Biotech Strategy Blog

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

Posts tagged ‘AACR Molecular Targets’

Boston – Preclinical data for PF-06463922 (Pfizer), a next generation ALK inhibitor, with potency for all known Crizotinib ALK resistant mutants and ability to cross the blood brain barrier was presented today at the 2013 International Conference on Molecular Targets and Cancer Therapeutics co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI) and the European Organization for Research and Treatment of Cancer (EORTC).

In addition to being a competitor to other next-generation ALK inhibitors in development such as AP26113 (Ariad), LDK378 (Novartis) and alectinib (Roche/Chugai), PF-06463922 shows activity in both crizotinib-naive and crizotinib-resistant cells, so could end up being a replacement for crizotinib (Xalkori) front-line if clinical results confirm preclinical efficacy.

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The 2013 Molecular Targets and Cancer Therapeutics Conference (twitter #targets13) takes place in Boston from October 19-23 at the Hynes Convention Center. It’s a “must attend” meeting for anyone with an interest in cancer drug development and I’m really looking forward it. Boston is an exciting place for cancer research!

Molecular Targets Meeting AppJointly organized by the American Association for Cancer Research (AACR), European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute (NCI), it alternates each year between Europe the United States.

The molecular targets meeting program and abstracts are now available online. There’s also a meeting App that’s well worth downloading if you plan to be there.

As for what’s interesting at the meeting – the three media briefings give a flavor of what to expect:

Sunday, Oct. 20, 10 a.m. “Emerging Therapeutics,” including research on investigational drugs AZD9291 and PF-06463922, which have the potential to overcome drug resistance in some lung cancers.

Monday, Oct. 21, 9 a.m. “Overcoming Resistance and Hard-to-Treat Cancers,” including research on a new antibody-drug conjugate MLN0264 for pancreatic cancer and a new nanopharmaceutical CRLX101 for cancers resistant to antiangiogenic drugs.

Tuesday, October 22, 9 a.m. “Guiding Treatment for BRAF- and BRCA-related Cancers,” including updated data on the clinical benefit of the PARP inhibitor BMN 673 and a new diagnostic platform to rapidly identify BRAF mutations.

The AACR press team led by Jeremy Moore have done a good job of identifying some of the exciting new drugs in development.

Readers of blog premium content have already read about the potential of AZD9291 in T790M resistant lung cancer from ECCO 2013 in Amsterdam.  While it looks like the ECCO late-breaker did steal some of the thunder from the molecular targets meeting, there’s going to be more granularity on the compound at AACR, and hopefully some updated clinical data.

There are three AZD9291 posters at the meeting, and I’ll be covering all of these while in Boston:

Sunday, Oct 20, 2013, 12:30 PM – 3:00 PM  A109: AZD9291: an irreversible, potent and selective third generation tyrosine kinase inhibitor (TKI) targeting EGFR activating (EGFRm+) and resistance (T790M) mutations in advanced lung adenocarcinoma.

Monday, Oct 21, 2013, 12:30 PM – 3:00 PM  B212: Integrating the pre-clinical pharmacokinetic, pharmacodynamics, and efficacy data for AZD9291, an oral, irreversible inhibitor of EGFR activating (EGFRm+) and resistant (EGFRm+/T790M) mutations and an active metabolite to predict the human pharmacokinetics and potential efficacious dose in patients.

Monday, Oct 21, 2013, 12:30 PM – 3:00 PM B94 Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor.

Another compound that I have been following with data at Molecular Targets is ABT-199/GDC-199.

You’ll find me in the poster halls every afternoon, so if you are going to be in Boston for Molecular Targets, I look forward to seeing you there!

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.

San Francisco – “Translational research is the key to successful drug development” according to William N. Hait MD, PhD, global therapeutic area head of oncology, Johnson & Johnson.

Hait presented a plenary session on “overcoming barriers to new drug development” at the recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference in San Francisco.

How do we define translational research?

The definition Hait most likes is from Duke Ellington: “if it sounds good, it is good

The challenge of drug development is that with rare exceptions the process is slow, inefficient and expensive.

Hait outlined several challenges to translational research, including:

  • Complexity – imagine blocking the traffic in mid-town manhattan. If you blocked one cross-town route, traffic would slow and then find another route.

This in my opinion is a good visual metaphor for the cross-talk that occurs in cancer. Block one target, and the cancer finds another route.  This highlights the need for combination therapy.

rational combinations of targeted agents may require studying two or more unapproved agents” said Hait.

Novel-novel combinations are something that many companies are nervous about, but if there is a solid scientific rationale then this is something I think we will see more companies doing.

For further insight into how academia is facilitating this type of combination trials, I recommend Sally Church’s interview on Pharma Strategy Blog with Gordon Mills at ECCO/ESMO in Stockholm.

  • Inaccuracy of preclinical models – our models don’t always predict preclinically what activity a drug will have in the clinic.
  • Efficacy of Clinical Trial Recruitment  – need to have alignment of incentives. 20% of US patients are eligible for clinical trials, but only 3% participate.
  • Developing Biomarkers.  Difficult to obtain serial biopsies for oncology biomarker analysis.  Circulating tumor cells may be future, but current instruments can only capture and enumerate and offer limited characterization. According to Hait, the next–generation platform will be exciting.  It will allow third parties to offer additional functionality that can be integrated with the platform.
  • Drug resistance – a nemesis that just doesn’t want to go away.
  • Overcoming the Regulatory Environment – challenges include: scientific complexity, endpoint consistency, global harmonization, companion diagnostic tests, proper comparators, equipoise.

In spite of this complexity, Hait noted the FDA approved 34 new drugs in 2011. Several cancer drugs had a short time from submission to approval and met their PDUFA target date.  “These are incredible accomplishments,” he said.

  • Market Access – Hait asked the audience: “Would you buy a Porsche 911 that only works for 20% of the people, but we don’t know if you are one of the 20%?” Healthcare authorities need to decide cost/benefit of drugs, and regulatory approval does not automatically mean a new product will be reimbursed. There may be need for future trials with health comparators, or innovative agreements where the healthcare authority only pays for those patients who respond.
  • Workforce – academic physicians may end up being segmented into three groups: master clinicians, clinical investigators, physician-scientists. This may provide better career development than the current system.

Hait offered a few suggestions for improvement:

  • Move to phenotypic screening rather than target-based screening. In vivo shRNA screening was discussed.
  • Disease based drug discovery teams – the hope is that in-depth focused teams will predict better results.
  • More intense academic-industry collaboration with a focus on complementary expertise.

The limitation of this plenary presentation was that it only offered the perspective of one senior industry professional. I would have welcomed a balance of views on the barriers to new cancer drug development, and more focused take-home solutions.

If you want to hear more on this topic, AACR have a free podcast that you can download of an interview they did with Dr Hait at the Molecular Targets meeting.

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San Francisco – the AACR-NCI-EORTC international conference on Molecular Targets and Cancer Therapeutics kicked off last Saturday with two educational sessions, including one that I attended on “Clinical Trial Paradigms in the Era of Novel Therapies.

The session had an impressive line-up of speakers:

  • New paradigms for early-phase trials (James Doroshaw)
  • Phasing out phase III trials: How much evidence do we need if the target is clearly hit? (Jaap Verweij)
  • Development of clinical trials incorporating genomic signatures: Lessons learned? (Lisa McShane)
  • Clinical trial designs for targeted therapies (John Crowley)

James H. Doroshow, deputy director for clinical and translational research at the National Cancer Institute, started his presentation by reviewing the causes of phase II trial failure:

  • 19% Safety
  • 51% Efficacy
  • 29% Strategic

He stated that the overall success rate of recent phase II trials was 18%.

As the debate continues about whether more cancer clinical trials should be done in Phase 2, the key issue according to Doroshow remains lack of a demonstrable proof of mechanism (POM) in many drug trials. That goes hand-in-hand with a lack of molecular markers which can be used to select trial subjects.

“Lack of molecular markers with proven clinical utility follows lack of clinically-demonstrable proof of mechanism”

He provocatively asked:

Should we perform early phase trials without generating evidence supporting POM patient by patient?

His view was that to obtain POM, you need to demonstrate drug action on intended tumor target early in development, prior to expectation of efficacy.

Jaap Verweij in his presentation used the examples of crizotinib, vismodegib, vemurafenib and imatinib in GIST as examples of drugs that had:

  • functionality for a target
  • aimed at a specific population
  • availability of a selection marker.

They are the poster children of targeted therapy, and he convincingly showed that the phase 1 trials of those compounds were largely predictive of the phase 3 results.

His conclusion was that phase I trial can be considered predictive of a phase III study so long as there is a large enough sample size.

We may need to look for bigger increments which should allow us to perform smaller trials,” he said. This would allow trials that are quicker and cheaper. However, he acknowledged that it was not likely we can completely eliminate phase 3 trials particularly for combination therapies or chemotherapies.

John Crowley reviewed the different phase III trial designs, including my least favorite, the “all comer” design.  The ridaforolimus sarcoma phase 3 trial presented at ASCO this year is a good example of how an “all comer” design yielded less than stellar results, and failed to identify the subset of sarcoma patients that optimally respond.  This is the type of phase 3 trial that runs the risk of failure if there are too many non-responders in the heterogeneous patient population.  This problem can often be avoided by more rigour in phase 2 trials to identify the optimal treatment period, relevant biomarkers and subsets of patients most likely to respond.

There is a lot of interest in how to design cancer clinical trials better, bring drugs to market more quickly and more efficiently.  While I enjoyed the content of this session, I did wonder whether it would have been better presented as a roundtable with more audience interaction and engagement rather than the perspective of a few.

A webcast of this session will be available on December 8 from the American Association for Cancer Research (AACR).

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.

 

Academic institutions are now bringing pharma/biotech companies together and facilitating rational combination trials that make solid scientific sense.

Combining at least two targeted drugs looks to be increasingly necessary in order to develop innovative new cancer treatments, where turning off one target may stimulate another, thus both need to be targeted for there to be an overall effect.

However, one company may not have all the pathways and drug targets covered by their portfolio.  The result is that companies may have to work together in combination trials with each providing one drug from their portfolio.

That was one of the key messages I took from Gordan Mills (UT MD Anderson Cancer Center) in his recent video interview with Sally Church from Pharma Strategy Blog:

Sally Church’s video interview with Professor Mills is well worth watching if you have not already done so.

Not only are universities and research institutions well placed to judge the scientific merits, but as Mills points out they can facilitate things as an independent third party and actively help bring partnerships together.  Given that combination therapies may be needed in order to turn off different parts of signaling pathways and cross-talk, I think we are likely to see more of this approach.

It’s going to be new territory for many companies – how to enter into a potential joint venture or alliance? However, if it results in a therapy that works, it is going to be win-win for all parties. It may also improve efficiency in drug development and lead to better use of patients in early stage development.

Some examples of where this is happening already in oncology include AstraZeneca and Merck with their MEK-AKT approach and GSK (MEK) with Novartis (PI3K), to name a couple.  This is a new trend we are likely to see more of in the future.

I can see universities hiring alliance managers who have industry experience to ensure these collaborations run smoothly.

The topic of the industry/academia interface in rational cancer drug development will also be discussed in a plenary session at the forthcoming American Association for Cancer Research (AACR) meeting on Molecular Targets and Cancer Therapeutics (November 12-16, 2011) in San Francisco.

How academia can better help the pharma/biotech industry bring innovative, rational drug combinations to market is a topic that I think we will be reading more about in coming months.

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