses under the Sanofi License Agreement. Pursuant to the commitment letter, loans under the Sanofi Loan Facility would bear interest at a rate of 8.5% per annum, paid-in-kind on a quarterly basis (2.06% per quarter compounded) and would become due and payable in full on the tenth anniversary of the effective date of the Sanofi License Agreement. We would be required to prepay any loans with net profits received under the Sanofi License Agreement. The commitment letter provides that our obligations under the Sanofi Loan Facility would be secured by a first priority mortgage on our facility in Valencia, California, a first priority security interest in certain insulin inventory located at our facility in Danbury, Connecticut and any contractual rights and obligations pursuant to which we purchase or have purchased such insulin, and a second priority security interest in our assets that secure our obligations under the Facility Agreement. The commitment is subject to customary conditions, including the effectiveness of the Sanofi License Agreement, the finalization of loan documentation and the entry into satisfactory intercreditor agreement with Deerfield.
The effectiveness of the Sanofi License Agreement and the Supply Agreement is contingent upon satisfaction of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, as amended, and the entry into the definitive loan documents relating to the Sanofi Loan Facility (unless we terminate the commitment letter for the Sanofi Loan Facility).
The Sanofi License Agreement will remain in effect unless either party terminates the Sanofi License Agreement in accordance with its terms. Either party may terminate the Sanofi License Agreement for a material breach the other party if such breach remains uncured for 90 days, or 45 days in the case of a non-payment breach; provided that if Sanofi breaches the Sanofi License Agreement for failure to comply with its obligation to use commercially reasonable efforts to file for, obtain and maintain regulatory approval for AFREZZA in certain major markets and countries and to market, promote and commercialize AFREZZA in countries where regulatory approval has been received, as set forth in the Sanofi License Agreement, with respect to (i) the United States, we may terminate the Sanofi License Agreement in its entirety, and (ii) certain major markets or countries, we may terminate the Sanofi License Agreement only with respect to such markets or countries and not in its entirety. Either party may also terminate the Sanofi License Agreement upon written notice to the other party in the event of the other party’s insolvency. Sanofi may terminate the Sanofi License Agreement at any time on or after January 1, 2016 (a) upon 90 days’ written notice if Sanofi determines in good faith that the commercialization of AFREZZA is no longer economically viable in the United States, and (b) without cause upon six months’ written notice in its entirety or on a country-by-country basis other than with respect to the United States, subject to certain exceptions. In addition, Sanofi may terminate the Sanofi License Agreement on a country-by-country basis upon 30 days’ written notice for certain safety or regulatory reasons.
