Biotech Strategy Blog

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

Posts from the ‘Translational Medicine’ category

One of the interesting questions raised by the recently announced and much-discussed Juno/Celgene collaboration is whether you really need a Chimeric Antigen Receptor (CAR) T cell therapy in your portfolio to succeed as a global cancer immunotherapy company?

One leading cancer immunotherapy company that believes you don’t is Roche.  At ASCO 2015 I had the privilege to talk about this with a leading cancer scientist, William Pao, MD PhD (pictured below). Dr Pao formerly worked with Nobel Prize-winning scientist Harold Varmus at Memorial Sloan Kettering, and subsequently led the Hematology-Oncology Division at Vanderbilt. He joined Roche in July 2014 to lead their early development of innovative oncology new products (see press release).

Dr William Pao Roche

I particularly enjoyed Dr Pao’s discussion of the T-cell centric strategic framework around which the Roche/Genentech cancer immunotherapy portfolio strategy is based.

If you haven’t done so already, do listen to Episode 3 of the Novel Targets podcast (ASCO Lung Cancer Show) in which you can hear an excerpt from my interview with Dr Pao.

This is the first in a series of interviews with scientific leaders at companies at the forefront of cancer research.

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Have you ever sat in a freezing cold scientific session and been so engrossed in the compelling presentations that followed, you simply forgot to take notes? Not one. That actually happened to me at the American Association for Cancer Research (AACR) in Philadelphia this year in one of the many fringe sessions that I attended.

Reading Terminal Clock

Reading Terminal Clock, Philadelphia

Granted, the hot topic of the conference was undoubtedly checkpoint inhibition, but I was anxious to escape to the comfort of some meaty and familiar basic and translational science, namely MYC.  MYC is largely thought to be a difficult to target, even undruggable protein, and along with RAS and p53, represents a formidable challenge for cancer researchers.  These three oncogenic proteins alone are probably responsible for more drug resistance developing and even death from cancer than any other proteins in a patient with advanced disease.

For cancer patients with advanced disease, the clock is ticking on time they have left.

Solve these three problems (MYC, RAS and p53) and we may have a shot at dramatically improving outcomes. As Dr Gerard Evan (Cambridge) noted:

“I think it’s fair to say that we don’t really know why interruption of any oncogenic signal actually kills cancer cells, but one of the reasons that we’re interested in MYC is because it seems to be a common downstream effector of many, maybe all cancers.”

Sure, the road to success is paved with an enormous graveyard of failures, just as metastatic melanoma was before checkpoint blockade came along, ironically.  What I heard at AACR both inspired and filled me with greater confidence… we’re finally getting somewhere.

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The Food and Drug Administration (FDA) today approved Roche/Genentech’s obinutuzumab (Gazyva), also known as GA101, for untreated Chronic Lymphocytic Leukemia (CLL) in combination with the chemotherapy chlorambucil. Updated CLL11 trial data will be presented at the 2013 annual meeting of the American Society of Hematology (twitter #ASH13) in New Orleans from December 7-10. Gazyva is the first drug with a Breakthrough Therapy Designation to be approved by the FDA.

“Gazyva is an important new medicine for people with newly diagnosed chronic lymphocytic leukemia as it more than doubled the time a person lived without their disease worsening compared to chlorambucil alone,” said Hal Barron, M.D., chief medical officer and head of Global Product Development in a press release this morning.

Blog readers who attended the Roche analyst event in Chicago during the ASCO annual meeting in June will have noted that Roche’s long-term corporate strategy is focused on combining cancer drugs to improve treatment outcomes; a theme echoed by Charles Sawyers, President of the American Association for Cancer Research (AACR) during his ASCO Science of Oncology award lecture on “Overcoming Resistance to Cancer Drug Therapy“.

One of the combinations that Roche COO Daniel O’Day highlighted in the analyst event at ASCO was obinutuzumab/GA101 (Gazyva) with GDC-0199 (ABT-199) for the treatment of B-cell hematological malignancies such as CLL & non Hodgkin’s lymphoma (NHL). Obinutuzumab is a glyco-engineered CD20 antibody, while GDC-0199 is a Bcl-2 inhibitor. Both cause apoptosis (cell death) through complementary mechanisms of action.

An abstract on the preclinical data for this combination will be presented at the ASH annual meeting in New Orleans. A phase 1 clinical trial in CLL with this combination is currently underway and recruiting patients (NCT01685892).

I had the great pleasure at the recent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics meeting in Boston to talk with Deepak Sampath, PhD the leader of Genentech’s Bcl-2 preclinical research about the rational for the obinutuzumab plus GDC-0199 combination.

In this SoundCloud, Dr Sampath introduces himself and what his lab does at Genentech:

What he said during the interview makes for interesting reading, and suggests this combo could have blockbuster potential!

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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.

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.

For many attendees, the most exciting news at the 2012 annual meeting of the American Society of Hematology (ASH) held last December in Atlanta was the prospect of personalized T cell therapy for the treatment of patients with B cell cancers such as chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL).

The potential of this new treatment option was recognized at ASH 2012 by the award to Dr Bruce R. Blazar, MD and Carl H. June, MD of the Ernest Beutler Lecture and Prize for research that generated major translational advances in T-Cell Infusions.

ASH 2012: Carl June, MD receives Ernest Beutler Prize

ASH 2012: Carl June, MD receives Ernest Beutler Prize

Dr June, in his accompanying lecture discussed preliminary data for the trial of CTL019 (formerly CART-19), a novel chimeric antigen receptor-transduced T cell therapy against CD19. Subscribers to premium content can login to read more below:

In the 12 patients (10 adults CLL and 2 children with ALL) who have received CTL019, the responses have been extremely promising with a clinical response (CR+PR) seen in 9 out of the 12.

There have already been several reports in the media about this trial with many news outlets reporting that one of the children with ALL had been “cured.” That this treatment has tremendous potential is undisputed, but in my view it is a case of “hype over hope” at this stage to say that anyone has been cured in the absence of long-term follow up over at least five years.

In August 2012, Novartis announced they had formed an alliance with the University of Pennsylvania and had obtained a worldwide license to commercialize CART-19 (now CTL019). In December 2012, Novartis purchased a NJ manufacturing facility from Dendreon for $43M that will used for the production of personalized immunotherapy.

Novartis, through their recent acquisition of the Dendreon facility in NJ, are fortunate to gain access to the technology, state-of-the-art tracking system that matches the product to each patient, as well as the Good Manufacturing Practices (GMP) that were pioneered in the production of sipuleucel-T (Provenge).

In the immediate future, Novartis and U Penn have the challenge of showing that the dramatic results seen in some of the initial patients are reproducible in a larger trial and also at institutions other than Penn.

ASH 2012 Carl June Ernest Beutler Prize LectureIn his ASH lecture, Dr June noted that there are side effects and toxicities associated with CTL019 including tumor lysis syndrome (TLS), and Cytokine Release Syndrome (CRS) was seen in all patients.

This suggests it is unlikely this therapy will be used outside of the hospital setting.  In the United States, I would not be surprised to see it only used at hematology transplant centers, where there is the necessary expertise to deal with both the process and any complications that arise. Novartis may end up with a high priced therapy targeted at a small niche market.  It will be interesting to see the commercial strategy that Novartis decide to adopt.

I expect we will hear a lot more about chimeric antigen receptor technology in 2013. Personalized immunotherapy is a complex topic and one that will require significant investment in medical education by Novartis if a broader audience is the intended target. Dendreon failed miserably at launch in explaining how sipuleucel-T (Provenge) worked and did not convince large numbers of medical oncologists that their immunotherapy worked.  Even to this day, there remains considerable sceptism amongst that physician segment.

If you would like to know more about the science behind CAR therapy and it’s potential in hematology, Sally Church, PhD (who co-launched Gleevec in the US while at Novartis Oncology) will be offering insights in a monthly newsletter to be launched soon. Check out Pharma Strategy Blog for more information.

 

The “Hallmarks of Cancer” paper by Douglas Hanahan and Robert Weinberg is a classic, and a must read (allow plenty of time) for anyone interested in cancer drug development.

The original 2000 paper, updated in 2011, identified six hallmarks of cancer, “distinctive and complementary capabilities that enable tumour growth and metastatic dissemination:”

  • Sustaining Proliferative Signaling
  • Evading Growth Suppressors
  • Activating Invasion and Metastasis
  • Enabling Replicative Immortality
  • Inducing Angiogenesis
  • Resisting Cell Death

Apoptosis or programmed cell death according to Hanahan and Weinberg is “a natural barrier to cancer development.” One of the ways cancer cells survive is by resisting cell death and disrupting the apoptosis signaling pathway; in other words the normal signals that trigger cell death don’t get through.

Researchers have shown that apoptosis is controlled at the cellular level, in the mitochondrion, by the Bcl-2 family of regulatory proteins (BCL-2, BCL-XL). Targeting BCL-2 (a protein that prevents apoptosis) could induce cell death and be a potentially successful anti-cancer strategy.

The result of our increased understanding of cancer biology has been the development of novel targeted drugs such as ABT-199, a potent and selective BCL-2 inhibitor. This is in early clinical development by AbbVie ($ABBV), a new biopharmaceutical company spun off from Abbott Laboratores ($ABT) last week.

I previously wrote about the potential for ABT-199 in Chronic Lymphocytic Leukemia (CLL) following Steven Elmore’s presentation at the April, 2012 annual meeting of American Association for Cancer Research (AACR).

The data presented at AACR has now been published in Nature Medicine, online ahead of print (AOP) on 6 January 2013: ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.”

Andrew Souers and colleagues from AbbVie and other institutions discuss how they re-engineered the since-discontinued navitoclax (ABT-263) to create a different and less toxic BCL-2 inhibitor. This new compound, unlike navitoclax, does not cause the thrombocytopenia associated with BCL-2-like1 (BCL-XL) inhibition.  It’s a compelling story of science-based cancer drug development.

ASH 2012 Annual Meeting BannerAt the December 2012 annual meeting of the American Society of Hematology (ASH) in Atlanta interim data was available from the phase 1 clinical trial of ABT-199 in Non-Hodgkin Lymphoma (abstract #304).

Matthew S. Davids, MD, Instructor in Medicine at Harvard Medical School & attending physician at the Dana Farber Cancer Institute, presented the results from the first-in-human phase 1, open-label, dose escalation, multicenter international trial in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL).

Of the 30 NHL patients enrolled, Dr Davids told the audience that 20 remained active, with a median time on study of 80 days (range 7 to 413).

ABT-199 particularly active in CLL & MCL

In 7 patients who had mantle cell lymphoma (MCL) in the 30 subject NHL trial, all seven (100%) obtained a partial remission.  A 72 year old man with stage IV MCL obtained complete clinical resolution of auxiliary node clinically and 2 x 1 cm neck nodes by day 8.

ABT-199 is also active in CLL. Dr Davids briefly shared data previously presented at the 2012 Congress of the European Hematology Association (EHA) last year.  The waterfall plot was quite impressive, unfortunately I could not obtain permission to share an iPhone photograph here.  However, by my eye, the plot appeared to show that 30 of the 37 evaluable patients had a greater than 50% reduction in nodal size!

Dr Davids shared by email some additional commentary on the potential of ABT-199 in CLL:

“ABT-199 appears to be very active in patients with relapsed refractory CLL irrespective of high risk features such as del(17p).

Given its distinct mechanism of action from the BCR pathway antagonists, it has the potential to become an important additional treatment option in the armamentarium of CLL therapies.

Whether ABT-199 will be most useful as a signal agent, in combination with chemotherapy, or in combination with other novel agents will be an important question moving forward.”

ABT-199 has an acceptable safety profile

ABT-199 related grade 3 / 4 neutropenia was experienced in 3 of the 30 NHL phase 1 trial participants (10%).  Dr Davids noted there were:

  • No discontinuations due to adverse events
  • No dose limiting toxicities observed in NHL patients
  • No evidence of dose-dependent thrombocytopenia

He concluded that ABT-199 had an acceptable safety profile and further research is ongoing in NHL, both as a single agent and in combination with bendamustine/rituximab.  The lack of severe thrombocytopenia is a definite improvement on its predecessor navitoclax.

Overall, ABT-199 is an exciting new agent in development with potential as a new treatment option for CLL & MCL.  I look forward to hearing more about it at future scientific meetings.

What is a Biomarker?

According to the Biomarkers Definitions Working Group, a biomarker is:

“a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”

An example of a common biomarker is blood pressure. High blood pressure is a surrogate for cardiovascular disease and risk of stroke.

Why are biomarkers important? Subscribers can login to read more below.

Why are Biomarkers important?

Biomarkers can be used for diagnosis and for monitoring the safety and effectiveness of treatments. They are increasingly becoming important in the selection of patients for clinical trials, and as potential surrogates for clinical endpoints that may take a long time to occur e.g. measuring how long someone will live in a cancer trial (overall survival).

Examples of the use of biomarkers include:

  • Diagnosis: high blood pressure is used as a biomarker for cardiovascular disease and risk of stroke.
  • Treatment Selection: CSF biomarkers that correlate with neurodegenerative diseases may help select the most appropriate treatment
  • Drug Effectiveness: biomarkers can be used to monitor treatment or drug effectiveness e.g. use of cholesterol levels as a measure of cardiovascular disease
  • Surrogate Clinical Endpoint: a biomarker based on scientific evidence that predicts or correlates with clinical benefit could be used as a surrogate for a clinical endpoint that may take a while to detect e.g. how long a patient lives or survives, and in the process speed up drug development. Recent prostate cancer trials sought to show that circulating tumor cell (CTC) counts correlated with the survival benefits seen. However, validation of a biomarker needs to take place before regulatory agencies will accept it as a surrogate endpoint in clinical trials.

Biomarkers can be divided into those which are prognostic and those that are predictive.

Prognostic Biomarker: a marker that provides information on the likely course of a disease in an untreated individual.

Prognostic biomarkers are used to identify high-risk cancer patients who should, therefore, receive adjuvant therapy.

Predictive Biomarker: a marker that provides information on how likely you are to respond to a particular therapy.

Predictive biomarkers are used to guide treatment choices i.e. selecting the therapy with the highest likelihood of success.

In breast cancer, estrogen and progesterone receptors are biomarkers that predict sensitivity to endocrine therapy, while HER2 levels predict response to Herceptin treatment. In colorectal cancer (CRC) patients, KRAS mutations have been shown to be a biomarker of resistance to EGFR targeting drugs such as cetuximab and panitumumab.

Predictive biomarkers allow expensive new cancer treatments to be given only to those patients who are likely to respond. As we move forward into the era of personalized medicine the aim is to develop more highly predictive biomarkers that will allow better detection, diagnosis and treatment of disease.

In addition, there’s also a need to develop biomarkers that can distinguish between subgroups of patients to separate those who might benefit from a therapy and those who have developed resistance. Biomarkers for resistance to cancer therapy is an increasingly important area of research.

For those readers interested in cancer biomarkers, the joint ASCO-EORTC-NCI “Markers in Cancer” 2012 meeting in Hollywood, FL (near Fort Lauderdale) from October 11-13 has an agenda that holds promise.

Some of the presentations that caught my attention and ones I particularly look forward to watching remotely via the “Virtual Meeting” include:

  • Biomarkers of Resistance to EGFR-Targeted Therapies in Lung Cancer
    Enriqueta Felip, MD, PhD – Vall d’Hebron University Hospital
  • Resistance Mechanisms to BRAF Inhibition in Melanoma
    Jeffrey Sosman, MD – Vanderbilt-Ingram Cancer Center
  • Complexities of Identifying Non-Mutational Biomarkers of Resistance:
    The VEGF Pathway Example
    Michael B. Atkins, MD – Georgetown University
  • Development of Biomarkers for PI3K Pathway Targeting
    Sherene Loi, MD, PhD – Jules Bordet Institute, Brussels
  • Emerging Functional Imaging Biomarkers
    Annick D. Van Den Abbeele, MD – Dana-Farber Cancer Institute

The next post in this mini-series will discuss new research that shows how a panel of 5 CSF biomarkers can be used to differentiate between neurodegenerative diseases that might otherwise be misdiagnosed. This is particularly important for clinical trial recruitment where early symptomatic patients could potentially be recruited in error if given the wrong diagnosis, and placed in trials that they will not respond to.

Imagine that you are born deaf and live in a world of silence – what price would you pay for a new treatment that might restore your hearing?

That is the market opportunity that may be available for biotechnology and pharmaceutical companies as the basic science around congenital hearing loss starts to yield insights that could translate into new products.

Research published in the July 26, 2012 issue of the journal “Neuron” by Omar Akil from UCSF and colleagues at the University of Pittsburgh and Ohio State University, showed the ability to reverse hearing loss in mice through the use of gene therapy (viral-mediated insertion) to replace the absent vesicular glutamate transporter-3 gene (VGLUT3).

VGLUT3 is a gene involved with the transport of the neurotransmitter glutamate that is required by inner hair cells in order to generate neural responses to sound. Mice lacking VGLUT3 can’t hear.

Insertion of the VGLUT3 gene into mice cochlear cells resulted in restoration of hearing that lasted for 9 months (that’s a long time for mice). The authors noted that:

“These findings represent a successful restoration of hearing by gene replacement in mice, which is a significant advance toward gene therapy of human deafness.”

Over 50% of all human hearing loss is genetically based, and as tools to understand the human genome develop, scientists have been able to identify a number of genes associated with hearing loss.

Research in animal models is ongoing, with the potential in the future that we may be able to replace, repair or correct a defect a genetic mutation.

Could this lead to the restoration of human hearing? The answer is “yes”.

An accompanying editorial in Neuron by Donna Martin and Yehoash Raphael from The University of Michigan describes the work by Akil and colleagues as a major breakthrough:

“Results presented in their paper are a true breakthrough because they show that gene therapy can lead to functional recovery from sensorineural deafness. Even more exciting is the direct relevance of this work to a large population of humans who have mutations in the VGLUT3 gene.”

There remain a number of challenges before gene therapy to correct human deafness becomes a reality, but biopharmaceutical companies such as GenVec (NASDAQ: GNVC) already see the market opportunity and potential for gene therapy to correct hearing loss. Novartis have a collaboration agreement with GenVec that is worth up to $213.6M in milestone payments.

The potential of gene therapy to restore hearing loss will offer hope to many with deafness. It is an exciting area to watch as innovative science translates into personalized medicine.

References

ResearchBlogging.orgOmar Akil, Rebecca P. Seal, Kevin Burke, Chuansong Wang, Aurash Alemi, Matthew During, Robert H. Edwards, & Lawrence R. Lustig (2012). Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally Mediated Gene Therapy Neuron, 283-293 DOI: 10.1016/j.neuron.2012.05.019

Donna M. Martin, & Yehoash Raphael (2012). Have You Heard? Viral-Mediated Gene Therapy Restores Hearing Neuron, 75, 188-190 DOI: 10.1016/j.neuron.2012.06.008

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