Monday, January 30, 2012
Afrezza is the first ultra-fast-acting insulin, a new class of prandial insulins. It achieves much more physiologic pharmacokinetics because MannKind has been able for the first time to create a stable formulation of regular human insulin monomers --- the very same single molecule of insulin that is released from a healthy pancreas to metabolize glucose, the fuel of the body. Afrezza peaks in less than 15 minutes and is virtually gone in less than 3 hours, compared to a peak in over an hour for the best rapid-acting insulin analogs and persistence of 5 – 7 hours. The physiologic kinetics of Afrezza far better address the clinical problems with current insulins. Moreover, rather than requiring injections, Afrezza, as a powder, is delivered by inhalation using a tiny, simple, discreet, breath-activated device --- another benefit.
So if Afrezza is so great why has it not yet been approved? That is a fascinating story. It seems that it was about to be approved over a year ago. Then the decision was reversed and a Complete Response Letter (“CRL”) was issued by the FDA asking for two additional trials. After already a year since the CRL, that action is delaying approval for about another 1½ to 2 years, depriving patients from access to this game-changing treatment and damaging MannKind and the thousands of investors in that company. What happened to change the FDA’s decision to approve this unique therapy last January?
The answers to that question are very interesting. As said above, Afrezza was about to be approved at the end of 2010. The FDA utilizes a confidential intranet for communication to its enormous staff. In late December 2010 when the FDA was about to approve Afrezza the decision was disseminated on the agency’s confidential intranet. Chang Yi Liang, a chemist at the FDA with access to the FDA intranet, noted the imminent approval and purchased 18,000 shares of MannKind at $8.41 per share. It has been learned that Mr. Liang had a history of improperly using confidential FDA information for personal gain. He has been arrested and is in jail awaiting trial for breaching the “Standards of Ethical Conduct for Employees of the HHS – Conduct on the Job – Use of Official Information.” He has been indicted for “unlawful insider trading in advance of 27 different announcements concerning FDA decisions on drug applications involving 19 different publicly-traded companies.” Liang profited on all those purchases except for the purchase of those 18,000 shares of MannKind that he bought for $8.41 on January 4, expecting imminent approval.
On that date the FDA was reconsidering its decision to approve Afrezza. The question that ultimately led to the change of direction had not yet been inserted into the confidential FDA intranet. What initiated that reevaluation? That is another fascinating part of the story. It turns out that at 7:02 PM on Christmas Day, Saturday, December 25, 2010, Martin Shkreli, the principal of MSMB Capital Management, wrote a letter addressed to 12 senior people in the FDA asserting among other things “that approval of Afrezza without a new clinical program …….. does not comply with the FDA’s mandate to secure public health interests. Specifically, the sponsor requested an inhaler for commercial approval without appropriately studying its efficacy and safety.”
MSMB is a hedge fund notorious for short selling stocks of early stage public biopharmaceutical companies. Mr. Shkreli often publishes negative reports on companies whose stocks he has shorted. MannKind is but one of a number of such companies that Mr. Shkreli has thus damaged. Such market manipulation is illegal and on January 26, 2012 CREW (Citizens for Responsibility and Ethics in Washington) wrote to Roleart Khuzami, Director of the SEC’s Division of Enforcement, requesting an investigation into “short-selling activities of Mr. Shkreli and possibly others to determine if there has been illegal manipulation of the market price of stocks in the biotechnology and pharmaceutical industries.”
Surely Mr. Shkreli’s Christmas day letter to the FDA had a significant impact, so there is no doubt that he succeeded in his objective to cancel approval and thereby trash MannKind’s stock. The FDA staff is under extraordinary pressure. If they do not explore every question regarding a drug and if that drug ever encounters a safety problem after approval, they must face aggressive, acrimonious questioning by Congress for many weeks. Thus there is a strong incentive for the staff not to approve a drug if there is any unanswered question.
In extensive clinical trials Afrezza has shown absolutely no safety signals and has demonstrated important improved clinical benefits. MannKind had been developing its new, superior inhalation and did resubmit its NDA with the improved device. The company relied on a carefully conducted bioequivalency trial which showed that the new device quickly delivers the same amount of the same powder through the lungs into the blood where the clinical efficacy can be easily measured. Scientifically there is no justification for requiring the extended trial demanded by Shkreli.
Nevertheless, the FDA staff was faced with the demand from Shkreli. The agency pondered over the situation for several days. On December 28 they apparently contacted MannKind saying that they would need several additional weeks to complete the review of Afrezza. Then, on January 18 they issued a CRL primarily requiring a small clinical study bridging the new device to the long-term pivotal study that was conducted with the earlier inhalation device.
Reversal of the approval decision and the intention to issue a CRL was then added to the FDA’s intranet record that was seen on January 19 by the chemist, Chang Yi Liang. That was the day when the FDA was preparing to make a public announcement of the CRL. At 3:34 PM on January 18, just before the market close, Mr. Liang sold his 18,000 shares at about $5.07 per share, limiting his loss to $60,047. The next morning, MannKind issued a press release announcing the CRL. The stock subsequently dropped to as low as $2.20.
The regulatory effect of the CRL is to delay the approval of Afrezza probably until the second half of 2013. From what has been published, the two trials being conducted seem simple and almost without risk. The company has announced that before starting those trials it wanted complete agreement with the FDA. The trials were therefore not initiated until there was agreement on the protocols. The trial in type 1 includes three cohorts, two with the two devices and one with standard injection therapy. In the many completed trials Afrezza has been shown to be superior in many measures, but in HbA1c only non-inferiority. The company has said that the agreed protocol includes tools to ensure compliance, and they say that this will enable this trial to show advantages in that last measure as well. This time MannKind hints it may even be able to show superiority in this measure.
The FDA has also guided MannKind to do a second study to show superiority in early-stage type 2 patients. This is amazing --- it should enable Afrezza to be launched initially with a label allowing it to be promoted to almost the entire diabetic population.
In closing, it is clear that a better prandial insulin is needed. In an extensive survey of diabetologists by Close Concerns, 94% said a faster-acting insulin is needed and only 4% said not. To another question 95% of the clinicians said they would use Afrezza in their practices after approval. Afrezza is a game-changing product and surely will be approved. No safety signals have been reported and this product has already been shown to fill a poorly-met and significant need. The delay in approval for almost 3 years will cost a great deal of money. Nevertheless, in a couple of years most early type 2 diabetics will be able just to take a simple puff at mealtimes. How simple, how discreet and how much better. Type 1s and late-stage type 2s will still need a basal insulin. Hopefully some company will develop a simple basal pump that will be easy to use and will not add significantly to the cost.
The legal challenges against Liang and Shkreli will proceed. Although their actions have damaged MannKind, its stockholders and the diabetic community, perhaps this experience will lead to a more sensible regulatory process in which the FDA staff is given the freedom to use their judgment in approval of medical products without the fear of abuse by the press and the Congress.
There are two parts to this possible scandal about Afrezza, one involving Cheng Yi Liang, a chemist at the FDA's Center for Disease Evaluation and Research and the second and most compelling has to do with Martin Shkreli who is chief investment officer for Kew York based hedge fund MSMB Capital Management, LLC
Cheng Yi Liang has been charged by the Securities and Exchange Commission in United States District Court for making 27 trades in 19 companies in advance of announcements concerning the FDA's decision on these drug applications. Liang typically began building his stock positions 2-3 weeks prior to PDUFA date using non-public details and results of FDA reviews. One thing is certain, by virtue of his position within the CDER, Liang was privy to confidential FDA information including impending decisions regarding approvals. Liang had computer access to nonpublic FDA information of the review process for each drug.
Mannkind Corporation was one of the companies in which Liang bought stock using this non‑public information. He used that information when he purchased 18,000 shares of MannKind stock before the PDUFA date knowing the FDA was planning on approving Afrezza. The PDUFA date for Afrezza was December 29, 2010 but at the last moment, MannKind received an action date delay of 3-4 weeks. With that being said, Liang, with his advance details of the FDA review, knew MannKind's Afrezza was on track for approval. This is consistent with Mann Kind's comments that the dialogue with the agency has been positive, and that there is no reason to believe that we will not get approval.
Now the second part of this scandal. It involves Martin Shkreli, chief investment officer for New York based hedge fund, MSMB Capital Management, LLC. MSMB is notorious for short selling stocks and then creating questionable issues and making negative public comments and projections to drive down the stock price of the companies. In some cases, such as Mannkind, he went further for self gain. CREW, the Citizens for Responsibility and Ethics in Washington has requested that the Security and Exchange Commission open an investigation of Martin Shkreli who appears to be illegally manipulating the market prices of stocks in the biotechnology and pharmaceutical industries. CREW claims Martin Shkreli has attempted to insert himself into the FDA approval process of at least 4 pending drugs in which he held a short position by contacting several FDA officials and working behind the scenes to affect the outcome of the FDA regulatory process. His claims to the FDA, arguably were biased and possibly fraudulent. Regardless, the FDA is supposed to rely on their own review by its medical doctors, chemists, statisticians, microbiologists, pharmacologists and their other experts and not a letter by an outsider who was trying to manipulate the FDA so that he would make millions if the FDA gives a negative response.
The FDA review process is supposed to be nonpublic information, but on December 25, 2010, Martin Shkreli emailed 12 FDA officials including Margaret Hamburg, Janet Woodcock, Mary Parks among others asking that the FDA deny MannKind's Afrezza application. Very coincidental, three days later and one day before PDUFA, Mannkind is informed by FDA on December 28, that they will need 3-4 additional weeks to complete the review. Then on January 18, 2011 MannKind received a Complete Response Letter from FDA. The principal issue raised by the FDA concerned the data to bridge the Gen2 (Dreamboat) inhaler and the MedTone used in the phase 3 trials. This in itself is very concerning given that the FDA told MannKind in a meeting that they would accept the bioequivalence trial to bridge the two devices and when MannKind submitted the trial, the FDA accepted it. There has never been a question about safety of Afrezza.
So in conclusion it seems clear based on Liang's method of operation that he purchased MannKind stock knowing from the confidential internal FDA files that Mannkind's Afrezza was on track to be approved. Then Martin Shkreli sends emails to 12 FDA officials on December 25, 2010. On December 28, MannKind is notified they need 3-4 more weeks. Three weeks later on January 18, 2011 MannKind receives a CRL. So one has to ask, what unlawful undue influence Martin Shkreli had on the FDA to change their decision when outside influence should never come into play. One can only imagine when so much serious money is on the line.
No matter how you look at this scandalous sequence of events, I think Martin Shkreli and his company should be thoroughly investigated and the FDA also has some explaining to do. Other than MannKind and its shareholders, the only people that got hurt by this are the tens of millions of diabetics that would benefit by this clearly superior therapy than anything currently on the market.
1) SEC investigation against Cheng Liang: http://www.sec.gov/litigation/complaints/2011/comp21907.pdf
2) CREW requesting SEC to investigate against Martin Shkreli
Sunday, January 29, 2012
Betting on the FDA rather than MannKind has earned short-sellers tidy sums over the years. However, the thought that an inhalable insulin has no place in the pharmacopeia for diabetes is ludicrous. That position only suggests that there is a lack of understanding of the worldwide diabetes epidemic and the therapeutic options that are currently available. I suggest reading the most comprehensive scientific analysis of AFREZZA to date --- it was published last November by Keith Markey, Science Director at Griffin Securities.
If you take the time to read it, you’ll see that today’s medicines are inadequate to prevent the serious complications associated with diabetes and are incapable of slowing disease progress.
Several factors give AFREZZA the potential to address these unmet medical needs. For one, the drug is based on the physiologic, natural and most effective compound known to control glucose levels, natural insulin. Every formulation of insulin ever commercialized thus far has relied on a zinc-stabilized hexameric version of the hormone and that preparation takes time to be absorbed. MannKind uses a patented delivery molecule called Technosphere to stabilize natural monomeric insulin and a simple, proprietary device to deliver the powder into and quickly out of the lungs rapidly entering the bloodstream. Thus, AFREZZA delivers the very same natural insulin used by the body in response to food consumption when it is almost immediately available and delivers it in a manner that closely replicates its release from the healthy pancreas. MannKind has consistently found that its drug causes fewer episodes of hypoglycemia. Indeed, one clinical study showed that type 2 diabetics could take their normal dose of AFREZZA at the start of a meal and then even skip the meal entirely without suffering dangerously low glucose levels. As a result, AFREZZA should give most diabetics considerable latitude in matching the amount of insulin taken prior to a meal with the number of calories subsequently consumed. In fact, that trial showed that with the very same dose prescribed for a patient, that patient can eat nothing or almost anything up to a huge, carbohydrate-rich meal without experiencing serious high or low glucose values.
Another study has shown that AFREZZA can be administered two hours after a meal to help prevent hyperglycemia, should conditions warrant. No other diabetes medicine offers such flexibility. There is one other aspect of AFREZZA that needs to be considered and that is its ease of use. Most type 2 diabetics postpone the use of insulin as long as possible. AFREZZA does not require the injections that so many diabetics fear and it does not cause the weight gain that comes with today’s insulin formulations. But then, I nearly forgot --- many short-sellers simply refuse to believe the results obtained from AFREZZA clinical trials.
The two trials that MannKind is conducting go beyond simply providing evidence to gain regulatory approval of AFREZZA. The MKC-171 trial has been designed with FDA guidance not only to demonstrate that two inhalers (an early generation and more recent model) are equivalent in a clinical setting, but also to show that AFREZZA is superior to widely-used short-acting insulin analog in controlling postprandial glucose levels and with fewer episodes of hypoglycemia. But even if it merely increases patient compliance and reduces hypoglycemia, the drug would constitute a significant improvement in diabetes care. Moreover, this trial will satisfy the requirements of the European Medicines Agency, thus setting the stage for AFREZZA’s entry into Europe. The MKC-175 study with guidance from FDA is designed to prove AFREZZA’s clinical benefit to early-stage, type 2 diabetics who are insulin-naïve when it is added to their existing regimens of one or two oral antidiabetes drugs. Since the first medicines prescribed for type 2 diabetics usually are inadequate within 1 - 3 years after initiation of therapy, the MKC-175 trial will open most of the diabetes market to AFREZZA. More important, MannKind’s drug has the right attributes to be used as an intensive therapy to prevent the hyperglycemic episodes that gradually destroy the pancreatic beta cells, thereby causing disease progression, and that lead to serious diabetes-related complications.
It is true MannKind will need to raise additional funds to sustain operations, including the clinical trials, until AFREZZA’s launch. The financing efforts that have been undertaken thus far might be considered unorthodox, as management has sought to raise funds in the debt market. But current stockholders should appreciate the work as an attempt to avoid a dilutive equity financing. So far, the debt deal has not been completed. But Al Mann, who is the company’s CEO and largest stockholder with nearly $1 billion invested personally, has extended the terms of a credit line into March 2013. Meanwhile, MannKind has been talking with potential marketing partners, and the CEO has reported that considerable progress has been made. Such an agreement might come with an upfront payment, but even if it didn’t, it would certainly have a positive effect on the stock price. And that would lower the cost of capital in the equity markets and it might even facilitate a bond deal.
Overall, MannKind is working on behalf of its stockholders. The ongoing clinical trials are designed to support AFREZZA’s approval both in the US and also in Europe to expand the market to include early-stage type 2 diabetics, and to provide evidence of superiority over short-acting insulin analogs in preventing hyperglycemia, hypoglycemia and weight gain also to show better average control (i.e. A1cs). Financing efforts have focused on non-dilutive or minimally dilutive sources of capital, while partnering discussions have been held to secure international marketing support for AFREZZA. It doesn’t seem like investors can ask for much more at this point.
Wednesday, January 25, 2012
Thursday, January 12, 2012
Jan 1, 2011
The pulmonary market represents about $25 billion sales per annum--approximately 3% of the global pharma market sales ($837 billion, 2009). The main chronic therapies addressed by this delivery route are asthma and chronic obstructive pulmonary disease (COPD), which affect a patient population of 350 million. The nasal market represents $7.1 billion sales per annum, but it implies many more therapies, such as allergic rhinitis (42% share), nasal systemic therapies (for example, pain, migrain) and nasal over-the-counter (OTC) medications, each about 30%. Both the pulmonary and the nasal drug markets have experienced a growth in terms of units though the values of these market segments (in USD) are affected by the somehow recent generic penetration.
For asthma and COPD, there are two key portable inhaler platforms available. Pressurized metered-dose inhalers (pMDIs) are still the gold standard representing more than two thirds of the drug products (in volume) while dry powder inhalers (DPIs) represent about 25% and the remaining being soft mist inhalers. A combination of reliability, accuracy and reproducibility of dosing, as well as patient familiarity, convenience and cost effectiveness has made pMDIs a pulmonary drug delivery success.
A significant proportion of patients prefer DPIs to pMDIs, which are breath-actuated and require 'hand-lung coordination.' There are, however, notable geographical and demographic variations in DPI and pMDI preferences. In addition to these two dominating technology platforms, a third portable inhaler technology called Soft Mist Inhalers is making inroads in this market segment. The pulmonary market represents about $25 billion sales per annum--approximately 3% of the global pharma market sales ($837 billion, 2009). The main chronic therapies addressed by this delivery route are asthma and chronic obstructive pulmonary disease (COPD), which affect a patient population of 350 million. The nasal market represents $7.1 billion sales per annum, but it implies many more therapies, such as allergic rhinitis (42% share), nasal systemic therapies (for example, pain, migrain) and nasal over-the-counter (OTC) medications, each about 30%. Both the pulmonary and the nasal drug markets have experienced a growth in terms of units though the values of these market segments (in USD) are affected by the somehow recent generic penetration.
Future Key Drivers
Patient compliance is a major issue in the long-term management of chronic diseases. Poor patient compliance with a prescribed drug regimen could result in ineffective therapy management and eventually dangerous health consequences with cost implications as well. When designed with a patient-centric approach and quality-by-design principles, an adequate drug delivery device can contribute to enhance patient compliance. The development of the novel side-actuated device Latitude for nasal sprays, which leveraged frequent medical research to drive better convenience, is one example of practical patient-driven innovation.
Another example is the development of cost-effective dose indicators and counters for pMDIs. These are designed to meet regulatory guidelines and help improve patient compliance, which in turn increase drug effectiveness and reduce the overall cost of chronic respiratory therapy to healthcare providers.
The application of innovative IT, electronics and communications solutions to healthcare is an area of growing interest and is seen as a potential market opportunity. During the next 10 years or so, the introduction of innovative e-health telemedicine and personal health records is expected to facilitate access to healthcare, help prevent disease, and improve the monitoring and control of chronic conditions.
Realtime monitoring of pMDI use by asthma patients is on the horizon, allowing both patients and doctors to receive warning of changes in device use patterns that might indicate a change in a patient's medical condition. In the longer term, electronics solutions are likely to enable the creation of new delivery devices with new functions and widespread connectivity.
by Michael J. Cawley, PharmD, RPh, RRT, CPFT
Pulmonary drug delivery will continue to evolve, and respiratory care practitioners are on the forefront to assist and potentially administer future pharmacotherapeutic agents.
Pulmonary drug delivery continues to be an exciting and evolving method for new pharmaceutical agents. Recent data has estimated that the global pulmonary drug delivery technologies market may reach US$37.7 billion by 2015.1 Aerosol-based formulations offer a number of advantages, including limited systemic side effect profile, alternatives to self-injections, and limited dependence on infusion delivery devices. Based on this need, the pharmaceutical industry is investing major resources in aerosol drug delivery and biotechnology, including research in particle engineering, dry powder formulations, protein and peptide-based therapeutics, dispersion technology, drug delivery methods, and drug delivery device design. This research is leading to a frontier of newer pharmacotherapeutic alternatives to be administered for aerosol delivery. These comprise antibiotics, antidiabetic agents, analgesics, antiemetics, nicotine replacement, hormone therapy, and vaccines. As pharmaceutical technology advances, the future of pulmonary drug delivery via aerosol will continue to represent another alternative delivery method for patients. The potential result of this new technology is improvement in health care-related outcomes, including decreasing disease-related patient morbidity and mortality.
Aerosol Aztreonam (Cayston®)
Aztreonam is a monobactam antibacterial antibiotic, which has been traditionally administered via the intravenous route for patients with infections involving Gram-negative pathogens including Pseudomonas aeruginosa, Haemophilus influenzae, Proteus mirabilis, and Escherichia coli. The drug is traditionally administered in adults as a 30-minute IV infusion every 8 to 12 hours.2 Based on its effectiveness for Gram-negative pathogens within the lungs and unique chemical structure, studies ensued to determine its effectiveness as an aerosol formulation. Gilead Sciences Inc (Foster City, Calif) received US Food and Drug Administration (FDA) approval in February 2010 for Cayston (aztreonam lysine for inhalation or AZLI). Aztreonam lysine for inhalation is indicated to improve respiratory symptoms in cystic fibrosis patients >7 years of age with P. aeruginosa infection in the lungs.3 Aztreonam lysine has been studied in multiple phase 2, phase 3 (AIR-CF1, AIR-CF2, and AIR-CF3), and phase 3b (AIR-CF4) studies. Results of the studies demonstrated that AZLI significantly improved respiratory symptoms, pulmonary function, and sputum P. aeruginosa density compared with placebo.4-7 When used after a course of tobramycin inhalation, it delayed the time to need intravenous antipseudomonal agents.5 Aztreonam lysine is a sterile lyophilized powder in a vial with a 1 ml ampule of sterile solvent. After both are reconstituted, the nebulizer solution contains 75 mg aztreonam lysine formulation. The drug is administered as 75 mg three times daily over a period of 28 days and is delivered via the Altera Nebulizer System®, which delivers the 75 mg dose over a period of 2 to 3 minutes.8-9 The minimum interval is 4 hours between doses, and the minimum AZLI free period between treatment courses is 28 days.3 This Altera Nebulizer System uses the eFlow® Technology Platform, developed by PARI Pharma GmbH. The eFlow technology is a vibrating perforated membrane with thousands of holes that produce the aerosol mist. The drug should be used only in the Altera Nebulizer System and should not be mixed with any other drugs in the nebulizer device. A short-acting bronchodilator is recommended before administering AZLI. The most frequent adverse effects (>10% of patients) include cough, wheezing, nasal congestion, or pharyngolaryngeal pain. Caution is advised in patients with a documented allergy to beta-lactam antibiotics, such as penicillins, cephalosporins, and/or carbapenems, since cross-reactivity may occur.
Dulera® (mometasone furoate/formoterol fumarate dihydrate)
Dulera is a combination inhaled corticosteroid (mometasone furoate) with a long-acting beta2-agonist (formoterol fumarate dihydrate). Merck Pharmaceuticals (Whitehouse Station, NJ) received FDA approval in the United States in June 2010 for mometasone furoate/formoterol fumarate dihydrate (MF/F).10 Mometasone furoate/formoterol fumarate dihydrate is a new fixed-dose combination asthma treatment for patients 12 years of age or older. A 26-week placebo-controlled trial evaluated 781 patients 12 years of age and older comparing MF/F 100 µg/5 µg (n=191 patients), mometasone furoate 100 µg (n=192 patients), formoterol fumarate 5 µg (n=202 patients), and placebo (n=196 patients), each administered as two inhalations twice daily by MDI. Mometasone furoate/formoterol fumarate dihydrate 100 µg/5 µg demonstrated significant improvement in FEV1 from baseline to week 12 compared to placebo (0.13 L vs -0.05 L, P < 0.001). Secondary endpoints also demonstrated improvements in nocturnal awakenings (-60% vs -15%), change in total rescue medication use (-0.6% vs +1.1 puffs/day), change in morning peak flow (+18.1 vs -28.4 L/min), and change in evening peak flow (+10.8 vs -32.1 L/min) of MF/F compared to placebo.11 In a 12-week, randomized, multicenter, double-blind, parallel-group study, patients >12 years of age were randomized to MF/F 200 µg/10 µg, MF/F 400 µg/10 µg, or MF 400 µg twice daily after a 2- to 3-week open-label run-in with MF 400 µg twice daily; 728 were randomized. Significant improvement in baseline to week 12 occurred in FEV1 with MF/F 400 µg/10 µg versus MF 400 µg (4.19 L/hr vs 2.04 L/hr; P < 0.001). Both MF/F doses were superior to MF in improving asthma control and decreasing nocturnal awakenings due to asthma requiring short-acting beta agonist use.12 Mometasone furoate/formoterol fumarate dihydrate is available in two strengths: 100 µg/5 µg and 200 µg/5 µg. It is supplied as a pressurized aluminum canister. The canister is equipped with a dose counter that will display "124" actuations at purchase. Before initiating the first dose, the patient should proceed with initial priming with four actuations, the dose counter will read "120," and the inhaler is now ready for use. A "black box" warning is included in the package insert that warns of asthma-related deaths associated with long-acting beta2 adrenergic agonists (LABA), such as formoterol, one of the active ingredients of MF/F.11 Although data has identified that MF/F is safe and well tolerated in patients with persistent asthma, other adverse effects that may occur include adrenal suppression, decreased bone mineral density, and immunosuppression.
Insulin (Exubera® and Afrezza®)
Insulin is one of many pharmaceutical agents to maintain glycemic control for diabetic patients. Diabetes is considered one of the fastest-growing disease entities in the United States, encompassing 23.6 million people (17.9 million diagnosed and 5.7 million undiagnosed) who represent 7.8% of the US population.13 Subcutaneous insulin injections and various classes of oral antidiabetic agents have been the two primary delivery methods for treatment of hyperglycemia in type 1 and type 2 diabetes mellitus. New advances in aerosol delivery have developed inhaled formulations to assist in glycemic control and to provide another therapeutic delivery method for patients. In February 2006, Pfizer Pharmaceuticals (Collegeville, Pa) in conjunction with Nektar Therapeutics (San Carlos, Calif) received FDA approval for their inhaled insulin product Exubera.14 Exubera was considered to be a potential blockbuster drug, with projections of US sales greater than $1 billion. Unfortunately, approximately 2 years after approval and dismal sales, Pfizer withdrew Exubera from the US market. Although the drug demonstrated efficacy in assisting in glycemic control, withdrawal was based on a number of factors, including patients requiring periodic pulmonary function testing due to potential pulmonary complications of the inhaled product, cumbersome apparatus that was not designed for portable transport, concern over lung cancer associated with its use, and losing US$2.8 billion in development costs.14-15 Although removal of Exubera was a major setback for the use of inhaled insulin, there is hope for another inhaled insulin product.
MannKind failed to win US approval for its first product, Afrezza (insulin human [rDNA origin]), an inhaled insulin for diabetes. The FDA wants the company to do two new studies of the device in patients with Type 1 and Type 2 diabetes. This action will delay the drug from coming on the market by 18 to 24 months, according to CEO Alfred Mann.
MannKind Pharmaceuticals (Valencia, Calif) completed phase 3 trials in 2009 and submitted a new drug application (NDA) to the FDA in May 2009 for the drug Afrezza (insulin human [rDNA origin]) inhalation powder.15 Insulin human (rDNA origin) is indicated for use in adult patients with type 1 and type 2 diabetes mellitus for the treatment of hyperglycemia. The drug was headed for FDA approval, when, in March 2010, the FDA asked for more information on the phase 3 trial as well as the delivery device.16 This agent has many advantages of Exubera, including a premetered, light, discreet delivery device. Further, peak insulin levels are achieved within 12 to 14 minutes after administration. Some experts estimate that insulin human (rDNA origin) will receive FDA approval in early 2011.