Commercial Train Wrecks for Postmenopausal Osteoporosis Train Wrecks

Posted by Jeff Berk; BOLT International

 

I’m in a foul mood tonight.  Just pissy.  This lil’ feller with eight hairy legs sums up what I look like right now. I’d tell you why, but the BOLT Pharma Blog isn’t supposed to be TAHT kind of blog.  You want touchy-feely?  Watch reruns of Oprah. Truth be told, I never had the afternoon off, so I never actually saw a single one of her shows.  All I know is that she was a great role model for a lot of people.  Boy, that lady could convince a cretin that he was qualified to run the country.  Sucks for the rest of us, but I’ve got to admit, that was SOME bit of positive visualization.  Oh, and she stuck her foot in her mouth once about the beef industry.  What was THAT all about?.  Or that other guy, Phil (Mr Phil?  Dr Phil?  Mr Rogers???).  No, we’re JUST not a “touchy-feely” kind of blog here.  So to get back on the approach… I really don’t have a nice word to say about anything today.  As fortune would have it though, it was pretty easy to reach back a couple of months and pull out some snide comments on next-generation parathyroid hormones for osteoporosis.  There’s a class of drugs that doesn’t warrant a nice word.  So, hey, they’re PERFECT (for this blog, not for the treatment of postmenopausal train wrecks). And so let’s land this plane…

Oops.  Wait.  To clear the air, I would not change places with a single one of the patients who have contacted me through this blog.  You win.  My day wasn’t so bad after all.  For the record.

 

 

BA-058 (Radius / Novartis)

 

  • As with Prolia, BA-058 is another molecule for which we say, “differentiable from the competition, but so what?”.  In this case the basis for developing this PTH fragment is lower rates of hypercalcemia than are seen with Forteo.  Managed care doesn’t care a lick about this rare safety issue.  And osteosarcoma hasn’t been a real world issue for Forteo either.  Net, to be commercially Novartis has to generate fracture data for BA-058, and sell it at a price point closer to Prolia than Forteo.

 

“Novartis has a drug they hooked up with a PTH fragment that they got with a deal with Radius, a subcutaneous PTH that looks like teriparatide to me. Yeah, well Radius would put a different spin on that.  I remain again skeptical about this.  I think whether one is looking at other PTH analogs or is looking at a PTH RP derivative that continues to sort of perk along out there.  I think the proof is going to be in the proverbial pudding.  You commented that Radius would put a different spin on the PTH RP. Yeah, I am not sure again how much of it is in the public domain.  I think some of it is because they have been shopping this around for a while now and they have a very smart advisory board and some really good people on there. I mean their scientific staff is outstanding.  Can you make an argument that there is going to be an anabolic moiety that has a better efficacy/safety profile than Forteo?  Yes, you can make that argument.  Now show me the data.  Show me that in a real world setting that your favorite molecule is giving you better fracture outcomes with better safety than Forteo.  Even though Forteo has had this black box warning on it for the full time it has been out there has been no real safety signal Forteo.  Hypercalcemia, which is the most recent concern, is not a big deal in clinical practice.  It really isn’t.  If you come out with your favorite molecule and say we give less hypercalcemia than Forteo.  Who cares because Forteo isn’t the big problem anyway in terms of hypercalcemia.  They certainly can’t go out there and say we give you less osteosarcoma because osteosarcoma hasn’t been a big issue with Forteo either.  I think Forteo has been limited not by its safety concerns, but rather by its cost and to some extent by its route of administration.  Yeah, I agree with the cost issue.  Let me just cycle back to the Radius drug.  So here Novartis has picked up co-development with them.  Does that mean Novartis actually has to fund a head-to-head trial against Forteo? I don’t know the answer to that.  The way forward from a regulatory perspective is obvious to me.  No one is ever going to fund that head-to-head study.  I guess they could do a short term head-to-head study looking at changes in bone density.  There is certainly a precedent for doing that kind of comparison.  In fact, there has been a lot of it over the past 20 years to which I think the world in large would again be uninterested.  It might give Novartis a little bit of leverage against Forteo.  But the real issue, if I were sitting in a managed care perspective, would be show me that your molecule works better in my patients in my managed care world.  I don’t care about bone density and I don’t care about one in 500 patients who will have some sort of strange transient adverse reaction.  I don’t care.  What I care about is fracture and cost”.

 

“So Novartis licensed a PTH fragment from Radius.  I know the drug as BA058.  Supposedly they had their phase II results in June. Is the PTH RP?  Exactly.  So what is the advantage of that – it is subcutaneous – between that and teriparatide? I haven’t seen anything recently on it but I wasn’t impressed that there was any advantage at all, and I thought that there was more hypercalcemia.  But I haven’t seen anything recently. This is like old data I had reviewed for the company it has got to be two years ago.  I certainly was not that impressed.  And at the beginning there were these really prominent hemodynamic problems.  I have heard that they worked those out.  People were really getting hypotensive with it”. 

 

 

 

 

 

 

ZP-PTH; PTH transdermal (Zosano)

 

  • Zosano’s ZP-PTH 40 mcg transdermal continues to be in the ironic position of having arguably a better PTH than teriparatide 20 mcg sub-q, based on the sharpness of the pulse of drug that’s delivered with ZP-PTH, but a more challenging regulatory path than Lilly/TransPharma have with ViaDerm-PTH.  We believe this is the reason that neither Merck nor Novartis have closed deals with Zosano for ZP-PTH.  The preliminary data reported on ZP-PTH, the PK/PD data is not the same as is seen with teriparatide, which rules out the possibility of an approval under a 505-b registration.  ZP-PTH produces a more rapid, higher peak, and a more rapid falloff.  This is more likely to produce the desired pulse of parathyroid hormone, and least likely to cause hypercalcemia.  But since this beneficial profile is conjecture, FDA is likely to make Zosano run a vertebral fracture endpoint study to demonstrate non-inferiority with teriparatide sub-q.

 

“I thought they were taken over by J&J? I don’t think so.  I talked to the guy a few months ago and they were trying to negotiate with a bunch of different partners.  The last I heard nothing was coming to fruition.  Is that something that happened in the last few months?  Somehow there is some sort of relationship with J&J. They used to be a subsidiary of J&J and they were called Macroflux Corp.  But it was part of J&J.  And then they broke off and they changed their name to Zosano.  They were in fairly kind of last level negotiation with Novartis and then that fell apart.  I have been trying to get the Merck folks to look at it.  I think it is a really viable option.  I don’t understand why they haven’t been able to move it forward with a partner and start the phase III program.  I just simply don’t understand it. Here is the explanation that another panelist gave me.  He said that as opposed to the Lilly TransPharma approach, which seems pretty similar to the pharmacokinetics, pharmacodynamics you see with teriparatide, the argument for the Zosano patch was that it is a sharper on and sharper off and doesn’t exactly look like the profile you would get with teriparatide.  And so this person thought that the FDA was going to require Zosano to do a full- fledged phase III fracture trial as opposed to Lilly who they said, because it looks so much like teriparatide they could get away with just showing pharmacokinetics pharmacodynamics.  I don’t know if that is true but that would certainly make a big difference in the cost of getting your drug approved. That is correct and I know they did discuss this with the FDA and I think we were probably moving towards a noninferiority trial against teriparatide.  But it would be like vertebral fracture endpoint.  And noninferiority trials, boy, unless you really power it carefully you are going to end up being okay.   But of course, any time you do a noninferiority trial you may get pigeonholed into the same population of patients and that is a problem in terms of where you are indicated for use because teriparatide probably should be being used in more individuals.  Certainly if it was in a patch that was more acceptable to people in terms of the regimen it would be potentially given a broader application and so doing the phase III as a noninferiority against teriparatide could really limit you down the line in terms of how you promote the compound.  So that may be.  That is possible.  I hadn’t heard people really talking about that.  I think the point is that anabolic therapy is still really untapped.  If you really want to make a more fundamental difference in somebody’s fracture risk I think you have to go with anabolic therapy.  My thinking is, and probably I have said before, is that if you had something that was a little bit easier to tolerate and not so expensive that you would use it maybe for a year in everybody to get to a certain point above osteoporosis range.  Then you could just think about maintaining with intermittent use of antiresorptives.  I think that is kind of the paradigm for the future.  So maybe those are some of the answers.  But in terms of the pharmacokinetic profile, yes, it does look different than Forteo, but it looks better.  Most of us would say that the shorter the peak the better.  So the high peak and the quicker rise to peak and the quicker fall off is probably an advantage.  And in the phase II study, granted that it was only six months, but in the phase II study the spine BMD change was very similar to what you saw with Forteo and the hip BMD change was definitely superior and significantly superior.  And specifically, just be specific, we are talking here about which of the patches? The 40 mcg Zosano patch which was the one that has the same bioavailable teriparatide as the 20 mcg injection because it is about I think 40 percent bioavailable.  I think we have a picture of the pharmacokinetics profile in there and it is really a rapid T-max and a high C-max because it is a 40 mcg patch at a very rapid fall off.  And that peak, Forteo looks like dull and sustained compared to this.  Most people would say just based on the thinking about how sustained PTH elevations differ from short intermittent pulses that this is the most extreme of that.  This is a really short, high pulse and that it might be even more, it might favor anabolic activity more than even Forteo does.  So although it looks different and maybe that creates problems in terms of the practical design of the study in comparison to Forteo and so forth, it may actually be a better drug.  Although I want to say that very cautiously because six-month data it is just six-month data.  Actually we are worried about the biochemistry.  If you look back on that paper you will see that Forteo produces much bigger increases in the markers, both formation and resorption.  But I think when you have these big increases in resorption it is not a good thing.  It is always trying to understand the ratio of how formulation is stimulated versus resorption is stimulated, ultimately determines your response.  And not that you can do it kind of mole by mole with the serum markers because, of course, you don’t know what is happening at the bone level to produce these things in the serum.  But some understanding of, well, if both are going up a lot that may not be as good as if formation is going up moderately and resorption is not going up at all that is likely to be better.  That is a bigger anabolic window as we talked about it”.

 

 

“We don’t actually know what pharmacokinetic profile is ideal.  We can assume if it looks something like Forteo that it probably works, but I again would find it hard to believe that a patch would give you a profile that would be so identical to injectable Forteo that you could then rest comfortably that what you are going to see clinically is going to be the same”.

 

 

“I think the whole area of PTH is unclear because to my surprise no one has really systematically looked at different doses and frequencies of PTH and the spike height and duration in relation to the anabolic effect.  I guess from the FDA’s point of view they can say well we know when you can give teriparatide in this dose subcutaneously it works.  And that is about all we do know.  So knowing what the safety and the efficacy is likely to be if the shape of the spike is somewhat different is completely unknown.  So I guess from a cautious regulatory point of view the position that they seem to be taking makes sense.  But I think we need to know a lot more.  It is really surprising to me that we don’t have once every two days or once a week studies with PTH.  I mean there was one once a week study from Japan quite a long time ago and I believe other people have been duplicating that but I haven’t seen that data yet.  So yeah, I think we need to know a lot more in that area.  I think the same thing applies to the PTH secretagogues where there are PTH secretagogues that seem to be having slightly different pharmacological effects from what teriparatide has.  Yet you wouldn’t necessarily have predicted that from looking at the PTH profile that they produce”.

 

 

“The other thing also is the Zosano issue.  The big issue is the Zosano compound is really stuck a little bit with the way you do that because the bone marker pattern with the Zosano micro lancet delivery system is not equivalent to the regular teriparatide which you can’t do an equivalence trial.  So all these new delivery systems are going to get encumbered.  The question is will the FDA allow them if they have a different bone marker profile, if they have the same BMD response with different bone markers, could you get approval without doing a fracture trial?  Most of us think not.  That is a big barrier.  Are they pushing ahead anyway? Well they are stuck.  They are not sure what to do financially because the fracture trial costs a fortune.  So my understanding is they are momentarily stuck deciding what to do money wise.

 

 

“What is going on in the PTH patch world? I am not sure there has been a huge advance since I last spoke to you.  I think that is potentially going to be really successful and I think patients are going to much prefer that.  And I just like the whole concept and, if anything, it looks better if you look at the initial data.  I think it might turn out to be better.  Again, how you ultimately prove that will be key and whether surrogates will be accepted.  So that is the key question.  That is the key question here. It is a very key question.  If I was in charge of it I would say, yes, surrogates are fine.  PTH is PTH.  You have shown interesting.  You have shown me the pharmacokinetics, you have shown me your CT data. You have shown me your bone density data and off you go.  Of course it is never as simple as that.  It is going to vary from country to country, but I don’t see why you shouldn’t do that.  A bit like a generic bisphosphonate.  I would support that and I would use it.  I would quite confidently use transdermal or however delivered PTH once I have seen the pharmacokinetics, plasma profile, bone density data, marketing data.  I would have no hesitation in using it.  Here is where I am going with this; there are two patches I know of.  There is the one that Lilly licensed from TransPharma and that has a profile that Lilly is trying to say is better than subcutaneous teriparatide but it actually looks very similar. Is this the micro needle thing?  That is the TransPharma, correct.  So there is the one.  Then the other is from Zosano which is the spinoff from J&J and they say they have a really sharp peak.  So most panelists have said to me, you know that sounds better, but evidently FDA is putting up some sort of stink saying better is not the same as.  I think they are going to make Zosano do a whole BMD trial or something.  Whereas Lilly who may have the worst one… That is the same so carry on guys.  That is very ironic isn’t it?  That is very interesting.  I hadn’t heard that.  I kind of sort of understand it a bit.  The FDA is so twitched at the moment.  That is interesting.  But that would be mainly a safety thing I guess?  I don’t think it really makes sense, but you would believe it was for safety reasons.  Whoa you have got a peak there.  So they are concerned about hypercalcemia? Yeah, hypercalcemia and even over stimulation of osteoblast I suppose.  Yeah, I mean that is a possibility isn’t it.  And then there is the dose issue and etc, etc.  I haven’t thought of that.  That is a bit unlucky”.

 

 

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