Novartis said today it will file LAF-237 in the first half of 2006 - this is its DPPIV inhibitor. Talk at EASD focused on safety of the class, particularly in the wake of the FDA panel on inhaled ~ lots to watch out for. (By the way! Did anyone really focus on the fact that two out of the nine votes that were _no_ were both from pulmonary specialists and that there were only three pulmonary specialists total?)
I liked how Novartis discussed LAF-237 in depth on its pipeline update call BUT the most critical element of the drug, the long-term safety, wasn't really addressed in depth in my view. They discussed how there are fewer GI side effects with this drug vs Metformin, etc. but they didn't address the worries that many have, what else (<--italics) is being inhibited with this compound.
Surprisingly, and unfortunately for Novartis, metformin worked very well in the studies presented, so much so that the primary endpoint, non-inferioritity vs metformin, wasn't met (as it were). In 52-week study of about 750 people, the high dose of LAF237 resulted in an A1C drop from 8.7 to 7.5, while metformin had a drop from 8.8 to 7.1. This was statistically significant. The headline on this slide said "52 week data with monotherapy confirm early and sustained A1C reductions..." It is true the reduction is a good reduction, but not versus metformin's reduction (which was better than some would have expected, at over 1.6 points). They noted then that LAF237 is better tolerated. True, in the sense of traditional annoying side effects, but we think there are still some uncertainties on the long term impact of this new class, and without it beating traditional therapy, this isn't a place a company wants to be, in our view.
Novartis also did an Actos comparison and on this one, Actos had a 1.9% A1C drop, while LAF237 (100 mg) had a 1.6% drop. And this was using 30 mg of Actos not 45 mg! We're not major TZD fans overall (but we are for the right patients) but doing a study not using a fully powered dose seems wrong. Lest you note how impressive nearly 2 points drop is, we point out this is from a 10 A1C - impressive, yes, but it's not like the baseline was 7.0.
There was one 12 week study that was pretty impressive - the only point was to show dose-proportional drops in A1C, and that they did, but on the 50 mg and 100mg arms, they got drops of 1.0 and 1.2, respectively, from baseline A1Cs of 7.4.
Then! They had an add-on insulin trial that showed a non-wow 0.5 drop for LAF237 vs 0.25 drop for placebo plus insulin, over 24 weeks. What was impressive here was that there were six (count 'em six!) hypo events for the insulin group (defined at 3 mmol or less - that is 3x18=54 mg/dL for those that also always forget how to translate mmol).
Novartis also said it's working on a range of products with the FDA, one on manufacturing methods, a secnd on biomarkers to develop new therapies, and a third, interestingly, to look for "the simultaneous development of a particular therapy and a diagnostic test kit that would enable the identification of patients who are most likely to benefit from the particular therapy."
LAF237 appears to be weight neutral, which is better than insulin, but not as positive as Byetta.
Our main issues with the data summary is that they make a very big deal about LAS237 being well tolerated, but they don't say anything about unknown side effects that could be issues longer term AND they try to position as "ideal profile as first drug of choice" - this would never be first drug of choice given what isn'tknown and it seems irresponsible to position it as such.
At the start, Novartis positioned current oral therapies as not addressing multiple defects in type 2 - right! - but GLP-1 (Byetta) has been shown to address two labeled as "unmet need," namely inadequate glucagon suppression (beta cell dysfunction) and beta cell decline.
They also show key requirements for new therapies: 1) clinically meaningful a1c drop; 2) sustained a1c reduction; 3) weight neutrality; 4) well tolerated; 5) low hypos. We agree these are great requirements but they need to show what recently approved drugs can do, in our view.
Other problems: 1) they showed Novartis as the most productive big pharma company - in terms of approvals, they didn't give Lilly any credit for Byetta, which we thought was wrong; 2) They say there are 150 mm type 2 patients worldwide, but 194 million is a widely quoted number; 3) we don't necessarily know if this drug should be approved or not, but the panel meeting will hopefully focus on some of the uncertain safety issues and we would hope the panel would be very well informed. On that note - the FDA should in our view use more experts on panels that are close to industry but just get them to promise they are unbiased. Among the smartest endos in our view are the ones driving the studies, and it seems patently absurd to exclude them due to a suspicion they cannot put forward unbiased views.
Third to last comment - the name that seems to be catching on for this class is incretin enhancer - that's a great name.
Second to last comment - very interesting studies upcoming, including diabetes prevention (this will be very tough indication to get) in about 2009 and reduction of CVM complications in about 2011. Excellent!
Last - Novartis does a great job at melding CVD and diabetes. Just overall, the call really reinforced how hot diabetes is becoming/has become in Big Pharma. There is some chatter that the cardiologists are taking over, and we have certainly started to see it. This is happening at the same time that medical students aren't entering endocrinology as it is such a poorly-reimbursed speciality. Overall, we look for more and more critical data to be presented at CVD meetings rather than diabetes meetings ... onward!
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