It’s not everyday that insulin is in the news. In fact, far more attention seems to hit the press over irrelevant diabetes studies and dumb PR dressed as “news” intended to position yet another new type 2 diabetes drug favorably for investors and regulators which occurs almost daily. Comparatively speaking, insulin seldom makes any sort of news, which is why today was quite unusual.
FDA Unveils List of 20 Drugs In Side-Effect Probes
First of all, on Friday, the U.S. Food and Drug Administration (FDA) unveiled a report listing 20 drugs that the agency is investigating for potential side effects, as part of a new policy to warn patients and health-care professionals as early as possible. One of those drugs happened to be Humulin® R, and the issue was pertaining to the ultra-highly concentrated U-500 version, which is aimed exclusively at highly insulin resistant type 2 patients. U-500 is available by prescription only, but apparently, many pharmacy technicians are unable to discern the difference, and many patients do not even think it necessary to verify the potency of the insulin they receive from their pharmacist.
Back in July, I posted a YouTube video from the Institute for Safe Medication Practices (ISMP) on TuDiabetes, which had recently described a sharp increase in reports about mixups between insulin U-100 and insulin U-500.
Those errors could result in dangerous hypoglycemia or hyperglycemia, with the issue of hyPOglycemia being a far more urgent matter that typically results in hospital Emergency Room treatment, and that usually impacts patients with type 1 diabetes. The clinical literature published suggests that patients with type 1 typically suffer a 25-fold greater incidence of emergencies pertaining to low blood glucose levels, due mainly to a faulty counterregulatory response relative to their type 2 counterparts. By comparison, the most urgent issue related to hyPERglycemia is DKA, which once again, hits the type 1 population disproportionately because most people with type 2 still have some endogenous insulin production. Apparently, mistakes have occurred when prescribers (e.g. pharmacists) accidentally selected U-500 regular insulin from computer screens instead of U-100.
As I wrote back in March, much of this stems from the fact that patients diagnosed today do not typically learn about various potencies, and diabetes educators are failing to even address a potentially critical issue that anyone diagnosed in the 1970’s or before were very routinely knowledgeable of since they needed to specify what potency they wanted the pharmacist to provide. U-100 insulin was only introduced in the U.S. back in 1973. Prior to that, insulin was sold in a variety of different strengths, including U-80 (80 units per milliliter) and U-40 formulations (40 units per milliliter), so there was an effort made to “standardize” the potency sold in the U.S. mainly to reduce dosage errors and ease doctors’ job of prescribing for patients. But standardization did not eliminate the possibility of error, and now we see a growing incidence of problems do mainly to the large (and growing) type 2 population.
At the time, ISMP identified several possible reasons for these kinds of errors and made several recommendations for pharmacies to address the growing incidence of this problem. The FDA is now again raising the issue via of possible Adverse Effects.
Biodel, Inc. Announces Preliminary Phase III Clinical Trial Results for VIAject
Ont the brighter side, as some of you know, I have been watching the development of Biodel, Inc.'s VIAject™ insulin closely for a number of reasons (see my posts here, here, here, here and here for more background). VIAject is a proprietary injectable formulation of regular human insulin which is designed to be absorbed into the blood more rapidly than currently marketed rapid-acting insulin analogues. At issue is the fact that VIAject is, in fact, plain old regular insulin that just happens to work faster than a rapid-acting insulin receptor ligand (a.k.a. an insulin analogue). It does this without altering the genetic structure of the molecule using already FDA-approved “additives” as the company likes to call them. In the comapany’s Q3 Financial Results, the company disclosed that “Biodel entered into a supply agreement with Organon on July 7, 2008 to purchase specified quantities of recombinant human insulin for use in the company’s VIAdel [sublingual, now in clinical trials] insulin formulations. The company believes that its current supplies of insulin, together with the quantities of insulin that Organon has agreed to supply, will be sufficient to complete the company’s current and anticipated clinical trials of VIAject and support the company’s needs for approximately three years following the commercial launch of VIAject.”
Today, at the 44th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Rome, Biodel released the the preliminary results from its Phase III Human Clinical Trials for VIAject insulin. The reported results from its two pivotal Phase III clinical trials designed to compare the efficacy and safety of VIAject to Humulin R, a regular human insulin (RHI). The two trials looked at the the treatment of patients with Type 1 and Type 2 diabetes. The company conducted clinical trials at the Mills Peninsula Health Service in San Mateo, California (south of San Francisco and North of San Jose on the Peninsula), at the Institute for Clinical Research and Development (IKFE) in Mainz, Germany as well as a third leg of the trial conducted at Care Hospital, in Hyderabad, India. As anticipated, the results showed that the company achieved it goals in both studies, and the American and German trials produced exactly the results the company was predicting, namely a smaller dose required, reductions in hypoglycemia relative to regular human insulin (also referred to as RHI), and a slight reduction in weight. However, the company reported that there were some undisclosed problems with the type 1 trial undertaken in India which they were still investigating to try and determine the cause.
The company said that the India type 1 trial data are not comparable to the rest of the data for several reasons including: (a) markedly increased HbA1c levels both prior to and after study drug initiation, (b) medically improbable doubling of intra-subject variability in HbA1c results both prior to and after study drug initiation and © markedly reduced reporting of any hypoglycemic events. These data anomalies were observed in both the VIAject and RHI treatment groups and are under investigation. Biodel believes including the data from India is not valid for determining non-inferiority. Nevertheless, because the cause of the data anomalies has yet to be identified, Biodel also analyzed the HbA1c data including India. If HbA1c data from India are included in the analysis, the adjusted treatment group difference increases slightly to -0.3 which is generally considered to be not clinically meaningful. However, the increased variability from this data extends the lower limited of the confidence interval to -0.6 and as a result would not establish non-inferiority. As a result, the company presented the results for the type 1 trial based only the American and German type 1 trials while excluding the results from the type 1 study that came from India due to anomalies in the data. The type 1 study would apparently not have met all of its expected trials results had the India data been included.
Wall Street immediately hammered to company’s stock price which fell 66.3%, or $11.29, to close at $5.75. Biodel began trading on the Nasdaq stock exchange in May and had previously not been below $9.60. Investors are concerned that the anomalies seen in the India type 1 trial data could potentially delay the approval of the drug by the FDA, or else could cause the FDA to only look at the drug for type 2 patients, which would really kill the prospects for the drug since 75% of the patients who use insulin have type 1 diabetes. The company said that it is talking to the FDA about filing its new drug application and is looking into the data anomalies. Biodel will hold a conference call tomorrow morning (Tuesday, September 9, 2008) to further discuss the impact of the results.
Some analysts reacted negatively to the news over concerns it could delay the FDA approval or at the very least, complicate it. Natixis Bleichroeder analyst Corey Davis said in a note to investors, “We believe the company’s explanation that the extreme variability from India was a fluke and that it ruined the study. However, one simply cannot fail the primary endpoint and expect approval.”
Not all investors shared that dire outlook, however, believing that more information was needed before they could realistically evaluate the prospects for VIAject.
“We await further clarity from the company in order to more accurately gauge the implications of the Indian data,” said Leerink Swann analyst Jonas Alsenas in a note to investors. “We remain confident of the ultimate clinical and commercial prospects of VIAject and believe the problems are eminently fixable, though they could results in significant delays.”
Stay tuned (watch Tuesday) for more detail. (see here for the presentation)
Pseudo-News: Novo Nordisk Launches a Next Generation of FlexPen
Not to be left out of the insulin news, the world’s largest insulin manufacturer, Novo Nordisk A/S announced what it called “The launch of a next generation of the Novo Nordisk FlexPen®”. The new disposable insulin pen was compared to Sanofi Aventis’ SoloSTAR® disposable pen (which is not yet available in North America), and the company claimed it required "30% less force when injecting, resulting in a significantly lower injection force compared with SoloSTAR®. The new FlexPen also provides superior dose accuracy in comparison to SoloSTAR, and provides a range of new design features aimed at improving safety and simplicity for people with diabetes.
Among the new design features are colored cartridges, labels and packaging designed to aid insulin type identification for patients. For ease of handling everyday insulin injections, the new pen also has a simple twist mechanism to attach and detach the needle, which Novo Nordisk claims makes the device the first pen to be designed for use with a new generation of needles, which have a patented state-of-the-art attachment interface (whatever that means).
I call this Pseudo-News, because this is really does not represent a significant new treatment option, merely a “new and improved” version of an existing pen device. Also, the insulin itself is not new, so it may be interesting to know about, but will not fundamentally change treatment options for patients.