?Will pulmonary drug delivery achieve rich promise?

[cm5]

Will pulmonary drug delivery for systemic application ever fulfill its rich promise?
Expert Opinion on Drug Delivery
DOI:10.1080/17425247.2016.1218466
David Cipolla
Published online: 05 Aug 2016
www.tandfonline.com/doi/full/10.1080/17425247.2016.1218466

MannKind (Valencia, CA, USA) entered the inhaled insulin race late but was unfazed by the Pfizer termination of Exubera and continued development of Afrezza inhaled insulin in a small, palm-sized device, addressing the most obvious shortcoming of Exubera, its large size. Afrezza’s formulation adsorbs insulin to fumaryl diketopiperazine crystals, an excipient that increases insulin transcytosis in the lung, resulting in even more rapid absorption of insulin compared to the other inhaled insulins, a claimed potential advantage even to SC faster-acting insulin analogs [14]. The clinical development program was subsequently delayed due to a change from the MedTone to the Dreamboat inhaler requiring an additional Phase 3 trial in both T1D and T2D [15]. The clinical efficacy data from these trials for Afrezza met the primary end point of non-inferiority to SC rapid-acting insulin (insulin aspart) in prandial blood glucose lowering in T1D and had superior blood glucose lowering in T2D compared to inhaled placebo powder [14,15]. Additionally, in T1D, treatment with Afrezza resulted in significantly lower fasting plasma glucose levels, less hypoglycemia, and lower bodyweight gain [14,15]. For the dry powder insulin formulations, including both Exubera and Afrezza, cough was the most common adverse event compared to SC insulin [12,14,15]. Afrezza was approved by FDA in June 2014 with Sanofi (Bridgewater, NJ, USA) as the marketing partner [12]. Due to poor sales, Sanofi recently returned Afrezza marketing rights to MannKind who continues to market Afrezza. Does this spell the end for inhaled insulin?

Expert Opinion

The future of inhaled insulin certainly looks bleak from the commercial perspective; however, many diabetic patients on inhaled insulin continue to be strong advocates for the product. I believe that an opportunity exists not only for inhaled insulin, but also for use of the inhaled route to deliver systemic therapies, and I am not alone in that belief [12,13]. The perception that an opportunity exists is based not on projections of near-term commercial profit calculations, but on patients with medical needs who currently have inadequate treatment options (Table 1).

In diabetes, like many diseases, it takes time to educate patients and health-care personnel about the benefits of new therapies. Most patients already on injectable insulin are unlikely to switch to an alternative product, like inhaled insulin, until a long-term comfort level has developed, and that takes time. However, many T2D patients are not on injectable insulin, with an average delay of 5–10 years from diagnosis to insulin prescription, even though the recent guidelines recommend that insulin treatment be initiated within 2–3 months of diagnosis [12].

Delaying insulin treatment in T2D has profound health-care implications for both the individual, leading to increased morbidity and mortality, and society at large [12]. To change the established treatment paradigm, the focus should instead be on transitioning insulin-naive T2D patients onto inhaled insulin, if they are reluctant to transition to SC insulin which is a real concern for many patients [12]. But this strategy requires patience and a long-term focus [12].

References cites, with author's comments:

Patton JS, Porter L. Re-thinking inhaled insulin’s role in the global challenge to treat diabetes. In: Dalby RN, Byron PR, Peart J, et al., editors. Respiratory drug delivery Europe 2015. Vol. 2015. River Grove (IL): Davis Healthcare Int’l Publishing; 2013. p. 49–58, 237–242.

• Explanation for the marketing failure of Exubera and the future of inhaled insulin.

13. Hickey AJ. Back to the future: inhaled drug products. J Pharm Sci. 2013;102(4):1165–1171.

• Forward-looking review on the future of pulmonary delivery for both local and systemic applications.

[sportsrancho]

cm5, this is excellent. And also new T1's are so much more willing to use Afrezza than the ones who are used to the pen. My clients son took to it quicker than his sister. But then she followed his lead. He had thought his life was going to be hell after seeing what his sister had gone through all those years! So when he found out he was T1 also he just had a melt down. His dad got him on Afrezza right away and all is great. His sister was use to life as a T1 and didn't know what freedom felt like! This is what I hear from many. ( Oh I'm fine, or I can deal with it.) They have no idea what they are missing.

[cm5]

And, please read about David Cipolla. 

www.aradigm.com/products_pipeline.html

www.aradigm.com/about.html

David Cipolla currently leads the preclinical R&D, pharmaceutical sciences and intellectual property efforts at Aradigm Corporation in Hayward, California. Aradigm is a specialty pharmaceutical company specializing in the development of inhalation treatments for severe respiratory disease. Aradigm’s lead product is an inhaled sustained release formulation of ciprofloxacin in phase 3 clinical development for non-cystic fibrosis bronchiectasis.

Prior to joining Aradigm, David worked at Genentech, Inc. in the Pharmaceutical Research and Development Group (1988-1996). His research investigated the development and characterization of the delivery of protein aerosols to the airways, culminating with the approval of Pulmozyme® rhDNase for the management of cystic fibrosis in 1993. David also made contributions to a number of marketed antibody products including Herceptin® Trastuzumab indicated for breast cancer and Xolair® Omalizumab for asthma.

David was elected to two terms (2011-2015) on the Board of the International Society of Aerosols in Medicine (ISAM). He was one of the organizers for the 2009 ISAM conference in Monterey, CA and served on the scientific advisory board for the 2011, 2013 and 2015 ISAM Congresses.

David chaired the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) in 2006-2008, which is addressing significant scientific and regulatory issues that affect development of respiratory products within the pharmaceutical industry; e.g., foreign particulates, cascade impaction methodology, delivered dose uniformity.

He is a pharmacist (University of Sydney, PhD) and chemical engineer by training (MIT, S.B.; University of California at Davis, M.S.)

Specialties: Drug Delivery, Inhalation, Biologics, Proteins and Antibodies, Formulation Development, Pharmaceutical Intellectual Property

See Linkedin

[sportsrancho]

Aug 7, 2016 14:49:16 GMT -5 sportsrancho said:

cm5, this is excellent. And also new T1's are so much more willing to use Afrezza than the ones who are used to the pen. My clients son took to it quicker than his sister. But then she followed his lead. He had thought his life was going to be hell after seeing what his sister had gone through all those years! So when he found out he was T1 also he just had a melt down. His dad got him on Afrezza right away and all is great. His sister was use to life as a T1 and didn't know what freedom felt like! This is what I hear from many. ( Oh I'm fine, or I can deal with it.) They have no idea what they are missing.

[peppy]

cm5 and all,

Keying  in  on " However, many T2D patients are not on injectable insulin, with an average delay of 5–10 years from diagnosis to insulin prescription, even though the recent guidelines recommend that insulin treatment be initiated within 2–3 months of diagnosis [12].

Can we verify the recent guideline changes?

This would be huge.

[cm5]

Hmmm----after rereading the above posted article, this leaped out. This is a powerful, brief description of why Afrezza is so amazing--
it's not just that it's inhaled, it's the FDKP onto which so many beneficial pharmaceuticals can be attached---

Afrezza’s formulation adsorbs insulin to fumaryl diketopiperazine crystals, an excipient that increases insulin transcytosis in the lung, resulting in even more rapid absorption of insulin compared to the other inhaled insulins, a claimed potential advantage even to SC faster-acting insulin analogs




Read more: mnkd.proboards.com/thread/5963/pulmonary-drug-delivery-achieve-promise#ixzz4Gh17o7Md

[cm5]

Re:  Peppy's request--

Here's the full reference cited, (12) below. I'm searching, trying to find it online, but always welcome fellow searchers!


12. Patton JS, Porter L. Re-thinking inhaled insulin’s role in the global challenge to treat diabetes. In: Dalby RN, Byron PR, Peart J, et al., editors. Respiratory drug delivery Europe 2015. Vol. 2015. River Grove (IL): Davis Healthcare Int’l Publishing; 2013. p. 49–58, 237–242.

[cm5]

www.rddonline.com/rdd/rdd.php?id=11  Respiratory Drug Delivery Europe

RDD Europe:  The meeting, co-organized by RDD Online and Aptar Pharma, hosted 440 participants from 31 countries around the world, including delegates from Asia, Australasia, Europe and the Americas. Delegates represented various science and business functions within academia, generics, pharma, biotech, legal and regulatory.

RDD Europe celebrated its tenth anniversary in Antibes, France, May 5-8, 2015, with an innovative program of podium speakers, a variety of workshops, and a scientific poster and technology exhibition. Highlighting novel approaches to respiratory drug delivery and bringing together participants from across the globe, the Respiratory Drug Delivery® symposium reaffirmed its place as a leading international conference at the forefront of pulmonary and nasal pharmaceutical development. RDD strives always to deliver value by bringing the best and brightest together and RDD Europe 2015 succeeded in that

Peer-reviewed presentations by all speaker and poster presenters at RDD Europe 2015 were summarized and provided to each conference participant either in a two-volume set of books or as electronic access in the form of a one-year subscription to the entire RDD archives, over 2000 articles. RDD articles, available as instant downloads from a comprehensive, searchable database, have become a frequently cited source of quality information to which numerous institutions and individuals subscribe worldwide.

So, the specific reference, 12. Patton JS, Porter L. Re-thinking inhaled insulin’s role in the global challenge to treat diabetes. In: Dalby RN, Byron PR, Peart J, et al., editors. Respiratory drug delivery Europe 2015. Vol. 2015. River Grove (IL): Davis Healthcare Int’l Publishing; 2013. p. 49–58,
237–242, is not available online without paid subscription at meeting----

But, someone out there, either with ready/immediate access to research library, or perhaps a subscriber, could find this now?

[cm5]

Reference 12, above cited article:

12.00 noon
/ Wednesday, May 6, 2015/Respiratory Drug Delivery Europe 2015


Re-thinking Inhaled Insulin’s Role in the Global Challenge to Treat Diabetes

John S Patton, Ph.D.,

Dance Biopharm, Brisbane, California, USA

Diabetes is a vast global health problem that is increasing in severity. Unfortunately, half of the people with diabetes do not know they have it, even as it works its destructive effects on the body.

Insulin has traditionally been used as a treatment of last resort in type 2 diabetes (that comprise more than 90 percent of patients worldwide) but treatment guidelines have recently been revised and now outline a more individualized approach to insulin treatment including recommendations to initiate insulin if diet, exercise, and oral agents do not control blood glucose within a few months of diagnosis, or if patients present signs of diabetes complications upon diagnosis.

Reluctance and refusal to take injected insulin is well documented, as is the strong patient preference for inhaled over injected insulin. Inhaled insulin has been studied in over 10,000 patients across more than 100 clinical trials, demonstrating safety and efficacy. After the premature demise of the first approved inhaled insulin product, Exubera®, inhaled insulin is commercially available once again in the US in the form of the ultra-rapid-acting dry powder product, Afrezza®. Dance Biopharm is developing an aqueous inhaled insulin product, Dance 501®, with unique characteristics which will provide patients with another option to obtain insulin non-invasively.

[peppy]

Aug 7, 2016 19:54:57 GMT -5 cm5 said:

Reference 12, above cited article:

12.00 noon
/ Wednesday, May 6, 2015/Respiratory Drug Delivery Europe 2015


Re-thinking Inhaled Insulin’s Role in the Global Challenge to Treat Diabetes

John S Patton, Ph.D.,

Dance Biopharm, Brisbane, California, USA

Diabetes is a vast global health problem that is increasing in severity. Unfortunately, half of the people with diabetes do not know they have it, even as it works its destructive effects on the body.

Insulin has traditionally been used as a treatment of last resort in type 2 diabetes (that comprise more than 90 percent of patients worldwide) but treatment guidelines have recently been revised and now outline a more individualized approach to insulin treatment including recommendations to initiate insulin if diet, exercise, and oral agents do not control blood glucose within a few months of diagnosis, or if patients present signs of diabetes complications upon diagnosis.

Reluctance and refusal to take injected insulin is well documented, as is the strong patient preference for inhaled over injected insulin. Inhaled insulin has been studied in over 10,000 patients across more than 100 clinical trials, demonstrating safety and efficacy. After the premature demise of the first approved inhaled insulin product, Exubera®, inhaled insulin is commercially available once again in the US in the form of the ultra-rapid-acting dry powder product, Afrezza®. Dance Biopharm is developing an aqueous inhaled insulin product, Dance 501®, with unique characteristics which will provide patients with another option to obtain insulin non-invasively.

Insulin has traditionally been used as a treatment of last resort in type 2 diabetes (that comprise more than 90 percent of patients worldwide) but treatment guidelines have recently been revised and now outline a more individualized approach to insulin treatment including recommendations to initiate insulin if diet, exercise, and oral agents do not control blood glucose within a few months of diagnosis, or if patients present signs of diabetes complications upon diagnosis

the author used some artistic license. The change has to show up in

 care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-of-Care.pdf

[peppy]

Aug 8, 2016 6:45:05 GMT -5 peppy said:

Aug 7, 2016 19:54:57 GMT -5 cm5 said:

Reference 12, above cited article:

Insulin has traditionally been used as a treatment of last resort in type 2 diabetes (that comprise more than 90 percent of patients worldwide) but treatment guidelines have recently been revised and now outline a more individualized approach to insulin treatment including recommendations to initiate insulin if diet, exercise, and oral agents do not control blood glucose within a few months of diagnosis, or if patients present signs of diabetes complications upon diagnosis

the author used some artistic license. The change has to show up in

 care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-of-Care.pdf

here it is; page  53

Recommendations
c Metformin, if not contraindicated
and if tolerated, is the preferred
initial pharmacological agent for
type 2 diabetes. A
c Consider initiating insulin therapy
(with or without additional agents)
in patients with newly diagnosed
type 2 diabetes andmarkedly symptomatic
and/or elevated blood glucose
levels or A1C. E
c If noninsulinmonotherapy atmaximum
tolerated dose does not
achieve or maintain the A1C target
over 3 months, then add a second
oral agent, a glucagon-like peptide
1 receptor agonist, or basal insulin. A

some change seen in algorithms.

[peppy]

added; page 53
A patient-centered approach
should be used to guide the choice
of pharmacological agents. Considerations
include efficacy, cost,
potential side effects, weight, comorbidities,
hypoglycemia risk,
and patient preferences. E
c For patients with type 2 diabetes
who are not achieving glycemic
goals, insulin therapy should not
be delayed. B
An American Diabetes Association/

care.diabetesjournals.org/content/suppl/2015/12/21/39.Supplement_1.DC2/2016-Standards-of-Care.pdf

[agedhippie]

A couple of points on the Standard of Care - the evidence class for immediate insulin is E which is as low as you can get (Metformin is A), and the insulin they are talking about is basal and not prandial. Afrezza would only be prescribed after triple therapy had failed.

[peppy]

Aug 8, 2016 7:33:52 GMT -5 agedhippie said:

A couple of points on the Standard of Care - the evidence class for immediate insulin is E which is as low as you can get (Metformin is A), and the insulin they are talking about is basal and not prandial. Afrezza would only be prescribed after triple therapy had failed.

good points, the caveats

look that mealtime was added to the algorithms that is huge.

and the do not delay.  All new?

Does B mean something there aged?

A patient-centered approach
should be used to guide the choice
of pharmacological agents. Considerations
include efficacy, cost,
potential side effects, weight, comorbidities,
hypoglycemia risk,
and patient preferences. E
c For patients with type 2 diabetes
who are not achieving glycemic
goals, insulin therapy should not
be delayed. B
An American Diabetes Association/

[agedhippie]

Aug 8, 2016 7:37:59 GMT -5 peppy said:

Aug 8, 2016 7:33:52 GMT -5 agedhippie said:

A couple of points on the Standard of Care - the evidence class for immediate insulin is E which is as low as you can get (Metformin is A), and the insulin they are talking about is basal and not prandial. Afrezza would only be prescribed after triple therapy had failed.

good points, the caveats

look that mealtime was added to the algorithms that is huge.

and the do not delay.  All new?

Does B mean something there aged?

A patient-centered approach
should be used to guide the choice
of pharmacological agents. Considerations
include efficacy, cost,
potential side effects, weight, comorbidities,
hypoglycemia risk,
and patient preferences. E
c For patients with type 2 diabetes
who are not achieving glycemic
goals, insulin therapy should not
be delayed. B
An American Diabetes Association/

An evidence weighting of B is good and definitely actionable. The problem is that it is referring to basal insulin. I am not sure that there have really been any studies or trials on the early use of mealtime insulin but there may well have been. A lot of the focus in treating people revolves around minimizing number of times a day you have to take things so a daily pill is preferred over a twice daily pill, etc. as it improves compliance. This is a long winded way of saying that I don't see meal time insulin displacing basal.

I was thinking about the whole Type 2 aspect though. A big issue with Type 2 is the sheer volume of insulin you have to take. What would be a 3u dose for a Type 1 can easily be a 50u dose for a Type 2. This is dealt with by using more concentrated insulins to reduce the volume injected. The typical mealtime insulin is Regular at 5x concentration. I can see no reason why Mannkind could not produce 5x insulin encapsulated with Technosphere. I think there is a reasonable sized market there that could really use Afrezza especially when you get to people who are taking 100+ units per meal.