Mipomersen Efficacy Surprises to the Upside, on Track to Become First Commercially Meaningful Antisense Therapeutic

ISIS Pharmaceuticals and co-development partner Genzyme reported today top-line data from the final 2 out of 4 phase III studies with the ApoB-targeting antisense compound mipomersen for the treatment of hypercholesterolemia. The efficacy results came in above my lowered expectations and support mipomersen to be an attractive treatment option for the many patients with severe hypercholesterolemia for which current care is still inadequate and who are therefore at a high risk of suffering cardiovascular events. Further studies, however, will be needed to better understand the clinical relevance of the observed liver enzyme and fat elevations.

As I wrote earlier this year, the first 2 phase III studies in patients with homozygous (25% LDL-cholesterol reductions) and heterozygous (28% LDLc reductions) familial hypercholesterolemia raised concerns that the efficacy of mipomersen could be less than one might have expected based on the initial phase I/II trial results. Couple this with a number of safety and tolerability issues such as elevated liver enzymes, fat accumulation, plus wide-spread injection site and flu-like reactions, the overall profile may not have looked that attractive. The 36-37% reductions in LDLc reported today for the severe hypercholesterolemic and high-risk/high-cholesterol patient populations, however, put efficacy concerns to rest, and it is possible that intact LDL-receptor function contributes to LDLc lowering, somewhat similar to statins.

Actually, due to the high drop-out rates in the latest studies (31-41% for those on drug), the LDLc reductions are likely to be quite a bit higher, at least on par or superior to LDL-apheresis which many of these patients are eligible for, but not widely used due to cost and safety/tolerability/patient convenience reasons. Moreover, the on-target efficacy, and not 2^nd gen antisense as a class, may indeed be responsible for some of the safety issues as the companies strongly suggest that the liver enzyme and fat elevations were in fact correlated with the speed and degree of the LDLc reductions. In some cases apparently more than 80% reductions in LDLc were achieved!

If this were the case, one can easily imagine that in real life, patients could be simply monitored for liver enzymes and fat content as they go on drug, similar to what is already routine for other widely used drugs such as warfarin. Although clearly something that regulatory agencies will want to see studied further (e.g. the ~200 persons that have received full 26-week course of drug may alone not be sufficient to argue against liver tox based on Hy’s Law), at this point it is actually not clear to what degree ApoB knockdown-related enzyme and fat elevations would be clinically relevant. The strategy of the companies to pursue a step-wise filing strategy starting with the highest risk patient populations (planned for early 2011) before seeking to expand the label is therefore very reasonable. For commercial success, the severe hypercholesterolemia population should be key and could already be part of the first filing cohort.

SNALP-ApoB in light of mipomersen data

Now a few words on how the mipomersen results may impact Tekmira’s RNAi Therapeutics candidate SNALP-ApoB which targets the same gene as mipomersen for the treatment of hypercholesterolemia. Assuming that liver enzyme and particularly fat elevations are indeed a function of ApoB knockdown, then some of the same strategies such as gradual dose adjustments may be applicable. In general, as the runner-up, Tekmira has a lot of valuable lessons to learn from mipomersen especially with regard to its regulatory path.

At the same time, to differentiate itself in the market, Tekmira may also want to take advantage of some of the challenges that mipomersen is encountering when it comes to drug tolerability, particularly the injection site reactions and flu-like symptoms that appear to be responsible for quite a few of the study drop-outs and where I believe that SNALP-ApoB could do better. Although I had never thought that being intravenously administered as opposed to the subcutaneous administration of mipomersen would be a major issue, competitive or otherwise, for the high-risk patient populations we are talking about, the fact that ISIS and Genzyme are now considering daily injections as an option to address the injection site reactions even makes intravenous infusion every 2-4 weeks look like a competitive advantage now.

Meanwhile, due to the satisfactory efficacy of mipomersen and the fact that you probably don’t want to overdo it with lowering ApoB as long as it is in the 32-40% range, efficacy should not be too much of a differentiating factor.

All of this is in no way to suggest that the current value of SNALP-ApoB is comparable to ISIS’ mipomersen. Tekmira has yet to enter the clinic with its improved SNALP-ApoB candidate and we all know that clinical development is fraught with surprises. In any case, it is quite satisfying to see oligonucleotide therapeutics progress in the clinic on so many fronts and I wish ISIS and Genzyme well for the commercialization of mipomersen as it would also reflect well on the commercial value of the entire space in general.