Skip to Content

Clinical Trials

Cathepsin K: A Promising Target Fades Out

Here’s another one for the file of huge, long, costly drug discovery efforts that came to nothing (and that no one outside the business ever hears about): cathepsin K inhibitors. I remember “Cat K” from my own (relatively brief) days in osteoporosis drug work some years ago. It’s a target that’s been around since the mid-1990s, and Merck alone has been trying to develop their drug, odanacatib, for over twelve years now. But not any more.

The enzyme is able to break down collagen, elastin, gelatin and other proteins, and it’s a key player in the activity of osteoclast cells as they break down and resorb bone tissue. Recall that your bones, at a microscopic level, are constantly being remodeled – osteoclasts are breaking things down, and osteoblasts are building them back up. A longstanding theory of osteoporosis is that the balance between these two activities has gone off, with bone destruction running ahead, and you’d certainly think that anything that slows down osteoclast activity would help with bone loss. It’s very hard to do that, though, without slowing down osteoblast activity as well, so some osteoporosis therapies sort of settle for bringing things to a standstill rather than allowing bone regrowth to take place at the levels you’d probably want.

Thus cathepsin K inhibitors. Osteoclasts secrete acid to break down the mineral component of bone tissue, and they set cat-K loose on all the protein components (the enzyme works best at acidic pH). It’s found almost entirely in this cell type, giving you a real hope of targeting osteoclasts selectively. Protease inhibitors themselves are a type of small molecule that, in general, we have pretty good success with in drug discovery, so what else do you want? Well, there is one little thing. A lot of people have looked at this target over the years, but osteoporosis (although a big market) is not one that you get into lightly, because the patients are elderly and the disease moves so slowly. The clinical development costs will eat you alive unless you have significant piles of cash to risk.

A number of companies took a crack at it (here’s a table from 2012), but Merck was widely thought to be in the lead. The Novartis compound on that list, balicatrib, wiped out in Phase II because of dermatologic side effects, and the GSK compound, relacatib, went into Phase I and then just sort of hazed off into the limbo that awaits problematic clinical development candidates in that organization. Both companies published patents showing that they were following up with other chemotypes, but I’ve no idea what happened to all of those. Sanofi had a dual cathepsin K/S that also dropped out of the clinic for reasons unknown. A number of smaller companies have also been developing compounds, no doubt hoping to sign a deal with a larger outfit to get through Phase II and III (I think that Medivir is the only one left in the game).

Merck’s odanacatrib phase II trials went on for five years, but they showed that the compound did, in fact, slow down bone resorption and increase bone mineral density. The Phase III trials ended up with over 16,000 female patients, 65 and older, at nearly 400 clinical research centers, and if you think that one wasn’t a beast to run then you ought to come on down and try it sometime. The good news for everyone was that the trial was actually stopped early for efficacy, whereupon the control group got a chance to switch over to the drug. Analysts cheered and raised their earnings forecasts.

But no story is simple in this business. Cathepsin K, it gradually became clear, was involved in a lot of other things besides bone resorption. (Here’s a good review). Thyroid function, learning and memory, processing of vasoactive peptides, adipose tissue – it may not be expressed at high levels in some of these tissues, but it might well be a player nonetheless. People kept waiting for news on odanacatib after the success in Phase III, but as time went on, it became likely that there was something complicating the picture.

And earlier this month, Merck announced that they were discontinuing development of the compound. Analysis of the clinical data showed that while it was indeed efficacious, it also increased the risk for stroke, which is something that you really have to be on guard for in this patient population. As far as I know, no one quite knows the mechanism behind this problem or saw it coming. It’s quite possibly a mechanistic problem, which would probably doom any other cathepsin K inhibitors, but who knows? You’ll need to get a really good compound together and dose a few thousand patients to be able to answer that one, and if that sounds like a good time to you, again, come on down. Note as well that by the time you make it through the clinic, your patent will have the majority of its lifetime eaten away, leaving you with a narrow window in which to charge for the fruits of your efforts before the compound goes generic. Merck, for its part, spent at least 12 years on odanacatib, and who knows how much money. We now know much more about cathepsin K than we ever did, but this knowledge did not come cheaply. . .

 

58 comments on “Cathepsin K: A Promising Target Fades Out”

  1. clueless says:

    Well, *someone* has to fund basic science…

  2. 404 file not found says:

    “Note as well that by the time you make it through the clinic, your patent will have the majority of its lifetime eaten away, leaving you with a narrow window in which to charge for the fruits of your efforts before the compound goes generic.”

    Wouldn’t it be sensible if we had a system where, for pharmaceutical patents, the 20-year patent clock resets if & when a drug gets approved by the FDA? That way you could protect your IP the moment you have it, without having long clinical trials be a problem.

    1. Janex says:

      I was just thinking the same thing. Cat K aside, there are a lot of very long term projects that never get developed for this reason.

      And by making pharma a separate category of patent this has the bonus of getting pharma and the software industry out of their more or less permanent fight over how patents should be regulated.

    2. Dr. Manhattan says:

      A point that has ben discussed for some time in various forms. One problem would be the significant concessions on pricing & subsequent price increases by the industry would have to come along with any such change. That would impact the investment landscape, especially for biotech startups. Also, that would require rewriting patent law with a clause specifically for the pharmaceutical industry. I don’t think the legislative climate right now (or anytime soon)

      1. Anon says:

        Copywrite on the molecular structure would give protection for the “author’s” (inventor’s) life plus 50 years. If only we could rely on that for drugs, and I don’t see why we couldn’t:

        1. Thomas says:

          Copyright applies to creative works (works of beauty), not functional works.
          This would open another can of worms, with patents having infinite life (just like Mickey Mouse). Which would stop all innovation as there is no freely available base to build on (hey hydrogen bridge, you are my copyright) and because money would be flowing in anyways.

          The ‘FDA approval as start date’ seems reasonable but also needs some thought. Is likely possible to get a new approval for a new dosage? – that shouldn’t increase the patent life IMO. Probably not hard to arrange if the patent date is only set once, at first approval.

      2. HTSguy says:

        Of course you are right from a practical standpoint, but such a change in patent law would make chronic disease drug development a lot easier to fund (think of the length/cost of disease-modifying Alzheimer’s trials).

      3. Anonymous Chemist says:

        In fact, patent law has already been rewritten in many jurisdictions to compensate pharmaceutical and agrochemical companies for losing the first years of the patent term while awaiting regulatory approval.

        The original 20-year patent term may be extended for up to 5 additional years by applying for a Supplementary Protection Certificate in Europe or Patent Term Extension in the US. Similar provisions exist in Japan, South Korea and Australia.

        A list of US patent terms extended under 35 U.S.C. 156 (“Extension for Delays at other Agencies”) can be found at:

        http://www.uspto.gov/patent/laws-and-regulations/patent-term-extension/patent-terms-extended-under-35-usc-156

        For example, the basic patent US 5,780,454 covering Velcade (“Boronic ester and acid compounds”) was filed almost 22 years ago, on October 28, 1994 but is still in force today because its term has been extended until May 3, 2017.

      4. Nick K says:

        I agree that prices would have to come down with patents whose clock started the day the FDA approved a drug, but the income stream would last 20 years or more, and would be far more predictable and steady. Everyone would benefit, including patients.

    3. ab says:

      @404:
      This would slow down the process of drug discovery and development. As it stands currently, companies are highly motivated to get their drugs through clinical trials and across the finish line as quickly as possible due to the ticking patent clock. You don’t want to take away this motivation.

      1. Phil says:

        ab: There is a middle ground. A minimum exclusivity period (5, 7, 10 years?) would keep companies working on projects where the original patents have expired but no approved therapy has resulted.

        Also, the “ticking patent clock” is far from the only thing driving drug discovery programs to move quickly. There is inherent pressure to get a return on your investment as soon as possible regardless of exclusivity.

        1. Anon2 says:

          See: Time Value of Money

      2. loupgarous says:

        ab: “…companies are highly motivated to get their drugs through clinical trials and across the finish line as quickly as possible due to the ticking patent clock. You don’t want to take away this motivation.”

        Which leaves patients in the post-marketing phase to be the real safety trial cohort in many cases – always assuming that pharmacovigilance works and companies are motivated to exercise it after the NDA is granted. With fluoroquinolones it wasn’t until two groups of clinical researchers did retrospective studies to examine incidence of aortic aneurysm and dissection and other adverse events that an association was observed.

        On the other hand, if the patent went into effect after NDA, and if the cost of Phase III trials could be contained, and those trials were all with large enough cohorts to make studies of safety and efficacy more statistically powerful, the chance would be greater that (as with odanacatib) we’d catch the AEs in Phase III.

        After the NDA is granted, we’re only likely (according to the FDA) to see 10% or so of adverse events associated with a given medication. If the patient had two or more conditions likely to cause death, the chance increases we’d miss a fatal AE with a given compound.

        Which brings me to another condition I’d like to see placed on patent extension for a given period after the NDA is granted: some sort of enhanced, rigorous drug experience reporting during that patent period. It might even help drug manufacturers rebut allegations that they were lax in monitoring patient outcomes or withheld information on risk associated with administration of a given drug. It’s another thing that the Zuckerbergs and Microsoft might be good at helping out with (it’s sure Big Data).

  3. watcher says:

    The cost & time of developing a compound for this disease is high and long. Many across the industry felt that resources spent on this development path was not worth the economics, resources and time that would be involved. In my company, it was felt that bisphosphinates would be cheap generics before a Cat K inhibitor would be able to get approved, and hence would not be competitive nor cost effective. Even though I’ve not seen an analysis for many years, this evaluation may be even more true today than it was 20 years ago when this target became a rage across the industry.

    1. Barry says:

      the business development calculation of what’s worth pursuing could change as the consequences of chronic bisphosphonate use are better known.

  4. annonie says:

    This is not your first rather snide comment about GSK. What’s your problem with the company? Let’s see, they had a candidate in the clinic that was stopped (presumably due to a development issue such as a toxicology result), decided not to pursue the area, and moved on. You haven’t seen or experienced such a set of events during your long career at your many places of employment? It’s the business Derek; get over it.

    1. anonymous says:

      @ annonie-Don’t be hard on yourself. It’s just Derck’s comments and his way with the words. I betcha even GSK does not give it a damn!

      1. Anon says:

        Well to be fair, GSK does seem to have a culture of organizational procrastination and avoidance of making any kind of firm decision. At least that’s my perception.

    2. AmILloyd says:

      Annonie: Are you sure you aren’t confusing “snide” with “good writing”?

    3. ex-SKG says:

      Having lived the GSK R&D experience, I can say Derek’s comment was actually quite merciful and restrained.

      Cat K is yet another example of biology calling the shots. Even if you’re exquisitely on-target, there’s always layers to biology. Mother Nature determines the clinical realities and the Patent Office sets the clock. Knowing if/when you can resolve key biological or medical questions, within a fixed time window, is a little different from typical engineering problems. As others have pointed out, it would be nice to see a different patent life paradigm for NDEs, particularly first-in-class.

    4. Chrispy says:

      GSK lost what credibility they had with the purchase of snake-oil Sirtris. Yeah, it is well known that the internal scientists tried to stop the deal, but the fact that their opinion apparently carried no weight underscores the hubris and poor leadership in the company. Sorry, Annonie — GSK isn’t the only pharma in this position, if it is any comfort.

    5. Derek Lowe says:

      If we’re counting up snide comments about particular companies, it’s going to be a long evening. My point about GSK is that (from my own impressions) the organization tends to let abandoned compounds sit in their presentations and on their web site longer than many other companies do. Merck, for all their faults – and they, like any other large company, have plenty to go around – did come out and forthrightly say that they’re dropping this compound. GSK just doesn’t seem to do that as often.

    6. loupgarous says:

      Annonie: I haven’t noticed Derek spares any particular company his sharp wit when it’s called on. Most of us show up for chuckles at those firms who for some reason or another haven’t thought things through. He generally saves his best efforts for those compounds which have done their best to do him or other chemists in, or for the foibles of drug development in general.

      1. Hap says:

        Merck got whacked hard with the “Lawyers Lying Badly” fiasco, and Roche (or their ex-CEO) got whacked for their CEO’s ill-advised truth-telling. If GSK didn’t do dumb things in public (like pay lots of money to biotechs with sketchy data), or act like PR was its main product sometimes, they wouldn’t get whacked for it. It’s not like pharma couldn’t use the jobs that might accrue were GSK successful, and most people here don’t have a reason to inherently dislike GSK. On the other hand, they’re not going to wallpaper over its mistakes, either.

  5. Curt F. says:

    Very minor typo: it appears to be balicatib, not balicatrib.

    1. Another_Anon says:

      Also odanacatib, not odanacatrib.

  6. Barry says:

    Bone biology has advanced since the first Cathepsin K programs were launched. It’s now possible to tune down the production of osteoclasts (e.g.by blocking RANKL signalling) rather than just hobbling their degradation of old bone. But whereever you intercede in osteoporosis, you face long expensive Clinical trials

    1. Eric says:

      True, but drug development in bone biology is essentially dead (which is why I got out of the field). Major companies aren’t investing in new development projects. The ongoing sclerostin inhibitor efforts may be the last drugs developed for osteoporosis for the foreseeable future. This is despite the fact that osteoporosis is a therapeutic area where the animal models are quite predictive of clinical outcomes so further development should be possible.

      It’s a problem outlined by several comments above. Trials are very long, very large, very expensive, and have to compete with generic competition. The economics just don’t work. Treatment for osteoporosis is not likely to improve over the coming decades beyond what is already available. Unfortunately one can envision this same pattern (early success with a few approvals followed by a complete halting of future research) will likely play out for other large multifactorial indications (e.g., CVD, Alzheimer’s). It’s a problem that the current funding paradigms can’t solve.

      1. john adams says:

        Tragically, I think you can now add type 2 diabetes to that list. What a crime !

      2. Barry says:

        Perhaps the incentive structure will look different if physicians acknowledge the problems with chronic bisphosphonate use? This is not a solved problem

      3. zero says:

        NASA and other space agencies are mighty interested in slowing or preventing microgravity bone loss. I’d bet progress in the field could be made since you’d have a pool of astoundingly healthy people whose symptoms develop rapidly and predictably in microgravity, yet progression can be stopped by returning them to Earth. That includes mouse model testing on ISS.

  7. Christophe Verlinde says:

    I would agree that for a minority of patients unlucky genetics leads to osteoporosis. But for the vast majority of people with osteoporosis a vigorous daily exercise plan with load bearing would lead to stronger bones. The major problem is that most people would rather sit down all day and solve the problem with a pill.

    1. Eric says:

      Yes, but couldn’t you say the same thing for almost every disease afflicting the elderly? Eat healthier and exercise more. It might not stop cancer, but certainly would help with CVD, diabetes, osteoporosis, etc.

  8. Ted says:

    Co-workers at my old (very old now…) employer, Darwin Molecular, identified sclerostin, the protein product of the SOST gene. SOST gene dysfunction was associated with sclerosteosis, a disease of excessive bone density. This is back when the gene jocks were first trying to mine genetic subgroups for ‘surrogate drug disorders.’

    The target has been percolating through industry (originally with Amgen) for almost 15 years now, with a few Ab drugs nearing PIII endpoints. We never had a chance to work on it back in the day, as small molecule med. chem. to interrupt soluble protein/protein interactions was a stupidly unlikely venture in the early ’00s.

    The current Ab, romosozumab, could be a game-changing therapeutic.

    -t

  9. steve says:

    Off topic but what happened to the thread about Bob Sheridan and the number of meetings at Merck?

    1. Derek Lowe says:

      Have to make sure that I’m not getting anyone in personal trouble there before I leave the post up!

  10. Barry says:

    a cartoon in C&ENews some years ago quipped that “it might make you immortal, but it’ll take forever to test”. You might say much the same about an osteoporosis therapy (it was irresponsible to approve the bisphosphonates for decades-long dosing on a too-brief safety Clinical)
    Although the US patent law has been very very important to the Drug Industry for the last century, creating incentives to invest and innovate (and disclose those innovations, enabling competition), it is not a perfect general solution. It obviously fails for the case of a hypothetical drug for which Clinical Trials would take longer than the 20yrs of market exclusivity that the law grants.
    Our FDA has created other forms of exclusivity beyond the patent clock (witness recent gouging by Mylan and Turing) and the TPP proposes more. Both trespass on the USPTO’s proper authority. Calls for overhaul of our Intellectual Property Law have mostly come from the Software Industry, and have mostly been resisted by the Drug Industry. But the current law is plainly imperfect.

    1. exclusive says:

      “Our FDA has created other forms of exclusivity beyond the patent clock … Both trespass on the USPTO’s proper authority.”

      The FDA already regulates the entry of drugs into the market in a negative way, by requiring approval. I don’t think it’s overstepping it’s mission or authority by also granting incentives (exclusivity) for market entrants.

      I agree with some of the other commenters that a guaranteed market exclusivity of perhaps 5 years post-approval might help persuade companies to invest in challenging projects.

      On that note, does anyone know of any comprehensive reference for the FDA’s exclusivity programs, like orphan drug designation, the Unapproved Drugs Initiative, etc.?

      1. Barry says:

        The U.S. Supreme Court ruled long ago (“Schechter Poultry”) that the proper powers of one branch of government cannot be delegated to another. U.S. patent law is not sufficient to drive investment and innovation in indications for which Clinical trials would take longer than the patent life. But no other authority has the legal power to extend that. $Billion and ten or twenty years is a lot to gamble on the bet that no one will be granted standing to challenge that in court.

      2. Barry says:

        Great discussion. I’ve learned that the USPTO (not the FDA) does offer up to 5yrs additional market exclusivity where a regulatory agency (e.g. FDA) has eaten up the patent clock

        https://www.law.cornell.edu/uscode/text/35/156

  11. tangent says:

    This is one of the big problems, right? We turn a knob and discover it’s connected five other places too. But I wonder, what if we magically had perfect knowledge of the biology, and magically could make a drug selective for any target — even then could we get a desired effect?

    Look at it stepwise: we discover that inhibiting A also raises B and lowers C. So we go in, lower B (which +D -E), and raise C (which +F +G). The ripples spread, but do they decay, so that a little tweak to D-E-F-G will suffice and the slight side effects on H-I-J-…-Z can be ignored? Or do they amplify, so this whole thing is a fool’s errand?

    One intuition may be that it has to decay, or we could never get anything done, just be metabolism flapping all around chaotically. I wouldn’t count on that though; a system that’s chaotic may be controllable, and biology uses that. But the controller has to be dynamic itself.

    I will actually bet this has pretty good odds of being reality: that many of the outcomes we want can never be achieved by applying any static drug effect, but they could by a dynamic control system.

    Drugs are dead, long live devices.

    (What do you think, do you buy it? Would you invest in my company named after some notation in control theory?)

    1. loupgarous says:

      No real data to base that on, but I’m willing to concede a feedback loop-like mechanism in which inhibition of one particular enzyme’s activity may simply cause the cells that make it either to make more and more of the enzyme (and do it in places other than the organ in the target disease entity). A number of hitherto-unexplained drug-related adverse events might happen that way.

      Osteoporosis in particular seems to be a symptom of a natural process selected for in some way. It could be that Cathepsin K and related enzymes serve valuable purposes elsewhere in the body than osteoclasts, and inhibiting them may be the cause of the adverse events seen in Merck’s early clinical studies. Or it may be just rotten luck.

      It’s interesting that Cathepsin K is expressed in some cancer cell types and not others. Whether this holds out hope for an indication for Cathepsin K inhibitors where a low but present risk of collagen-related AEs might be something for Merck or other Big Pharma players to look into.

      1. loupgarous says:

        Seems that Cathepsin K antibodies are already out there as a tool in the differential diagnosis between different types of cancer.

        What I was speculating on in the comment above this one is whether anyone had investigated just what Cathepsin K does in those cancers which express it. Is it a way of allowing the cancer to dissolve the integument around normal cells?

        If that’s so, the next questions which occurred to me were
        “Would inhibiting Cathepsin K give patients more time for other therapies to attack and destroy cancers which express it?”
        and
        “Would it be a valuable adjunctive therapy despite an elevated risk for stroke and other adverse events?

        Here’s a link to the free Am J Clin Pathol paper on the work I cited earlier reporting the differential expression of Cathepsin K in various cancers. The link I posted before was the authors’ manuscript.

    2. matt says:

      I absolutely believe that about medicine targeted toward brain functions, all of the neurotransmitter receptor agonists and antagonists. Just like a dead clock is right twice a day, and just like sticking a constant five volts potential on a wire from a thermostat to a heat pump could only accidentally and occasionally turn out to be helpful, I think we’ll find our current treatment attempts are similarly hamfisted and Cro-Magnon. Problem is, of course, it may be a hundred years before we know enough to do much better.

      Are you going to call your device company Novel Excitations? I think a lot of people would go for that.

    3. loupgarous says:

      Drugs aren’t dead, but the idea we can drop a potent drug into the digestive tract or circulation without adverse events might be doddering.

      Cathepsin K inhibitors are promising. Cathepsin K is known to be active in the process of loosening arterial plaque, plays a role in cerebral aneurysms and has been shown to be expressed in a variety of cancer cells, so that it may be a valuable adjunct to therapy of much more severe and life-threatening diseases than osteoporosis.

      I’ve had “targeted” radiotherapy and chemotherapy for a rare cancer, and I understand the power of targeting tumors and other lesions. In my case, the targeting was done in two ways – a systemic delivery of a relatively short-lived radioisotope attached to a protein taken up preferentially by the tumors, minimally by healthy tissues (kidneys protected by co-administration of amino acids), and local delivery (by transluminal catheter) of two traditional chemotherapy agents into tumors which had not been debulked after the radiotherapy, and which couldn’t safely be removed by surgery.

      The results in my case were lower radiotoxicity and lower chemical toxicity – I still experienced systemic effects from both therapies, but they were effects I could handle without a lot of secondary treatment. Others who’ve had the same chemo agents systemically that I’ve had delivered by transluminal catheter directly to the tumor have had much worse trouble than me with nausea and bone marrow suppression than I did, and the same goes for radiotoxicity after older methods of radiotherapy versus tissue-targeted radiotherapy.

      Looking at what Cathepsin K does in tumors and arterial walls, perhaps drugs which inhibit it should be administered locally or bound to proteins or other structures with high target organ specificity.

      Transluminal catheter delivery has an irreducible risk, which ought to be balanced against its potential benefit in derailing the way cancers invade healthy tissue. For aggressive, hard-to-treat cancers such as glioblastoma, a Cathepsin K inhibitor might buy time for a patient while another, more potent treatment can be fashioned. That’s precisely the sort of deadly disease process where Cathepsin K inhibition’s risks are more acceptable and can be minimized with local or targeted delivery. A sharp tool ought to be used to cut where other tools don’t work as well.

      1. Barry says:

        many proteins are inappropriately expressed in cancer cells. It does not follow, however, that their expression is necessary or even beneficial to the cancer. These cells are deranged. Efforts to stop cancer’s spread by blocking the proteases is exports (see twenty years of work on matrix metalloprotease inhibitors including tanomastat, prinomastat, batimastat and marimastat) never changed one clinical outcome. Cathepsin B was also explored and dropped.

  12. Reg says:

    Why the lamentation about patent life? As a med chemist who made the jump into regulatory I wonder what the fuss is about here: FDA grants a 5-year exclusivity for your drug substance when they approve your NDA. This means that competitors cannot cross-reference your IND or drug master file in development and hence would be required to do their own phase III studies to get your molecule to market and could not file a generic based on your docs. Although patent-expired this is still pretty good protection.
    Plus there ARE incentive programs to extend that, such as paeds, new formulations, new uses etc. Play your cards right, the 5 years will extend beyond 7.
    So theoretically a company could work with your IP, but only really worth it for a usage extension into another disease, and then they run the risk that you know about it already and you CAN cross-refer to your own IND for PK/tox etc so could likely scoop them anyway.

    1. Barry says:

      the problem is that this is beyond the FDA’s proper authority. Market exclusivity is a power of the USPTO. The FDA’s authority is over safety and efficacy. While a period of market exclusivity that expires before your product gets to market is ridiculous, it is legal. The FDA’s end-run will eventually be found to be illegitimate.

      1. steve says:

        Apples and oranges. USPTO gives patent exclusion based on intellectual property, FDA gives regulatory exclusion based on clinical data. One domain has nothing to do with the other.

  13. Ref says:

    PS The GSK asset would not have a back- up since it would fall under the remit of MMPD CEDD which had pulled out of internal musculoskeletal work in the early 2000’s when I worked there.
    That unit now forms part of oncology and infectious disease. AFAIK musculoskeletal stuff is external-only now.

  14. loupgarous says:

    Messing with collagen metabolism/catabolism seems risky, but we’ve only found that out relatively lately (last decade or so) with the fluoroquinolones, which only in the past few years have gotten black-boxed by FDA for weakening tendons and even arteries (especially that big one you don’t want weakened, the aorta), and various and sundry CNS adverse events.

    Having written code for safety/efficacy reporting for various Big Pharma entities, I’m aware that not every adverse event associated with a medication is directly caused by that medication, but also aware that FDA wants to know about all the AEs, anyway, and make up its own mind on causation, risk-benefit, et cetera.

    My guess is Merck saw what Johnson &Johnson and Bayer are about to go through on their fluoroquinolone antibiotics because of collagen-related AEs, and decided they’d sit the “drugs which affect collagen adversely” dance out. Can’t really blame them, for the reasons you’ve outlined – Merck could either double-down on their existing financial outlays on that drug, or pass.

  15. loupgarous says:

    Another reflection on collagen-related AEs – in the Toronto and Taiwan retrospective studies on AEs associated with fluoroquinolone antibiotics, the association between the drugs studied and advanced age was especially high, so much so that the Toronto group concentrated on the patient cohort > 65 years of age. And cathepsin K inhibitors are targeted to treatment of osteoporosis, a complaint of the elderly.

    While cathepsin K inhibitors actually inhibit one of the enzymes responsible for breakdown of collagen, the increased incidence of stroke points to (even to a layman) the possibility of inhibition of the mechanism which controls intimal proliferation in blood vessels, causing them to occlude more than they otherwise would.

    This might be a bigger deal in a population which has more than its share of prone-ness to cerebrovascular events in general, and also more than its share of transluminal angioplasty for various conditions (restenosis of arterial occlusions being noticed regularly after those procedures, anyway).

  16. loupgarous says:

    Perhaps it’s early days to ring the death knell for Cathepsin K inhibitors. Osteoporosis, as you say, is a slow-onset disease, and arresting its onset can be done in less risky ways.

    It seems to me that the drug may have its uses not delivered systemically, but locally. There was work, back when I was with a group studying the Palmaz-Schatz intracoronary artery stent, on stents made to release heparin and antiproliferative agents slowly – thus performing the mechanical task of widening a narrowed artery and reducing the known risk that the stent itself would tear the lining of the artery enough to cause restenosis at the stent site.

    Two papers I turned up on a quick Google of the literature address Cathepsin K’s activity in arterial injury: “Human macrophage foam cells degrade atherosclerotic plaques through cathepsin K mediated processes” Natasha Barascuk et al and “Cathepsin B, K, and S Are Expressed in Cerebral Aneurysms and Promote the Progression of Cerebral Aneurysms”, Hiroharu Kataoka, et al..

    These papers point out what may have happened in the study participants who had strokes in the Merck Phase III trials, and its implications for targeted, local administration of cathepsin inhibitors.

    There’s not a lot out there about cathepsin K activity in cancers: “Expression Analysis of All Protease Genes Reveals Cathepsin K to Be Overexpressed in Glioblastoma”, “Expression And Activity Of Cathepsin K In Lymphangioleiomyomatosis (LAM)”, “Cathepsin K Is the Principal Protease in Giant Cell Tumor of Bone” and “Cathepsin K mRNA and Protein Expression in Prostate Cancer Progression”. Some of it points to another indication for cathepsin K inhibitors, again, delivered locally so that the drugs’ effect is mostly limited to a target lesion.

  17. Mol Biologist says:

    IMO vigorous daily exercise plan with weight load could be new biology layer for cathepsins.
    https://www.ncbi.nlm.nih.gov/pubmed/26699421
    It is well known that part of exosomes or extracellular vehicles will not be excreted from cells but go to lysosomes. Besides many well-known functions cathepsins being involved in protein turnover and digestion, they ALSO build an important part of the antigen presentation. Cat K may have additional functions which directly or indirectly involved in muscle growth but through other pathways for example Toll-like receptors pathway. And skeletal muscle cells express multiple Toll-like receptors (TLR).
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735460/
    http://jvi.asm.org/content/79/5/2847.full
    So, inhibitions of Cat K may have a very unexpected effect, and stroke one of them. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115675/

  18. Joe says:

    So the verdict is out…target based discovery and phenotypic discovery is garbage. Why is everyone and their brother doing it?

  19. Mol Biologist says:

    Multicellular organisms are able to be fully functional only because they have a peace treaty. The mechanism of communication and mutual aid between close or distal neighbors brought to perfection. Every single cell could get cooperative assistance if necessary. The cathepsins have ancient and one of most important in this process. IMO med chemistry can bring only part of a solution but if you do not understand biology it will never work. During open heart surgery, a healthy artery or vein is grafted (attached) to a blocked coronary artery to bring fresh blood to the heart.
    I have serious doubts that Cat K have important role in osteoporosis since Derek’s favorite Plasmodium falciparum has no bones 🙂 http://www.nature.com/articles/srep23690

    1. Barry says:

      that a homologue of cathepsin K in an invertebrate does something else doesn’t mean that it’s not involved in bone remodelling. Darwin’s all about repurposing existing machines. Many snake venoms are repurposed digestive enzymes, ion channels that are key to the functioning of our brains have homologues in organisms without a Central Nervous System.

  20. Mol Biologist says:

    Good things happen when you get your priorities straight. Plasmodium falciparum is able to succeed when operated by very limited resources BUT exploring vulnerable places in human biology where Cat K is important part of this.
    IMO Cat K function in human bones is secondary and just reflection of weak muscles.
    https://en.wikipedia.org/wiki/Enzyme_promiscuity
    Inhibition of Cat K primary function mostly affect different totally different mechanism. It would ensures failure to provide mutual aid or ready-made protein parts . It was nicely described by loupgarous in previous posts.

Comments are closed.