Biotech Strategy Blog

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

Posts tagged ‘ARN-509’

We hope that everyone had a relaxing holiday break and now it’s time to get back to work.  Tomorrow I will review some more of my thoughts in the immuno-oncology space, since that area had a tremendous amount of progress in San Diego with lots of new ideas to process and summarise.

In the meantime, a few people have written in and asked about what was happening with overcoming resistance in various tumour types, was there anything new to say in that space that was in addition to the the detailed previews we covered before the conference?

Actually, there was a quite a few posters and presentations that caught my eye, so I thought this would be a good idea to review them here:

Lung Cancer: HER2, VEGF, T790M, EGFR, erlotinib, gefitinib, trastuzumab, bevacizumab, CO-1686, AZD9291

Prostate Cancer: mTOR, PI3K, Androgen Receptor, enzalutamide, abiraterone, CC214–2, ARN–509, BET Bromodomian inhibition, ODM–201, GDC–0980, GDC-0068, PF–04691502, BKM120, BEZ235

As 2013 comes to an end, rather than look back as many are doing, I’m looking forward to 2014. January is a busy month for cancer meetings with the ASCO organized gastrointestinal cancers symposium (ASCO GI) and genitourinary cancers symposium (ASCO GU) both taking place in San Francisco a few weeks apart.

In fact, looking at the calendar of forthcomings meetings, 2014 looks to have a West Coast focus, with the annual meeting of the American Association for Cancer Research (AACR) taking place in San Diego in April, and the American Society of Hematology (ASH) annual meeting also heading to San Francisco in December.

Transcontinental airfares are notoriously expensive at the last minute so if flying from the East Coast, do make travel plans early!

The ASCO GU symposium takes place at the San Francisco Marriott Marquis from Jan 20 – February 1, 2014. The abstracts for meeting go online at 5pm Eastern Time on Jan 28.

ASCO in a December 19 press release have already announced what will be highlighted on the January 28 press cast, and what many of the media can be anticipated to write about from the meeting.

Perhaps not surprisingly the Medivation PREVAIL trial data (LBA1) is top of the list; the abstract for this presentation has already been published online as Professor Tombal (@BertrandTOMBAL) kindly highlighted on Twitter.

This preview highlights some of the prostate cancer abstracts and presentations to watch out for at the meeting:

Drugs discussed in this post include: enzalutamide (Xtandi), abiraterone (Zytiga), ODM-201, ARN-509, ipilimumab (Yervoy).

Subscribers to premium content can login and read the ASCO GU 2014 prostate cancer preview below:

Amsterdam – Earlier today, I had the great pleasure at the European Cancer Congress to interview Oliver Sartor, MD, the Piltz Professor of Cancer Research in the medicine and urology departments of Tulane School of Medicine in New Orleans, LA.

A recognized expert in prostate cancer, Dr Sartor was gracious enough to give me an impromptu interview in the poster hall at ECCO 2013 and share his thoughts about the prostate cancer clinical data presented in Amsterdam.

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).

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Prostate cancer is the second leading cause of cancer death in men, so it was good news this morning when Medivation & Astellas issued a press release that showed positive data from the phase 3 AFFIRM trial for MDV3100.

MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo.

MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

To put the 4.8 month survival advantage in context, this compares favorably with 3.9 months for abiraterone (Hazard Ratio =0.646), in the COU-AA-301 trial.

Positive data was expected given the sound scientific rationale behind MDV3100 and the preliminary data (abstract 4501) presented at the ASCO annual meeting this year. J Clin Oncol 29: 2011 (suppl; abstr 4501).

The drug has a high affinity for the androgen receptor (AR) that is highly expressed on prostate cancer cells.  You can read an excellent interview on Pharma Strategy Blog with Charles Sawyers, who was one of the co-inventors.

MDV3011 blocks the androgen receptor (AR) from moving into the nucleus and activating growth genes and is a more complete inhibitor of AR than bicalutamide.

One hot topic of conversation at ASCO was the potential to combine MDV3100 (androgen receptor blocker) with abiraterone acetate (Zytiga) (androgen synthesis inhibitor), thereby shutting down upstream and downstream activity of the driving receptor in advanced prostate cancer.  The scientific rationale for this appears sound, so it is likely that a combination clinical trial may well be done to test this hypothesis at some point in the future.

MDV3100 has a significant advantage over abiraterone acetate (Zytiga) in that concomitant steroids are not required. Daily steroids have their side effects.  Urologists in particular will be attracted to MDV3100 and its ease of use.

Clinical trials in prostate cancer are ongoing with a multitude of new emerging therapies including TAK-700, Cabozantinib (XL184), radium-223 chloride (Alpharadin), BPX-101, Prostvac-VF, ipilumumab, Custirsen (OGX-011), dasatinib (Sprycel), lenalidomide (Revlimid) and ARN-509 to name but a few.

It is a therapeutic area with a lot going on after very little activity for a decade. The positive interim data for MDV3100 announced today is good news for prostate cancer patients, and we await presentation of the data next year.

Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012, so US approval could be possible later next year.

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!

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

The 102nd Annual meeting of the American Association for Cancer Research (AACR) ended yesterday in Orlando, and it was only the diehards who kept going till the last session of the last day for an update on “Novel Androgen Receptor Antagonists.”

As I mentioned in an earlier post, there is a lot of excitement in the prostate cancer field at the moment with three new therapies approved last year (cabazitaxel, sipuleucel-T, denosumab), and more expected over the next two years (abiraterone acetate, MDV3100, cabozantinib/XL-184).

What I took from the AACR session I attended, is that there are also other products in the pipeline that are worth watching.  Below is a list of some of the products that were mentioned. It’s not intended to be a comprehensive review of the prostate cancer landscape, only my notes and thoughts on some of the new products that the speakers touched upon.

Abiraterone Acetate: The postive phase III trial results were reported last year at ESMO and ASCO GU, and the approval of this drug is currently being considered by the FDA.  Approval is expected shortly, and possibly in time for launch at the forthcoming annual meeting of the American Urological Association (AUA) meeting in Washington, DC.

Abiraterone (brand name Zytiga) inhibits the enzymes (17-alpha hydroxylase and C17, 20 lyase) responsible for adrenal androgen formation.

The phase III results were impressive in very sick patients who were close to the end of their lives in very advanced disease.  Overall survival increased from 10.9 to 14.8 months in the second line chemotherapy setting post docetaxel.  It’s expected that the results will be more dramatic pre-chemotherapy.

Once the FDA approval is obtained, it’s hard to see how oncologists will not consider abiraterone instead of cabazitaxel in the second-line chemotherapy setting.  An easily taken pill with fewer less side effects may be a more convenient option for elderly or frail men with prostate cancer.  Abiraterone’s approval will not be good news for sanofi-aventis.

I also expect we will see significantly off-label usage of abiraterone pre-chemotherapy by urologists as they seek to maintain hormone-sensitivity in their patients after several lines of anti-hormonal therapies.  There is a phase III trial ongoing in this setting that is expected to show promising data by the end of the year.

However, it’s a good strategy to come market as soon as possible to provide wider access to patients in need, and the post-docetaxel second line setting allowed the overall survival benefit to be shown before the pre-chemo data would be available.

However, what I learned at the meeting is that abiraterone acetate may not be the best product in the long term.  Currently it requires the corticosteroid, prednisone, to be given at the same time to attenuate the mineralocorticoid effects.  Questions that were raised in the AACR session about long-term treatment with abiraterone included, “Must a corticosteroid be given concurrently?” and “What about hypertension?”

Other questions remain, such as possible development of resistance to abiraterone. Often the first drug to market is not the best, and it’s possible that second generation new products in the pipeline may be better than abiraterone and delay the time to resistance further.

However, what abiraterone does have is first mover advantage and depending on the pricing strategy adopted by Johnson & Johnson, the ability to capture market share earlier.  It will be interesting to see what happens with this drug, but it’s certainly an exciting time for patients with prostate cancer.

TAK-700: This drug from Takeda/Millennium is a more potent inhibitor of C17α-hydroxylase than abiraterone.  One of the panelists at AACR believed that TAK-700 “may in the long run surplant abiraterone acetate due to less need for mineralocorticoids.” TAK 700 entered phase III clinical trials late last year.

MDV3100:  This drug is being developed by Medivation/Astellas and is also in phase III trials, with data expected by the end of this year or early 2012.  It has a high affinity for the androgen receptor. However, what came across in the AACR presentation by Howard Scher, was his view that the second compound developed by Charles Sawyers, ARN-509 may be better than MDV3100.

ARN-509: This drug from Aragon Pharmaceuticals is in phase I/II clinical trials and is definitely one to watch.  As Dr Scher pointed out, ARN-509 is more potent than MDV3100 and I expect we will see publication of more data on ARN-509 in the near future.

If you are interested in prostate cancer, AACR are offering webcasts and podcasts of scientific sessions this year.  Further information can be found on their website.  AACR have also announced a scientific special session on “Advances in Prostate Cancer Research” from February 6-9 2012.  It’s certainly an interesting and exciting time in this field as new products become available, something that is likely to make a real difference to how this disease is treated.

 

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