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 2nd 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.
7 comments:
ISIS has issued press releases in the past that claim patent protection for ApoB targeting with both single-stranded and double-stranded oligos. Has Tekmira publicly addressed any potential patent infringement issues with their SNALP-ApoB candidate?
I remember having studied the claims in the ISIS patent and I could not find anything to suggest that it would cover RNAi approaches to knocking down ApoB.
Even assuming that RNAi triggers comprised antisense compounds, why did they exclude ribozymes? This suggests to me that if it was indeed possible to claim other mechanisms of actions through obviousness (very doubtful esp. here since RNAi in mammals was little understood at the time of the priority date of the ISIS patent), then that already applied to the previous ribozyme-ApoB literature and ISIS lost the ability to claim the whole genus. Moreover, the guide/antisense strand in Tekmira's ApoB candidate is unlikely to be 100% complementary to target as the ISIS claims demand. If Tekmira really thought that patent was relevant, they could easily change a single nucleotide (e.g. in the overhang) to work around the ISIS patent.
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Daily subcutaneous injections should not represent a major hurdle. I use an insulin pen for my diabetes that is coupled with a 3/16's of an inch 31 gauge needle. Mipomersen is dosed with a 31 gauge needle and although I am not sure of the needle length I suspect it too is very short. Such an injection is truly easy and painless.
An intravenous infusion is hardly simple, painless, or cheap.
I wonder if they have shown the antisense mechanism for mipomersen.
Tet- based on the 50mg cohort in the phase I study (Kastelein et al., 2006), it seems that increasing frequency while lowering the dose should not necessarily get rid of the injection site reactions.
Also, these patients are likely to be closely monitored by their specialists, and why not get the infusions at the same time when seeing their doc anyway? With dosing being in the hand of the docs, outcomes are likely to be better, it may ensure better safety (regulatory agencies and payors may like that), and some docs may also see a financial incentive in having them administer the drug.
Let's not blow this out of proportion though, an ApoB knockdown drug is likely to be quite valuable for many patients, whether associated with injection site reactions or not and ISIS/GENZ would have a couple of years exclusivity in this area.
Yes, Kirsten reported in 2006 that 5 out of 8 patients at the 50 mg dose, and 4 out of 8 at the 100mg dose had injection site reactions. “These reactions were typically described as areas of mild, painless erythema that presented within 24 hours of subcutaneous injection and resolved spontaneously after a median of 5 days.”
You are correct in asserting that further lowering the dose to 30mg (daily) might not solve this issue. Even though mild and painless, any regular occurrence of injection site reactions might prove problematic.
Still, biweekly IV injections represent a very significant and limiting hurdle. While doctors may profit (promote) from such a protocol, as I said, it is hardly simple, painless, or cheap. It would also limit the target population to the very sickest of patients.
Once mipomersen is approved, recruitment for any SNALP-ApoB drug candidate could be difficult. The patient population for FaHO and FaHE hypercholesterolemia is small to start with; offering such patients an experimental me-too drug or a placebo when mipomersen is available may present problems.
ISIS has stated that the platform for their next generation (2.5) of antisense drugs will be introduced this year. They claim it will represent an order of magnitude increase in potency and allow for oral formulations. If that is the case, it will be interesting to see how a biweekly sc 20mg injection or an oral form of mipomersen affects the competitive landscape.
most docs other than oncologists don't want to invest in infusion chairs, nurses, the whole enterprise is expensive and a high risk venture because you need nearly 100% collections to make ends meet. Now about 1/3 of rheumatologists have infusion chairs for their biologics but they have 3 biologics plus cytoxan and rarely methotrexate for polymyositis to infuse. No doctor could do this for one drug and a few patients. Its done as a separate visit for billing purposes not "when seeing their doc anyway".
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