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Posts tagged ‘Aragon ARN-509’

Johnson & Johnson (JNJ) just announced the acquisition of privately-held Aragon Pharmaceuticals and the rights to ARN-509 a second-generation androgen receptor antagonist that will be a future competitor to Medivation’s Xtandi.

The deal, valued at $1billion, with $650M upfront and $350M based on contingent milestone payments, is a blow to Medivation who have been locked in litigation with Aragon and the University of California over ownership of the rights to ARN-509.  Both ARN-509 and Xtandi were developed in the laboratories of Charles Sawyers and Michael Jung at UCLA.

The Aragon acquisition is a sound strategic decision for JNJ, offering them the ability to develop their prostate cancer franchise after Zytiga goes off patent and more importantly, offer a product that at the very least is equivalent to Xtandi, and potentially, may be superior.  ARN-509 will also allow JNJ to compete in earlier stages of prostate cancer with a drug that does not require use of steroids, something that has always been a major problem for Zytiga in the chemotherapy-naïve setting.

JNJ now have a corporate strategy for life post-Zytiga. They have the resources and expertise to fund large phase III clinical trials for ARN-509, not only in prostate cancer, but potentially also in breast cancer.  Aragon being bought out by a big Pharma with deep pockets is a blow to Medivation/Astellas.

What this acquisition also tells us is that Johnson and Johnson lawyers consider the Medivation appeal over intellectual property rights to be weak.  They will no doubt have done considerable due diligence on Medivation’s claims and consider the risk to be low or manageable.

My personal view was that cash-rich Medivation should have acquired Aragon themselves and neutralized the competitive threat rather than pursue a scorched-earth litigation strategy.

The JNJ acquisition of Aragon also suggests that ARN-509 may be perceived as the best in class of the second-generation androgen receptor inhibitors in development. There are others that JNJ could have sought to acquire or licence, including ODM-201 (Orion).  The fact that JNJ chose ARN-509 or a better version of Xtandi is not good news for other companies with AR antagonists in early-stage development.

Medivation are unlikely to feel the competitive threat from ARN-509 in the prostate cancer market for a few years, because registration trials against the current standard of care are needed to show that the drug offers an equivalent or better survival benefit.  ARN-509 will most likely be compared against Zytiga, offering yet another benefit of the deal – the ability to provide free comparator drug in the clinical trials.

The JNJ acquisition is good news for men with advanced prostate cancer who may in 5 years see another new treatment option become available.  It is, however, a blow to Medivation and Astellas who now have a serious competitor to deal with in the future in a space where they may have thought they had a major competitive advantage.

Galeterone (Tokai Pharmaceuticals) is a new prostate cancer drug in development that has an interesting triple mechanism of action in that like abiraterone (Zytiga) it acts as a CYP17 lyase inhibitor, but it also acts as an androgen receptor (AR) inhibitor and is an AR degrading drug that decreases AR levels.

How effective it is compared to AR antagonists on the market such as enzalutamide (Medivation) or second-generation AR antagonists in development such as ARN-509 (Aragon Pharmaceuticals) or ODM-201 (Orion Pharma) is one of the many unanswered questions with this drug.

The poster (abstract #184) from Tokai scientists presented at the recent 2013 American Society of Clinical Oncology Genitourinary Cancers Symposium in Orlando (ASCO GU) showed preclinical laboratory work using cell lines whereby galeterone was a potent CYP17 lyase inhibitor. It may offer an advantage over abiraterone in not requiring concomitant administration of steroids.

Despite being a clinically focused meeting, no patient data using the new formulation of the drug was presented at ASCO GU; this was disappointing given the potential safety concerns that were raised with the original formulation.

AACR 2012 data showed drug-related rhabdomyolysis & acute renal failure, both Grade 4

Last year at the 2012 AACR annual meeting, Mary Ellen Taplin, MD presented data from the ARMOR1 clinical trial of galeterone in chemotherapy-naïve castration resistant prostate cancer (CRPC).

Of particular concern was the one serious adverse event of drug-related Grade 4 rhabdomyolysis and acute renal failure she reported. Some commentators have dismissed this as a “fluke” but it was clearly taken seriously by the company in the AACR presentation I saw with several slides discussing this and liver safety considerations.

Dr Taplin concluded her AACR presentation by stating that further work was planned to optimize the formulation of galeterone, and that a new phase 2 study with a better formulation was planned for later in 2012.

Critical clinical questions remain unanswered

As Professor Johann de Bono, who was the discussant at AACR 2012 noted, a future trial with galeterone has a number of critical questions to answer:

  • Can galeterone achieve sufficient exposure?
  • Can galeterone block CYP17? AR? Degrade AR?
  • Can galeterone reverse MDV/abiraterone resistance?

So why haven’t I written much about galeterone, as one blog reader recently wrote in to ask?  It’s largely because I don’t think there is enough data to make any conclusions yet and both the liver toxicity and rhabdomyolysis issues will overshadow its development until Tokai address this convincingly.

I certainly haven’t seen any pharmacokinetic data on the new formulation to show that safety and efficacy are acceptable, nor any data to show that it has a definite effect on disease progression over and above abiraterone or enzalutamide.

Tokai announced on December 13, 2012 that they had treated the first patient in the Phase 2 ARMOR2 trial, which will evaluate the safety and efficacy of the new formulation.

Hopefully, the clinical data from ARMOR2 will show no repeat of the drug-related grade 4 rhabdomyolysis and acute renal failure seen in the ARMOR1 trial.  Only then will we know whether this was a “fluke” or not as some commentators have suggested.

The company has shown a proof of concept but until we see more data, I don’t think we really can assess what potential galeterone may have in the treatment of advanced prostate cancer.

For those interested in the data on galeterone presented at ASCO GU, here’s a link to a PDF of the poster available on the Tokai Pharmaceuticals website.

Galeterone Commercialization Challenges

Some of the challenges that Tokai may face in bringing galeterone to market include:

1. Need for a new formulation has delayed drug development

There are multiple new prostate cancer products in development in what will before long be a much more competitive market than it is today.  Although galeterone received a fast track designation from the FDA , I can’t help but think that the company has lost a year as a result of the need to develop a new formulation. Given the market dynamics, this delay could impact Tokai and the potential market opportunity for galeterone.

2. Abiraterone patent expiration is on the horizon

The short patent life for abiraterone and prospect of the availability of a generic version in a few years, could negate some of the advantages of having a CYP17 “combination product”. Galeterone may not require the concomitant administration of steroids, but this benefit may not be sufficiently attractive on its own to justify a premium price when a generic version of abiraterone becomes available.

3. How good an AR antagonist is galeterone?

We don’t yet know how effective an AR antagonist the new formulation of galeterone is. At the scientific meetings I have attended, I have only seen one slide on the mechanism of action, and it’s unclear to me what effect galeterone may have (if any) on AR splice variants. Other questions that come to mind are:

  • Is galeterone a more complete antagonist of AR like enzalutamide or does it have antagonist and agonist properties like bicalutamide?
  • Will galeterone offer benefits over using an AR antagonist such as enzalutamide in combination with abiraterone?
  • Are the AR antagonist effects of galeterone better than second-generation AR antagonists in development such as ARN-509, ODM-201?

4. Randomized registration trials will need to be done against the standard of care

If your registration trial is not already underway, the days of placebo controlled trials in advanced prostate cancer are over. It would be unethical to give men an inactive placebo when effective new therapies are already available, especially in the post chemotherapy setting. Tokai will most likely have to do a randomized registration trial of galaterone against abiraterone. Will it be superior or only equivalent in efficacy and tolerabilty?

5. To charge a premium price, Tokai will need to show men live longer

The competitive landscape is moving fast, and I predict as the cumulative cost of prostate cancer treatment increases, the market will become more price sensitive as new drugs are approved. If Tokai desire to charge a premium price, then they will need to show that galeterone is superior to the standard of care i.e. men live longer when taking it compared to taking abiraterone or enzalutamide.

Abiraterone had the first mover advantage as the first drug to seek approval in the pre-chemotherapy CRPC setting. Johnson and Johnson obtained FDA approval based on the totality of the COU-AA-302 trial data, which included the absence of a significant overall survival advantage, although this would most likely have been reached had the trial not been stopped early. In future, I can’t see other companies being equally blessed. Medivation will most likely run their PREVAIL trial until a significant overall survival advantage is obtained, and in the process raise the bar for future competitors such as galeterone.

Other combinations may offer more benefit than galeterone

It is good news for men with advanced prostate cancer that new treatment combinations are on the horizon.  While I remain sceptical about galeterone, at least until they show compelling clinical data, I am excited about new treatment options such as radium-223 (Alpharadin) that will soon be approved by the FDA.

Professor Bertrand Tombal in his recent ASCO GU interview with Sally Church, PhD said the trial he’d most like to do is radium-223 + enzalutamide. I share his enthusiasm for this. If you haven’t already read the interview, here’s a link to it on Pharma Strategy Blog.

While I didn’t think galeterone was worth writing about from AACR 2012 given that it was headed back to the lab for a new formulation, a novel prostate cancer treatment that did catch my attention was AZD3514 from AstraZeneca. Here’s the link to my AACR 2012 post in case you missed it. This is one that I am watching, and I hope there will be phase 1 clinical trial data for AZD3514 at the ASCO annual meeting later this year.

My Conclusion

In my view, Tokai Pharmaceuticals have yet to show the new formulation of galeterone is safe and effective or that men with advanced prostate cancer live longer when taking the drug compared to taking abiraterone or enzalutamide either sequentially, or in combination. While galeterone may offer an innovative mechanism of action, it is too early to say whether this will translate into any meaningful clinical benefit in the treatment of advanced prostate cancer or whether it’s just another me-too drug in development.

One of the late-breaking abstracts (not yet published) that I am looking forward to at the forthcoming annual Congress of the European Society for Medical Oncology (ESMO 2012) in Vienna is on ODM-201 (Orion Pharma):

LBA25-PR:  ARADES trial: A first-in-man, open-label, phase I/II safety, pharmacokinetic, and proof-of-concept study of ODM-201 in patients (pts) with progressive metastatic castration-resistant prostate cancer (mCRPC)

ODM-201 is a new antiandrogen from Finnish company, Orion Pharma, and is being developed in partnership with Endo Pharmaceuticals (NASDAQ: ENDP).

Orion Pharma LogoIn a corporate presentation, Orion Pharma describe ODM-201 as:

  • Potentially best-in-class antiandrogen
  • Does not enter brain in preclinical models
  • No testosterone increase in animal models
  • Well tolerated

“We are studying and developing an anti-androgen with qualities that currently cannot be found in any of our or our competitors’ drugs”

says Mika Mustonen (@MikaMustonen), Head of Oncology, Research and Development at Orion in an article, “Pursuing a targeted drug for prostate cancer” published by the company. Mustonen says:

“The research on our new drug candidate, ODM-201, suggests that we may be able to provide patients with a new alternative for the treatment of prostate cancer.”

Of note, is Orion’s focus on biomarkers, which may help predict which patients are more likely to respond to the therapy. According to Mustonen:

“Biomarkers increase the chance of success.  By following them we can study topics that have not been considered before in this type of research.  We can predict different phases of the disease, survey any safety risks associated with the drug and find out what kind of patients benefit most from the drug.”

At ESMO 2012 (Twitter hashtag #ESMO12) I expect we will hear preliminary data from the ARADES 3104001 phase 1 dose escalation study (NCT01317641) with ODM-201.

According to clinicaltrials.gov this multicenter, non-randomized clinical trial is being undertaken at sites in Finland, Czech Republic, France, United Kingdom and the United States.

After 12 weeks in the phase 1 dose escalation study, patients with stable disease can continue treatment in a phase 2 extension study on the safety and tolerability of ODM-201 (NCT01429064).

As of May 2012, Orion Pharma reported that the ARADES 3104001 phase II expansion component had 105 patients enrolled, with 3 dose levels to be expanded.

Company senior management have told me they “are very excited about the ODM-201 data,” to be presented at ESMO. I have not seen the data, but presume the results will be positive. After all, company executives don’t get excited about negative data!

Is there a market for a new antiandrogen?

Although Medivation are first to market with their androgen receptor (AR) inhibitor, enzalutamide/MDV3100 (Xtandi) that does not mean that other companies will not be able to make in-roads into the market with cheaper or more effective AR antagonists.

In a Pharma Strategy Blog interview with Sally Church, Dr Charles Sawyers noted that Aragon’s ARN-509 (another AR inhibitor in development) is “more potent” than enzalutamide and “might produce a higher percentage of responders or longer duration of response.”

Medivation recently announced that enzalatumide is available in the United States for patients with metastatic castration resistant prostate cancer previously treated with docetaxel.

At a price of $7,450 a month, however, Xtandi is considerably higher than Johnson & Johnson’s Zytiga.  This aggressive premium pricing strategy opens the door to competitors who may offer equally effective, but less expensive drugs.

The prostate cancer market remains a dynamic one and very much one to watch over the next few years.

I look forward to learning more about ODM-201 at ESMO 2012.

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Launch of Zytiga (abiraterone acetate) at 2011 annual meeting of American Urological Association (AUA) in Washington DCThe market for prostate cancer therapies is set to expand from $1 billion currently to $5 billion by 2015, according to analysts reported by this morning’s Washington Post/Bloomberg news.  This is perhaps no surprise given the recent approval of abiraterone acetate (Zytiga®) from Ortho Biotech (JNJ).

New clinical data on prostate cancer clinical trial results is expected at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago this weekend from many of the prostate cancer therapies in development such as MDV3100, TAK700, ARN-509, cabozantinib (XL184), ipilimumab, custirsen (OGX-11), BPX-101, alpharadin, denosumab (Xgeva®) and Prostvac-VF.

Indeed, one could argue that prostate cancer is becoming a competitive marketplace.  Any emerging biotechnology company that is not already developing a prostate cancer drug is likely to find it a hard market in which to create a blockbuster.  By the time any drug comes to market, there will be incumbents with effective products who have captured market share.

Prostate cancer is an exciting market to watch from a marketing strategy and patient perspective, as several companies potentially bring new products to market over the next few years.

However, the bottom line is that patients will live longer as a result of all the innovation that is taking place.  Not only that but physician education and awareness of how to treat this disease is also likely to improve as they seek out knowledge on new therapies and treatments.  This to many will make a major difference.  At the recent American Urological Association (AUA) annual meeting, the sessions on treatment of prostate cancer were standing room only.  There is clearly a demand for knowledge out there as the treatment paradigms change.

At the other end of the spectrum, there is also innovation taking place in terms of improved diagnosis and treatment of prostate cancer.  Whether we should screen all men for PSA remains a controversial topic, although use of risk calculators do appear to offer less false positives.  Indeed, calculating risk is going to be one of the key areas that primary care physicians and urologists need to focus on, particularly in the light of the PIVOT trial data that was presented at AUA, showing radical prostatectomy (with risks including incontinence and erectile dysfunction) was not better than watchful waiting in low-risk, early stage disease.

However, a presentation I am looking forward to at ASCO 2011 is on circulating tumor cells (CTC) and whether these can be a prognostic or even a predictive biomarker.   Both the phase III MDV3100 and abiraterone acetate clinical trials captured CTC data.  It will be exciting news at ASCO 2011 if circulating tumor cells that require only a blood sample offer an improvement over PSA not only for detection of prostate cancer, but in monitoring the disease over time.

I will be at ASCO 2011 this weekend, and look forward to writing more on prostate cancer from the conference!

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