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Posts tagged ‘AACR 2013’

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.

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.

 

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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.

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.

Joyce Liu MD MPH. Photo: Dana-Farber Cancer Institute

Joyce Liu MD MPH

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.

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.

AACR 2013 Annual Meeting Banner Screenshot

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.

Cancer Discovery Research Article Chang Yang

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

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