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Post by lakers on Dec 13, 2015 15:23:22 GMT -5
Primary Objective: -To assess the safety and tolerability of Afrezza in children ages 4 to 17 years with type 1 diabetes mellitus (T1DM). Secondary Objectives: To assess the ability to titrate the prandial and supplemental doses of Afrezza at each meal. [This coincides w/ meeting in SD last week w/ early adopters on titration and suppl doses, Dr Steve Edelman's Sanofi sponsored TCOY/CME traing tour Incl titration guidance, and Ultra RA patent on split doses] mnkd.proboards.com/thread/4459/hilton-santa-clara-ultra-afrezzaTo assess pharmacokinetics (PK) following a prandial dose of Afrezza in children ages 4 to 17 years with T1DM. The Pediatric Trial from beginning to end takes 8 weeks. All measurement except one can be completed after 30 days. Only one long pole measurement is anti-insulin antibodies which can be up to 13 mos. So if all go well, the Phase 1 trial can finish in much less than a year. MNholdem said: The FDA wants a 2-part pediatric trial, with the Part 1 for type 1 diabetes and Part 2 for types 1 or 2. Part 2 of the trial includes a 52-week randomized intervention phase. Here is the FDA description of the post-market requirement: An open-label pharmacokinetic (PK), and multiple-dose safety and tolerability dose-titration trial of Afrezza in pediatric patients ages 4 to 17 years (inclusive) with type 1 diabetes (Part 1), followed by a prospective, multicenter, open-label, randomized, controlled trial comparing the efficacy and safety of prandial Afrezza to prandial subcutaneous insulin aspart used in combination with subcutaneous basal insulin in pediatric patients 4 to 17 years old (inclusive) with type 1 or type 2 diabetes (Part 2). Part 2 of the trial should include a 4-week run-in phase and a 52-week randomized intervention phase. Sanofi has not published nor have they begun recruitment of a trial that studies the FDA requirements for Part 2 studies, but it looks to me that in order to meet your estimate of completing the pediatric trial(s) by August 2017, they would have to recruit and start the Part 2 pediatric trial by May/June 2016 at the latest. Read more: mnkd.proboards.com/thread/3511/afrezza-pediatrics-trial-recruiting?page=3#ixzz3uEe4medY
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Post by lakers on Dec 12, 2015 10:49:00 GMT -5
I'd nominate Dr James Shannon BoD, former GSK CMO to be Mnkd new CEO. Let the good news roll.
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Post by lakers on Dec 11, 2015 12:46:21 GMT -5
Mnkd most likely will get $25M dev for qualifying Sny's insulin in 1H16, $30M for EU approval in 2H16, ~$150M TS pain, migraine upfront in 1H16. Consider the later as more than likely as mgmt is obliged to keep Hakan's promise to avoid SH litigation. It's in Mnkd's interest to expand quickly in more Territories. With 12 Territories, if each sells $20.84M in the same calendar year (a low bar), Mnkd will get $250M milestone bonus. This is achievable in 2017. $20M for Japan approval could be in 2H16 or 1H17. More upfront licensing $$ for MS, antiemetic, PAH, cancer in 2H16 and 2017. Yes, thumbs up. lakers seems to have some kind of inside insight, and this seems like a pretty accurate list. But it is a wish list at this point. It's not only possible, but probable. Some are highly probable. Think Different!
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Post by lakers on Dec 11, 2015 12:22:25 GMT -5
Mnkd most likely will get $25M dev for qualifying Sny's insulin in 1H16, $30M for EU approval in 2H16, ~$150M TS pain, migraine upfront in 1H16. Consider the later as more than likely as mgmt is obliged to keep Hakan's promise to avoid SH litigation.
It's in Mnkd's interest to expand quickly in more Territories. With 12 Territories, if each sells $20.84M in the same calendar year (a low bar), Mnkd will get $250M milestone bonus. This is achievable in 2017.
$20M for Japan approval could be in 2H16 or 1H17. More upfront licensing $$ for MS, antiemetic, PAH, cancer in 2H16 and 2017.
All of these are not pies in the sky but realistic. In hindsight, I'd ask for $0.5B upfront for Afrezza. Al was so confident about Afrezza that he thought $650M sales bonus was achievable in first 3 years.
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Post by lakers on Dec 10, 2015 17:26:53 GMT -5
Title: USE OF ULTRARAPID ACTING INSULIN WIPO Patent Application WO/2015/148905 www.freepatentsonline.com/WO2015148905A1.htmlAbstract: Disclosed herein are improved methods of treating hyperglycemia with a combination of an ultrarapid acting insulin and insulin glargine comprising prandial administration of the ultrarapid insulin, and administration of a first dose of insulin glargine within 6 hours of waking for a day. Inventors: BOSS, Anders, Hasager (285 Cold Soil Road, Princeton, NJ, 08540, US) [ Former Mnkd CMO, now Sanofi's Senior Medical Director Diabetes and U.S. Medical Lead] Anders Boss Chief Medical Officer at MannKind Corporation United StatesBiotechnology Current Chief Medical Officer at MannKind Corporation Past VP Medical Affairs at Rheologics, Sr Medical Director at Takeda Pharmaceuticals, Medical Director at Novo Nordisk Education University of London, Københavns Universitet www.linkedin.com/pub/dir/Anders/Bosswww.healthline.com/diabetesmine/six-things-know-starting-afrezzaPETRUCCI, Richard (917 Silvermine Road, New Canaan, CT, 06840, US) Application Number: US2015/022956 Publication Date: 10/01/2015 Filing Date: 03/27/2015 Claims: What is claimed is: 1 . A method of treating higher than targeted pre-meal blood glucose comprising: regularly administering a split dose of an ultra rapid acting insulin formulation, the split dose including an initial dose taken at mealtime and a second dose of between 10% to 100% of the initial dosage taken 30 to 150 minutes after beginning a meal; wherein when pre-meal blood glucose for a next meal had been regularly greater than desired. 2. The method of claim 1 , wherein the second dose is taken 60-150 minutes after beginning a meal. 3. The method of claim 2, wherein the second dose is taken 90-150 minutes after beginning a meal. 4. The method of claim 1 , wherein said regularly greater than desired comprises pre-meal blood glucose levels of greater than 120 mg/dl for a majority of the pre-meal blood glucose tests within a given time period. 5. The method of claim 1 , wherein the pre-meal blood glucose is greater than 120 mg/dl. 6. The method of claim 4, wherein said regularly greater than desired comprises pre-meal blood glucose levels of greater than 140 mg/dl for a majority of the pre-meal blood glucose tests within a given time period. 7. The method of claim 1 , wherein the pre-meal blood glucose is greater than 140 mg/dl. 8. The method of claim 1 , wherein the pre-meal blood glucose is regularly greater than desired when at least three pre-meal blood glucose readings are taken within 10 days and are greater than 100 mg/dl. 9. The method of claim 8, wherein the pre-meal blood glucose is regularly greater than desired when at least three pre-meal blood glucose readings are taken within 5 days and are greater than 100 mg/dl . 10. A method of treating hyperglycemia comprising: administering a secondary dose of an ultra rapid acting insulin formulation 30 to 120 minutes after a mealtime dose comprising between 10% to 100% of an initial dose, wherein the secondary dose is titrated so that median blood glucose 1 to 2 hours after the secondary dose is less than 180 mg/dl. 1 1 . The method of claim 10 wherein the secondary dose is administered to a patient in which increasing the dosage of the mealtime dose produces an undesirably lesser, non-proportional reduction is blood glucose as compared to an unincreased mealtime dosage. 12. The method of any of the preceding claims wherein the ultra rapid acting insulin formulation comprises 3,6-di(succinyl-4-aminobutyl)-, 3,6-di(maleyl-4-aminobutyl)-, 3,6- di(glutaryl-4-aminobutyl)-, 3,6-di(malonyl-4-aminobutyl)-, 3,6-di(oxalyl-4-aminobutyl)-, or 3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine. 13. The method of any of the preceding claims wherein the ultra rapid acting insulin formulation comprises 3,6-di(fumaryl-4-aminobutyl)-2,5-diketopiperazine. 14. The method of any of the preceding claims wherein the ultra rapid acting insulin comprises human insulin. 15. The method of any of the preceding claims wherein administration is by inhalation. 16. The method of any of the preceding claims wherein administration is by pulmonary inhalation.
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Post by lakers on Dec 10, 2015 16:06:49 GMT -5
No, the FDA does not allow that. It is not like a supplement where you can show one person that has lost 100 lbs with small type at the bottom of the screen saying "results may vary". This would circumvent the entire FDA process... and it is bad science. You can't pick a group of users because they have been proactive in promoting benefits of Afrezza (i.e. in scientific experiment terms... self selection) and present that as expected results for a wider population. That said, I think in doctor to doctor education meetings they might be able to use observational anecdotes as long as it is clearly presented as anecdotal (perhaps some of our docs would know the constraints in that case). Also, I really do not think a study to show superiority would need to be huge, long and expensive. SNY simply needs to do that. That will be what allows a better label and better marketing material and adverts for consumers. The results of the early adopters are real and I certainly think they are more indicative of the potential of Afrezza than were the FDA clinical trials with their very suboptimal protocols. I thought there was a recent court ruling that said a pharma company can make product performance claims if they believed them to be true or had some type of supporting documentation beyond trials. I know this would be a can of worms, sorry I do not have the link for it. When you say superiority you mean lower A1c, less volatility in day to day blood glucose readings, weight loss or some or all of these combined with xx% reduction in basal dosage? Insulin Human (Afrezza) Compared with other rapid-acting insulins: • Peaks faster and offsets faster • When added to basal insulin, equivalent A1C lowering • Lower postprandial blood glucose • Less delayed hypoglycemia Can be used in Type 1 diabetes in addition to a basal insulin (long acting insulin or basal rate via an insulin pump) Can be used in Type 2 diabetes in addition to orals alone, orals and basal, or MDI regimens Clin. Ther., 2014;Vol 36:Number 8: 1275-1289. Read more: mnkd.proboards.com/thread/4459/hilton-santa-clara-ultra-afrezza#ixzz3txDZDhwE
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Post by lakers on Dec 10, 2015 12:35:20 GMT -5
Three New Insulins Recently Added To Our List Of Options* Both approved by the FDA and now available for patients 1. U-300 glargine (Toujeo) a long acting basal insulin 2. U-100/200 degludec (Tresiba) a long acting basal insulin 3. Technosphere Inhaled insulin (Afrezza) an ultra rapid acting inhaled insulin Prandial Dosing In Type 2 Diabetes • Start with 4 to 5 units or 10% of the total basal dose, of a rapid acting analog or inhaled insulin • Add 2 units every 3 days if median BS before the next meal or bedtime (only for the pre- dinner dose) until at goal (140 to 180mg/dl) • Add 1 unit every day if the BS before the next meal or bedtime (only for the pre-dinner dose) until at goal (140 to 180 mg/dl) • Reduce the dose by 2 units if patients has hypoglycemia below 70 mg/dl tcoyd.org/PDF/2015-postp-santaclara-slides.pdfInsulin Human (Afrezza) Compared with other rapid-acting insulins: • Peaks faster and offsets faster • When added to basal insulin, equivalent A1C lowering • Lower postprandial blood glucose • Less delayed hypoglycemia Can be used in Type 1 diabetes in addition to a basal insulin (long acting insulin or basal rate via an insulin pump) Can be used in Type 2 diabetes in addition to orals alone, orals and basal, or MDI regimens Clin. Ther., 2014;Vol 36:Number 8: 1275-1289. Prandial Dosing In Type 1 Insulin to Carbohydrate Ratio Calculation: I:CHO (Type 1 and Type 2 on MDI) } Start with a ratio of 1:15 for insulin sensitive type 1 diabetics } Start with a ratio of 1:10 for insulin resistant type 2 diabetics } Formula: divide Total daily insulin dose into 500 } Example: 34 year old male with type 1 diabetes currently on 25 units of glargine (Lantus) every night and 20 to 25 units of aspart (Novolog) each day: 500/50=10 So the initial Insulin to carb ratio is 1:10 Correction Factor (CF) or Insulin Sensitivity Factor (ISP) (Type 1 andn Type 2 on MDI) Giving your patients a correction factor is a very practical tool whether they are on a pump or not The CF is an estimate of how much the BS will drop with one unit of fast acting insulin The CF usually 1:50 for insulin sensitive (<50u) patients and 1:25 for insulin resistant patients The CF can be estimated by taking the total daily insulin dose and dividing it into 1800 (the 1800 rule) You also need to pick a target glucose level for the patient (between 100 and 150) Walsh JA, Roberts R. Pumping Insulin 5th edition. 2011 Example of Determining the Correction Factor • Used at meal time AND for unexpected hyperglycemia in between meals • 21 year old female on insulin glargine 15 units at night and taking approximately 15 – 20 units a day in boluses with insulin glulisine - (1800/35 units = 51)~ CF 1:50
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Post by lakers on Dec 10, 2015 3:11:00 GMT -5
Matt was right. It's a common practice to postpone the good news announcement until a new CEO is on board, then let him announce the good news to establish a credibility beachhead for him before SH and investment community. It looks like mgmt is obligated to keep Hakan's promise. They have to to avoid litigation.
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Post by lakers on Dec 5, 2015 14:16:42 GMT -5
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Post by lakers on Dec 4, 2015 12:37:08 GMT -5
Good luck with that. The way Sanofi is operating, attendees may have to sign a non-disclosure agreement to be admitted. Sam is bound by NDA jut as he was in the first sales trainiing before launch. Ditto some folks here. You know who you are. We shouldn't tempt them to talk.
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Post by lakers on Dec 4, 2015 3:25:24 GMT -5
Lyxumia's CV results may help Sanofi's case for approval, but they won't score it points against SGLT2s The New England Journal of Medicine has laid out the data from a cardiovascular outcomes trial of Sanofi's ($SNY) GLP-1 diabetes hopeful Lyxumia, and the good news for the French drugmaker is that the drug didn't raise the rate of major cardiovascular events in patients with acute coronary syndrome. But it didn't lower it, either. Results published Thursday show that 406 Lyxumia patients--13.4%--recorded a heart attack or stroke, were hospitalized for unstable angina, or died of cardiovascular causes, compared with 399 patients on placebo, or 13.2%. There were no significant differences in the rate of hospitalization for heart failure, either, and Lyxumia didn't increase serious side effects such as pancreatitis. Confirmation that the drug is safe is just what Sanofi was looking for when it pulled its Lyxumia FDA application back in 2013. At the time, the agency was tightening up on diabetes newcomers--wary of another safety scandal like the one spurred by GlaxoSmithKline's ($GSK) Avandia--and Sanofi decided to hold back until it had positive results from a CV outcomes trial. Sign up for our FREE newsletter for more news like this sent to your inbox! Problem is, since then, a drug from another class--Eli Lilly ($LLY) and Boehringer Ingelheim's SGLT2 entrant Jardiance--has shown it can do one better. In September, the partners rolled out data showing their med had cut the combined risk of heart attack, stroke, and death from cardiovascular causes by 14% in high-risk diabetes patients. But while those findings may heat up the competition, they don't necessarily mean doom for Lyxumia and its fellow GLP-1s--or other diabetes classes, for that matter. As Peter Stein--VP of clinical research in diabetes and endocrinology at DPP-4 powerhouse Merck--told FiercePharma earlier this year, "patients with diabetes need more than one agent, and often more than two agents, to get to goal." And earlier this week, Novo Nordisk ($NVO)--maker of GLP-1 superstar Victoza, which will compete with Lyxumia if Sanofi wins approval--unveiled a new meta-analysis showing that its med beat SGLT2s at reducing the blood sugar metric HbA1c. The analysis of 17 controlled trials suggested that patients using Victoza had a better chance of hitting their blood-sugar goals, too. Sanofi, for one, will have to hope its CV results don't set it back if and when it reaches the marketplace. Its diabetes sales are sagging already, and last month, the company announced plans to cut $1.6 billion in costs and hive off its animal health and European generics businesses to offset their drag on profits. www.fiercepharma.com/story/lyxumias-cv-results-may-help-sanofis-case-approval-they-wont-score-it-point/2015-12-03
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Post by lakers on Dec 4, 2015 1:58:38 GMT -5
China speeds up drug approval process, favoring high-quality generics China’s Food and Drug Administration (CFDA) recently issued a policy, aiming to shake off its long-term reputation for being extremely slow on new drug approvals, as well as largely improve the quality of Chinese made generics, reports The Pharma Letter’s local correspondent, Wang Fangqing. Under the policy, which was out on November 11 and took effect immediately, Abbreviated New Drug Applications (ANDA) are in principle reviewed and approved only if they are therapeutically equivalent to their brand-name version. If a brand-name drug is not available in China, the generic version manufacturer has to import it into China to conduct bioequivalence (BE) comparison tests. Previously, brand-name drugs were preferred, but not necessary as China allowed generic versions to be the reference. One serious result is the poor quality of Chinese-made generics, which “have great difference from the branded version,” according to a 2014 report by the RDPAC, the Beijing based lobbying organization for multinational pharmas in China. In 2009, the CFDA tested the high blood pressure treatment hydrochlorothiazide from five Chinese manufacturers, and had four very different dissolution profiles. Clinical data fraud With such a quality issue, perhaps it is not a surprise that clinical data fraud is not rare in China. In late October, the CFDA disclosed 11 ANDAs from eight Chinese manufacturers used fraudulent clinical data. Among them are the hypertension drug candesartan cilexetil tablets from Huahai Pharma, a leading Chinese pharma based in Linhai, Zhejiang province, azithromycin capsules from Yuansen pharma in Hebei province, and ibuprofen suspension drops from Shandong province-based Shandong Dayin Ocean Bio-Pharmaceutical. The new policy makes it clear that applicants using fraudulent data will be blacklisted and in some cases will be handled to the police for criminal investigations. To speed up the process for ANDA approvals, the CFDA reviewers now first review the comparative testing results, and reject any application failing to achieve the equivalence without going through other provided documents and testing data. Also, from December 1, drug manufacturers in China will be able to conduct BE testing without the approval from the CFDA. Since 2007, ANDA applicants have to get two approvals – one for BE testing, one for manufacturing – which largely delayed the process. The overwhelming amount of ANDAs of already oversupplied generics is another reason for the delay, said a CFDA official. “Companies complain about our low efficiency, but how about they stop filing these low-level ANDAs so we could cut some duplication of work?” he told the Pharma Letter, asking not to be identified. Most copied drugs Among the most copied drugs, are cefdinir, atorvastatin calcium and lurasidone, according to the CFDA, which receives about 7,000 new drug applications each year, the majority of which are ANDAs. With only 115 reviewers, it typically takes up to five years for a company to get an ANDA approval, and eight years for an NDA approval. In comparison, the US FDA has about 4,000 reviewers. The CFDA will soon release a list of the generics oversupplied by multiple manufacturers. ANDAs for these listed drugs, called “category 6 new drugs” in China, will be “suppressed.” The list will be updated regularly. Price of NDA and ANDA approvals increased Some measures to discourage such applications have already been taken. In May, the CFDA spiked the price for NDA and ANDA approvals. A company now has to pay 624,000 renminbi ($97,696) for an NDA approval for a Chinese-made drug, and 970,000 renminbi to bring an imported new drug into China, compared with the previous 48,300 renminbi for both. For ANDA approvals, the new price tag is 183,600 renminbi for Chinese-made drugs and 367,600 renminbi for imported drugs, while before companies were only charged less than 20,000 renminbi. The CFDA expects such a prick hike could rebuff low quality applicants. Meanwhile, the industry watchdog gives priority to ANDAs for drugs in urgent clinical demand, as well as for pediatric and geriatric treatment; NDAs for drugs in areas including oncology, AIDS, rare diseases and major infectious diseases. It also favors the imported novel drugs that will be manufactured inside China. A draft of detailed requirements for the drugs to receive such priority was released on November 13 for public comments.The deadline is December 13. www.thepharmaletter.com/article/china-speeds-up-drug-approval-process-favoring-high-quality-generics-by-wang-fangqing
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Post by lakers on Dec 4, 2015 1:47:48 GMT -5
China has a unique set of demographic, economic and genetic factors that make diabetes an epidemic there; the country is now considered to have the highest rates of this disease in the world, with half the population pre-diabetic. Over the last three decades, China gained economic strength, taking more than 500 million people from poverty and moving much of the country into middle class status but not without effects - more than 7% of the population of 1.4 billion developed diabetes due in part to a diet heavy in carbohydrates and salt, smoking, and inactivity. Worse, Chinese, with a tendency to store fat around the gut, are more susceptible to Type 2 diabetes and develop the disorder at a lower body mass index (BMI) than people of other ethnic origins. Coupled with this, pancreas beta cells, whose job is to store and release insulin, undergo more rapid deterioration with Chinese in early diabetes than those of different race backgrounds. So said, China has a highly vested interest in attacking the disease to uphold ongoing growth and stability. In an effort to bolster healthcare delivery, Chinese regulatory officials earlier this year issued new drug approval guidelines in hopes to shrink application backlogs and get medicine to more people, sooner. Good for Oramed, clinical study results for ORMD-0801 done elsewhere in the world will count towards approval, a big step for them in China given its lengthy regulatory process. Expedited review will also become available, as will easing of study trial rules. Prior to these positive changes, only drugs approved in other countries could be imported and Chinese patient data only considered in the approval process. All this points to a country where better solutions for diabetes has become paramount. www.marketwatch.com/story/50-million-plus-royalties-deal-indicates-blockbuster-future-for-orameds-oral-insulin-2015-12-01
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Post by lakers on Dec 2, 2015 15:22:41 GMT -5
Shorts is covering. They are smart not standing in front of 1Q16 international expansion and TS pipeline partnership. Follow the Smart Money.
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Post by lakers on Dec 2, 2015 11:39:32 GMT -5
Sanofi/MannKind does not want a rubber stamp, IMO. Unlike the FDA label, we want the EMA label to show superiority has been demonstrated. That may involve additional study data, unless the EMA interprets the FDA data differently, which wouldn't be likely. Depending on how Sny submits MAA, presents data, and EMA interpretes data, Afrezza can get a better label. Toujeo didn't get better hypo label in U.S. It did in EU. That's why Mnkd needs an old pro as a partner who knows how to play the game. Lower A1c data from Affinity 2 needs to be submitted to EMA and presented in a different light. It's not uncommon to have drugs get different labels in different Territories.
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