Tuesday, June 10, 2008

ADA Scientific Sessions-Coming Soon: Humalog Plus?

This past weekend, the American Diabetes Association's 68th Annual Scientific Sessions began in San Francisco and today (Weds., June 10, 2008) they end. The press releases and reporters were on overdrive, largely releasing the same, recycled stories containing tidbits from the ill-fated type 2 studies which also investigated cardiovascular disease -- even though that news came out months ago. Nevertheless, there were a handful of interesting findings revealed in these sessions, although I previewed the extracts about a month ago and decided that this year's event wasn't really worth a trip cross-country to be inundated with more of the same. A fair proportion (if not the majority) of the findings presented at this year's meeting weren't truly "new" findings, but those already published in various medical and scientific journals.

As you might imagine, diaBusiness carefully coordinated numerous press releases to go along with findings of their less-than-vigorous "scientific" findings. Without a doubt, Novo Nordisk was the worst offender (although certainly not the only one; we shouldn't leave out Merck and Eli Lilly and Company from doing largely the same thing). For example, virtually all of the wire services and news headline servers publish the same, carefully crafted press-release, that of Novo Nordisk's new drug liraglutide being "superior" at controlling blood sugar in patients with type 2 diabetes according to a small clinical trial comparing itself to to Eli Lilly and Co's and Amylin Pharmaceuticals Inc's first-on-the-market drug in the same category Byetta (exenatide).

First, let's look at the reality here. Notably, the company reported that in a 26-week head-to-head trial involving a mere 464 people, the reductions in HbA1c was 1.1% vs. 0.8% for Byetta. The company made special note that this was a "statistically significant" reduction. Based on these findings, the San Diego Union Tribune reported on Saturday that Amylin's shares fell more than 8% based on the news.

In a scathing note to subscribers, our own "Diabetic Investor" David Kliff wrote in his newsletter, "With their Bush-league tactics, Novo was deliberately trying to control the news flow, damage Amylin's share price and steal Amylin's thunder." Kliff is a longtime AMLN/Byetta bull. He also says he does not own any stocks of the companies he covers.

Positive results for Amylin's once-weekly version of its type 2 diabetes drug Byetta were released Monday evening, and that may partially erase the damage imposed by Novo Nordisk's press release.

But we should not forget that the same Wall Street analysts also once predicted that Pfizer's Exubera would be a blockbuster, with sales in excess of $1 billion annually, and we need not look too far back to see what happened with that brilliant forecast. Let me disclose that I am not an Amylin shareholder (nor a San Diego resident) so these results don't really impact me one way or another -- but I'd like to think I can be a bit more objective about what this actually means.

As I noted, this was a relatively small study of less than 500 people observed for a relatively short period of time -- a little over 6 months. Whenever you deal with sample sizes that small, the mathematics may indeed indicate that a finding is "statistically significant," but let us not forget just how much that difference actually is: a whopping 0.2%!! No offense, but I've had lab results differ by that much from blood samples taken on the same morning! What does this really mean? Assuming their HbA1c was 9.500 to start with, a patient might expect to see an average HbA1c after using liraglutide of 9.498 vs. 9.499 with Byetta? That may be statistically significant based on a tiny sample of less than 500 people, but frankly that isn't enough to compel someone to even bother switching brands, let alone adjust to a new medication (unless of course, they have a financial incentive, such as insurance coverage). But it might be sufficient to make more doctors prescribe it, and that's exactly what Novo Nordisk wants to happen.

We should also realize that Novo's drug is a "me-too" drug in pharmaceutical industry parlance, which means its not truly novel, rather its a similar copy of an already-existing drug on the market. I would add that Byetta is already well-established in the U.S. and there's a once-a-week version in the pipeline, so the Novo Nordisk has to work very hard to posture its drug to ensure it is successful when it finally launches.

Let us also keep in mind that the market has changed since they launched Novolog (known as Novorapid elsewhere in the world) received FDA approval to market that product in the U.S. in June of 2000 vs. Humalog's approval in 1996. For a variety of different reasons, Lilly was ill-prepared when Novo Nordisk seized upon that opportunity to capture a slight majority (as of September 2005, Novo Nordisk overtook Eli Lilly & Co. in as the market leader in the U.S. insulin market based on the September 2005 data for total insulin sales volume reported by IMS Health, see here for details), but that is not the case today, and I don't expect Eli Lilly to go down without a fight this time around.

Incidentally, Novo's press machine also reported that new data from a head-to-head study "Confirms Once-Daily Levemir Is as Effective as Glargine (known as Lantus) Over a 24-Hour Period in Subjects With Type 2 Diabetes", again, with the company trying hard to present, at best, weak scientific "evidence" to show superiority of its "me-too" product against a very successful competitor. As I reported in January 2007, sales of Levemir have been disappointing for the company. Of note, however, is that Lilly is now working to develop a long-acting insulin analog of its own similar to Lantus or Levemir, but they are at least a decade behind the curve here, so anything they come up with must be offer an improvement upon what's already out there. On the other hand, if the company wants to remain in the insulin market, they really do not have a choice. But as I reported quite a while ago, Levemir has done little damage to Sanofi Aventis' market share lead, which remains far and away the leader among long-acting insulin analogs.

Coming Soon: Humalog Plus?

Perhaps more interesting was what is undoubtedly a glimpse into the future. While the press didn't really cover it, but I think we can expect to see a "Humalog Plus" come out in the coming years. I base this on one of the late-breaking abstracts (I'm not certain how long it will remain available online):

Pharmacokinetics and Glucodynamics of an Insulin Analog Injected with Recombinant Human Hyaluronidase: Fast-Acting Insulin Analog Made Faster

(see http://www.halozyme.com/images/ADA%202008%20Poster%20legal.pdf for detail)

What does this mean? Well, first we need to look at who's behind this abstract. A quick search reveals the following affiliations (as of June 10, 2008, anyway): Richard C. Yocum (Halozyme Therapeutics Inc., San Diego), Barry Sugarman (I'm not sure where he's from), Daniel Vaughn (Daniel Enterprises, Indianapolis, IN), Andrew Vick (Eli Lilly and Company, Indianapolis, IN), Rocco Brunelle (B2S Consulting, Indianapolis, IN), Gregory Frost (Halozyme Therapeutics Inc., San Diego).

In other words, a bunch of current Lilly or former Lilly people, along with some other biotech people in San Diego did this study. It seems almost certain (from my perspective, anyway), barring any major adverse events or problems in larger clinical trials (remember, this is based on a study with just 12 people) that we are likely to see a "new and improved" Humalog emerge in the coming years, one that is faster thanks to the addition of recombinant (meaning synthetic) "human" hyaluronidase (rHuPH20). To be sure, a lot could happen, but keep in mind that we're talking about the addition of already FDA approved ingredients, but this would enable Lilly to extend patent protection for another 7 years on their "Humalog Plus" (MY term, not theirs), as the patent on Humalog expires just a few years from now.

I would dare say that we can expect to see such "New and Improved" versions of insulin analogs trials (Phase I anyway) wrap up around 2010, allowing enough time to effectively kill the old products and make doctors and patients view today's state-of-the-art treatments as "bad" or "less effective" than today's insulin analogs. No doubt, the price tag will also go up appreciably to reflect this! I will be around to tell you "I told you so!".


Kevin said...

I have absolutely nothing at stake here, but I think some statistical errors should be cleared up:

1) It is MUCH more difficult to achieve statistically significant results with smaller sample sizes.

2) The magnitude difference is MUCH larger than you've described. It appears that Terri Somers (the woman who wrote the San Diego Union Tribune article you referenced got it wrong). The reduction was "percentage points", not percent (see the Reuters coverage). I.e., in your example, 9.5 -> 8.4 vs. 8.7. Which roughly translates to average blood sugar readings of 225, 194, and 202 respectively (using the "new" A1c-to-mean glucose regression results of 28.5*HbA1c - 45) and these represent a statistically significant difference between a 13.8% reduction in average bloodsugar vs. a 10.2% reduction. Again, not an easy thing to accomplish with less than 500 observations.

3) The expected patient compliance with taking a one shot/day vs. two shots/day should not be underestimated. That's largely why the once-a-week version of Byetta is getting so much attention.

Anonymous said...

thanks for the information

Scott S said...

Kevin, thanks for your comments, but the reality is that Novo's product is nothing to get excited about. Whether it is statistically significant is missing the point: its a "me-too" product similar to something already on the market and offers at best, marginal improvements over the product already on the market. This is akin to Novolog coming out after Humalog did; its a similar product with similar features, nothing new. Personally, I have no interest anyway, the drug is completely irrelevant to the type 1 market.