Biotech Strategy Blog

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

Posts tagged ‘Selective Androgen Receptor Down Regulator’

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.”

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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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