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The challenge of prostate cancer drug approval versus reimbursement

By MaverickNY on February 27, 2012

Scenes from EAU - Arc de Triomphe

Here at the European Association of Urology (EAU) congress in Paris, there are some interesting debates amongst delegates attending the meeting regarding new therapies either recently – or about to be approved – for castrate-resistant prostate cancer (CRPC).

For example:

How should abiraterone and MDV3100 be sequenced pre or post chemotherapy?
Would combining the two drugs post chemo be a better strategy that leads to superior outcomes?
Where does chemotherapy fit into this emerging paradigm? Do we need chemotherapy in an new era of oral therapies? If yes, which patients should be considered eligible?
How will immunotherapies such as Provenge be used once approved – before or after abiraterone in the pre-chemo setting, but likely not together given the steroid component?

Reimbursement remains a challenge in Europe

Now, these are all valid clinical questions, but there is an elephant in the room that isn’t being discussed so far (Dendreon got a lot of stick over the US price last year, which was publicly considered ‘very expensive’ or ‘too expensive’ by many thought leaders for Europe), namely, reimbursement.

Consider that the US wholesale price for Provenge is $93K and abiraterone is ~$48K, depending on how many months are needed (likely more in the pre-chemotherapy setting), you can already see that both sequencing and combinations are going to take the economic costs much higher for European health care systems. That’s without figuring in the price for MDV3100 and Alpharadin, which have not been filed yet or cabazitaxel, which costs around $42K in the US depending on the number of cycles taken (from memory).

However, with Taxotere now generically available, it’s not hard to imagine many centres repeating docetaxel in second-line if the patient had a good response rather than administer the more expensive cabazitaxel. In general, though, there is little doubt that the impact of either sequencing therapies, or using in combination, will add to the cumulative cost of treatment in an upwards manner.

The bigger questions for Europe in this scenario then become:

How to best manage available resources from the allocated healthcare pot?
The majority of money in cancer care is spent on the last 6 months of people’s lives – how should that be addressed ethically, economically and medically?

By the way, for American readers of this blog, please don’t call European provision ‘socialist healthcare’ – this is a silly misnomer, because:

It isn’t free – people pay for it – it’s deducted at source from wages in most countries
Several EU members such as the UK have a conservative, not socialist, Government in power
In Germany, a model of private providers similar to the US exists, and even in the UK additional private care can be bought through an employers offering, proving that not all European countries provide healthcare in the same way.

Abiraterone will likely be reimbursed at a discount in the UK

Meanwhile, J&J’s abiraterone is an interesting case study in point. While approved by the EMA/CHMP, it isn’t available in all EU countries yet, as it wenders its way through the reimbursement approval process. As I understand from delegates here, it is available in Ireland, for example, but was rejected by NICE in the UK as ‘too expensive’.

What was interesting here at EAU was learning from some EU thought leaders and competitor manufacturers that Janssen have apparently negotiated a discount of 40% of the list price in order for it to be available in the UK, although nothing official has been announced yet.

Will UK pricing have a broader impact on continental Europe?

Given the severe pan Europe economic hardship at present, one wonders how low this pricing strategy might go given that Greece is usually the lowest priced country. If the 40% discount being bandied about here at EAU is correct, will other other EU countries look at the UK price and demand a similar discount? It’s one thing the UK and say, Spain and Greece being 10-20% lower than Germany, but nearly half the price might upset the natural basket negotiations and wheeler dealing that usually occur.

You can almost imagine a satirical cartoon in Private Eye or The Economist, whereby jaundiced eye balls loom eerily out of a map of Europe, as each country warily looks at its usual reference baskets.

It will be interesting to watch what happens in the near future, because what happens in the advanced prostate cancer arena may have broader implications, not only for all EU countries, but also other manufacturers in the cancer marketplace. Everyone involved is going to be following this evolution carefully.

Update on new data in prostate cancer

By MaverickNY on May 9, 2011

The interview with Dr Charles Sawyers from Memorial-Sloan Kettering recently, talking about his role in Medivation’s MDV3100, turned out to be rather good timing. On Friday, Medivation announced their 1Q earnings and clinical progress.

The big news is that aside from the ongoing phase III trials in castrate-resistant prostrate cancer (CRPC) before (PREVAIL) and after failure of docetaxel (AFFIRM), the company are seeking to explore the use of MDV3100 earlier in the disease. This makes a lot of sense, both clinically and strategically. A phase II trial is already open in the pre-chemotherapy setting, comparing MDV3100 to bicalutamide (TERRAIN).

Highlights

The first phase II trial evaluates the combination of MDV3100 with bicalutamide in the treatment of advanced prostate cancer patients who have progressed while on LHRH analogue therapy or following surgical castration. TERRAIN is expected to enroll approximately 370 patients in North America and Europe. The primary endpoint of the trial is progression-free survival. This trial is ongoing and patients are enrolling.
A second phase II trial has now opened and is the first trial to examine the effects of MDV3100 without medical or surgical castration. Patients will be given MD3100 monotherapy and “enrolled patients would not have had any previous hormonal therapies for the treatment of prostate cancer.” In other words, both hormone and chemotherapy naive, so very early in the prostate cancer treatment cycle where LHRH analogues are traditionally given. On Friday, Medivation announced that the first patient has now begun treatment with MDV3100 in this setting. Approx. 60 patients will be enrolled in Europe, with PSA as the primary endpoint and will take MDV3100 orally for 24 weeks (160 mg dose).
The main phase III registration trial, AFFIRM, is a randomized, double-blind, placebo-controlled study in 1,199 patients with advanced prostate cancer who were previously treated with docetaxel-based chemotherapy. MDV3100 was compared to MDV3100 versus placebo. The primary endpoint is overall survival. The study completed enrollment last November, so Medivation plan an interim analysis by the end of the year.

Interestingly, MDV3100 is now being positioned as “a triple-acting oral androgen receptor antagonist.” As Dr Sawyers noted in the interview, MDV3100 and abiraterone (Zytiga) have very different mechanisms of action in throttling either the androgren receptor signaling directly, or by inhibiting testosterone production that drives tumour growth through CYP17 inhibition.

What does all this data mean?

On Friday this week, I’ll be heading off to the annual meeting of the American Urology Association (AUA) and will be live tweeting, blogging and vlogging the event to see what urologists and oncologists think of these new developments.

Essentially, abiraterone’s recent FDA approval means that they will compete head to head with Sanofi’s cabazitaxel (Jevtana) in the post Taxotere setting, and Medivation look to be about 18 months behind with MDV3100, although the latter are aggressively expanding their trial program earlier in the disease, where I think it will have a more lasting impact. The proof of concept for androgen receptor antagonists has already been proven with bicalutamide, so the question there is whether MDV3100 will be a more complete and effective inhibitor. In the long run, a phase II trial combining abiraterone and MDV3100 to take advantage of their different mechanisms of action in early prostate cancer makes a lot of sense.

The last few weeks have provided some amusement with naysayers insisting that the PDUFA date for abiraterone wasn’t until October instead of realising it was getting Priority approval early (oops) and that the MDV3100 phase III trial couldn’t possibly be mature for an interim analysis by year end (another oops). I’m glad I called both of those correctly 🙂

This leads me to ponder the next controversy – will urologists use these new hormonal agents in the pre-chemo setting once approved in the post chemo setting? My hunch is yes based on the overwhelming feedback I heard this year at both ASCO GU and the European Association of Urology meeting in Vienna.

I say this with hindsight, knowing that many people insisted when imatinib (Gleevec) was approved for CML in refractory and advanced disease, that it wouldn’t be used front-line without FDA approval. When we looked at the data at the end of 7 seven months from approval, guess what? There was a fair bit of front-line use even without compendia listing, so it can happen when there is pent up demand and high desire to use a product.

My sense is that will happen here too, especially as bicalutamide and ketoconazole are already well established in the prostate cancer treatment paradigm as patients cycle through multiple therapies, but we will see. Urologists, we all know, much prefer pills over the complexity of infusional therapies.

What’s next?

In the meantime, with another round of urology and cancer conferences coming up, we can expect to see the final OS survival data from the FDA submission for abiraterone presented at AUA by Fred Saad and an update on the much awaited circulating tumour cells (CTC’s) data from Prof De Bono at ASCO. All in all, it’s going to be a very interesting two months!

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Two new cancer drugs approved – cabazitaxel and nilotinib

By MaverickNY on June 18, 2010

Yesterday brought two new approvals in a day from the FDA in completely different cancer types.

In the morning, sanofi-aventis' cabazitaxel (Jevtana) was approved in castrate-resistant prostate cancer after failure of docetaxel (Taxotere) several months ahead of schedule. This approval comes hot on the heels of Dendreon's sipuleucel-T (Provenge) in asymtomatic metastatic prostate cancer last month.

What this means is that once androgen ablation therapies stop working, there are three new treatment options for men with prostate cancer, none of which compete with each other, with the possible exception of the chemotherapies, since docetaxel is often given in second-line in men who previously responded well and have had a treatment break. It will be interesting to see if this approach continues or if oncologists will prefer cabazitaxel in those with a good performance status.

The real impact of cabazitaxel though, is on other agents in development. Currently, abiraterone (Cougar Biotech/J&J) and MDV3100 (Medivation/Astellas) were being tested in docetaxel refractory prostate cancer, but now there is a new standard of care, whereas previously there was none. Clearly, common sense suggests that their role might be more impactful earlier in the disease, either after hormonal therapies fail, instead of or in combination with them, especially given that they are oral therapies, making them attractive to urologists.

Classic drug development usually means starting in the relapsed or refractory metastatic setting. The next few years will be thus be interesting to watch, especially if the agents in clinical trials prove successful. For now, Dendreon have a couple of years breathing space until the market potentially starts to get more crowded.

The other Priority approval yesterday was for Novartis' nilotinib (Tasigna) in newly diagnosed chronic myeloid leukemia (CML) on the basis of higher and earlier response rates versus the current standard of care, imatinib (Gleeevc). Full approval follows later once the survival data is more mature, but the early 12 month data looks interesting with a significant advantage to nilotinib over imatinib. It's still early though, survival curves can do strange things over time and can cross over.

Still, it's a promising start and a good result, especially since the bar was raised very high by imatinib. Prior to imatinib, ten year survival in CML was 10 to 20% at best with high dose interferon, but imatinib raised that dramatically to 90%. The second generation TKIs such as nilotinib and dasatinib (BMS) will thus potentially represent incremental survival improvements to 93 or 94%, to put them in context.

Of course, nilotinib's approval will possibly impact dasatinib (Sprycel) since they have just filed for the same indication, making Priority review more unlikely. The last time that happened to two drugs in the same cancer type was for Erbitux (ImClone) and Avastin (Genentech), who filed a few weeks apart, but in two different indications (newly diagnosed and 3rd line).

If dasatinib does get a Priority review after nilotinib it will set a new precedent, but if it doesn't get Priority review, I wonder if an ODAC will occur given that's usually what happens with standard 12 month review?

What's fascinating about the dasatinib data is that it also demonstrated earlier and deeper responses than imatinib, but the front-line data presented by Drs Kantarjian and Baccarani at ASCO and EHA respectively, did not appear to show any earlier survival benefit at 12 months for dasatinib vs imatinib, unlike nilotinib. I say 'appear' because the curves were very close together and no P value was given, so my assumption is that they weren't significantly different at this stage. That may change over time, but for now, the DASISION data presented by Dr Kantarjian showed a 12 month OS of 97.2% to dasatinib and 98.8% to imatinib, presumably not a significant difference. Deaths in the two arms were 10 and 6 respectively, again favouring imatinib, but not significantly.

Obviously, comparing these curves at 5 years would be a much fairer comparison for overall survival, but for now, the 12 month data is all we have to go on and there are early differences between nilotinib and dasatinib.

It was also interesting to watch the often hyped and inelegant reporting of the data by the media at the Congresses proclaiming superiority. We know that in solid tumours, shrinkage or tumour response does not always lead to an improved survival benefit for the patient. Similarly, in leukemia, we also measure response rates – in this case – complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR), as initial surrogate markers for initial approval, but survival is also critically important for full approval in the US. Interestingly, the early log 4 reduction (CMR) rates seemed to slightly favour nilotinib over imatinib (but not significantly), however none were presented at ASCO or EHA for dasatinib over nilotinib (unless I missed the slides).

Ultimately, ASH will herald the 2-year and 18-month data for nilotinib and dasatinib respectively, which will hopefully be an important milestone on the way to seeing how the mature five year surviv
al data will evolve.< /p>

Disclosure: I'm a former Novartis employee and marketing director for Gleevec, so naturally I'm slightly biased towards imatinib :). Many thanks to @erohealth for proofreading suggestions.

#AUA2010: The beginning of a new era for prostate cancer?

By MaverickNY on May 30, 2010

Past American Urological Association (AUA) meetings have seen a lot of same old, same old with very little that is new in the way of truly innovative and exciting new developments. In many ways, prostate cancer is the male equivalent of ovarian cancer, with pharma companies considering it after the breast, lung and colorectal cancers, despite prostate cancer being fairly large in terms in epidemiology, from a pure numbers perspective.

Why is this?

Firstly, we need to consider the natural course of the disease, which unlike breast and lung cancers, is fairly indolent. Men diagnosed early with prostate cancer can live for 10-15 years, often with long periods of watchful waiting, making adjuvant trials necessarily long ones.

Secondly, once hormonal therapy begins to enable castration and reduction in the levels of testosterone that drives the cancer's growth, patients are seen and managed by urologists, who prefer to treat with oral therapies. Until recently, Pharma focused very much on intravenous infusions designed for oncologists and never the twain really met in the middle.

Thirdly, traditional drug development for chemotherapy begins in the latest stage of treatment after failure of existing therapies (typically 2nd or 3rd+ line) and moves earlier up the disease stage in a classic niche by niche development strategy.

These factors combine to essentially create 3 distinct, albeit crude, phases of treatment for prostate cancer:

Watchful waiting
Androgen deprivation therapy (ADT)
Chemotherapy for stage IV metastatic disease

How are things changing?

Dendreon recently received approval for their autologous cell vaccine, sipuleucel-T (Provenge) in asymptomatic metastatic castration resistant disease, meaning that in men where hormonal therapies cease to work but have some early evidence of metastatic disease, now have a completely new and relatively non-toxic therapeutic option prior to chemotherapy with Taxotere, mitoxantrone or even prednisone.

Much has been written about the potential for vaccines earlier in the disease when the tumour burden is much lower, so hopefully we will see some future exploration in this area now that the proof of concept for the first commercial cancer vaccine exists and Dendreon will have more funds to reinvest in R&D as revenues are generated. They have a real opportunity here.

Past studies with docetaxel (Taxotere) have shown an improved survival benefit of 2.4 months over prednisone alone in androgen independent (hormone refractory) population that was essentially symptomatic. Two phase III Provenge studies reported a median survival benefit of 4.1 and 4.5 months respectively, meaning that 50% of the men did better and 50% did worse than 4-4.5 months.

There are now at least 8 other compounds in phase III development for the treatment of advanced prostate cancer. One of these, sanofi-aventis' cabazitaxel (Jevtana) has already been filed and DDMAC review is expected in the summer, meaning the drug could possibly get approval in the 2nd-line setting after Taxotere by September in an area of high unmet need since there are few options available in this setting. The data is expected to be presented at ASCO next week, so more on that then.

So now we have two potential therapeutic options before and after Taxotere in 2010 alone, which is progress indeed.

What other compounds are there?

There are a number of agents that I like. Cougar and J&J's abiraterone is probably the most advanced. It is an inhibitor of 17,20 lyase that essentially throttle testesterone production in the testes and adrenal glands. Millennium-Takeda also have a similar compound in earlier development called TAK700. The two appear to differ in that one is steroidal and the other is non-steroidal, but whether this will make any meaningful difference isn't yet clear. Time will tell.

The abiraterone trials are not scheduled to complete until mid 2011 at the earliest, so assuming the data is positive, approval likely won't happen until the 2nd half of 2012, giving Dendreon a two year commercial advantage over the competition, who are mostly testing their compounds in the post Taxotere setting, at least initially.

Perhaps the most exciting agent from a biology perspective is MDV3100 from Medivation/Astellas, which I have written extensively about in past blog posts. Essentially, the current androgen blockers are fairly ineffective at controlling aggressive disease so a more complete inhibitor of the Androgen Receptor (AR) may offer a better chance of making an impact. Medivation have quickly realised that their real opportunity may well be either after hormonal therapies, in combination with them, or perhaps even in place of them earlier in the disease and have announced several new phase II and III trials will commence later this year. Astellas have significant advantage over J&J as a partner since they already have a strong urology franchise, which is vitally important going forward.

Several other therapies interest me too, but they will be the subject of another blog post later during this meeting as the mutations and critically expressed pathways as the disease progresses may well drive future therapeutic interventions.

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American Urology Association AUA 2010 annual meeting

By MaverickNY on May 25, 2010

On Friday, I'm heading off to the annual American Urology Association (AUA) meeting in San Francisco and looking forward to catching up on the hot topics in prostate and renal cancers.

It promises to be a good meeting this year with lots of new data expected from a number of marketed products, newly approved products and of course, products in development.

I'll be tweeting snippets from the meeting under the hashtag #AUA2010 as some attendees are already actively using that one. Unfortunately, #AUA already seems to be used for something else, which is a shame as those extra 4 characters make a huge difference on Twitter!

More to follow at the meeting, where I'll summarise some of the key findings over the weekend as they are published.

If you're attending the event and would like to meet up, please contact me either via email or via Twitter - it's always fun to meet people in real life!

Photo Credit: Alain Picard

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