Biotech Strategy Blog

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

Posts tagged ‘radium-223’

If you had told me several weeks ago that we would write over 28 posts on #AACR16 and become very interested in mouse models, then most likely I would have laughed out loud and told you not to be so ridiculous!  Here we are with the 29th one and, another, on the bromododomain landscape yet to go.  Such was the vast richness of data and concepts being discussed or presented in New Orleans for those who chose to look.

Today, I want to start the segue from AACR to ASCO coverage.

Nawlins MGRAS FIOne way to do that is through the second part of the Gems from the Post Hall series. This latest one looks at a range of intriguing new targeted therapies and novel targets that are emerging, including a pharma company with a particularly interesting early pipeline.

Several pharma companies presented interesting data on their very early compounds currently in development, plus I noticed a trend for a new class of targeted therapies to emerge, MNK inhibitors, which we will also discuss.

Companies mentioned: Bayer, Orion Pharma, Lilly, Novartis, Pfizer, Agios.

Targets mentioned: PI3K, CDK, Akt, TWEAK, FGFR, BUB1, IDH1, SMYD2, MNK

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The recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics international conference in San Francisco was an informative meeting.

What I particularly liked was the strategic overview that took place in many of the plenary sessions.

As an example, Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research/The Royal Marsden in London highlighted the potential drug development targets based on prostate cancer biology:

  • Androgen Receptor (AR)
  • Heat Shock Proteins (Hsp)
  • Signaling: HER3, MET, IGF-1R, CCL2, IL-6, Src
  • PI3K/AKT/TOR signaling
  • PARP and BRCAness
  • Estrogen receptor (ER)
  • c-MYC & CHK1

His presentation discussed the possible therapeutic approaches, and complexity involved in developing novel targeted therapies for prostate cancer.

This is something that I expect we will hear more of at the AACR special conference on Advances in Prostate Cancer Research early next year.

In particular, de Bono discussed drug development strategies to target androgen receptor signaling, and some of the future challenges including:

  • Proving to the regulatory authorities that circulating tumor cell (CTC) count falls are a robust immediate endpoint of overall survival
  • Developing improved imaging for bone metastases

As a side note, there were several posters for cabozantinib (XL184) at the meeting (available on the Exelixis website), including preliminary research on computer-aided quantitative bone scan assessment.

However, as de Bono mentioned in his presentation, “diffusion weighted MRI shows hot spots not detected by bone scans.”

2010 and 2011 were good years for prostate cancer drugs, and with new approvals for MDV3100 and radium-223 (Alpharadin) expected, 2012 is set to be another “grand cru” year, to paraphase Bertrand Tombal.

If you were not able to make it to San Francisco for the Molecular Targets and Cancer Therapeutics conference, webcasts of many sessions will be available on the AACR site.


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.

In the video interview, Dr Parker talks about why he believes combining radium-223 with abiraterone acetate (Zytiga) makes sense.

He also talks about some of the challenges that radium-223 still faces, such as how to monitor treatment and work out the optimal dose.  It is hard to believe that Algeta/Bayer would undertake a phase 3 registration study of a novel bone targeted agent without any bone imaging in the protocol!

As Cora Sternberg mentioned in the educational session at EMCC 2011, in advanced prostate cancer, “80% of the disease is in the bone.radium-223 is an exciting radiopharmaceutical that is likely to be “practice changing” once approved.

That’s not to say there are not going to be challenges and issues with its commercialization.  Algeta/Bayer have a lot of work to do now that it is clearly on fast track for FDA approval next year.

Dr Parker also mentions in his interview that radium-223 is a weak alpha emitter and the radiation can be blocked by paper or glass. It therefore requires no special facilities, such as lead lined rooms, for its administration, unlike beta emitters.  The latter have been challenging commercially in the past for this reason.

However, it does require a radiopharmaceutical license, which means that community based oncologists and urologists in the United States will most likely have to refer patients to receive their injection at an approved facility where there is a nuclear medicine/radiology department or equivalent expertise.  In Europe, this is less of an issue given most cancer patients are treated in outpatient clinics associated with hospitals, whereas in the US, the majority of patients are seen in the community setting.

Despite that, it is hard to believe that radium-223 (Alpharadin) will not have a major impact on the advanced prostate cancer market if it can be commercially supplied without difficulty and the details are worked out on how to use it optimally and monitor progress. I am sure we will hear more on these issues at cancer conferences next year.

Looking at the other indications for bone targeted agents such as denosumab and zoledronic acid, radium-223 or a similar radiopharmaceutical could offer potential benefits in other tumor types such as breast cancer, were there are also skeletal related events (SRE’s) associated with treatment.

The video interview I did with Dr Chris Parker is well worth watching, and I am grateful to him for taking the time out of his busy schedule at the recent Cancer Congress in Stockholm. Since this is a first for Biotech Strategy Blog, do let me know if this is something you’d like to see more of moving forwards.

Challenges & opportunities for radium-223 (Alpharadin) in advanced prostate cancer – an interview with Dr Chris Parker 

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The phase 3 ALSYMPCA prostate cancer trial results for radium-223 chloride (Alpharadin) were presented at the recent ECCO ESMO ESTRO 2011 European Multidisciplinary Cancer Congress in Stockholm. This was the highlight of the meeting for me.

There was also exciting data in Breast Cancer (BOLERO-2) that you can read more about on Pharma Strategy Blog.

Alpharadin from Norwegian company, Algeta, is the first new treatment for advanced prostate cancer that not only prolongs overall survival (OS) but delays time to first skeletal related event (SRE) in metastatic castration resistant prostate cancer patients.

Leading physicians at the meeting believe that it will be “practice changing.

The Alpharadin data may also have an impact on other bone targeted agents in development for prostate cancer such as cabozantinib (XL184).

Sally Church, PhD (who writes the Pharma Strategy Blog) is quoted by “The Street” as saying that “Alpharadin raises the bar for Exelixis. They have to produce overall survival data now.” Overall Survival (OS) remains the primary regulatory endpoint in prostate cancer drug development.

Prostate cancer experts Johann de Bono and Cora Sternberg also mentioned, in presentations at the Stockholm meeting, that in the future it will be increasingly difficult to do placebo controlled trials in Prostate Cancer given the new treatment options available.

Alpharadin is not yet approved in Europe or the USA, but is on fast track for approval by the FDA in 2012.

Chris Parker (Royal Marsden Hospital) presented the Alpharadin ALSYMPCA trial data as a late breaking abstract in the presidential session at ECCO ESMO 2011. He also conducted a media briefing that I was fortunate to video.

You can watch this below. In it he explains how radium-223 choloride works and why he (and others) believe this may change the standard of care for prostate cancer patients with bone metastases. It is well worth watching!


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Radium-223 (Alpharadin) will be “Practice Changing” is how Michael Baumann, President of the European CanCer Organisation (ECCO) and Jean-Charles Soria, Co-Scientific chair of the 2011 Stockholm Multidisciplinary Cancer Congress described the prostate cancer clinical trial data to be presented in the Presidential (plenary) session on Saturday September 24, 2011.

Alpharadin is the first bone targeted therapy to show an overall survival (OS) advantage in metastatic castration-resistant prostate cancer (mCRPC). To date, none of the other therapies targeting bone in prostate cancer such as zoledronic acid (Zometa), denosumab (Xgeva) or cabozantinib (XL184) have shown any overall survival benefit.

The Alphardin data from the phase 3 ALSYMPCA trial that will be presented in Stockholm shows an increase in overall survival of 2.8 months compared to placebo (median OS of 14 months with Alpharadin versus median OS of 11.2 months with placebo, p=0.00185, HR=0.695).

What is big news is that Alpharadin also significantly prolongs time to first skeletal related event (p=0.00046; HR=0.610). This is tremendous news for prostate cancer patients given the number that experience bone metastases.

It is not, however, good news for Amgen and denosumab (Xgeva). Amgen have tried to associate the improvement in symptoms and decline in skeletal related events with survival, but have failed to obtain any overall survival data (OS). This is something that Alphardin achieves as well as a significant reduction in time to first skeletal related event (SRE).

What Alpharadin has effectively shown is that by nuking bone metastases using a weak alpha emitting radium-223, overall survival (OS) can be prolonged in a way that targeting rank ligand does not. This is ground breaking news and the 2011 Stockholm Multidisciplinary Congress have rightly recognized the importance of this data with a plenary session. For further information on how Alpharadin works – see my previous blog post about the ASCO 2011 phase 2 data.

At the press briefing late friday afternoon in Stockholm, Dr Chris Parker of the Royal Marsden Hospital and PI of the ALSYMPCA study said that “Radium-223, a novel alpha-pharmaceutical, may provide a new standard of care for the treatment of  CRPC patients with bone metastases.”

There is no doubt in my mind that it will lead to a new standard of care. What’s more as Dr Parker speculated in the press briefing, there is no reason why Alphardin could not be combined with androgen receptor antagonists such as the recently approved abiraterone acetate (Zytiga).

Both are well tolerated and operate by different mechanisms of action.  It’s hard not to believe that the overall survival of CRPC patients will be increased by such a combination.

When approved, Alpharadin and any possible combination with Zytiga, may further delay the use of sanofi-aventis’ cabazitaxel (Jevtana) in the post-doctaxel CRPC setting. It may also potentially have an impact on the use of sipuleucel-T (Provenge) in the asymptomatic population.

The Alpharadin phase 3 trial results is exciting news from the 2011 Stockholm Multidisciplinary Cancer Congress. I will be writing more after Dr Parker presents the data in the Presidential session later today.

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Earlier this week Bayer & Algeta announced that Alpharadin™ (radium-223 chloride) had received Fast Track designation from the FDA for the treatment of castration-resistant prostate cancer (CRPC).

Bayer signed an agreement with Norwegian based Algeta in 2009 for the global commercial rights to Alpharadin™, with Algeta retaining a 50/50 co-promotion and profit-sharing in the United States.

According to the Algeta August 23, 2011 press release, in light of the FDA fast track designation they plan on filing for United States approval in mid-2012, ahead of previous expectations.

At the ASCO annual meeting in Chicago this year, phase II clinical trial data for Alpharadin™ was presented during the poster session (Abstract #4620).  You can obtain a copy of the poster here.

ASCO Alpharadin™ Phase 2 Data showed increase in Overall Survival

What impressed me when I saw the poster and talked to Gillies O’Brien-Tear, the Chief Medical Officer for Algeta, was the increase in overall survival (OS) seen. In the phase 2 study presented, Alpharadin™ improved OS by 4.5 months versus placebo when added to the standard of care in patients with CRPC and bone metastases.

To me this stands out from other drugs that are targeting bone metastases in CRPC, such as cabozantinib (XL184) and denosumab (Xgeva®), where to my knowledge no overall survival benefits have yet been seen.

Despite the lack of OS benefit, Amgen announced earlier this week on Aug 22nd, they had made a supplemental BLA application for denosumab to expand the indication to include the prevention of bone metastases in CRPC. The PDUFA date is April 12, 2012.

Will Xgeva® and Alpharadin™ be viewed as potential competitors or used synergistically? It will be interesting to see any data that shows the impact of Alpharadin™ on bone pain and quality of life, and how physicians view the new treatment options that may be available to them.

How does Radium-223 chloride act? 

It is a calcium mimetic that is taken up by bone, where the radium then emits alpha-particles that act on the prostate cancer bone metastases.  The radiation is only short range (2-10 cell diameters) which limits its toxicity to healthy tissue and results in localized and focused radiation that kills metastatic cancer cells in the bone.

The day after the phase 2 results were presented at ASCO, Algeta and Bayer announced on June 6, positive data from the interim analysis of the phase 3 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer patients) trial.

This study began in June 2008, with enrollment of 922 patients completed in January 2011. According to the June 6 press release, the interim analysis of the ALSYMPCA trial showed a statistically significant increase in overall survival in CRPC patients receiving Alpharadin™ compared to placebo.

Median overall survival was 14.0 months for Alpharadin™ and 11.2 months for placebo (two-sided p-value = 0.0022, HR = 0.699)

As a result of the interim analysis, the independent data monitoring committee recommended that the trial be stopped and patients on the placebo arm offered treatment with Alpharadin™. Dr Chris Parker, from the Royal Marsden Hospital, and Principal Investigator of ALSYMPCA, said:  

“Based on the observed survival benefit and its safety profile, Alpharadin may become an important treatment for patients with bone metastases from advanced prostate cancer.”

At the forthcoming European Multidisciplinary Cancer Congress in Stockholm (co-sponsored by ECCO, ESMO and ESTRO), the phase III Alpharadin data for the ALSYMPCA trial will be presented as a late breaking abstract on September 24, 2011 in the Presidential Session.

The abstracts for the meeting are not yet available, but in the light of the FDA Fast Track designation earlier this week, and the fact the ALSYMPCA trial results will be presented in a plenary session at Stockholm, positive data is expected.

The prostate cancer market is certainly heating up with the approval earlier this year of Zytiga™ (abiraterone acetate) and several products in late stage development such as Alpharadin™, MDV3100, TAK-700 and custirsen (OGX-011). It’s good news for patients that new treatment options may be available before too long.  As to how these new therapies are used, sequenced and combined, that is set to be the topic of conversation at medical and scientific meetings over the coming year.

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