Biotech Strategy Blog

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

About Pieter Droppert

Here are my most recent posts

Posts by Pieter Droppert

ASCO 2013 CLL Runners and Riders in Race to Market #ASCO13

THE data of the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) that starts later this week in Chicago is expected to be the early clinical trial results for new breakthrough immunotherapies that target PD-1/PD-L1.

However, I’m also excited about the data being presented for the treatment of Chronic Lymphocytic Leukemia (CLL), a disease that kills 75,000 people a year around the world. ASCO typically does not have a strong focus on hematology and blood cancers, so it’s a reflection of the clinical significance of the data that it’s a hot topic at the meeting.

Several companies are in the race to bring promising new CLL drugs to market, and have presentations in Chicago.

Earlier this year, the FDA gave it’s new Breakthrough Designation to two CLL new products: ibrutinib, a bruton’s tyrosine kinase inhibitor from Pharmacyclics and obinutuzumab, an anti-CD20 monoclonal antibody from Roche Glycart. The breakthrough therapy designation recognizes the potential of these drugs to change the standard of care in CLL and meet unmet medical needs.

In many ways the changing CLL landscape reminds me of where prostate cancer was a few years ago just before new treatments such as enzalutamide and abiraterone came to market.

If you haven’t already done so I encourage you to watch the ASCO 2013 preview video from Sally Church (@MaverickNY) in which she highlights several of the key CLL oral presentations and posters. Update Sept 18: this video is now available on the Premium Content Video page.

A few of the CLL new products I’ll be looking out for at ASCO 2013 include:

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

This content is restricted to subscribers

AACR 2013 Posters offer Insights into Biotech Drug Development

In my final post from the 2013 annual meeting of the American Association for Cancer Research (AACR), I wanted to share some more reflections from my time in the poster sessions. It’s certainly not all mice, and test tubes, and there were some interesting data from biotechnology companies to consider.

Sometimes the data presented is completely new, other times if you are following a product or company you can see the next stage of development and track progress. AACR posters are often not available if you don’t attend the meeting.

Additionally companies use AACR to showcase potential early licensing opportunities and new targets, so like Bitcoins a few nuggets can be mined from the meeting.  Here are a few examples of what the AACR poster sessions had to offer from a biotech perspective.

Gilead $GILD – Following a new combination

At the 2012 American Society of Hematology (ASH) annual meeting in Atlanta last year, Russell Burke and colleagues from the Knight Cancer Institute at OHSU (Brian Druker’s lab) presented a poster (abstract 3876) on the rational for Combining idelalisib (GS-1101/CAL-101), a PI3 kinase delta (PI3Kδ) inhibitor and a novel highly selective Spleen tyrosine kinase (Syk) inhibitor, GS-9973. In their abstract they noted that,

“Simultaneous inhibition of multiple pathways downstream of the BCR [B-cell receptor] has the potential to result in a synergistic response that may overcome the resistance observed with single compound use” 

Furthermore, they also demonstrated that,

“both PI3Kδ and Syk inhibition reduces CLL survival” and that “combination therapy targeting both PI3Kd and Syk may provide a novel treatment approach, especially in patients with poor risk disease that may not respond optimally to single agents.”

This year at the AACR annual meeting, a Gilead poster (abstract  26) evaluated the safety, pharmacokinetics and pharmacodynamics of this combination in female healthy subjects.  The poster concluded:

  • Co-administration of GS-9973 with idelalisib displayed markedly higher PD effect vs. either agent alone.
  • Overall, GS-9973 and idelalisib were well tolerated when administered in combination or alone.
  • Phase 2 studies in B cell hematologic malignancies evaluating GS-9973 + idelalisib are ongoing.

We will most likely have to wait to ASH meeting later this year in New Orleans to see what the clinical benefit of this combination is, but you can see how you can follow progress from a poster at ASH, to a poster at AACR and then a phase II or III clinical trial presentation at ASH or ASCO in the future.

Ariad $ARIA – a new potential target for ponatinib?

Ponatinib (Iclusig) is a multi-targeted tyrosine kinase inhibitor (TKI) of several targets including Bcr-Abl, FGFR, ALK and RET.  Several posters were presented at AACR last week.  In one that caught my attention (abstract 2084), Ariad researchers showed it is a highly potent inhibitor of activated variants of RET Kinase, which is often dysregulated in medullary thyroid cancer (MTC) and non-small cell lung cancer (NSCLC).

Vandetanib ($AZN) and cabozantinib ($EXEL) are other multi-kinase inhibitors that received FDA approval in the last year or two for MTC, albeit in different lines of therapy, so the activity of other TKI’s in MTC should not come as a surprise.

The Ariad poster demonstrated the preclinical activity of ponatinib over other TKI’s in variants of RET in MTC and NSCLC.  The poster concluded:

“These results provide strong support for the clinical evaluation of ponatinib in patients with RET-driven cancers.”

From a scientific rational the above statement makes sense, but from a commercial perspective it’s more questionable if this were the lead indication.  However, it could make strategic sense to add on small niche indications for a compound that is generating its primary revenue elsewhere.

The challenge is that the medullary thyroid cancer market is not large especially in the relapse setting, as Exelisis have found, plus the tumour is a slow growing one.  While NSCLC sounds promising, the number of NSCLC patients with RET is small (~1%).

This means it will most likely require the screening hundreds of patients to find one patient with RET into a clinical trial, assuming they are willing and meet the inclusion criteria.  This is likely to be an expensive and time-consuming process, so the commercial rational will need to be carefully considered.

BioMarin $BMRN – a prostate cancer licensing opportunity or a “dead donkey”?

Companies also use posters at AACR to showcase potential licensing opportunities and one example I came across was BioMarin’s poster (abstract 2049) for BMN860 a novel CYP17 inhibitor.  Based on some limited preclinical data that showed BMN860 to be more potent than abiraterone acetate (Zytiga), the company are seeking to license out their compound.

Interestingly, the BioMarin poster showed no data comparing BMN860 to other second-generation CYP17 inhibitors such as TAK-700 (orteronel), and the presenter admitted they had no plans to do further preclinical work on it themselves.

Given the costs of bringing a new prostate cancer drug to market and the uncertainty of the market opportunity in the face of generic abiraterone and competition from other CYP17 inhibitors far head in development, it’s hard to see the commercial opportunity for BMN860.

If you are a Pharma BDL professional looking to in-license a novel CYP17 inhibitor, then BioMarin do have one on offer.  However, for those used to British vernacular, it struck me as a “dead donkey” being too little too late to really capitalise on the market opportunity.

This is the end of my coverage of AACR 2013.  I am looking forward to the AACR-EORTC-NCI Molecular Targets and Cancer Therapeutics meeting in Boston later this year.  Given the focus of Boston biotech on cancer drug development, I expect this to be a high quality meeting.

If you are interested in more coverage from AACR 2013, I encourage you to check out Pharma Strategy Blog, which will have some in-depth pieces in the coming days.

AACR 2013 posters show potential new Pfizer cancer drugs

My overriding impression of large cap Pharma R&D from the 2013 annual meeting of the American Association for Cancer Research (AACR) was that Novartis and Genentech remain the front-runners in cancer drug development, with Pfizer very much up and coming.

AstraZeneca, however, reported data for several drugs that have or soon will be going to “dog drug heaven.”  If AstraZeneca receives an “A” for effort but a “C” for execution, then Bristol Myers Squibb (BMS) was in my view a “D” at AACR with little presence.

What interests me at a meeting such as AACR is trying to spot some of the early trends in the 6,000+ posters, and identify new products in development that are worth watching. I was generally impressed by the quality of the posters on Pfizer cancer drugs.

One of the Pfizer compounds that attracted my attention in the AACR posters (before news of its FDA Breakthrough Therapy designation in breast cancer) was palbociclib (PD-0332991), an inhibitor of cyclin dependent kinases (CDK) 4 and 6.  Karen Sheppard from the Peter MacCallum Center Centre in Melbourne, Australia (abstract #3416) presented a poster on genomic alterations of the CDK-4 pathway in melanoma and evaluation of the CDK4 inhibitor PD-0332991. According to Sheppard:

“Genomic alterations in the CDK4 pathway are frequent and are associated with worse survival”

Sheppard’s preclinical research supports the evaluation of CDK4 inhibitors in melanoma, so it will be interesting to see if clinical data supports the development of palbociclib in this indication. In the meantime palbociclib appears to be a winner in breast cancer.

Another Pfizer compound to watch is dacomitinib (PF-00299804) a second-generation inhibitor of the pan-epidermal growth factor receptor (EGFR) family of tyrosine kinases (ErbB family).  Previously, Pfizer had another pan ErbB inhibitor in development (neratinib) from their merger with Wyeth, but licensed it out to Puma Biotech and focused their development efforts on dacomitinib instead. That may well turn out to be a smart R&D decision.

A poster presented by Brett Broussard from the University of Alabama at Birmingham (abstract #2446) showed the effects of dacominitib on pancreatic ductal adeoncarcinoma (PDAC) and cancer-associated fibroblasts.  In his abstract, Broussard notes a possible reason why anti-EGFR therapies may have had little effect in PDAC:

“Indirect activation of Epidermal Growth Factor Receptor (EGFR) signaling through ErbB3 heterodimerization and stromal ligand production has been shown to act as an escape mechanism for EGFR directed therapies.”

Broussard’s research showed that dacomitinib targets multiple ErbB receptors, including ErbB3, and was an effective inhibitor of pancreatic ductal adenocarcinoma (PDAC) cell proliferation and tumor progression in vitro and in vivo.

He told me that Pfizer are expected to start phase 2 trials in pancreatic cancer with this compound later this year. There remains an unmet medical need in pancreatic cancer, so while it is too early to evaluate dacomitinib’s potential as a new treatment option, it is good to see translational research being done and new compounds entering the clinic.

Overall, my take home from AACR was that Genentech and Novartis remain the powerhouses of cancer drug development. I was impressed by the number and quality of the posters from Pfizer Oncology R&D and left the AACR poster hall thinking that Pfizer may well have some new cancer products in development that are well worth watching.

AACR 2013 Cancer Scientists fail to embrace Social Media

I will be writing in the next few days about some of the Pharma and Biotech winners and losers at the 2013 annual meeting of the American Association for Cancer Research (AACR) that just finished in Washington D.C.

However, what was noticeable to me was the disappointing lack of Twitter conversation from the 18,000 cancer scientists at the meeting.

Part of this may reflect the culture of AACR, where it is forbidden to take photographs, record or transmit information. “Thou shalt not tweet” may be thought of as a logical extension of this.  It’s certainly not easy to distil complex science into 140 characters.

However, some people did tweet from the meeting and a quick look at the Symplur analytics for the #AACR meeting hashtag, shows the following:

  1. Highest number of tweets came from Dr Naoto Ueno (@teamoncology), a breast cancer medical oncologist from MD Anderson Cancer Center in Houston, who was not even at the meeting, but clearly would have liked to have been.
  2. The second highest number of tweets came from Dr Philippe Aftimos (@aftimosp), a hematologist/oncologist from Institut Jules Bordet in Brussels.  Philippe wins my award for the most outstanding social media contribution from AACR 2013.  He shared insights throughout the meeting in English; I could not do that in a foreign language.  Outstanding!
  3. Also on the AACR twitter leader board was patient advocate/cancer survivor AnneMarie Ciccarella (@chemobrainfog) who presented a poster at the meeting on the power of social media for breast cancer advocacy (#BCSM). Blog readers may recall AnneMarie and other patient advocates did a phenomenal job of live tweeting #SABCS last year.

There were many others too numerous to mention who live-tweeted from AACR this year, and my post is not intended to showcase some people over others, but offer my impression that cancer scientists have not embraced social media in the way that cancer doctors and patient advocates have at clinical meetings such as ASH and ASCO.

There was no public display of Tweets or a conference Twitter Board, as there is now at leading medical meetings organized by ECCO, ESMO, AUA or ASH where delegates can watch meeting tweets in real time in the common areas.  A heavily tweeted session will attract new attendees while it is ongoing.

At these meetings, I have often seen people go to sessions based on how interesting the tweets are.  I follow the “law of two feet” that says if the tweets are more interesting in another session, time to get up and move there.  It’s funny to watch others do the same thing and converge on a room at the same time.

While watching the Twitter board at ECCO or ESMO, I have been asked how to sign up for Twitter in order to follow the conversation (and hopefully be part of it). There was no twitter board at AACR to encourage such behaviour.

Those attending the ASCO annual meeting, will know the unofficial Tweet-up attracts a large party.  The AACR unofficial tweetup had just 5, and did not as far as I am aware even merit a RT from @AACR!

To highlight the enormous gap between cancer researchers and cancer physicians when it comes to social media, one only has to look at the annual meetings of the American Society of Clinical Oncology (ASCO) and American Urological Association (AUA).

In recent years both ASCO and AUA have offered a workshop on how oncologists or surgeons can use social media in their practice.  It is increasingly important as a tool for sharing and communicating information.  There was no workshop at AACR on how cancer researchers could use social media to collaborate or share their research.

Why is this important you may ask?  The reason that I am taking the time to write this is that if cancer researchers want the public to support the funding of research, then they need to communicate the value of what they do.

Last year, leading cancer researchers, including a past president of AACR and several Professors of Medicine, tried to obtain 25,000 signatures for a White House Petition in support of maintaining the budget for the National Institutes of Health (NIH) given the important role it plays in funding cancer research.  AACR decided not to support this initiative and the petition sadly fell short by a few hundred signatures of the number needed to force an official response.

This year during their annual meeting, AACR organized a Rally for Medical Research (#RallyMedRes) to protest against the forced NIH funding cuts that were implemented as a result of the failure of the United States Congress to agree a budget deficit program.

An expensively organized rally with a stage that resembled a rock concert preached to the converted on the need to spread the word on the value of medical research. Whether it will have any effect in reversing NIH cuts remains to be seen.  I fear it was too little too late and an attempt to metaphorically close the stable door after the horse has already bolted.

If cancer researchers want the public to fund their research, in my view one of the things they need to do is communicate the value of the scientific research they conduct.  One way to do this is to embrace social media more, particularly at meetings such as AACR, where there is the opportunity to share information with a worldwide audience.

Next year at AACR, I hope we will see a Twitter board at the entrance to the meeting and more cancer researchers encouraged to participate in the conversation and share their thoughts and experiences.  AACR could learn a lot from medical oncologists and patient advocates on how to embrace the true power of social media.

 

4 Comments

AACR 2013 GDC-0032 a next generation PI3K Inhibitor shows early promise in breast cancer

Genentech’s next generation PI3-kinase inhibitor, GDC-0032, was the topic of two presentations yesterday at the 2013 annual meeting of the American Association for Cancer Research (AACR) taking place in Washington D.C.

Genentech have put substantial resources into developing new agents that target different elements of the PI3K pathway.  These include: GDC-0941, GDC-0980, GDC-0084, GDC-0349, GDC-0068.  At this year’s AACR, data on their latest compound, GDC-0032, was presented. This agent is a selective inhibitor of PI3K alpha, delta and gamma but spares inhibition of the PI3K-beta isoform.

In the New Drugs on the Horizon session, Alan Olivero from Genentech gave a fascinating talk (if you are a medicinal chemist) on how the chemical structure of GDC-0032 was rationally developed. He described how a slight change in structure can lead to a very different selectivity profile.

One way in which GDC-0032 is novel, is that it spares the beta-isoform of PI3K, which Genentech hypothesize may reduce some of the undesired side effects such as effects on metabolism, previously seen with pan PI3K inhibitors such as GDC-0941.

Olivero noted that GDC-0032 has greater maximal efficacy and more potency than GDC-0941 in PI3K alpha mutant xenograft tumors as compared to wild-type ones.

The results of a first-in-human phase 1a dose escalation study for GDC-0032 were presented at AACR 2013 in yesterday’s Clinical Trial Symposium (Abstract LB-64).

Dejan Juric MD (Massachusetts General Hospital) presented promising early clinical data for GDC-0032 in PI3KCA mutant cancers, especially breast cancer.

The results showed that in PI3KCA mutant breast cancer there were 4 cPR (RECIST -30 to -70%) and 2 SD out of 6 patients, all of whom had measurable disease with pre-treatment.  

One confirmed partial response in PI3KCA mutant breast cancer took place after 11 lines of prior therapy in a 74 year old woman with HER2- breast cancer, who subsequently became triple negative.  Another patient with a confirmed partial response had HER2+ ER+ metastatic breast cancer.

While this early data is promising, further clinical trials are needed to validate it.  Dr Juric concluded his presentation by noting that,

“GDC-0032 is being further explored as a single-agent in solid tumors and in combination with endocrine therapies in breast cancer including letrozole and fulvestrant.”

If you are interested in GDC-0032, then other presentations at AACR this week to watch out for are:

Abstract 2382 (Tuesday Apr 9, 8-12 am Poster Section 2, Board 2) Development of predictive biomarker gene expression signatures that associates with drug sensitivity and kinase activation in breast cancer.

Abstract 4470 (Tuesday Apr 9, 1-5 pm Poster Section 41, Board 28) Mechanisms of acquired resistance to the PI3K inhibitors in colorectal cancer cell lines.

AACR 2013 DMUC5754A is a novel agent for Ovarian Cancer

The cherry blossoms are finally blooming in Washington DC for the 2013 annual meeting of the American Association for Cancer Research (AACR).

With AACR in DC this year, the following traditional Japanese haiku published on the National Park Service website struck me as appropriate for cancer researchers and survivors to reflect on:

Yo no naka wa, Mikka minu ma ni, Sakura kana

“Life is short, like the three day glory of the cherry blossoms.”

Yesterday at AACR was predominantly an educational day, but several studies were highlighted to the assembled media.  One of the late-breaking clinical trials that caught my attention was the preliminary phase 1 data on Genentech’s novel new agent DMUC5754A.

LB-290 Targeting MUC16 with the Antibody-Drug Conjugate DMUC5754A in patients with platinum-resistant ovarian cancer.  This data will be presented by Joyce Liu, MD, MPH from Dana-Farber Cancer Institute in the Clinical Trials Symposium on Tuesday, Apr 9 at 4.00 pm.

Dana-Farber issued a press release yesterday  – here’s the link. The picture of Dr Liu is from her Dana-Farber profile.

Ovarian cancer causes more deaths in women than any other cancer of the reproductive organs, with an estimated 20,000 women diagnosed with this cancer each year.  The majority of women are treated with traditional platinum based chemotherapies, and most of these relapse and develop drug-resistant disease.  This makes the development a new novel agent such as DMUC5754A that will treat platinum-resistant ovarian cancer a major potential breakthrough.

In an AACR media release, Dr Liu commented on how the drug works:

“This drug consists of an antibody and a potent toxin joined by a cleavable linker. The antibody identifies a protein, MUC16, which is highly expressed in ovarian cancers, and targets the toxin to kill the cancer cells.”

Liu went on to note that, “Unlike other cancer treatments, the antibody-drug conjugate releases the toxin with relative selectivity to the MUC16-positive cancer cells.  This allows delivery of drugs that would otherwise be too toxic for treatment.”

According to Liu, “If the activity of this drug is confirmed in additional trials, this will represent a novel type of therapy for ovarian cancer, with effectiveness in platinum-resistant ovarian cancer, which is the hardest type of ovarian cancer to treat.”

Genentech are particularly good at sharing early data at AACR, and based on the promising responses in MUC16 IHC 2/3+ patients, this new ADC compound is likely to progress to phase 2 – a compound to watch out for in the future.

What is the potential for galeterone in advanced prostate cancer?

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.

This content is restricted to subscribers

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.

Inhibitors of Apoptosis Target one of the Hallmarks of Cancer

The forthcoming annual meeting of the American Association for Cancer Research (AACR) in Washington DC is a must attend for anyone interested in cancer research and new cancer drugs in development.

 

Many readers will know that one of the hallmarks of cancer is the evasion of apoptosis or cell death.  Drugs in development that act as an inhibitor of apoptosis proteins (IAP) are starting to show promise against this target.

Novartis IAP Inhibitor LCL161

At the 2012 San Antonio Breast Cancer Symposium (SABCS), a phase 1 trial with LCL161, a novel-IAP antagonist from Novartis, showed promising responses in triple negative breast cancer when given in combination with paclitaxel chemotherapy. The SABCS data showed that in the 52 patients treated with LCL161, a complete response was observed in 1 patient, and a partial response was seen in 15 patients.

Caution must obviously be expressed at extrapolating from early-stage data in a non-randomized trial.

Several other companies have IAP antagonists in early development, including Curis (CUDC-427).

  • Curis announced in November they had licensed GDC-0917 from Genentech. I am hopeful there will be new data on CUDC-427 at the AACR annual meeting.  At the recent Citi Global Healthcare Conference on Feb 25, 2013, Curis stated they could start phase 2 development of CUDC-427 by mid-2013 and were looking at it in combination with capecitabine (Xeloda) in breast cancer as well as monotherapy.
  • Ascenta Therapeutics licensed their IAP inhibitor AT-406 to Debiopharm in August 2011.

Nature Reviews Drug Discovery has a review article on “Targeting IAP proteins for therapeutic intervention in cancer” for those interested in learning more about some of the compounds in preclinical and clinical development, and the scientific rationale behind this target.

IAP inhibitors are an interesting class of compounds to watch as they move forward in clinical development.

IAP Inhibitors may promote Bone Metastasis

Research published in the February 2013 issue of the AACR journal Cancer Discovery shows that in mouse experiments a side-effect of IAP inhibitors is promotion of osteoclast activity.  Whether these preclinical results in animal models translate to man remains to be seen, but the research by Chang Yang and colleagues from the Washington University School of Medicine in St Louis, MO is worth noting.

 

In simple terms, osteoclasts are the cells that remove bone as part of a dynamic equilibrium with osteoblasts, the cells that produce and lay down new bone.

An increase in osteoclasts caused by IAP antagonists activating alternative NF-κB signalling through NF-κB-inducing kinase (NIK) results in the disruption of normal bone metabolism.  In mouse experiments, this led to over-degradation of bone and osteoporosis (pathological bone loss), as well as providing a microenvironment that favors tumor expansion and metastasis.

Osteoclasts embedded in the bone matrix also release tumor growth factors, so if there are more osteoclasts then more growth factors are produced resulting in the creation of a more favourable microenvironment for bone metastasis.

In addition to showing the effects of IAP antagonists on the bone microenvironment, Chang Yang and colleagues demonstrated that drugs that prevent bone resorption such as zoledronic acid were able to decrease the incidence and severity of bone metastasis.

Many breast, cancer, prostate and lung cancer patients end up with bone metastases, which is why bone targeted agents have an important role to play in the treatment of the disease.

They conclude in their Cancer Discovery research paper that “future clinical trials of IAP antagonist-based therapy may require detailed examination of this potential for enhanced bone metastasis and osteoporosis, as well as possible combination with antiresorptive agents.”  

The potential implications of this research is that bisphosphonates such as zoledronic acid and RANKL-targeted compounds, such as denosumab, may need to be used in conjunction with IAP antagonist treatment.

This is an important finding. If the animal results translate to humans, then concomitant administration of a bone target agent may be necessary.  Future clinical trials of IAP antagonists could end up with more complex and expensive study designs if bone side effects needs to be monitored and addressed.

I look forward to learning more about IAP antagonists at the AACR meeting in April, and to following progress in this novel class of new drugs that seek to address one of the hallmarks of cancer.

ResearchBlogging.orgYang, C., Davis, J., Zeng, R., Vora, P., Su, X., Collins, L., Vangveravong, S., Mach, R., Piwnica-Worms, D., Weilbaecher, K., Faccio, R., & Veis Novack, D. (2012). Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation Cancer Discovery, 3 (2), 212-223 DOI: 10.1158/2159-8290.CD-12-0271

2 Comments

ABT-199 clinical trials suspended after patient death $ABBV

Following a death due to tumor lysis syndrome, AbbVie ($ABBV) have suspended the ABT-199 clinical trial program.  ABT-199 is a promising new drug in development for chronic lymphocytic leukemia (CLL) that was about to enter phase 3 drug development by the company.

The company has issued no press release, but the clinicaltrials.gov web site shows that that clinical trials are suspended, information confirmed at the BIO CEO 2013 meeting in New York earlier this week. Here’s a quick snapshot taken on Feb 14, 2013 of what the clinicaltrials.gov site shows:

Clinicaltrials.gov snapshot Feb 14, 2013

I first wrote about ABT-199 last year at the 2012 AACR annual meeting where Steven Elmore from Abbott (the predecessor of AbbVie) presented data showing it to be a new Bcl-2 inhibitor that overcame the side effects seen with navitoclax (ABT-263), which led to dose-dependent thrombocytopenia.

At the 2012 annual meeting of the American Society of Hematology in December, Matthew Davids, MD presented the results from the first-in-human phase 1 multicenter trial in patients with relapsed or refractory CLL and non-Hodgkin lymphoma (NHL).

Dr Davids declined to offer any comment on the suspension of the ABT-199 clinical trial program. By email he wrote, “I’m not able to discuss any data from the ABT-199 study that has not yet been publically presented.” 

I thought this was a rather weak response given the fact the trial suspension is public knowledge. There’s more to being a thought leader than just being a company trial spokesperson who presents company prepared slides at scientific meetings.

It was also disappointing given the expertise at the Dana Farber Cancer Institute with BCL-2 antagonists, as evidenced by a recent publication on ABT-199 in the journal Cell by Dr Davids and Dr Letai earlier this week.  Dr Letai previously wrote in the journal “Blood” that the “antagonizing function of Bcl-2 is an attractive goal in chronic lymphocytic leukemia (CLL) and other lymphoid malignancies.”

According to a reliable source, the ABT-199 clinical trial program has been suspended due to the trial participant dying from tumor lysis syndrome.

Tumor lysis syndrome (TLS) is a life-threatening cancer treatment complication where large number of cells die and deposit their contents into the blood stream. The kidneys and liver are overwhelmed trying to process and excrete the dumped intracellular contents.  Acute renal failure may result.  TLS is most common in fast growing cancers such as acute leukemias and less common in indolent disease such as lymphomas and CLL.

This last factor makes the issue for AbbVie and those medically supervising the trial more challenging in deciding whether the event was a one-off fluke or whether the TLS was drug related i.e. there is something in the way ABT-199 acts that poses a risk of TLS in the same way navitoclax caused dose-dependent thrombocytopenia.  It could be related to dose-scheduling, for example, or the compound structure itself.

A patient death is something to be taken seriously, particularly in early stage development. Far better to find out you have a problem soon before spending multi-million dollars on a phase 3 drug development trial as AbbVie were poised to do.

Hematology industry expert Sally Church, PhD who writes Pharma Strategy Blog tells me that she thinks the ABT-199 clinical trials program will re-start, and sees this as a temporary setback once the dose-scheduling has been modified.  Her view is that:

“There are risks associated with any new drug in development largely because so much is unknown.  We don’t know what dose the patient was taking or for how long, but it’s possible that the agent is very effective and caused a much more rapid effect than expected at a high dose.  They may need to be more cautious about the dosing going forward.”

ABT-199 if it makes it to market will compete against other promising new compounds in development for CLL such as ibrutinib, which received breakthrough designation from the FDA earlier this week.

Update Feb 15, 2013 AbbVie says they expect ABT-199 trials to continue but advise there are 2 patient deaths!

Thanks to Derek Lowe on “In the Pipeline” for picking up on the ABT-199 story this morning and for providing additional commentary and insight on tumor lysis syndrome.

His updated post this afternoon now includes a response from AbbVie, in which the company spokesperson confirms the voluntary suspension of the trials, that the problem is indeed tumor lysis syndrome and they expect dose escalation to control it.

They go on to say in their email that “we have every expectation that the clinical trials will come off hold and that we will be able to initiate Phase 3 trials as planned.”  I encourage you to read Derek’s post if you have not already done so.

Fierce Biotech in their updated piece report that AbbVie have confirmed there are in fact 2 patient deaths.

The fact there are 2 patient deaths from tumor lysis syndrome (I was only aware of one when I wrote this piece) now raises the question of whether the cause of this may indeed be related to the chemical structure of ABT-199. It’s clearly a serious matter that will at the very least delay AbbVie’s phase 3 drug development program for ABT-199.

Update Feb 18, 2013 Tumor Lysis Syndrome explained

Sally Church, PhD has published a post on Pharma Strategy Blog that is well worth reading: “Tumor Lysis Syndrome – what it is and why it is important in cancer research.”

In addition to commenting on ABT-199, Church discusses the potential for delayed Tumor lysis syndrome (TLS) seen with CTL019, the novel Novartis chimeric antigen receptor therapy (CART) in early stage development.

Update May 29, 2013 Clinical data on ABT-199 at ASCO 2013

In my pre-ASCO 2013 post on Chronic Lymphocytic Leukemia (CLL) that I published on May 28, 2013, I included commentary on ABT-199. Here’s the relevant excerpt:

At ASCO 2013 there will be updated phase 1 results for ABT-199 (GDC-0199) in CLL, and the main topic of discussion will be two clinical trial deaths that occurred due to tumor lysis syndrome.

At the recent 2013 AACR annual meeting, Rod Humerickhouse, MD, PhD from AbbVie Global Pharma R&D, said the company plans to start an ABT-199 phase 2 single agent study and a phase 3 combination study in CLL later in 2013/early 2014.

He told the AACR audience that Tumor Lysis Syndrome (TLS) adverse events occurred in 9 out of the 74 patients enrolled in three ABT-199 CLL clinical trials.

Two CLL trial participants died from TLS, and one had acute renal failure.

Notwithstanding the early promise of ABT-199 that I wrote about from the AACR 2012 and ASH 2012 annual meetings, these deaths have in my mind placed a substantial question mark over the safety of ABT-199, especially if other less-toxic therapies are available by the time it potentially comes to market. TLS is a sign of a highly effective drug, but whether dose modification can make it safe while maintaining efficacy remains to be seen. We don’t yet have the data to show this, and even assuming this data is forthcoming at the very least the development of ABT-199 has been set back in terms of time to market.

Whether the tragic deaths should have been avoided we may never know, there remain unanswered questions as to whether the dose escalation was too aggressive, whether the risk of TLS was known, and if so whether patients were properly monitored.

Relatives of both patients who died have sent in comments to the blog, highlighting the personal tragedy of losing a father or husband in this way. I can appreciate that after 33 years of marriage suddenly losing a husband at age 56 is pretty devastating, especially when the AbbVie company response appears to have fallen short in compassion and empathy:

“All I got was a quick phone call, after I left a message that he dropped dead in my bathroom, to thank me for letting them know of his passing and a condolence card.”

Although the development of ABT-199 looks set to continue, in my view it is no longer a front runner in the race to market in CLL. You can read more about the companies in the race to market in CLL in my pre-ASCO 2013 post.

 

Dasatinib fails in Prostate Cancer #GU13

It’s disappointing to learn from the ASCO 2013 GU symposium abstracts published today that Bristol Myers Squibb’s tyrosine kinase inhibitor, dasatinib (Sprycel), has failed in prostate cancer.

Dasatinib now joins a large graveyard of cancer drugs that showed promise in early clinical development in solid tumors, yet the data was not confirmed in a large scale randomized phase 3 trial.

This content is restricted to subscribers

The phase 1 / 2 trial results for dasatinib in advanced prostate cancer were published by John Araujo, MD and colleagues last year in the journal “Cancer” (Jan 1, 2012).

The paper concluded on the basis of two trials with 46 men that “the high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC.”

Fast forward to the dasatinib phase 3 trial results published at ASCO GU 2013, where the data from a large scale randomized trial involving 1,522 men with advanced prostate cancer showed no significant difference in survival between men receiving dasatinib plus docetaxel (chemotherapy) versus men receiving docetaxel alone. The median survival between the two treatment arms was 21.5 vs 21.2 months (HR 0.99 P=0.90).

As the FDA comes under pressure to grant approval to promising cancer drugs based on early clinical trial data, the failure of dasatinib reminds us why large randomized trials are needed to show that a drug truly works, and the potential nemesis that may occur if phase 2 hubris alone is relied upon.

The news of dasatinib’s failure in prostate cancer is a disappointing result, but does not affect it’s role in CML where it is already approved.

Update Feb 13 – dasatinib may be effective in a subset of patients

I corresponded by email today with Evan Yu, MD, Associate Professor of Medicine & Oncology at the University of Washington School of Medicine and one of the co-authors on the dasatinib abstract presented at ASCO GU 2013.

BSB: Do you have any thoughts on why the phase 1/2 trial was promising yet the phase 3 trial ends up a failure?

Dr Yu: The challenge comes from identifying patients who have tumors that are being strongly driven by SRC.  The phase 2 monotherapy data was promising, but the greatest effect was on bone turnover.  And we know that SRC is expressed on
osteoclasts.  The phase 1/2 combination docetaxel with dasatinib trial also showed promising results.  However, it was a single arm trial without randomization.  The phase 3 trial was definitely solid, well-run, and BMS should be congratulated for running such an impressive trial.

BSB: Given there was a good scientific rational for targeting Src, any thoughts on what happened from a scientific perspective that might explain the lack of any survival benefit?

Dr Yu: One must ask whether overall survival was the right endpoint for this trial?  My suspicion is that the drug has potent effects in the bone for most patients, but significant direct antitumor effect for a small subset that is yet undefined.  Hopefully, smaller translational studies down the road performing tumor biopsy analysis and quantitative fluoride PET imaging will help identify those populations.

Dr Yu’s perspective highlights the challenge of oncology drug development, where increasingly companies need biomarkers to identify those patients who are likely to respond and to monitor the response to treatment. His comments add weight to the notion that companies need to spend more time in phase 2 development before rushing to costly, large-scale phase 3 trials. If you don’t know who is likely to respond to your drug, then you run the risk that those who don’t respond will turn your trial into a negative result.

Update Feb 15, 2013 – dasatinib fails to show a survival benefit in any subgroup

There is additional commentary from the presentation of the dasatinib READY phase 3 trial results in my piece on Xconomy about the prostate cancer drug winners and losers at ASCO GU.

4 Comments
error: Content is protected !!