I must admit that I have been very wrong about how clinical results from the ApoB-lowering drug candidates by Tekmira (ApoB-SNALP RNAi, phase I) and ISIS Pharmaceuticals (mipomersen antisense, phase III heterozygous FH) would turn around the sentiment for RNA Therapeutics. In both cases, investors sold off the stocks on results that I believe bring both approaches closer to commercialization. It is almost as if the market is one in which home-run clinical results get rewarded with a doubling in share price, while those in-line with expectations are sold off by about 20%.
Compounding the problem for mipomersen is that investors were secretly hoping for slightly better LDL-cholesterol reductions. This was particularly the case because the modest 25% reduction observed in the previous homozygous FH trial had always been down-played by management as being attributable to a challenging patient population, and that we should expect much more from the subsequent phase III trials. Well, technically, the reduction was slightly improved, but with 28% not too much to get anybody excited.
While analysts were largely focused on potential safety problems, particularly questions about the seriousness of observed liver enzyme elevations, I believe that this attention was very much caused by the disappointment about the degree of knockdown. This is because in order for mipomersen to become a commercially successful drug, it needs to tap the market outside the ultra-orphan homozygous FH population, especially the severe hypercholesterolemic patient population that does not respond sufficiently to current maximal drug therapy and are either on LDL apheresis or eligible for it. Tapping this market or not can make all the difference, the difference between $10M and $500M-$1B in annual sales.
The reason why the LDL apheresis population is so attractive is because mipomersen would aim to replace another procedure that specifically aims at lowering LDL-cholesterol, and demonstrating a comparable knockdown should be sufficient to get approval without time-consuming and costly outcome studies. It could also lead to adoption of mipomersen by some of the other high-risk populations, but this would only be gravy.
LDL apheresis is somewhat unpleasant and, depending on the particular apheresis technique applied, removes good stuff like coagulation factors and HDL cholesterol, too. It does, however, do a fairly good job in removing LDL-cholesterol, by about 30-55%, and in order for mipomersen to be considered an alternative, it needs to get into that range. At the moment, mipomersen is on the lower end of this spectrum where safety could tip the balance, and with lots of questions regarding the safety being left unanswered, this can explain the sell-off we have witnessed.
On a positive note, the 28% LDL-cholesterol reduction may be a very conservative number. This is because it does not take into account the +5% increase in the control group and the fact that the number was on an intent-to-treat basis, i.e. they included also those patients in the drug-treated group that dropped out early, so that the adjusted number could well be in the -36% range. Moreover, the natural person-to-person variation could mean that about half of those that stayed on the drug achieved very meaningful LDL reductions which could prove crucial during the regulatory application process. The roll-over rate into the open-label, uncontrolled phase of the study was also said to be ‘good’ and would be quite meaningful as this provides a good measure about the adoption of mipomersen in real life. However, given a slight tendency by ISIS to over-promise, we really have to await the precise numbers that are to be presented at an upcoming scientific conference.
In summary, the heterozygous FH results were very likely not as bad as the market reaction would suggest and eyes are now on the full data presentation and, probably even more importantly, results from the phase III study in the critical severe hypercholesterolemic patient population. The reaction highlights, however, that slight differences in knockdown potencies can make a huge difference for RNA Therapeutics. The upcoming dose-fractionation study by ISIS and Genzyme, while labeled as being for the ‘convenience’ of patients, may actually be driven by the hope it might provide for improved knockdown due to different pharmacology. And finally, for RNAi Therapeutics, and Tekmira in particular, the good news is that the pioneering work by ISIS provides them with a very good idea of what their ApoB candidates will have to achieve in order to be commercially successful. A modest 35-40% knockdown should be well within the grasp of current SNALP-siRNA delivery technology.