Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Prostate Cancer Drugs’

Medivation investors hoping for a windfall will be disappointed to hear that on December 20, 2012 a California judge ruled the company had no rights to what is now known as Aragon Pharmaceuticals’ ARN-509, a next-generation androgen receptor (AR) antagonist for advanced prostate cancer, similar in chemical structure to enzalutamide (Xtandi).

Enzalutamide (formerly MDV3100) was developed in the UCLA laboratory of Drs. Charles Sawyers and Michael Jung and licensed by Medivation from the University of California. Medivation believed their licensing and sponsored research agreements gave them rights to any follow-on compounds. However, instead of giving Medivation first right of refusal, the University licensed what is now ARN-509 to Aragon Pharmaceuticals, a privately-held company whose owners include Sawyers and Jung.

You can read more about ARN-509 on Pharma Strategy Blog: “Is ARN-509 potentially better than MDV-3100?” Sally Church (@MaverickNY) also interviewed Dr Charles Sawyers in May 2011 just before Medivation commenced a lawsuit against the University of California, Sawyers and Jung claiming breach of contractual agreements.

Concern about the ownership of intellectual property rights to ARN-509 has overshadowed Aragon with many thinking Medivation had a strong case. This has likely hindered the ability to raise capital or obtain a potential partner, although Aragon did announce on October 4, 2012 they had raised $50M in series D financing. However, ARN-509 has been slow to move through development and has yet to enter phase 3 clinical trials.

Based on the limited public information available about the lawsuit between Medivation, University of California and Aragon, my thoughts last year were that the case would settle as none of the parties would want a trial that exposed sensitive intellectual property and financial information.

However, in a December 20, 2012 Order, Judge John E. Munter of the Superior Court of California granted summary judgment to The Regents of the University of California on a number of issues, finding that Medivation’s contracts with the University gave them no ownership or licensing rights to ARN-509.

Medivation v University of California IP dispute court docket

Many thanks to biotech investor (@lomu_j) for sharing the news on Twitter – definitely worth following if you do not do so already.

 

Based on the evidence submitted by the parties, Judge Munter decided that the University of California did not breach the Sponsored Research Agreement (SRA) with Medivation.

According to the court Order, the SRA provided that Medivation would have “a time-limited first right to negotiate an option or license, which may be exclusive” with respect to “Subject Inventions” that occurred during a specified performance period i.e. the University of California was required to disclose follow-on compounds such as ARN-509 to Medivation during this time.

However, anyone who has been involved in contractual disputes will know the devil is in the detail, and the court Order explains why Medivation did not prevail, as many had expected.

The SRA defined “Subject Invention” to be an invention that was “first conceived” and “actually reduced to practice” during the performance period which it was agreed would start on November 1, 2005. However, during discovery The Regents of the University of California presented evidence from a research scientist, Dr Samedy Ouk that A52, the compound that became ARN-509, was conceived and reduced to practice prior to this date. You can read more in the following excerpt from Judge Munter’s Order:

Superior Court of California Order excerpt MDVN Aragon ARN-509 dispute

Since the University was only obligated to disclose inventions after November 1, 2005, the court found they did not breach the SRA by failing to give Medivation the right to option or license a compound that was invented prior to this. A close call when you look at the dates, but that is what the parties agreed to in writing.

The court Order discusses several of the claims and disputes between the parties, some of which remain ongoing. It is of course possible that Medivation might appeal, but I was persuaded by Judge Munter’s cogent opinion. In essence the court ruling, unless it is overturned on appeal, means Aragon can move forward unhindered with the development of ARN-509.

Here’s my take from this case:

  1. When negotiating a contract, the devil is in the details. Good contract drafting should avoid the need for future litigation. Negotiating contracts can take months, but it’s never wise to sign anything just for the sake of expediency.
  2. A contractual dispute can occur years after an agreement was signed highlighting the importance of document retention, e.g. laboratory notebooks, especially where intellectual property is involved.
  3. Contracts typically have an integration clause that says what is written reflects the “entire understanding of the parties.” This means a court will only look to what is in written down and not what may have been said or verbally agreed prior to signing the agreement. It’s important to make sure the written contract is clear and unambiguous.
  4. IP litigation can delay a potential competitor and deter others from investing or partnering. By the time ARN-509 makes it to market, the prostate cancer landscape will be more competitive than it is today.  Through the delay Medivation ends up winning irrespective.
  5. Aragon may now be an attractive partner for companies with an established urology/prostate franchise who would like to compete against Medivation.

While many are excited about ARN-509 in advanced prostate cancer, it must be noted that Aragon have yet to show that ARN-509 is more effective than enzalutamide in patients. A phase 3 clinical trial of ARN-509 in the post-docetaxel prostate cancer setting will not be easy given it will most likely require comparison to the current standard of care (Xtandi or Zytiga) and not placebo.

The prostate cancer market remains a dynamic one with multiple new products in development and the potential for combination approaches. The forthcoming ASCO GU meeting in Orlando, from February 14-18, 2013 is worth watching for new updates.

Update May 29, 2013: Medivation announces they will appeal decision in favor of Aragon

According to the SEC filing that @ColfaxCapital kindly shared the link to last month on twitter, Medivation have not unsurprisingly announced they will appeal the California court decision in favor of Aragon.

The Medivation SEC 8-K filing notes that the appeal was filed on April 15, 2013 and will most likely take 12-18 months, so a California Court of Appeals decision is not expected until sometime in 2014.

There is also ongoing litigation between the University of California and Medivation over whether the company has to make royalty payments to the University when it receives commercial milestone payments from Astellas and a trial on this issue is scheduled for July 2013. Another trial over Medivation’s allegations of fraud against Dr Jung is set to start in October 2013.

There’s still plenty of legs left in this story and a time to go before we have a definitive outcome given that any trial decisions will most likely also be appealed in due course.

Update June 17, 2013: Johnson & Johnson announces acquisition of Aragon Pharmaceuticals with $650M upfront payment

J&J have this morning announced the acquisition of Aragon, and the rights to ARN-509 in a deal with a $650M upfront payment and contingent milestone payments of upto $350M.

Here’s a link to the press release published on the WSJ.

 

TBMS Sprycel Logohe results of the phase 3 clinical trial of dasatinib (Sprycel) plus docetaxel/prednisone versus placebo and docetaxel/prednisone in men with castration-resistant metastatic prostate cancer (CRPC) are expected soon.

BMS recently updated the clinicaltrials.gov website to show that the dasatinib phase 3 randomized prostate cancer “READY” trial (NCT00744497) of 1500 men completed data collection in August.

Data is expected before year end and, If positive, could be a late breaker at the ASCO Genitourinary Cancers Symposiusm (ASCO GU) in Orlando from Feb 14-16, 2013.

Dasatinib inhibits Src-family kinases (SFK)

Dasatinib is approved for Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL). It is a BCR/ABL, LYN and Src family tyrosine kinase inhibitor.

Src-family kinases (SFK) are involved with tumor proliferation and bone metabolism.

In the phase 1 & 2 clinical trials of dasatinib with docetaxel, many of the men with prostate cancer saw a decrease in PSA from baseline, reduction in tumor size and bone scan improvement and stabilization. Encouraging early results led to the start of a phase 3 randomized trial of dasatinib in combination with the chemotherapy, docetaxel.

However, the results for Src inhibitors in prostate cancer have been mixed to date, with not all agents generating positive data. Astra-Zeneca’s saracatinib (AZD0530), for example, showed little clinical effect on its own in a phase 2 prostate clinical trial.

It has been suggested by KOLs at numerous conferences that Src inhibitors may potentially be more effective in combination with other cancer agents. Data suggests that Src might be a resistance mechanism to enzalutamide (MDV3100), so it would be interesting to see whether a dasatinib/enzalutamide combination may be more effective than enzalutamide on its own.

Meanwhile, we await the data to see whether the combination of dasatinib with docetaxel generates a significant increase in overall survival over docetaxel alone. While some are “hopeful”, Dr Oliver Sartor, Professor of Cancer Research at Tulane Medical School noted in a prostate cancer session at ESMO 2012 that, “the docetaxel-combination graveyard is big!

Update Jan 26 2013: Dasatinib Phase 3 Data at ASCO GU

Results from the dasatinib phase 3 prostate cancer trial are a late breaking abstract at the 2013 ASCO Genitourinary Cancer Symposium (ASCO GU) in Orlando. The data will be presented on February 14 by John Araujo MD PhD, Assistant Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

LBA #8: Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the phase III READY trial.

Radium-223 (Alpharadin) is a novel bone targeted treatment for advanced prostate cancer.

At the recent European Multidisciplinary Cancer Congress in Stockholm (EMCC 2011), Dr Chris Parker from The Royal Marsden Hospital presented results of the phase 3 ALSYMPCA trial that showed both delayed time to first skeletal-related event (SRE) AND an overall survival (OS) benefit for those men with advanced prostate cancer taking radium-223.  This is the first time a product in the bone category has shown such a survival benefit – neither denosumab or zoledronic acid can claim that distinction.

Unlike the recent regulatory approvals for cabazitaxel (Jevtana) and abiraterone acetate (Zytiga), which focused on the post-docetaxel setting, the ALSYMPCA trial included not only those who had already received cytotoxic therapy, but also pre-docetaxel patients, who were unable to take chemotherapy.

As Dr Parker mentions in the interview that he kindly gave in Stockholm (the first video interview on Biotech Strategy Blog), radium-223, assuming it gains regulatory approval, will provide a new treatment option for the considerable population of men with bone metastases who may be too weak, too old or otherwise unable to take chemotherapy such as docetaxel.

Radium-223 is, therefore, potentially good news for this “neglected” population of prostate cancer patients.

To learn more insights on this intriguing topic, subscribers can log-in or you can purchase access to BSB Premium Content. 

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With the collapse of the Dendreon share price today following poor sales data (Adam Feuerstein on The Street has an excellent write up about this), attention has again focused on the prostate cancer market.

Zytiga (abiraterone acetate) was recently approved by the European Medicines Agency (EMA), following FDA approval earlier this year.

The EMA Committee for Medicinal Products for Human Use granted the marketing authorization for Zytiga at it’s July 2011 meeting.  The approval noted,

“The poor prognosis of the target patient population represents a high unmet medical need while the novel mechanism of action of abiraterone has the potential to offer an alternative therapeutic option for these patients.”

What does this mean for sales of sanofi-aventis’ cabazitaxel (Jevtana), which was approved in Europe earlier this year?

Given that both drugs have approval in the same indication for metastatic castrate resistant prostate cancer (mCRPC) post-docetaxel chemotherapy, and the price is likely to be comparable, my guess would be that Jevtana sales will take a big hit.

After a sick prostate cancer patient has undertaken several cycles of chemotherapy with docetaxel, why would they not want to take an oral pill as opposed to another chemotherapy drug, which does have a less than stellar adverse-event profile.  The answer is they will probably take a chemo-holiday and use Zytiga.

Jevtana simply came to the market too late in Europe, and Zytiga gained accelerated approval.  It’s a reminder that we live in a dynamic pharmaceutical market place, as the news last night from Dendreon has also reminded us.

One of the sessions that I attended at the 2011 annual meeting of the American Urological Association (AUA) focused on research into advanced prostate cancer.  A particularly thought provoking presentation was:

Time trends of biochemical recurrence (BCR) following radical prostatectomy (RP) among 1574 BCR patients (Abstract #639)

Presented by Alex Haese from Hamburg, Germany, this paper was a retrospective analysis of 1,574 patients who had a biochemical recurrence (PSA > 0.2 mg/dl) following RP. Researchers looked at clinical progression and cancer specific survival rates and compared their findings to published United States data.

The results appeared to be somewhat depressing for European patients who experience a BCR, with a time to BCR of 1.8 years, compared to 2.1 years in the US research by Pound from Johns Hopkins and 2.4 years in the data published by Hull, at Memorial Sloan Kettering Cancer Center (MSKCC).

Once a BCR is experienced, the time to metastases is faster in Europe, 4.7 years in the research presented by Haese at AUA, as compared to 8 years in US research by Pound. Risk factors for metastasis free survival include time to BCR i.e.

“The longer the interval between RP and BCR, the greater the probability of being met-free.”

In other words delaying time to progression is associated with longer survival.

Following BCR, time to Prostate Cancer death was 6.0 years in the 1,574 European patients, compared to 13 years in the US Pound research.  Again, the data presented showed that,

“The longer the interval between RP and BCR, the greater the probability of being alive.”

This research must be put into context, as metastasis and death in BCR patients are rare (92% of the 1,574 patients with BCR were free of metastases at 5 years, 81% at 10 years).  However, for those patients who did progress, the results appear significantly different between the US and Europe.

What could explain this?

The presentation left this question unanswered, although in Q&A it was briefly touched upon. One person raised the question of whether differences in screening could be the difference in Europe vs. US?

Other questions that come to mind are whether the subject populations in the Hull and Pound data were comparable.  The German data also had more patients (1574) compared to 304 in the Pound research and 147 (Hull) raising the question that the larger sample size may be more accurate data?

Other factors that might possibly explain the difference include:

  • Androgen deprivation therapy (ADT)
  • Radiotherapy
  • Supportive care (eg bisphosphonates)

All of which tend to be more aggressively pursued as treatment options in the USA.

Overall, this presentation raised the interesting question of US/European differences in Prostate Cancer progression that hopefully will be answered by future research.

I am off to Washington DC tomorrow for the annual meeting of the American Urological Association (AUA).

If you are not able to attend, then you can follow the Twitter coverage on Pharma Strategy Blog where Sally Church (@MaverickNY) will be aggregating the tweets.  The conference hashtag is #AUA2011.  I also expect to be live-tweeting from the conference.

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Like many medical conferences in the United States, the AUA meeting kicks off with independent continuing medical education (CME) satellite symposia on topics of interest.

As a lawyer who has to pay for his own continuing legal education (CLE) credits, I have to confess that I am somewhat cynical that other professionals such as physicians expect to have their CME paid for through free industry-sponsored events.  These symposia are certainly not cheap to run.

However, compared with Europe, CME events in the United States are usually well-produced and fair balanced, albeit with a topical theme that obviously relates to the sponsor’s interest.

The two satellite symposia that I will be attending at AUA are Friday evening’s Amgen supported “Managing Skeletal-Related Events in Patients with Prostate Cancer” and the Saturday morning Astellas/Medivation supported “Reason for Hope: Key Advances in the Management of Castration-Resistant Prostate Cancer.”

While at Quintiles, I was lead CRA/European Project Manager for the phase III trial trial of risedronate in elderly women at risk of hip fracture, so I am interested in bone related treatments, and am looking forward to hearing more about denosumab (Xgeva®) and its impact on skeletal related events (SRE).

Oliver Sartor (Tulane) raises some excellent questions in a recent paper published in the Asian Journal of Andrology, “if a patient has a SRE, does it affect the way a patient feels, functions or survives?”

Sartor argues that a better definition of the benefit a drug has on SRE’s would be “a reduction in pain, analgesic consumption or improvement in quality of life (QoL)” instead of the current “feel, function or survive” standard.

He notes that patients with bone-metastatic castrate resistant prostate cancer (CRPC) have a limited life expectancy, so that QoL is a key issue. “An asymptomatic event linked to a future adverse event is less meaningful in a patient with metastatic CRPC.

Sartor concluded his paper by saying:

“The lack of effect of bisphosphonates or denosumab on patient-reported outcomes including QoL, pain or analgesic consumption continues to be a disappointment for this entire field.”

When we talk about a reduction in SRE’s what does this really mean for the patient?  I look forward to hearing what the expert panel at Friday evening’s symposia on this topic and hope it will be addressed.

Moving on to the other satellite symposium, supported by Medivation/Astellas, that I will be attending early on Saturday morning.  I expect this symposium will focus on new drugs in the pipeline such as MDV3011 and ARN-509 that target the androgen receptor. Hopefully they will also discuss other therapeutics, such as the recently approved abiraterone acetate (Zytiga®), as well TAK-700, which has a similar mechanism of action to abiraterone, i.e. they both inhibit CYP17 and testosterone production.

I’m looking forward to hearing what the expert panel has to say about the need to take prednisone with abiraterone, and whether there are any issues surrounding long-term usage if abiraterone ends up being used earlier in the pre-chemotherapy setting.  Updated data from the COU-AA-301 trial will be presented at AUA on Monday, and I expect a lot of interest from urologists in this.

The satellite symposia are set to be a good warm up act to the start of the main AUA meeting that runs from May 14 to 19 in Washington DC.  I’ll be writing more from the AUA 2011 over the next few days.

ResearchBlogging.orgSartor, O. (2011). Denosumab in bone-metastatic prostate cancer: known effects on skeletal-related events but unknown effects on quality of life Asian Journal of Andrology DOI: 10.1038/aja.2011.33

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