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Cardiovascular Disease

Takeda Gets A Surprise

DPP-IV is short for “dipeptidylpeptidase IV”, understandably, and we need a good abbreviation for it. It’s an important enzyme target for diabetes therapy, since under normal conditions it breaks down glucagon-like-peptide 1. Longer-circulating GLP-1 would actually do a lot of diabetics good, and people have actually made such proteins as separate drugs, so inhibiting an enzyme that clears it out looks like a good bet. Of such reasoning are drug targets made.
A lot of companies have bought into this reasoning, for sure. For quite a while, Novartis looked like the leader in the area, with the most advanced clinical candidate and a lot of publications in the literature from their development work. But Merck turned out to be running a big effort of their own, and actually got to market first with Januvia (sitagliptin). Novartis’s drug (Galvus, vildagliptin) looks as if it will never make it at all here in the US.
They had to slow down development due to some troubling side effects, giving Merck the edge. There are several DPP subtypes, and you need to be pretty selective, as it turns out – at least some of the problems stem from that consideration. This wasn’t fully appreciated in the first wave of development in this area – the pioneers had to figure it out the hard and expensive way. But a number of companies have come up behind, trying to get a piece of the market, and they now have a clearer idea of what they need to accomplish.
Or do they? Takeda recently heard from the FDA that their DPP-IV inhibitor alogliptin has been turned down for now. What’s more, the agency wants more cardiovascular safety data from them and from anyone else who comes in with a drug in that category. Cardiovascular problems have always been the weak point for Type II diabetes drugs, to be sure. The patient population tends to be older and overweight, often with elevated blood pressure, so you really don’t have much room to work in when it comes to side effects. That’s led to a lot of attempts to come up with therapies that address the CV side of things at the same time as glucose levels (such as the ill-fated disaster of the PPAR alpha-gamma compounds, all of when went most expensively down in flames). DPP-IV inhibitors wouldn’t be expected to have any direct CV benefits, but they do have to avoid making things any worse.
So Merck looks to have the market to itself for a while longer, but as the only DPP-IV drug on the market, they’re going to be under a good deal of scrutiny. The company has already had its share of post-launch cardiovascular nightmares; you’d think that they’re going to work hard to avoid any more. And now all we have to do is assure ourselves that the actions of the DPP-IV inhibitors are all through making GLP-1 last longer. Because even if you’re selective for that one enzyme, it has a lot of other substrates. So the story may well swing back to the biochemical mechanism again before we’re through.

20 comments on “Takeda Gets A Surprise”

  1. drug_hunter says:

    Back around 2006-2007 or so, there was a fellow from Takeda (Syrrx at the time) on lots of the yahoo bulletin boards who was crowing about how great their compound was – much better than Merck’s and all that. My gray hair told me his confidence was o’erweening … sad when these things happen but hardly surprising. Diabetes is just as challenging as antibiotics, only you fail in a more spectacular (and expensive) fashion! And DPP4 is indeed a very messy mechanism with a lot still to be learned. Glad we steered clear of this one.

  2. darwin says:

    As an ex-employee of Merck with few nice things to say about its culture, I have to give them credit for their aggressive development of Januvia. They characterized differences early on with their compound and pumped resources into fast tracking it through development. Unhealthy patient population with many complications and a growing unmet medical need which calls for prudent risk taking. It was pretty astonishing to see what a large company with capital can do when it wants to flex. Doesn’t happen enough.

  3. Sili says:

    DPP-IV is short for “dipeptidylpeptidase IV”, understandably, and we need a good abbreviation for it.

    Le gasp!
    Does that mean you call 2-ethanoyloxybenzoic acid Aspirin, too?

  4. MedChemMan says:

    FDA has raised the safety bar, probably, due to the concerns on the CV safety of TZDs and also due to the following general reasons (
    1)More than 23 million people in the U.S. have been diagnosed with type 2 diabetes or diabetes mellitus.
    2)Patients with diabetes have a two- to four-times greater risk of heart disease than do their nondiabetic counterparts.
    3)None of the currently approved antidiabetic therapies has been convincingly proven to reduce that risk.
    4)Because diabetes often requires lifelong treatment, prescribers and patients need to know more about whether their antidiabetic therapies put patients at increased risk of heart attack.
    It is now mandatory that the clincal trails for T2D should include assessment of CV risk. It remains to be seen whether Saxagliptin (another DPP-IV inhibitor, developed by BMS) will be approved in the near future. The path for developmental candidates like dapagliplozin (SGLT inhibitor) is also not going to be easy anymore.

  5. Hap says:

    1) It just amazing how these surprises never turn out to be good ones. Amazing I tell you.
    2) The Yahoo stock board sounds like a real dispassionate and unbiased resource for stock information. When someone advocates a stock strongly there, I think hard about some…or just buying a lottery ticket, which is probably the better investment, anyway (I only expect to lose half my money there).
    The only thing better is when they wander out of their basements and dens to complain how unfair Dr. Lowe is being for revealing some unpleasant fact about their investments. You can smell the burning egos and self-delusion in the air on those days, and urban areas consider issuing air quality warnings.

  6. RB Woodweird says:

    “Does that mean you call 2-ethanoyloxybenzoic acid Aspirin, too?”
    Nope. Me and Mr. Dr. Prof. Woodweird call it good old EOBA. Unless it’s buffered, then we call it BEOBA. Or if it’s in a child dose, then we call it Old Man’s EOBA.

  7. RB Woodweird says:

    “Does that mean you call 2-ethanoyloxybenzoic acid Aspirin, too?”
    Nope. Me and Mr. Dr. Prof. Woodweird call it good old EOBA. Unless it’s buffered, then we call it BEOBA. Or if it’s in a child dose, then we call it Old Man’s EOBA.

  8. Morten G says:

    What about isosteviol?
    What about exercise?
    Do any of the DDP-IV inhibitors cause weight reduction like the GLP-1 analogues?

  9. peej says:

    There must be more to the story here.
    The BMS/AZ compound is going to go to an advisory board in April. Why would an advisory board be called for one DPP while Takeda’s was told they dont have the CV data? I find that odd.. if the issue is long term CV studies, why bother to bring the AZ/BMS drug to committee?

  10. Lucifer says:

    Have anyone of you considered that a 25 g dose of ethanol with lunch and dinner would have a larger effect on blood glucose in Type 2 DM (and reduce CV risk) than Januiva or related drugs.

  11. Ty says:

    peej, it makes you wonder all right. There was not much of a difference between Januvia and Galvus (you know, neither is the safest drug in the market). If anything, Galvus had much more data to show (and therefore be looked at and knitpicked on). Galvus has been approved in Europe.
    Merck and BMS vs Novartis and Takeda… Do I smell something fishy here? It just makes you wonder…

  12. Pharma Guru says:

    Sounds to me like many of you haven’t done your research. Galvus wasn’t selctive enough to inhibit only dpp-4 (it also inhibited dpp-8 and 9). Many of the others have the same problem, excluding Januvia. Ty, you might want to take this into consideration when you imply Galvus is similar to Januvia (it’s not).

  13. BioDude says:

    Did Takeda think they could slide the ‘ol application into the FDA before they came out with 12/2008 guidance report….and be excused from the recommendations? I’m guessing the ink was still wet and ‘etc.’ was used often in the application to beat the clock…..nice try Takeda…

  14. CMC Guy says:

    #12 BioDude one of the links Derek provides indicates Takeda submitted NDA in 2007 so do not think any subterfuge involved. I don’t know the history on this particular guidance but usually there is a long run up period to issuance of such and FDA often drops “hints” of what is coming long before. At the same time FDA is famous for application of “today’s rules” to activities done years before when different priorities or focuses drove requirements. That is one of the most difficult aspects of drug development, particularly clinical trials, in that is long and expensive road so hard to adjust on the fly to either own info learned or more so influences from outside/similar products.

  15. Ty says:

    Guru; thank you for refreshing my memory. I was aware that Januvia had better in vitro selectivity profile. But I was also told that the selectivity concern did not really materialize in the clinical setting. [Maybe Novartis had to prove it.] Anyway, by ‘similar’, I was refering to the clinical outcomes. I may be wrong, but I don’t think that the regulatory decision (“approvable”) on Galvus was based on the concern related to dpp8/9 activity and it’s potential implications in any way.

  16. BioDude says:

    CMC guy – point well taken. I thought, for some reason, they had applied in early 2008, after the initial FDA guidance.

  17. srp says:

    This business of targeting one mechanism, getting through clinical trials, and then finding out that some other mechanism is really what’s being modified reminds me of doing crossword puzzles.
    Sometimes I put in the wrong “down” word, say, but there are enough correct letters in the mistaken answer that I am able to correctly guess some of the “across” words. Without my incorrect hypothesis I would never figure out the correct words. Of course, building off the adjacent correct words eventually exposes my original error.

  18. doctorpat says:

    Hap on March 17, 2009 11:55 AM writes…
    1) It just amazing how these surprises never turn out to be good ones. Amazing I tell you.

    Not true. In one word: Viagra
    That was clearly a good surprise.

  19. Hap says:

    Duh. That was a good surprise for a lot of people.

  20. provocateur says:

    Do you guyz beleive in anything called ‘too much data’….Thats what killed galvus!
    I heard that a 18 wheeler truck carried all the relevant data of galvus..januvia just slipped thru with far less because the fda did not really know much abt dpp4

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