Monday, June 24, 2013

Coming Soon: Ever-More-Concentrated Varieties of Insulin. Buyers Beware!

Recently, Lilly held what it called its second diabetes social media summit, although in truth, the company did not fly anyone into Indianapolis for the first summit (that was a forum gathering at Friends for Life with people already there), so in reality, this was the company's first.  I was not invited, which frankly doesn't surprise me, because I've been critical of the company and I honestly think they're terrified of me - seriously, they were looking for people who wouldn't challenge them on much (like their decision to outsource some insulin manufacturing away from its own plant in Indianapolis to Hospira in McPherson, Kansas only to bring it back in-house this year), and that's probably not me.  I ask pharma difficult questions and they prefer bloggers who generally won't challenge them on such issues.

On Twitter, the hashtag #LDSummit13 has some of the Tweets from participants regarding the Lilly summit.  DiabetesMine covered it HERE.

Having said that, Lilly really just kind of danced around the topic of glucose-responsive insulin, and company executive David Moller made a point of noting that Lilly had an active research program on smart insulin, claiming "we are looking at the science that would allow us to pursue it in a smart way".  However, both he and David Kendall kind of bad-mouthed the concept saying "Smart insulin was 'aspirational' and over-hyped on timeframe."

See the following Tweet:

I responded that's a logical response for a company that doesn't have anything real in its pipeline for glucose-responsive insulin.  Lilly had to bring in Boehringer Ingelheim to offer a long-acting analogue to market -- they didn't have one that was anywhere close to market from their internal researchers.  That's because resource reallocation internally largely gutted the R&D in the diabetes business.  In other words, they had to bring the Germans in to help them develop a Lantus-like product.  Its worth noting that most of the company's brightest have moved elsewhere.  Insulin legends like John Galloway retired years ago, and countless others have left the company to start their own businesses or work for competitors.  Lilly pursued neuroscience in the 1990s which brought them blockbusters such as Prozac and Zyprexa while they invested little in diabetes.  The partnered with Amylin before dumping that partnership for one with Boehringer Ingelheim.

The company realized its diabetes business had not been prioritized and brought in a new executive named Enrique Conterno to turn the flagging business around.  He's done what was necessary, even though most of it has been to turn to partners to do what Lilly hadn't done on its own.

But this post isn't about Lilly specifically, but a trend Lilly and rival Sanofi Aventis are pursuing: selling ultra-concentrated versions of existing insulin products to market those products to the booming, insulin-resistant type 2 market.  On April 24, 2013, Lilly released its quarterly earnings to investors.  They realized net income of $1.55 billion, or $1.42 per share, which compared to $1.01 billion, or $0.91 cents per share at the same time last year. The company credited sales of its treatments for diabetes, depression and lung cancer. Among the insurance companies it had landed was the big Kaiser Permanente account, and it had become more aggressive in competing with Novo Nordisk on price. But the transcript of the recent conversation revealed another important take-away (see http://goo.gl/2hYGi for the full transcript).

Specifically, that Lilly had applied for FDA Approval to Sell U-200 Humalog (insulin lispro).

Philip Johnson, Vice President of Investor Relations said:

"We also submitted in lispro U-200 in the U.S. for type 1 and type 2 diabetes patients and we are pleased to announce that [indiscernible] patient with the FDA we received Fast Track designation and have initiated BLA submission for ramucirumab as monotherapy treatment for second-line gastric cancer."

In other words, they've applied for approval of U-200 Humalog, which is twice as potent as U-100. And, the FDA is fast-tracking it.  Lilly already sells U-500 Humulin R which has seen sales grow in recent years with almost no marketing.  That's supposedly for a product that's been described as a dinosaur (specifically regular insulin) in an era of ultra-rapid acting, patent-protected insulin analogues.  While some people with severe insulin resistance might benefit from that (although some might argue that point, but its irrelvant to my post).  The point is we can expect more-concentrated insulin varieties in the coming years.  There's zero new technology involved, its just an effort to sell more of an existing product - most likely for a higher price.

Lilly isn't alone.  Rival Sanofi just announced it, too, is looking at a more-concentrated variety of an existing insulin product.  Specifically, they've been toying with a U-300 version of Lantus.  (see the June 22, 2013 press release entitled "Sanofi Announces Positive Phase 3 Results for Investigational New Insulin U300" http://prn.to/11HtaTd).

Novo Nordisk is likely to move in this direction, too, although they've been much tighter-lipped about it.  But if big rivals do it, they'll undoubtedly launch a "me-too" version of its products.  They're still stinging from the fact that their latest generation "Lantus Killer" known as Tresiba (insulin degludec rDNA origin) was not approved a few months ago when the FDA demanded additional studies on cardiovascular disease risk.  The company once arrogantly predicted it would "likely" be sold in the U.S. by 2014.  But if the FDA fast-tracks double or even triple-strength  varieties for Lilly, why wouldn't the regulators do the same for Novo?

Let me remind you that back in 2011, there was some trouble with pharmacists. or far more likely, lower-skilled pharm-techs who may only have on-the-job-training depending on where they work.  In 2011, there were reports of many pharmacies mixing up U-100 Humulin R and U-500 Humulin R (both Lilly products), so the Institute for Safe Medication Practices (ISMP) reissued a safety warning about mixups (see http://www.ismp.org/Newsletters/ambulatory/archives/200708_2.asp)

This was the summary of ISMP's warning on mixups with the highly-concentrated U-500 insulin with standard U-100:

Mistakes have usually occurred when doctors accidentally selected U-500 regular insulin from computer screens instead of U-100. For example, sometimes the two dosage forms appear one line apart on the screen, which makes it easy to select the wrong one. Also, depending on the screen size, the prescriber may see only the first few words of the product listing, so the drug concentration may not be visible. And finally, since the use of U-500 insulin is not common at present, prescribers may just assume that the only regular insulin that's available is U-100 and not even look for the concentration on the screen.

ISMP suggested that the use of U-500 insulin may be increasing due to the higher prevalence of [insulin resistant type 2] diabetes, especially where patients are seriously overweight and may need higher insulin doses where they need U-500. The use of insulin pumps, and need for tight control of blood sugar in hospitalized patients are other reasons.

ISMP asked the major suppliers of drug information systems to add the word "concentrated" on their selection screens, immediately following the drug name and preceding "U-500", which they said should help solve the problem. The companies did agree to do that.

U-100, U-200, U-300, U-500 Will Soon Emerge

However, I have major concerns with U-100, U-200, U-300 and U-500 insulins on the market, the likelihood of mixups increases exponentially.  I, for one, intend to speak personally at the FDA on these approvals given the growing numbers of increasingly-concentrated insulin varieties and what safety issues need to be addressed.

Back in 2008, I wrote about what role color should play in insulin packaging.  I cited some meetings the FDA held back in 2005 on this subject.  See my post HERE for more background.  I would also remind my readers that in 1997, when Lilly gained approval for the first insulin analogue, they used a different color cap on the vials (purple instead of orange) intended to communicate there was something dramatically different about Humalog.  The other manufacturers did not do the same, but the point is, Lilly of all companies has experience with the use of color in packaging.  I expect the same with all the new varieties of insulin concentrations.

This is one area where I think patient safety could be a genuine issue because of how these Rx's are filled.  Put this on the "to-do" list for pending FDA applications.

Patients Should Ask the FDA the Following Questions:

  1. I expect the FDA gives consideration to revisiting the use of color in labeling.  Right now, color is voluntary.  It needs to be mandatory, will all companies adopting the same color-schemes.
  2. I think the companies also need to fund educational efforts to instruct patients to look for the correct concentration, and more importantly, education to all the pharmacy technicians about the potential for mixups and how they can avoid such mixups.

Both of these need to be part of any approvals IMHO, the risk is potential recipe for disaster unless the regulators  consider these issues when reviewing an drug application for approval.

7 comments:

Scott E said...

Use of color can definitely be a benefit, but I see that as possibly opening a Pandora's box leading to means to differentiate which consider the vision-impaired as well. I'll bet some manufacturer's just don't want to start down that route.

As for glucose-responsive (aka "smart") insulin, I hear that Merck, through an acquisition of a smaller pharma, are the closest to getting this working, and they've got the other manufacturers shaking in their boots. If such a product comes to market (and this is a big IF) it would be hugely disruptive and render all other insulin obsolete. So the other pharmas can either try to duplicate it or demonstrate why it won't work.

While it is worth researching, I am a bit tentative on the glucose-responsive insulin for one reason: the definition of a "target" BG range now rests in the chemical makeup of the product itself, and not in the dosing. This seems to imply a one-size-fits-all solution which people may be reluctant to adopt.

StephenS said...

Great post Scott... I totally agree with the ideas of color coding and additional education for patients, pharmacy technicians, and HCPs.

Thanks

Maria M said...

I just discovered this blog - good job!

However, on behalf of (only extremely competent) current and former (such as myself) Pharm. techs, the mistake need not necessarily be deemed to be that of the tech.
I have met just as many careless/incompetent Pharmacists as Technicians (if not more), and while it's true that Registered Techs (State & Nationally certified) run the game, it is still the pharmacists responsibility (and also required by law) to check every single Rx before it is bagged... They get a (sub?)-6-figure salary although they stand around doing nothing most of the time when it's not busy as the techs scramble around trying to get everything don.. The least they can do is check the final product and do it right!

Maria M said...

I also feel compelled to say that while I agree that some coherent color scheme may prevent some mistakes on the part of the pharmacy staff, I believe that it is ultimately always the patient's responsibility to double (triple?) check their medicine! These mistakes rarely happen with insulins (compared to pill switches, which happen all the time and have been caught at least 1/week by people like myself in a busy DT-Boston CVS, and other paces I've worked). Mistakes will happen no matter what, and having several points of control is the best way to prevent it, but ultimately, however, the patient (or their care-taker)is that last check-point. I think we all have to take more responsibility for OURSELVES. I really enjoy your writing :)

Allie Beatty said...

Human being are adaptive. As glucose concentrations in our food rose, people have become more insulin resistant. If manufactured insulin becomes more concentrated - will that spur greater insulin resistance or increase the incidents of hypoglycemia? Or both?

Allie Beatty said...

Human being are adaptive. As glucose concentrations in our food rose, people have become more insulin resistant. If manufactured insulin becomes more concentrated - will that spur greater insulin resistance or increase the incidents of hypoglycemia? Or both?

Anonymous said...

In a quick web search, I found several other glucose responsive insulin efforts:

- Sensulin - company, seems to be the most advanced
- GlycoStatis - company, not much to be found
- Zhen Gu - professor at North Carolina State
- a Montreal consortium has a glucacon-insulin bi-hormonal system
- Case Western has a well-funded academic program
- JDRF recently gave away GRI prizes to 3 other researchers.

It will be an interesting space to watch.