Ken Kam's Best Ideas Blog

The objective of a clinical trial is to see if patients treated with a new drug (the “treatment group”) do better than those who do not (the “control group”).  In most clinical trials, the control group is given a placebo so that any differences in the outcomes between the two groups can be attributed to the new drug. For this trial, however, Elan did something I think more companies should do. They gave the control group Aricept, which is the best available drug currently on the market instead of an inert placebo (which would be really cruel). This is the right thing to do for the patients in the control group, but it means the difference between the treatment group and the control group will be smaller than it otherwise might have been.

In order for a trial to be “successful”, the difference between the treatment group and the control group must be large enough to refute the possibility that it arose solely due to randomness. Scientists and regulators have generally agreed that if the difference is big enough so that there is less than a 5% chance that it is was a fluke of luck, then the trial has succeeded.

In Elan’s clinical trial, patient outcomes were measured in two ways; ADAS-cog and NTB. Using ADAS-cog, the difference between the treatment group and the control group is +2.3 (p=0.078). The “p value” of 0.078 means that probability that the difference could have arisen by chance is 7.8%. On the NTB scale, the difference was +0.13 (p=0.068).

Since there is more than a 5% chance on both measurement scales that the difference could have arisen by chance, it is fair to say that the trial did not succeed by generally agreed upon standards. After the announcement of these results, Elan’s stock dropped more than 40% which would be understandable if the drug was indeed a failure.

However, I don’t think it is accurate to conclude that the drug was a failure.

Using the ADAS-cog it would be accurate to say that we can be 92.2% confident that the differences were not due to chance. Using NTB, we can be 93.2% confident. In other words, using either measure we can be more than 90% confident that the drug had a beneficial impact over the best available drug on the market. Is this a failure? I don’t think so.

The results also show that patients who carry a gene called Apoe4 respond differently than those who do not. There were 79 patients in the trial who do not carry the gene. Of these, 47 were in the treatment group and 32 in the control group. On ADAS-cog, the difference between the two groups was +5.0 (p=0.026). On NTB, the difference was +0.35 (p=0.006). In other words, for patients who don’t carry Apoe4, the drug worked.

Everyone would now be celebrating that the drug worked for non-carriers of Apoe4 except for the fact that Elan did not specify at the start of the trial that they were going to separate the results between carriers and non-carriers. Instead, critics have accused the company of being dishonest with the statistics.

In truth, clinical trial data can often be twisted and contorted until the drug shows efficacy for some subgroup of patients. For example, it could turn out that the data shows the drug was effective for patients who are more than 6 feet tall. But, if it did, people would be justified in ridiculing the results because there is no reason to believe that efficacy should be related to a patient’s height.

The difference in results for carriers and non-carriers of Apoe4, however, is not so easy to dismiss. Apoe4 is suspected to be involved with Alzheimer’s disease (we don’t know exactly how) so it is not at all surprising to learn that a drug that might interfere with the progression of Alzheimers might affect carriers of the gene differently than non-carriers. The ridicule that the company has received for reporting this result is not deserved.

In the end, I think investors can be a little more than 90% confident that Bapineuzumab has a beneficial impact on Alzheimer’s patients above and beyond the best available medication. In addition, I think its fair to say that we have learned from this trial that there is a genetic marker that can be used to identify patients for whom Bapineuzumab may have an even better chance of working.

The Phase 3 trial was clearly designed with this lesson in mind. If the Phase 3 trial results confirm efficacy for just non-carriers of Apoe4, there are so many Alzheimer’s patients that this drug would still be a blockbuster.

I think Elan’s current price can be justified on the basis of their multiple sclerosis drug (Tysabri) and their drug delivery business. This means, that if you buy Elan now, you are essentially paying nothing for Bapineuzumab. That’s a bargain.

Posted by Ken Kam at 06:12 PM | Permalink