Biotech Strategy Blog

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

Posts tagged ‘AZD3514 Prostate Cancer’

AZD3514 is a novel Selective Androgen Receptor Down-Regulating Drug (SARD) that showed early preclinical promise for the treatment of Castration-Resistant Prostate Cancer (CRPC).

However the development of this drug in advanced prostate cancer has been terminated by AstraZeneca according to Dr Aurelius Omlin, a Clinical Research Fellow at The Royal Marsden Hospital who presented clinical data on AZD3514 at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

I previously wrote about the promising preclinical data for AZD3514 presented by Sarah Loddick at the 2012 annual meeting of the American Association for Cancer Research (AACR) and sometimes drugs when they transition to the clinic just don’t live up to their promise.

That’s what happened here, and it reminds us that testing of drugs on human volunteers remains a key part of drug development despite the inherent risks. (See my post on the TLS deaths on the AbbVie/Genentech ABT-199 CLL dose finding trial)

AZD3514 ASCO 2013 PresentationThe results from a first-in-human clinical trial with in men with CRPC were presented by Dr Omlin at ASCO 2013 (abstract 4511). In his oral presentation, he first noted that:

“AZD3514 is a first-in-class, non-steroidal small molecule androgen receptor (AR) down-regulator that inhibits nuclear AR translocation and results in proteasomal AR protein degradation.”

The phase 1 clinical trial to assess safety and tolerability explored doses ranging from 100mg once daily (OD) to 1000mg OD in capsule formulation, and from 1000mg OD to 2000mg taken twice daily (BID) in tablet formulation. A pretty comprehensive range, but……

“Tolerability of AZD3514 was problematic,” said Omlin. “80% of patients had Grade 1-2 Nausea (n=39 out of 49) and 49% Grade 1-2 Vomiting (n=24 out of 49).”  Additionally, grade 1-2 thrombocytopenia was seen in 33% of patients.  There was no dose limiting toxicity reported.

What killed it for AZD3514 was the fact that according to Omlin,

“Nausea and vomiting were characteristic from the very first dose level starting about 30-60 minutes after dosing and lasting for several hours thereafter.”

However, the drug did show activity in CRPC patients with several patients showing PSA declines including one patient with prior abiraterone exposure.  Two patients with soft tissue disease had confirmed responses according to Recist 1.1. There was also evidence of clinical activity from changes in the number of circulating tumor cells.

Industry analyst, David Miller (@BiotechStockRsr) commented on Twitter, while watching the presentation, that he thought it hard to see the drug progressing in development, and he turned out to be correct:

Dr Omlin concluded his presentation by stating that, “the development of this compound by AstraZeneca as a selective androgen receptor down-regulator in mCRPC has been terminated.”

Sometimes promising preclinical data just doesn’t hold up when it moves into human clinical trials. Another AstraZeneca drug with preclinical promise has gone to what Sally Church, PhD (@MaverickNY) refers to as “dog drug heaven.”

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.

2012 Annual meeting of American Association for Cancer Research in Chicago. Photo Credit: Pieter DroppertAs Sally Church, PhD noted on Pharma Strategy Blog, the 2012 annual meeting of the American Association for Cancer Research (AACR), recently held in Chicago, showcased many new cancer products in early development.

Cancer new products have a high attrition rate as they move through the development pipeline, so any promising results seen in early stages of development must be viewed with caution.

Results from laboratory studies using cell lines or trials in animals do not always translate into new drugs that work in man, e.g. they may have an unacceptable toxicity, not target the driver mutation, or adaptive resistance may just lead to the cancer bypassing the blocked pathway.

However, scientific meetings such as AACR do provide a window into the possible new drugs of the future. One prostate cancer new product that caught my attention at AACR 2012 as one to watch is AZD3514.

Sarah Loddick from AstraZeneca gave one of the few oral presentations at AACR on this exciting new compound.  This was the only AACR session I attended where I was able to access wifi. Some of my live-tweets are captured in the Storify below (click here to access this on Storify):

http://storify.com/3nt/aacr-2012-azd3514-in-prostate-cancer

Unfortunately, Sarah Loddick has not (as of time of writing) shared a copy of the AZD3514 prostate cancer poster that she presented later in the meeting, so I’m unable to write more about the preclinical prostate cancer data.

AZD3514 is a novel selective androgen receptor down-regulator (SARD) and has a different mechanism of action to drugs such as enzalutamide (MDV3100) that functionally inhibit AR signaling by binding to the AR & AR splice variants.

Sarah Loddick concluded at the end of her oral presentation that AZD3514:

  • inhibits prostate cancer growth in vitro & in vivo
  • has activity against wild-type and mutated AR
  • has activity in pre-clinical models that represent castration resistant prostate cancer (CRPC)
  • inhibits seminal vesicle growth in rats in the presence of physiological levels of circulating tumor cells.

AZD3514 is in a multi-center phase 1 clinical trial in patients with metastatic CRPC in Europe (NCT01162395) and Japan (NCT01351688). I look forward to seeing the presentation of the results from these trials.

From what I saw at AACR, AZD3514 is a new prostate cancer drug to watch.

Update April 20, 2012

I was delighted to receive an email this morning from Sarah Loddick of AstraZeneca with a copy of the AZD3514 poster that I requested (AACR abstract #3848): “Pre-clinical profile of AZD3514: a small molecule targeting androgen receptor function with a novel mechanism of action and the potential to treat castration resistant prostate cancer.

I am sensitive to the unpublished status of much of the research presented at AACR, but without giving too much away, some of the key messages from this poster are that AZD3514:

  • Binds to the androgen receptor (AR) ligand binding domain & reduces viability of prostate cancer cells in vitro. 
  • Inhibits AR transcriptional activity within 2h of exposure in LNCaP cells, and reduced both PSA & TMPRSS2 mRNA
  • Inhibits AR induced translocation to the nucleus
  • Causes AR down-regulation in prostate cells in vitro
  • Causes AR down-regulation in rat R3327H prostate tumors
  • Has activity in pre-clinical models of CRPC

A drug such as AZD3514 in prostate cancer could potentially be used to overcome resistance to enzalutamide (MDV3100), or alternatively it could be used ahead of enzalutamide if it has the potential to avoid resistance and offer better outcomes. We obviously will have to wait for clinical data to see what it’s true potential is and the data from AACR, while promising, is still only preclinical.

The prostate cancer market is a busy one and companies with AR targeted new products in development will have to offer drugs that are superior to enzalutamide if they wish to have lasting commercial success.

Update June 6, 2013: AstraZeneca terminates development of AZD3514 in Advanced Prostate Cancer

At ASCO 2013 it was announced that the development of AZD3514 in advanced prostate cancer has been terminated. You can read more about what happened in the first-in-human clinical trial in my AZD3514 blog post from ASCO 2013.

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