Prolia/Xgeva (denosumab), Steve Jobs & Bill Gates

Posted by Jeff Berk, BOLT International;  Tonight, I’m going to blog about Prolia/Xgeva (denosumab).  So here goes…  I’m a Mac guy.  Why? THEY JUST WORK.  I wrote my thesis up on a funky little box in the ‘80’s.  I still have those original files.  Somewhere.  But I digress.  Lots of enlightened people think that Macs kick the crap out of anything windows based (I suppose I could have capitalized that, but whatever).  And lots of people have asked how it could possibly be, given such a superior product, year after year, that until recently Bill was stealing Steve’s lunch money.  The less-than-idealistic amongst us know the answer to this question – while Steve was out designing a better product, Bill was simply out selling a product.  And Bill, if you don’t like what I’m saying, I have one final word for you:  VISTA.

 

My girlfriend just told me to get back to Xgeva.  Here’s the point: Nobody who’s ever looked at the science behind RANKL inhibition has ever thought that Amgen didn’t have the sexiest little technology going.  I knew Pirow Bekker when he had just joined Amgen, and I remember the first time he walked me through OPG and RANKL and specifically what would ultimately be called denosumab.  Now, I’ve moderated over 50 of BOLT International’s Osteoporosis Thought Leader panels (once a quarter for, well, a lot of years).  So we’ve been talking about both the science and the commercial potential of this drug since it was a preclinical baby.  Now that it’s a “young adult”, trying to make its way in the world, I want to share some of the most recent D-Mab related comments from our Thought Leaders.  Hopefully they’ll give you some idea on why our “Good Science Poster Child” is struggling just a bit in the osteoporosis world…

 

 

Prolia/Xgeva; denosumab (Amgen / GlaxoSmithKline / Daiichi-Sankyo / Dompe)

 

  • The general sense of our panel is that given one or the other, Prolia / Xgeva is better suited as an oncology franchise drug than an osteoporosis franchise drug.  The data for denosumab vs. zoledronic acid in prostate and breast cancer is quite favorable, and the cancer patients are receiving 12x higher doses of denosumab than the osteoporosis patients.

 

“I would move quickly to oncology and then go to bone field as that answer to the last question.  This is an oncological drug.  It is not really an osteoporosis drug.  It has been very surprising to me how slowly that they have moved into that area. I don’t understand that to be honest.  I am with you.  I think that is the area they should have moved into right away.  There are phase II data that suggest that they might actually be better than zoledronate in that circumstance.  They really have been very careful”.

“So back to the comments and these were some pretty sharp people on the board of directors on the Paget Foundation talking about it, they see that Amgen are going to throw most of their money, because they are going to be competing against generic zoledronic acid, they are going to throw it mostly at the cancer side because they think there will be better uptake”.
“I think Amgen must be very worried about it.  I was sitting at the Paget Foundation where everybody pointed out that Amgen is spending a fortune getting ready to ramp up whatever their new name is for the stuff the FDA just did for skeletal disease”.

 

  • The panel members are in agreement that Prolia looks more like an oncology drug than osteoporosis.  The question of how to succeed in the bone markets could be answered via leveraging success in the oncology indications, and also spending more time educating PMO patients that the Prolia label is overstating the risks and understating the benefits of denosumab.

“Final question. Just a poll question.  If you were to advise Amgen to stay in osteoporosis with Prolia or bail and simply focus on the oncology side what would you tell them to do? I would tell them to focus a lot of their effort on the oncology group right now  because getting back to the PI, if you look at the five-year data with PMO, the skin  infection SAE disappears.  And if you get doctors familiar with the oncology use of Prolia, which doesn’t have skin infections either and certainly it is not going to increase cancer because you are using the cancer patient, you might through the back door educate physicians that this a good drug.  I don’t know how to do it, but they need to educate patients on its use, maybe get some traction in oncology so both patients and docs will feel more comfortable and then come back to it in PMO”.

 

 

  • We said last time that “attributes tell and benefits sell”.  The science behind denosumab is sexy, and the drug works as well as bisphosphonates.  But at the end of the day, the reason why denosumab (Xgeva) is better suited for oncology is because in non-life threatening categories, such as osteoporosis (yes, we know that many patients die within a year of their hip fractures), patients take one look at the litany of AEs that Amgen is required to declare and they refuse to be put on Prolia.

 

“The reason for that is the litany of side effects that appear in the package insert, most of which are irrelevant because they are just numerically slightly greater on the Prolia group than they are on the placebo group, but that throws off all the primary care physicians and it certainly throws off the patients”.

“I have had patients tell me “this is a new drug” and ask “how many people have you prescribed it to?”  I tell them “you are the second or you are the third person”.  I definitely sense some concern when you describe it to folks.  Have you seen the warning sheet they want patients to get”?  What in particular are your patients honing in on in terms of the potential adverse effects? It is a new medication and I have to be truthful, this person would have been the second person to do it”.

 

  • Relative to Reclast, Prolia should have more uptake from a practical perspective, that most PCPs do not have the facilities to administer infusions as are necessary when administering zoledronic acid.  In making a therapeutic decision between Prolia and Reclast, a strictly clinical decision-making process may yield to the more practical advantage offered by a subcutaneous injection.

“I think in some ways the mechanism is neither here nor there.  It is an antiresorptive.  It is a much more potent antiresorptive than anything else we have had.  I think in general it probably hasn’t.  I think the advantage of denosumab is the subcutaneous injection.  I think if your family physician is not set up to give long-term infusions then it is very attractive.  Most of the people I talk to aren’t”.

“I think zoledronate is its principle competitor in most marketplaces.  It has the inconvenience for family physicians that you have got to infuse it.  So when I talked to the hospital doctors around the world they are pretty relaxed about it because they, like us, are set up to do that, but it is not particularly convenient for family physicians.  I think that is one of the reasons that uptake around the world is varied.  It really depends on how our particular medical system is set up to cope with intravenous infusions in the general practice setting”.

 

  • Specifically, much of the patient concern is centered on the perception that taking Prolia will give them an infection, in part courtesy of the contributions of both the popular media and FDA to increasing patient awareness of the safety issues from recombinant therapies.

 

“I think the infection does scare people.  So anyone who is seeing steroids, transplants and the like, people are going to be concerned about that.  Remember that we backed into the TNF-alpha blockers.  It was the same concerns initially.  People were sort of scared about it is now talked about in television ads.   If you listen to any of the TNF-alpha blockers ads on television they talk about the infection rate.  So I think it is going to be a hard sell”.

 

  • Amgen has determined a strong hip fracture reduction benefit in a cohort of elderly patients.  Will they attempt to link this effect to earlier data showing cortical bone thickness increase in primate models, ala the catK inhibitors?  If so, the proper prospective clinical trial will need to be completed.

“You know Amgen had data that in the primate models it stimulated cortical bone thickening.  And then when you add non-vertebral fracture actually including it was only 20 percent.  So there was very little correlation.  It is an interesting finding, but until we do the RCT I don’t know what it means.  But I just came back last week from a meeting in Singapore and Amgen just did a post-hoc data analysis of people over 75.  The hip fracture reduction of Prolia is actually 65 percent.  That is pretty good.  I haven’t seen it, no. What that has suggested Prolia is now confirming it”.

“I have had patients say “I don’t want it because the infection” or “because it is so new” but any one sophisticated enough knows what they are not saying is “it is because of cancer”.  We have had several people in whom we have recommended Prolia because the renal functions are all basic and they can’t take oral bisphosphonates, but the minute they look at this they go “I am not taking this; it is going to kill me. I had someone who has bad peripheral vascular disease and has got a GFR (glomerular filtration rate) around 40.  I said “I really wish you would consider trying the denosumab”. She was referred by a very good internist in town.  I gave her all the information.  I asked her to go talk to him and call me after the holiday.  People are scared”.

 

  • So even though the fracture data are great, and the 5-year malignancy data are “reassuring”, the image of the drug is quite toxic, and until Amgen addresses that image problem, denosumab sales outside of oncology are going to remain lackluster.

 
“I think the reassuring thing about the five year data was that the malignancy issue disappeared, which of course was the issue that the rheumatologists were all raising because of their experiences with antibody use.  Let me say that I think the fracture data are great.  I think it is probably a very good drug.  And it will create a niche but it won’t be the biggest niche in the world”.

 

 

 

  • With that said, Amgen will likely not abandon osteoporosis although the way forward in this category is far from certain as the company continues to probe opinion leaders for ideas.  Hope remains in increasing access to the vast undiagnosed and untreated osteoporosis  population.

 

“Now they are not going to abandon osteoporosis. No.  But the point is I think Amgen is having a tough time in osteoporosis.  I think they are having a very tough time.  They sent a rep around in the middle of the summer asking “what other data do you need to have”.  I said, “I don’t need any more. I want to use it.  But I am not going to pull people off zoledronic acid or bisphosphonates to put them on denosumab, especially if they are on a generic form and are doing okay.”

“But an important aside here is that you need to remember only 20 percent of the people who should be treated for osteoporosis are getting treated in America, even now.  There are a few pockets where it gets up to 60 percent, but most people are still not getting treated.  So there is opportunity for Amgen here is the point.  But I’m not privy to any of Amgen’s marketing strategies”.

 

  • The obvious PMO candidate for Prolia (instead of Reclast) is the patient who has failed generic alendronate, whether due to poor tolerability or efficacy, and has renal impairment.

“When you think about Prolia versus Reclast identify for me the best candidate for Prolia.  In other words, if Amgen were going to try to streamline down their message and target their best opportunity who is the best Prolia candidate? It really is head-to-head with Reclast.  At the moment, given the fiscal environment most of us have to at least try generic Fosamax in a treatment-naïve individual.  Most of us are sort of setting it up that we are going to give you a drug that is going to cause you upper GI symptoms in a month, you are going to call me and tell me you can’t take it anymore, and then I am going to go with what I really want to give you which is Reclast with Prolia.  Once we get to that stage then it becomes a question of insuring the renal function is okay.  If renal function is okay we still tend to use Reclast first.  If renal function is in anyway dicey then these people go to Prolia.  Who is the patient who if you could today who would you put on Prolia and who would you put on zoledronic acid? I think your question is bang-on here.  It tends to be the same person.  It tends to be the person that is not tolerating oral bisphosphonates or seems to be progressing to lose more bone density or fracture while taking an oral bisphosphonate.  And that is the same patient”.

 

 

  • The lesson of long-term oversuppression of bone with bisphosphonates teaches physicians that the rapid loss of bone effect at the tail end of the 6-month denosumab dose is a strong benefit.  At the same time, getting patients back in the office for their next administration has been and will continue to be problematic.  Unlike patients on bisphosphonates, patients on denosumab who don’t comply with extended treatment are afforded no long-term protection from earlier drug administrations.

“The big advantage to Prolia is also one of its big disadvantages and that is we know it lasts six months and then it goes away.  And so how do primary care physicians insure that their patients come back every six months because if they don’t they have got less increase in bone remodeling and dramatic reduction in bone mass and presumably a return to increase fracture risk”.

 

 

 

“And the second is this very rapid offset of activity.  So it means really if your patient comes in two months later for their infusion they might already have a fracture risk that is higher than before you started treatment.  That is the speculation but could infer that from the turnover data”.

 

 

 

  • Even with patients who receive their next injection at 6 months with clockwork-like regularity, denosumab’s rapid “on” means that physicians will transfer their concern to the potential morbidities that accompany frozen bone.   This concern has only been reinforced with all the recent bad press emanating from the alendronate litigation.

“I think there are two downsides with denosumab.  One is that it suppresses bone turnover so far that I think everyone in their heart of hearts thinks that has got to be bad for you sooner or later, even if it doesn’t seem to bad for you during the first three years of the study”.

  • Ultimately, the choice to use Prolia comes down to a rather complex risk-benefit tradeoff made by the physician in which patient compliance is a much more critical factor that that for the bisphosphonates.   One panelist puts it analogous to the complexities of driving a high-performance sports car vs. driving the family van.  Denosumab has the more responsive gas and brake pedals.

“Do you have Prolia available yet? No.  We have been involved in the trial program but we are not using it clinically. As you talk to your colleagues on an international basis, has the actual benefit to patients lived up to the sexiness of the mechanism? I think it is a little bit like a Ferrari; it has got a powerful accelerator and a powerful brake and actually just getting a comfortable drive in it is nothing like as easy.  But in terms of outcomes for the patients it doesn’t suppress turnover or anything like as much.  It has a much, much longer duration of action with a gradual offset so that the second or third infusions the timing is totally uncritical that if your patient turns up six months late who cares, that is fine.  And there are not too many other medications that are like that.  So you wind up with a sort of complicated trade off.  I think a number of people are a bit nervous of the Ferrari type aspects of the denosumab because it really means you have got to be a very skilled practitioner.  You have got to have a very elaborate set up and you have got to have very compliant patients for it ultimately to be good for them.  And if they are very compliant and have their injections every six months and you have got this lingering…if you think the subtrochanteric fractures are an issue then freezing bone turnover to that extent is going to keep you awake at night rather more than Fosamax does”.

 

  • As an attempt to connect directly with patients and increase compliance, the company offers Prolia Plus, a system whereby patients can sign up and be reminded when it is time for their next office visit.  But Prolia Plus smacks of Amgen, and patients don’t want pharmaceutical companies calling upon them.

 

“They say sign the patient up with Prolia Plus and they will call them.  But Prolia Plus smacks of Amgen and in New York patients don’t like to be put in touch with the pharmaceutical company.  We are supposed to sign them up for the REMS program.  Even that, ugh”.

  • Also contributing to the slow uptake is that Amgen have done very little to promote Prolia to community physicians in general, much less support physicians’ efforts to increase compliance.  Their sales force appears to be re-deploying to promote denosumab to the oncology community. 

“What is Amgen doing to try to help these physicians get their patients back in office? I can tell you what they are doing with us.  Nothing.  That is a short answer. Yep.  They have offered no help and no support.  First, in your area do the PCPs who you are seeing or who are using you for consult, are the PCPs prescribe any Prolia? Amgen are having trouble getting it out.  A good friend of mine who lives in Arizona said part of the uptake depends on the size of your sales force.  I don’t think they have a tremendous sales force to go out and get this into the community physicians’ hands.  I think they reorganized their sales force.  So it is going to ultimately not be a huge thing in that arena.  My rep told me they were reassigning people so I have no idea whether Amgen figures they are going to have better uptake from the cancer side”.

 

  • The office-based physician only earns $5-$10 dollars for administering Prolia, but has to lay out the cost of the drug and wait three months for insurance to reimburse him.    The financial risk doesn’t make any sense given how little money he will make on prescribing the drug. The only physicians for whom this model works is the guy who has a stake in the dispensing pharmacy.  Insurers and pharmacy benefit managers are also applying pressure on the formulary side by requiring prior BP use, particularly since a generic is available.

 

“Prolia is easier to use in office practice because you can give a subcutaneous injection much more easily than you can do an infusion but I have given several talks for Prolia and I get mixed messages from the audience.  One guy will say I am only going to get paid five or ten dollars for giving a subcutaneous injection why should I do it and I am not going to invest in buying the drug because I am not absolutely sure I am ever going to get repaid.  Medicare Part B is that easy for me because I work in a hospital environment, the hospital pharmacy buys it.  But in private practice, especially the non-rheumatologists who really don’t use these sorts of agents that is where the difficulty comes in”.

“I am looking forward to using it but it is the same problem I have in managed care in North Carolina.  If you have someone you want to treat for 733.01, that is osteoporosis, insurance companies are demanding you try oral bisphosphonates in people.  Our state has no money and that is even what Duke healthcare stipulates”.

 

  • In Canada, Prolia uptake has been negatively impacted lacking formulary acceptance on provincial health insurance plans.

“Are you free to dispense when you want? No.  In Canada, because we have these provincially run drug plans, people tend not to buy agents that are not covered by the provincial plans.  Prolia is still under review by the provincial drug plans.  It is a little early for it to really take off.  If people have private drug plans then they will go for it.  But I haven’t had the opportunity to prescribe it very much and I think in my particular area people watch what I am doing.  So if I am not prescribing it then other people aren’t”.

 

 

  • Prolia pricing in Canada is comparable to that of Actonel.   In the US, Prolia is more expensive than Actonel.   Different types of economic forces are at play in countries with nationalized healthcare policies compared to those based on free markets.

 

 

“The way pricing at least in the Canadian climate has been explained to me there was a speculation from the US that Prolia was going to be priced way more than bisphosphonates.  I asked one of the people at Amgen about that and he said this was false because they hadn’t set a price at all and, in fact, they would be forced by whatever International Pricing Commission there is to price themselves in a similar manner to other similar agents.  They don’t have any data that they are better than the bisphosphonates.  As he said, he told me at the time that our price will be somewhere around the bisphosphonates.  In fact, they came out almost identical to brand name risedronate in Canada.  Now the pricing arrangements in the States may be different.   We are paying considerably more.  I think we are in that $800 bucks per dose range”.

 

  • Prolia’s Canadian price is lower than that of zoledronic acid, even when the pharmacist’s dispensing and administration fees are considered, though as in the US not all Canadian pharmacists have the facilities to both dispense and administer.

“I don’t know what the price on Prolia is in the US, but in Canada it is quite a bit less than for a year than Aclasta or Reclast.  Its not a whole lot but maybe about 200 dollars less for a year of treatment.  What is the price of each? At the pharmacy it is a little over $300 (Canadian) per injection so the pharmacists will add a dispensing fee on top of that.  For Prolia? For Prolia. And does the pharmacist inject? Some of them do.  When you say dispensing you simply mean they give that to the patient and the patient… For handling a prescription some of them charge a percentage which may crank that up to about $50 to $75.  And then the patient brings that back to the physician? Right.  Though some pharmacies actually do have the ability to inject on site too.  For the most part they just bring it back to their physician’s office and get the injection by one of the physician’s office nurses or…”

 

“…my easiest comparison is going to be to Reclast or Aclasta where (in the US) by the time you do the cost of the drug and cost of administration they come out similarly. So here they are a bit lower.  Reclast would be about costing patients I think it is about $700 per year and then there is the pharmacy fee on top of that.  So I have seen it priced anywhere between $700 and $900 for patients here.   And what is risedronate?  What does Actonel cost you? That works out to about $600 a year”. 

  • In Europe, Prolia has been approved by the EMEA, but uptake has not begun due to remaining reimbursement issues.  Price-wise it will likely be similar to ZOL once the extra administration costs are figured in.  The rationale for Prolia in Europe may be based on the drug’s shorter half-life relative to the bisphosphonates, but it will not perform as spectacularly as Amgen predicts.

“So back to Amgen, is Prolia available in Europe yet? It is approved but it is probably not yet being prescribed because reimbursement hasn’t been fixed in all of the countries.  But it is at least approved now in both US and Europe.  Compared to Aclasta is Prolia more or less expensive? I think it is more expensive.  But with the cost of infusion I’m not sure.  It is probably close.  Is Prolia considered to be a better approach than bisphosphonates? In my opinion is probably a little bit better approach than bisphosphonates but it is not going to be a blockbuster that Amgen expected.  Why? I prefer drugs with a short half-life.  I think that is coming out more and more.  For a while longer half life was in vogue and drugs were progressing from being given once-a-day to once-a-week to once-a-month to once-a-year to once-in-your-lifetime.  I think it goes back and forth and I think people are moving back towards what I have said for a long time”.

 

  • On a more positive note for Prolia, interest has arisen in the potential for treating primary hyperparathyroidism, albeit with limited market potential.

 

“This kind of problem is one of the things that is most interesting for me right now with Prolia.  Actually we are talking about treating hyperparathyroidism right now with Prolia.  That is one of John Bilezikian’s concepts.  It looks like you might be able to, in  hyperparathyroidism, treat it by stopping the actions of PTH on resorption by use of Prolia.  What is the market size for that? Very small.  I mean most hyperparathyroidism I see is secondary not primary”.

 

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