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Posts tagged ‘abiraterone’

Update on advanced prostate cancer including enzalutamide (MDV3100) and abiraterone

This month has brought a flurry of regulatory activity in the prostate cancer landscape with several companies seeing noticeable action in the new product development area:

For this specific post, I want to concentrate on the new trends in advanced prostate cancer, as last weekend I attended the 2012 American Urological Association (AUA) annual meeting, focusing on the basic research sessions hosted by the Society of Basic Urological Research (SBUR) and Society of Urologic Oncology (SUO).  It’s hard to ignore the clinical data though, with so much activity in going on in advanced prostate cancer!

While at the oral and poster sessions, I enjoyed informal chats with urologists and researchers. Many of the urologists I spoke to at AUA were very excited about enzalutamide, certainly much more enthusiastic than in the last two years when we saw the arrival of sipuleucel-T (Provenge) and abiraterone (Zytiga) in the pre- and post- chemo settings respectively. The reasons for this were varied, depending on the respondents, ranging from understanding the mechanism of action (MOA) clearly to ease of logistics to lack of concomitant steroid therapy. The fact that the initial overall survival of 4.8 months for enzalutamide in the post-chemo setting, which hints at a more potent and effective therapy, probably helped as well.

With that in mind, I spoke with Dr Neal Shore, one of the AFFIRM trialists about his perspective of the impact of enzalutamide on his patients.  Firstly, we discussed the expectations for patients who have received chemotherapy:

“Patients who typically have completed a course of docetaxel have historically a 6-12 month life expectancy depending upon… on how symptomatic or asymptomatic they are.”

Secondly, what was the impact of treatment with enzalutamide?

“In the treatment arm, those who received enzalatumide, they lived at the median 4.8 months longer than patients who received the control placebo.

So in fact their survival extended beyond 18 months. I told you that normally this patient population has a 6-12 month survival expectancy range, that to me is dramatic.

It’s a dramatic life prolongation effect.”

Emphasis mine.

One of the things that makes enzalutamide exciting for me is the ability to target splice variants. This may explain why the agent has slightly better efficacy in the post chemo setting than abiraterone, which demonstrated a 3.9 month overall survival advantage over placebo when it was initially approved. This figure has since improved to 4.7 months with more mature data, suggesting that the initial 4.8 months improvement we see with enzalutamide may also potentially improve further with time.

Previously, I discussed the splice variants with Dr David Hung, the Medivation CEO:

Dr David Hung on Splice Variants:

Another area where we may see changes in mCRPC is sequencing, combinations and different trial designs. While it seems logical that good old fashioned sequencing, as with ADTs in earlier disease, will prolong time to disease progression by managing PSA levels, it should be noted that I don’t think any of those agents have actually shown a significant improvement in overall survival in patients. Unlike oncology, urology tends to have looser endpoints and this is something that we may well see changes in going forward as more rigour is applied in the clinical trial setting.

Combination therapy is something that I think we will also see more of in the future if we are to see real shifts in meaningful outcomes. As Charles Sawyers noted in a previous interview, shutting down the AR pathway more comprehensively with dual inhibition and ‘big guns’ makes solid scientific sense. This doesn’t just mean the obvious though, such as determining whether dual upstream and downstream AR inhibition with enzalutamide plus abiraterone versus either alone would work, but also targeting cross-talk and adaptive resistance pathways such as AR inhibition plus a PI3K inhibitor. Some of these trials are already underway, at least in phase II to see what the safety and efficacy signals looks like.

The arrival of multiple new therapies that change the standard of care also means that once the current crop of new drugs have been approved (abiraterone, enzalutamide and alpharadin) it becomes more difficult to conduct placebo controlled trials with OS any more, as Dr Shore astutely observed:

Dr Shore’s point about surrogate markers of survival in advanced cancer is a highly relevant one given the increasing level of competition in this tumour type.

In the pre-chemotherapy setting, both abiraterone (302 trial) and enzalatumide (PREVAIL) appear to have progression-free survival (PFS) and OS as co-primary endpoints. It will be interesting to see how the FDA react if only PFS is significant while OS is not, as many commentators suspect from the rather vague and woolly press release that J&J put out for abiraterone.  I don’t know what was agreed beforehand with the FDA regarding the study design, but I can see an interesting and highly charged ODAC ahead here as well as much speculation prior to the ASCO presentation of the data in the prostate cancer oral session next month.

OS is a clear, but challenging measure because ultimately, as Dr Shore noted, the endpoint is death.  Remember, recent breast cancer trials discussed here on PSB achieved a significant OS of 6 months or more, precisely because crossover wasn’t allowed. These trials had an active arm as a comparator, not placebo, though. We don’t yet know if patients in the placebo arm who relapsed were allowed to crossover to abiraterone early (ie before the IDMC recommendation). If they did, then OS was doomed from the start and the trial design itself was flawed, but we will have to wait for the presentation to see before jumping to conclusions.

I really hope that’s not the case here, because once crossover does occur, it is very hard statistically, to sort out a true survival signal. If the placebo patients didn’t crossover before the IDMC recommended study stoppage, then it’s hard to see why OS wasn’t met (if truly the case) unless the patients had long term compliance and adherence problems as a result of the concomitant steroid therapy. I do find it hard to believe, however, that an IDMC would stop a trial early if a primary registration endpoint was not met, for that would be akin to regulatory hari-kiri!

Overall survival has long been the standard of care in advanced prostate cancer and several drugs have either received approval or will receive approval as a result of meeting that high hurdle. Future entrants will find it very hard to ethically justify using placebo in the comparator arm and will likely need to be compared to sipuleucel-T, docetaxel, cabazitaxel or abiraterone as the currently approved new standards of care and potentially other options will be considered that are seeking approval such alpharadin and enzalutamide in the near future.

This improvement in care raises the bar for companies considering advanced prostate cancer in several ways:

  • Increased costs (active comparator arm, prolongation of treatment)
  • Increased time to market (OS takes longer than PFS)

In the end, though, for men with prostate cancer it’s largely all good news as new therapies that clearly prolong life become available and make a difference to their lives, not just in terms of more time with their families, but also in terms of improved quality of life and symptom management.

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J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer

By on March 8, 2012

The big cancer news that hit the news wires this morning was not entirely surprising:

“Janssen Research & Development, LLC today announced that it has unblinded the Phase 3 study of ZYTIGA (abiraterone acetate) plus prednisone for the treatment of asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (CRPC) who have not received chemotherapy.”

Source: Press Release

Given the accelerated approval of abiraterone in the post-chemotherapy setting last year, the results in the pre-chemotherapy setting were widely expected to:

  1. Be even better in earlier stage than the 3.9 months OS advantage already seen
  2. Likely to have an early study halt

Zytiga already has Compendia listing through mention in the NCCN Guidelines with level 2a evidence in the pre-chemotherapy setting, essentially listed with ketoconazole.  Several industry friends with access to market data have mentioned that the pre-chemotherapy share for abiraterone is already around 20-25%, not bad at all given it doesn’t have full approval prior to docetaxel use and has been on the US market less than a year.

No clinical details were provided by the Data Science Monitoring Committee (DSMC), but the data are expected to be presented at a clinical meeting later this year (Adam Feuerstein of The Street speculated that ASCO was a likely target).  I do hope so, but that would suppose an abstract was sent in with no data by the late breaking deadline of Feb 1st.

The company did state that:

“The company plans to submit for regulatory approval in the United States and around the world beginning in the second half of 2012.”

At this rate, J&J should receive the new indication in the first half of 2013, based on the 302 trial data, depending on whether the filing is accepted as an accelerated, priority or regular review.  No doubt this information will be apparent after filing has taken place.

One challenge with early stoppage of trials based on progression-free survival (PFS) is that determining whether patients truly live longer, as judge by overall survival (OS), becomes much more difficult, if not impossible.  Once patients on placebo are offered the active drug, there is a crossover effect confounding any subsequent data analysis.

The news today will impact several other companies in the advanced prostate cancer landscape

Medivation and Astellas are expected to file MDV3100 in the post chemotherapy setting soon based on the phase 3 AFFIRM study.  This agent has several attractive advantages over abiraterone in that:

  • no concomitant prednisone or steroid administration is required (hence less puffiness and related side effects) and
  • it targets splice variants as well as the AR, which may lead to less drug resistance.

Based on the post-chemotherapy data we’ve seen so far (MDV3100 saw a slightly longer improvement in OS, which may be related to the above), we can expect that the phase III PREVAIL trial prior to docetaxel to also show a similar trend to the Zytiga study.  It won’t surprise me at all if the interim analysis also leads to the DSMC recommending early unblinding.  Based on the Zytiga data, it wouldn’t surprise me if the interim analysis for MDV3100 came up as early as mid next year, which would be earlier than expected.

Two drugs that will be impacted by these developments with hormonal agents are Dendreon’s Provenge, which is approved prior to docetaxel and Sanofi’s Jevtana (cabazitaxel), which is approved after docetaxel.

The immunotherapy sipuleucel-T (Provenge) is an unlikely partner for combination with abiraterone given that steroids suppress the immune system, while many older men with metastatic would much rather take a pill than undergo the debilitating side effects of myelosuppressive cytotoxics such as the taxanes.  Certainly my Dad was in that category, as are many men in their 70’s.  Once approved, Alpharadin (radium-223) may well offer a useful option for that subset of patients, especially of they have already tried ADT and seen biochemical relapse with rapidly rising PSA levels.  Provenge is likely to be negatively impacted by Zytiga approval pre-chemotherapy.

Approval of Zytiga in the pre-chemotherapy setting will likely increase its share there, since many oncologists are somewhat sceptical about Provenge in terms of how it works, how effective it is, how to monitor patient progress on it (it doesn’t seem to affect pain, PSA or any of the usual markers of disease) and the hefty price tag ($93K for 3 infusions) doesn’t help either.  MDV3100 would likely have an even stronger impact, since urologists dislike using steroids and managing the complications, plus Astellas have a solid franchise in urology already.

At this rate, Jevtana will be pushed further out down the treatment paradigm and reserved for salvage therapy in the younger, fitter patients.  Its biggest challenge is competing with it’s fellow taxane, docetaxel, since many oncologists will re-challenge with the generic if the patient previously did well on it.  Any delay (through improved survival with newer, earlier treatments) will delay time to cabazitaxel uptake.  This will likely get worse once MDV3100 is approved, and oncologists can sequence them.

At what point will we see placebo trials go away?

I’m not a big fan of placebo-controlled trials, except where there are no standard of care or alternative clinical options for patients.  Until recently, the advanced prostate cancer market was relatively immature with few approved therapies, so placebo trials were de rigeur.  Going forward though, new entrants to the market will face the ethical dilemma of how can placebo-controlled trials be justified in a market where drugs such as abiraterone (or MDV3100 and Alpharadin, if approved) have a proven survival advantage?  It will push the bar for new market entries higher (and more costly).  Millennium’s TAK-700 (orteronel), which is similar to abiraterone but may or may not need steroids, may well have just made it into clinical trials in time before that window shuts off.

And finally…

The good thing is that after a decade of not much happening in the advanced prostate cancer market, we are seeing a lot if new therapies, often with different mechanisms of action, being developed for this disease.  There are others I haven’t mentioned here, including custirsen (Oncogenex) and cabozantinib (Exelixis) which are also undergoing clinical trials and we await those results too.

As more drugs for castrate-resistant prostate cancer (CRPC) are approved, sequencing and combinations will also come to the fore to determine optimal strategies for improving outcomes for men with prostate cancer.  It’s an exciting market to be following given the rapid progress over the last year or so, but hopefully, this is just the beginning and there will be much more yet to come.

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Video Report from 2012 European Association of Urology Congress in Paris

By on March 2, 2012

Amazingly, it’s been a year since I started doing conference highlight videos, with the first one rolling out at EAU meeting in Vienna last March. They’ve proven to be much more popular than expected! The good news is that the video recording, production and presentation skills have improved along the way.

Unlike last year, the 2012 EAU Congress wasn’t lit up with excitement about new data (abiraterone and MDV3100 dominated last year).  Instead, there were more reflective discussions about how to consider sequencing and combinations in a more crowded castrate resistant prostate cancer market going forward as well as some mention of new up and coming targets outside the androgen receptor (AR) such as ERG and Src.

Here’s the short (under 5 mins) video update:

If you can’t see the video, click here.

Meanwhile, the next conference update will be from the annual American Association for Cancer Research (AACR) meeting from March 31st-April 4th.

The challenge of prostate cancer drug approval versus reimbursement

By on February 27, 2012

Arc de Triomphe, Paris

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:

  1. How should abiraterone and MDV3100 be sequenced pre or post chemotherapy?
  2. Would combining the two drugs post chemo be a better strategy that leads to superior outcomes?
  3. 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?
  4. 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.

 

Is ARN-509 (Aragon) potentially better than MDV-3100 (Medivation) in advanced prostate cancer?

By on February 2, 2012

Many readers will have noticed that the advanced prostate cancer market is rapidly becoming crowded with three new therapies (cabazitaxel, sipuleucel-T and abiraterone) already approved and several more in late stage development, including Alpharadin (radium-223) and MDV3100, both likely to file this year. In addition, others are focused on bone complications, such as denosumab, which is expected to have a tough ODAC meeting this month, and cabozantinib, a multikinase inhibitor currently in phase III trials.

Unlike breast cancer, where progression-free survival (PFS) is a used as a surrogate measure of survival, in advanced prostate cancer, overall survival (OS) has pretty much become the gold standard by which prostate cancer trials are reviewed. This makes it much easier to judge whether the drugs are having a positive effect on true efficacy, i.e. do patients live longer as a result of treatment.  PFS is particularly difficult to measure in prostate cancer, so it’s not surprising this approach has evolved as the standard measurement.

Interestingly though, Health Authority approval does not always mean reimbursement coverage, as NICE showed yesterday in declining to approve abiraterone in the UK on the grounds that it is too expensive. The BBC quoted a patient who had been on abiraterone for only three months, with a positive impact:

“I have my life back. I have a lot more energy and no pain. My quality of life is excellent. I wouldn’t even know I have cancer now, it’s that good.”

The BBC also quoted his wife, who had an excellent point:

“We know NICE has to take a lot of things into consideration, but when you have a terminal illness an extra four months is very precious.”

Source: BBC

Of course, it’s very much a case of balancing available resources with potential benefits and unfortunately, advanced stage patients will inevitably take the lion’s share in terms of budget for disease management. Post EMA approval, some local UK health providers permitted the drug to be used on an individual basis, raising the old contentious issue of the rather unfair post code lottery (zip code for Americans).

Going forward, no doubt there will be much political posturing and pressure, as you can see from Cancer Research UK, who helped fund the research, but hopefully a deal can still be struck between NICE and Janssen, the manufacturer, on price to enable British men broader access to the drug.

One of the things that has struck me lately, though, is how prostate cancer is attracting serious research focus, such that a heterogeneous disease is slowly being more segmented based on the underlying biology of the tumour. Examples include Arul Chinnaiyan’s superb work on the TMPRSS2-ERG fusion gene and Charles Sawyers’ work on the Androgen Receptor.

Thanks to Sawyers work we now know that the old terminolgy ‘androgen independent’ prostate cancer is an incorrect way of descibing advanced disease because as Clegg et al., (2012) described Scher et al’s original research findings in 2005:

“Despite administration of androgen-depleting therapies, continued androgen receptor (AR) signaling is a common feature of CRPC, attributed to AR gene-amplification, AR gene mutation, increased AR expression or increased androgen biosynthesis in prostate tumors.”

In other words, the AR is very much an oncogenic driver of the tumour’s survival.

This week, we saw promising data for MDV3100, an AR antagonist in the post chemotherapy setting but what of the pipeline beyond abiraterone and MDV3100?

Previously, we came across Aragon’s ARN-509 AR antagonist, which is much further behind in phase I/II clinical trials. Sawyers and Michael Jung, the co-inventors of MDV3100 while at UCLA also developed (along with several other scientists) additional AR compounds, the most promising of which became ARN-509. Aragon is a privately held company formed out of the UCLA discovery with the intent of developing and commercialising this compound.

The obvious question arises – is it a ‘me-too’ or potentially better than MDV3100?

Preclinical data has just been published in Cancer Research by Clegg et al., (2012) addressing this issue. They argued that, based on their findings:

“In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100.”

Of course, preclinical data doesn’t always translate to the clinical setting, but my first reaction was ‘Whoa!’

Let’s take a look at the agent in more detail.  ARN-509, like MDV3100, is a pure antagonist of the androgen receptor, unlike bicalutamide (Casodex), which has both agonist and antagonist properties.  The idea behind this is that there will be less resistance and greater therapeutic potential for more comprehensive binding with the receptor.

We know from work in Sawyers lab that MDV3100 targets splice variants, which have been shown to cause resistance in CRPC, but we don’t yet know how ARN-509 will fare on that front.

So why did Clegg et al., (2012) suggest that ARN-509 might be superior to MDV3100?

“Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509, whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations.

Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists.”

In other words, it’s much more potent and has a greater therapeutic index; these things are important clinically. It also has a longer half-life:

“ARN-509 exhibits low systemic clearance, high oral bioavailability and long plasma half-life in both mouse and dog, supporting once-daily oral dosing.”

Androgen deprivation therapies are more commonly used in castrate-sensitive disease, so this begs the question of whether there is anti-androgenic activity in the non-castrate setting:

“At higher doses of 30 mg/kg/day, robust tumor-regression (>50% reduction in starting tumor volume) was observed in 6/8 ARN-509-treated animals, similar to regressions observed in mice castrated on the day treatment initiated.”

The promising results led the researchers to conclude that:

“ARN-509 is a next generation anti-androgen selected for pre-clinical and clinical development based on its efficacy and pharmacodynamic profile in mouse xenograft models of CRPC.”

They also stated that:

“Unexpectedly, given a similar in vitro profile, ARN-509 is more efficacious per unit dose- and per unit steady-state plasma-level in mouse models of CRPC than MDV3100.”

In other words, ARN-509 is a next generation AR antagonist with a good efficacy and PK profile in mouse xenograft models of CRPC.  It’s clinical development, although further behind abiraterone and MDV3100, will be well worth watching over the next few years.

In summary…

While there has been a lot of activity in the advanced prostate cancer market lately with new approvals making a difference to the lives of men with prostate cancer, there are also several other promising near term agents in development, as well as some potentially more potent and effective treatments in early clinical development.  What we have seen to date is merely the beginning of new advances in R&D.

The early and advanced prostate cancer markets are likely to see some significant changes over the next 24 months, as new products based on rational drug design and an improved understanding of the biology of the disease make it to market.

More on prostate cancer coming soon!

All this new data is very timely, considering on Monday I’m off to the AACR Special Conference on Prostate Cancer, jointly chaired by Drs Chinnaiyan and Sawyers.  I’ll be interested to learn what new events are emerging as biological targets and what factors can help us predict response to treatment.  If you’re going to this meeting do stop and say hello, it’s always good to meet new people in the field.

References:

ResearchBlogging.orgClegg, N., Wongvipat, J., Tran, C., Ouk, S., Dilhas, A., Joseph, J., Chen, Y., Grillot, K., Bischoff, E., Cai, L., Aparicio, A., Dorow, S., Arora, V., Shao, G., Qian, J., Zhao, H., Yang, G., Cao, C., Sensintaffar, J., Wasielewska, T., Herbert, M., Bonnefous, C., Darimont, B., Scher, H., Smith-Jones, P., Klang, M., Smith, N., de Stanchina, E., Wu, N., Ouerfelli, O., Rix, P., Heyman, R., Jung, M., Sawyers, C., & Hager, J. (2012). ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Research DOI: 10.1158/0008-5472.CAN-11-3948

Scher, H. (2005). Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis Journal of Clinical Oncology, 23 (32), 8253-8261 DOI: 10.1200/JCO.2005.03.4777

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Update on Medivation’s MDV3100 in advanced prostate cancer

This weekend heralds the annual American Society of Clinical Oncology (ASCO) Genitourinary (GU) meeting in San Francisco, although ASCO held their press briefing today to provide an update on some of the key topics.

For those of you interested in Alpharadin (radium-225) in castrate-resistant prostate cancer (CRPC), check out the update of Dr Oliver Sartor’s presentation, which is covered on Biotech Strategy Blog.

The key topic that most interested me though, was Dr Howard Scher’s update on Medivation’s Androgen Receptor antagonist, MDV3100, in CRPC.  Previously, Medivation announced that the data showed an improvement in median overall survival (OS) of 4.8 months and this is still solid (Note: J&J’s abiraterone was approved by the FDA based on an OS of 3.9 months in the same population and must be taken with prednisone).

Three new things were important in this presentation though:

  1. There has been some previous concern about the risk of seizures, after they were reported in an earlier trial, but that was at much higher doses.  In this study, the now standard (and much lower) 160 mg dose of MDV3100, demonstrated low levels of seizures (0.6%), which is very reassuring and not something I think many will worry too much about.
  2. MDV3100 has a nice effect not only on OS, but also median time to confirmed PSA Progression, i.e. 8.3 months vs. 3.0 months for placebo (HR 0.248, P<0.0001). Yes, I had to do a double take at that HR – it’s quite phenomenal!
  3. Aside from PSA drops, patients often like to know if their tumour is shrinking or not as evidence of activity and progress. Dr Scher showed the soft tissue response by CT/MRI imaging. There was a 28.9% response rate with MDV3100 compared with 3.8% for placebo (P<0.0001).

From this data we can definitely say that patients lived longer, saw a positive impact on their PSA levels, and felt better compared to placebo. In terms of serious adverse events, there were fewer in the MDV3100 arm (28.4%) versus the placebo arm (33.6%). There were also slightly more discontinuations in the placebo (7.0%) than MDV3100 (3.8%) cohort.

Overall, I wasn’t at all surprised when the host, Dr Nicholas Vogelzang (Medical Director of the Developmental Therapeutics Committee of US Oncology) exuberantly said he had only one comment to Dr Scher’s presentation of the MDV3100 data,

“Wow, that’s very impressive! It’s unprecedented.”

For once, I thought that ‘impressive’ was actually an understatement to apply to a cancer drug.

I also talked to Dr David Hung, CEO of Medivation afterwards. Many readers will remember my interview with Dr Charles Sawyers, the co-inventor of MDV3100, last year about the science behind the development. It was nice to see Medivation’s side of the R&D story, which has gone pretty rapidly so far.

PSB: Are you going to be filing soon based on this data?

David Hung: We are having a pre-NDA meeting with the FDA. Once we have that meeting we will be able to give much more concrete guidance on when we will be filing.

PSB: Some of the pre-chemo trials have started, would they be due to report some data soon?

David Hung: We haven’t given any timelines on any of our other trials.

PSB: When I interviewed with Charles Sawyers previously, he said that many pharma companies were not interested in what is now MDV3100. What did you see in it when many others said “no”?

David Hung: Charles didn’t approach me. I found him! I had read, with great interest, his work on the AR. I was very familiar with his Nature Medicine publication in 2004 showing that overexpression of the AR is a significant molecular change in patients with castration resistant disease. While I think a lot of people thought that targeting the AR would create just another AR antagonist, like casodex, the data suggested to me there was more here.

Because, in Charles’ lab by being able to over-express the AR, we were able to much more carefully assay and screen compounds for their ability to block androgen receptor signaling very thoroughly. And we found in the process that a number of compounds in the series that we were testing had ability to not only block just AR binding by testosterone, which is something that Casodex does, but unlike Casodex these compounds were able to inhibit nuclear translocation as well as DNA binding and activation by the AR.

I am an oncologist by training and was pretty familiar with this area, so when I saw the compounds and saw the data in more detail, I didn’t agree that it would just be another casodex like molecule. I thought the mechanisms suggested that this drug could be special, so when I went ahead and licensed the drug back in 2005. We then took the program forward rapidly through development. We had to do all the standard pharmacokinetics, metabolism, tox, formulation work, then take it into a clinical trial as quickly as we could, led by Howard Scher. So, we were able to develop the molecule very quickly.

One of the differences with MDV3100 over weaker AR antagonists such as bicalutamide, is it’s ability to target splice variants. This was a surprising but important finding. I asked Dr Hung about them:

PSB: Does that potentially mean that the patients in the current trial data presented by Dr Scher, may actually do better over time or is the 4.8 months OS probably going to be the final number?

David Hung: Well, I won’t know the answer to that until I unblind the PREVAIL trial. What is very interesting from our phase 1 / 2 data is that the time to PSA progression in post-chemo patients in that data set is about 203 days. Yet, the time to PSA progression in the pre-chemo patients was 4x longer than that, 812 days, suggesting that the drug may have even more robust activity upstream than it does downstream. Downstream it already has robust activity. We will be greatly looking forward to seeing the PREVAIL data, because that is the pre-chemo population. If we can recapitulate our phase 1 / 2 results, that would be great news for patients.

PSB: At AUA last year, I heard from Charles Sawyers that if you inhibit the androgen receptor, you often activate the PI3-Kinase pathway. His colleague Neil Rosen had also noticed that if you inhibit PI3K, you activate androgen receptor in prostate models. So Charles was saying in their joint paper that the logical thing to do would be to combine an androgen receptor inhibitor and a PI3K-inhibitor to potentially reduce the resistance and hopefully improve outcomes. Is that the kind of combination you might consider in the future?

David Hung: We actually are. You point out exactly the kind of things that we think about. We look to see how our drug works and we look to see what mechanisms might possibly complement our drug. That is the way we think about potential combination studies that we might do.

All this is very exciting news for both Medivation (and commercial partner Astellas), as well as patients with advanced prostate cancer. I hope that the discussions with the FDA go well and we will see a filing, perhaps even with Accelerated or Priority Review in the near future. Based on the data so far, the data clearly shows that MD3100 can make a difference to the lives of men with advanced prostate cancer.

Next week, I’ll be at the American Association for Cancer Research (AACR) Special Conference on Prostate Cancer, jointly chaired by Charles Sawyers (MSKCC) and Arul Chinnaiyan (Michigan) to learn more about the biology of prostate cancer. It promises to be both a timely and exciting meeting!

References:

ResearchBlogging.orgChen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, & Sawyers CL (2004). Molecular determinants of resistance to antiandrogen therapy. Nature medicine, 10 (1), 33-9 PMID: 14702632

Carver, B., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., Chandarlapaty, S., Arora, V., Le, C., Koutcher, J., Scher, H., Scardino, P., Rosen, N., & Sawyers, C. (2011). Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer Cancer Cell, 19 (5), 575-586 DOI: 10.1016/j.ccr.2011.04.008

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Pharma and Social Media: Update on abiraterone in advanced prostate cancer

By on August 3, 2011

“Fully 71% of online Americans use video-sharing sites such as YouTube and Vimeo, up from 66% a year earlier. The use of video-sharing sites on any given day also jumped five percentage points, from 23% of online Americans in May 2010 to 28% in May 2011.”

Pew Internet (2011)

This is a trend I’ve also noticed amongst my friends over the past year, largely driven by more of them using smartphones and iPads, which make sharing and watching video a whole lot easier.

In the past, I’ve been rather frustrated with Pharmaland and their resolutely horrid web 1.0 branded and unbranded websites that have tiny text, are heavy on flash or not mobile optimised, making sharing or even reading challenging, especially on mobile gadgets. Watching a useful video online, but not being able to share it on Twitter or Facebook with others, is one of those typical desk bang moments – why not if you can share the link to the website?  The world has moved on in terms of how we interact with websites and people online.

Thus I usually end up clicking out and forgetting about them altogether, unless I really need the Prescribing Information (PI) and have to spend a few minutes scrolling and hunting down a miniscule small link that is almost impossible to click without hitting the adjacent link next to it.

Then every once in while something beautiful comes along…

Yesterday, someone outside the US emailed me asking about access to abiraterone (Zytiga) outside the US, so I went on my iPad and to my delight and surprise found this on the Healthcare Professionals page:

abiraterone / Zytiga

Several key points to note here:

  1. You can share information with others by email and Twitter
  2. The PI was easy to find and click on
  3. The mechanism of action (MOA) video on Vimeo was high quality, interesting and sharable
  4. You can sign up for updates or view press releases easily
  5. The reimbursement support information was also easy to access
  6. The UI is uncluttered, has nice large text and is easy to navigate at a glance

In fact, the whole site was nicely laid out and easy to see things, click where you need to go and navigate with the well-thought out UI.  I didn’t have to pinch the screen once, which made a nice change.

Now, there are some glitches such as the patient information was a bit sparse and clicking the Contact Us section took me to the main Janssen website rather than a contact page, forcing me to scroll around looking for it there (hidden at the bottom in pale grey).  There’s no international number or email address when you finally find it, leaving me wondering what to advise my reader who contacted me for help.  This is where providing global Expanded Access Programs or local country contact details can be helpful – they will inevitably reach out, so not providing any help online is a tad antisocial.  There is more than just USA patients with advanced prostate cancer out there, after all.

If anyone from Janssen or Ortho Biotech Global is reading this and could point me in the right direction for helping patients and caregiver outside the US that would be great, as several enquiries a month come in on this topic.  There’s nothing worse than no information or not being able to help.  Companies ultimately live or die on seamless customer service and helping people with their needs.

The experience was pretty positive and I really liked the abiraterone website – it’s a good example of how nice UI design can make a huge difference to the UX for those visiting.  Whichever digital agency was responsible for this site did a very nice job so far and it breaks the cluttered, awkward to navigate with uncomfortably tiny font product website one normally comes across in this field – well done!

I’m hoping the Patient section will soon have some useful information to rival the HCP portal.  Putting in country contact details will be a good start in the right direction, as will information about ongoing clinical trials and a well designed, easy to read patient brochure about the disease, treatment and reimbursement information.  Yes – they do ask about the price and how they can save money – we get emails on that very topic every month too.

An excellent start overall – looking forward to seeing more developments in the near future!

A vlog update on advanced prostate cancer from the AUA 2011 meeting

By on May 16, 2011

After attending numerous basic research and clinical updates at the American Urologic Association (AUA) annual meeting in Washington DC, it is clear that the new and emerging therapies are not going to stop at the three grand crus from 2010.

Recently, abiraterone acetate (Zytiga) was approved, but there are a number of critical issues that need to considered, including:

  1. Sequencing
  2. Combinations
  3. Cost
  4. Patient selection

As we learn more about the molecular mechanisms behind resistance to androgen receptor signaling (up and downstream) and new targets emerge, so it may be possible to improve patient outcomes in castration-resitant prostate cancer.

Here’s a short video update of what I thought was interesting here at the conference:

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Aggregating the American Urology Association AUA2011 tweets

By on May 13, 2011

Today it’s Friday 13th and we’re heading off on the road again, this time to Washington DC for the much anticipated annual meeting of the American Urology Association (AUA).

We’ll be covering the hot topics on urologic cancers, including bladder and prostate cancers and renal cell carcinoma (RCC). I’m particularly interested in castrate resistant prostate cancer and updates on the abiraterone (Zytiga) data following the recent approval post chemotherapy in the US, and also the long term data for Medivation/Astellas’ MDV3100 from their phase I/II trial. It’s always important to know how patients in the early trials are doing.

We will post various updates here on Pharma Strategy Blog over the weekend including blog posts, podcasts and of course, video highlights. Do check back daily for news and snippets about what’s hot here at AUA.

In the meantime, you can also follow the aggregated tweets from the attendees – if you have a question, please don’t hesitate to ask me on Twitter (@maverickny) using the offical conference hashtag #aua2011 or in the blog comments below:

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Update on new data in prostate cancer

By 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

  1. 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.
  2. 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).
  3. 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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