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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« And You Thought Exubera Was A Disaster Before | Main | Free Sushi in the Cafeteria! »

April 10, 2008

Exubera, Safety, and No Guarantees

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Posted by Derek

As mentioned yesterday, I would have to say that Mannkind is in big trouble. I’d never heard of the company until the Wonder Drug Factory was closing back in Connecticut, but Mannkind was moving some of their operations into the state around then and interviewed a number of my former colleagues.

The whole inhaled-insulin idea had already taken some pretty severe blows. The massive failure of Exubera was the biggest, although a creative person could always argue that a better product with a more convenient delivery system could succeed in its place. But then Novo Nordisk and Eli Lilly (serious diabetes players, both of them) got out of the area before they’d even launched, deciding that it was better to write off their whole investment than to try to bring it to market. That didn’t help, which is one reason that Mannkind stock was down in the single digits, despite the company's efforts.

Well, as of yesterday it’s down in the really low single digits. And I honestly can’t see how they’re going to revive their flagship program if the Pfizer lung cancer data are real. The FDA is going to be very, very cautious about allowing any sort of inhaled insulin trials to proceed. I’d think that you’d have to show that your product is different from Exubera in its carcinogenic risk just to get one off the ground, and frankly, I have no idea how you’d do that. Anything that could will take years to develop and validate.

This latest result also shows some of the real difficulties and risks of drug development. After all, Pfizer and Nektar spent a very long time developing Exubera. The product was delayed and delayed while more and more clinical work was done. But in a slow-starting condition like lung cancer, those years may still not enough to quite pick things up by the time a product makes it to market. Think of what might have happened if Exubera had been a success. . .

And that brings us back to the regulatory pre-emption topic of the other day. This illustrates why either extreme of that argument is untenable. On the make-‘em-pay side, you have trial lawyers arguing that if companies just wouldn’t put defective products on the market, well, they wouldn’t have anything to worry about, would they? Test your drugs correctly and things will be fine! But Exubera’s pre-approval life was as long and detailed as could be. The testing went on and on – and after all, insulin itself has been on the market for more than half a century. What more would a company need to say something is safe?

Then there’s the other side – total pre-emption, which says that the FDA is there to regulate and sign off on safety and efficacy, and by gosh we should have them do it. Once this mighty agency gives its stamp of approval, that settles it. But again, the FDA put Exubera through all kinds of paces. If every drug took that long and cost that much to develop, we’d be in even worse shape than we are now, believe me. So what’s the agency to do?

The truth, as far as I can see, is that no one can guarantee the safety of a new drug. If you want to take that further, guaranteeing the safety of an existing drug isn’t possible, either. Every known drug is capable of causing trouble at some dose, and every known drug is capable of causing trouble at its normal dose in some people. Every new drug has the possibility of doing things no one ever anticipated, once it gets into enough patients for enough time. Every single one.

Complete safety doesn’t exist, and never has. You can have more safety, if you’re willing to take enough time and spend enough money. But you can take all the time we have on earth, and spend all the money available, and you still won’t be able to promise that nothing bad will ever happen. Pretending that either the drug companies or the regulatory agencies can make that fact go away is a position for fools and demagogues.

Comments (12) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Toxicology


COMMENTS

1. Kay on April 10, 2008 7:35 AM writes...

What does this say about the quality of data coming from our predictive toxicology group? Maybe they are just wasting our money and time?

I am guessing that the animals were not using the device according to the protocol.

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2. John Johnson on April 10, 2008 8:14 AM writes...

I would like to echo the above for efficacy as well.

A colleague of mine was saying the other day that if he could change one thing about drug development history, it would be to strike the terms "safety and efficacy" and replace it with risk/benefit ratio. I have to agree.

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3. Still Scared of Dinosaurs on April 10, 2008 10:26 AM writes...

I was going to make JJ's point with one distinction which maybe only I think is important - term should be "benefit/risk ratio". One reason is that I prefer endpoints structured to make bigger equal to better solely for the reason that it's easier to explain to other people. Another is that if you accept that no drug can have 0 risk but many have 0 benefit then this quantity is always defined. Not wicked important, though.

What is important, though, is that "risk" really means the aggregate of all risks which may be very different. FDA is rightly obsessed with the reversibility of unwanted effects. This generalizes to how well the effects can be detected and managed clinically. Symptomatic, reversible, and treatable problems won't kill a drug candidate.

And while I realize that Kay's tongue was firmly in cheek I just can't see how predictive toxicology will take us very far in managing these risks. They can often point out areas of particular concern and associated tests that may help inform how to manage risks to patients, but I don't think a factor of 10 difference in the results of preclinical tox assays tells you enough about the differences in risks to patients to make it, well, predictive.

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4. sroy on April 10, 2008 11:56 AM writes...

Even though this is an unfortunate and hard to foresee situation, I am sure the non-scientists at pfizer will find some way to snatch defeat from the jaws of victory

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5. Sigivald on April 10, 2008 1:26 PM writes...

Fools and demagogues?

So, Congress, then.

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6. hibob on April 10, 2008 4:54 PM writes...

We can't guarantee safety, but we can do a better job of making certain financial interests don't interfere with decisions about safety. I'd be a lot more friendly to the pre-emption option if:
1. All human clinical trial data had to be released, not just the trials cherrypicked for approval. There's already movement in that direction, but a hard line mandating that it all goes out in public well before approval is what's needed. Successful trials that end early would still have to monitor the patients until at least the original planned end of the trial; companies that try to pull a bait-and-switch with endpoints should still have to evaluate their original planned clinical endpoints and submit the results.

2. No financial conflicts of interest for people involved with approving/regulating drugs for one year before/one year after their involvement with the FDA. Yep, that would mean signing agreements for FDA staff and advisors that would determine which companies they can't work for for a year after their involvement.

3. Mandatory monitoring of the first ~20,000+ patients after approval for at least several years. Right now this is still just a patchwork, which allows marketing fiascos like Vioxx to go on far too long.

Just 'cause we can't guarantee safety doesn't mean we can't base decisions about it on the best possible evidence.

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7. Insider on April 10, 2008 10:41 PM writes...

hibob

Great ideas.

Also Big Pharma should be made to complete the post marketing trials they are asked to do by the FDA.

If not ..... then revoke their licence.

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8. Pete on April 11, 2008 7:28 AM writes...

I agree in principle, but because diseases vary widely in their prevalence, I'd make the requirement a percentage of the prevalence rather than a universal number.

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9. Pete on April 11, 2008 7:30 AM writes...

My comment above refers to Hibob's comment re mandatory monitoring of the first ~20,000+ patients after approval for at least several years.

ps, Derek, I've enjoyed your blog for a long time.

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10. dave on April 11, 2008 9:13 AM writes...

This may have nothing to do with the incidents of lung cancer. But in the world of cell culture development, everyone is worried about Fetal Bovine Serum in regards to BSE. In general, insulin (and some other stuff) is often used to replace serum, with insulin usually being the most widely used component across many different phenotypes. When your cells have adapted to this serum-free media with insulin, your cells often have the ability to grow anchorage-independent, and thus be grow freely in suspension.

I guess the reason I bring this up, is many people have done this with A549, a known lung cancer cell line. True, this is already a cancerous cell, but I believe I heard that Exubera was lyophilized to be a hexamer of insulin. Whereas liquid formulations should have insulin in a monomeric form, and so is Mankinds formulation. I am inclined to think that heterogeneous coverage upon dosing could lead to high concentrations of insulin continually hitting Insulin-like growth factor receptors. This could lead to oncogenic signaling pathways getting turned on. I would think that the FDA made them check this out, even though insulin has a lower affinity for these receptors than the insulin-like growth factors themselves. This may be 100 miles from what is actually going on, but in any case this certainly puts a damper on inhaled protein therapeutics. Whether or not Insulin is in a multimeric state or not is certainly another question, and I should add I don't work for MannKind or own their stock.

Derek, long time reader, first time commentator.

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11. Devices R Us on April 11, 2008 10:48 AM writes...

dave:
Liquid formulations of insulin are in fact hexameric, held together with zinc and in some of the newer analogs with m-cresol/phenol. Hexameric insulin is much more stable than monomeric insulin in terms of much physical stability. I am not sure that I believe that the Mannkind technosphere insulin is monomeric in the technospheres since if it is made from high concentration insulin, it will in fact be hexameric.

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12. Dan on July 23, 2008 11:11 PM writes...

The Pumpers: Better compliance for Insulin-dependent diabetic patients?

With some diabetic patients, the hormone insulin may be absent, yet necessary for their survival. As I recall, a man named Pauescu developed the concept of insulin replacement, and discovered a method of using insulin secreted from pigs as a replacement method for humans, which was effective at that time. Legend has it that this concept originated in a dream this man had on a night soon before his idea became reality several decades ago. Yet presently, this hormone which is naturally produced by the pancreas normally has advanced as far as treatment goes for the diabetic patient through synthetic engineering, as this is needed for survival for some diabetic patients.
Recently, the Denver Broncos’ quarterback, Jay Cutler, was recently diagnosed with diabetes, a disease that affects over 20 million people. As I recall, part of his treatment regimen involves what is called an insulin pump. They are approximately the size of a cell phone, and the users of such pumps are called, in the diabetic community, ‘pumpers’. Developed primarily for type 1, or insulin-dependent diabetic patients, the pumps can be used by some type 2 diabetic patients if they have some dependence on insulin replacement, which has steadily increased over the years. The importance of the device is improved management of the disease, which can cause life-threatening consequences if the disease of diabetes is not controlled properly. By the way, he takes it off for games, practice, etc.
The three elements The Pumps: A New Paradigm in diabetes management of an insulin pump include the pump itself and its components, such as the insulin tube for delivery of insulin, and a catheter that delivers basal and bolus doses, which are dependent on preset calculations. The amount of insulin is rapid acting to ensure maximal pharmacokinetics to create intensive insulinotherapy for required diabetes management. These insulin amounts are ultimately determined by the patient’s doctor, who is usually an Endocrinologist, including bolus doses determined by the patients glucose level calculated with their carbohydrate intake, also known as the meal- time dose. Furthermore, the amount of insulin delivered by these methods is quite small due to the nature of the medication being rapid acting.
The makers of such pumps tend to partner with associations relevant to the disease of diabetes, as well as local chapters of such organizations as the ADA and Endocrinology societies that may exist, along with contacting diabetes educators frequently at different locations throughout the country. Unfortunately, there are few Endocrinologists in the United States, as it is not one of the more lucrative specialties of a doctor, so treatment of diabetes is dependent on many others who are not doctors, but patient care specialists regarding this disease.
Competing companies are few, as there are approximately 5 insulin pumps in the market, with Medtronic having the largest share of 30 percent, as I understand. In addition, some pumps avoid the possibility of metabolic action therapy due to their dosing precision, in addition, there is at least one pump that has long acting lithium battery that averages about a 6 week lifespan, yet a pump user should have a battery replacement with them at all times. The personalized insulin and carbohydrate ratio provided by insulin pumps greatly reduces any incidence of such complications as hypoglycemia. Also, in addition to storing and recording glucose and carbohydrate values with a back up mechanisms, some insulin pumps have a low basal rate, which I understand is an advantage as well. Regardless, and in my opinion, the ultimate advantages of insulin pumps exist with all that are available to patients presently.
The cartridges of the insulin pumps hold a large number of units of insulin, which is an additional benefit. Further benefits include the fact that the pumps are convenient and reliable- especially if damage is avoided to the pump. Most importantly, the personal service provided to the patients by the caregivers of existing diabetic teams in health care facilities from hospitals to health care centers dedicated to the disease of diabetes ensures proper management of their disease, much to the benefit of those who have diabetes.
The market growth of insulin pumps is anticipated at over 10 percent a year, as only 20 percent of type 1 diabetic patients have utilized these pumps out of over a million type 1 diabetics in the United States. The market is speculated to be greater than one billion dollars and is expected to increase due to speculated growth of the Insulin pump market. Many believe this therapy is superior in comparison with previous treatment options available to diabetic patients, along with being less cumbersome for these patients. Because of this, there is decreased mortality along with increased quality of life for diabetics, as they are assured of better control of their disease in this rather convenient way. This has been proven by better A1C blood tests and glycemic control of diabetic patients.
The steady dosing maintains the patient’s metabolic requirements and decreases long term consequences associated with diabetics. It has also been proven that insulin pumps result in fewer hospitalizations, ER visits, and episodes of hypoglycemia due to the excellent control provided by the insulin pumps while providing the necessary intensive therapy for their disease state. The fast acting insulin used in these pumps is created through genetic engineering, I believe. In addition, patients are encouraged to check their blood sugar greater than three times a day while on the insulin pump. So this system is both friendly to the user and is clearly a very convenient form of treatment for them. The A1C test, by the way, is a blood test that reflects the diabetic patient’s average blood sugar over a period of a few months.
Those who may be interested in insulin pumps will include those described already, along with hospitals, long term care facilities, home health care agencies, pediatricians, and possibly dialysis clinics, to name a few. Most likely, those considered for insulin pumps will be diabetic patients that are unable to achieve compliance with their current treatment regimen, along with other benefits of insulin pumps stated so far.
The diabetes team for a diabetic patient may include an Endocrinologist, a diabetes educator, a dietician, along with the insulin pump representative. Follow ups with this team may include review the progress of the insulin pump for the patient and how the patient is tolerating the treatment. Often, classes can be scheduled through an institution or center regarding insulin pump training a few times a month. Education and training about the insulin pump may include the following:



Ultimately after training others, it is important that the patient acknowledges understanding of how the device works, as well as the consequences that may occur if directions are not followed that are ultimately determined by the patients doctor. And fortunately, doctors and others who treat diabetes now have a new tool or device to assure compliance and longevity of these patients.

Innovation is a wonderful thing, such as what has been described. Control of such a large and devastating disease is of great importance, so there seems to be a much desired need for pumpers now and likely in the future. Especially for those patients who slack on following their prescribed treatment regimen. And this will have to do until relevant transplants to reverse diabetes become more frequent and less complicated.

“Death destroys a man. The idea of death saves him.” --- E.M. Forster


Dan Abshear

Author’ note: What has been annotated is based upon information and belief

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