Simple Cancer Biomarkers are Inadequate to Enable Personalized Medicine

It seems that researchers are finding that using single cancer biomarkers to develop companion diagnostics (CDx’s) to be used with future targeted therapeutics is very challenging. An article in the November 15 issue of Genetic Engineering and Biotechnology News, called Traversing the Cancer Biomarker Labyrinth, by Kathy Liszewski, is a very interesting read.

Apparently progress in this field has slowed in finding clinically useful biomarkers for diagnostics and making other tests that guide doctors for disease prognosis and prediction. Researchers are using a variety of reductionist technical approaches that range from analysis of certain glycans, key microRNAs, and epigenetic changes, to big data analysis of massive data stores of genomic data to tease out more clues to what is going on in cancers.

Scientists seek to develop early detection blood tests that can detect cancers of interest.  Such a blood test could be considered a ‘liquid biopsy’ and might include a panel of a dozen or more miRNAs that represent a biomarker signature.  An oncologist might one day be enabled to quickly screen certain patients with a blood test that would help them diagnose, stage or predict the potential outcome of a cancer.

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Acute Need for Early Warning Dx for “Silent Killer” Cancers

There is a need for early warning diagnostics to detect “silent killer” cancers such as pancreatic, liver, GI and lung cancers. Most of these cancers are discovered at the late stage when acute symptoms appear and no cure is possible.  Maybe an annual simple screening test could be developed that could accurately detect a molecular signature of these cancers.

It is a very sad situation indeed to see patients die just after two, four or six weeks post-diagnosis.  Just this past weekend, our co-writer and industry analyst for this blog and our market research firm succumbed to an aggressive cancer of unknown primary origin that spread to the liver.  She died in less than five weeks from diagnosis.  The FDG- PET CT scan showed active cancers in the liver, pancreas, uterus and breast. Ultimately the oncologist concluded that the cancer likely came from the pancreas. May she rest in peace.

Close relatives interested in getting a PET scan for themselves were advised that the Radiology Dept. would only offer a PET scan after a patient was already diagnosed to have cancer.  Whereas a PET scan is good at detecting cancer, it is a very expensive resource that hospitals choose to limit access to.

What is needed is an annual pre-symptomatic, accurate, low-cost multiple-molecular-marker, blood test that can screen for cancer at the earliest point – before a tumor is formed. The screening test would likely use a panel of biomarkers associated with the “silent cancers.”

ThermoFisher Aims to Get FDA OK for its Ion Torrent PGM

By Paula Myers

At this year’s CHI Molecular Medicine Tri-Conference at the Moscone Convention Center, San Francisco, February 11th, there were over 3000 attendees and more than 200 exhibitors. I visited some of the many booths on the exhibit floor. One of those was the ThermoFisher booth. I spoke with Zhen Mahoney,Sr. Clinical Sales Specialist/Pharma Business. Mahoney talked about the acquisition of Life Technology and how it affects ThermoFisher.  Thermo will have to absorb Life’s 9,000 employees. Thermo currently has 40,000 employees. Mahoney pointed out that Life has a broad product portfolio. Ion Torrent, which Life acquired in 2010, is located at Oyster Point near South San Francisco. The rest of company is located at Carlsbad, California, near San Diego, including the Invitrogen and Gibco brands. These groups are staying intact, according to Mahoney.

She also pointed out that the company submitted an application for 510K marketing clearance to the FDA for its Ion PGM system for use as a diagnostics medical device. They are hoping for a 3 to 4 month approval timeframe. By comparison, the Illumina MiSeq took about 9 months to get FDA 510K approval because it was the first of its kind. The Illumina MiSeq received a relatively fast approval because the company worked closely with FDA reviewers so that they can understand its technology. The MiSeq platform serves as a template to the FDA for follow-on platforms from Illumina and other desktop sequencer vendors. Mahoney said that the next revision for their Ion Torrent electronic P-2 Chip is coming later in 2014. It will have 660 million wells.

Some of the other firms that I visited included: Guardant Health, Diagenode, and Epitomics. I focused on companies involved in epigenetics. Guardant Health is a two-year-old service company for individuals. In February, they released GUARDANT360, the first pan-cancer blood test that provides doctors with real-time genetic information to help them prescribe the right treatments for their cancer patients.

  Diagenode is a company originally from Belgium and sells Japanese made disruptor shearing machines such as the Bioruptor Pico for DNA, chromatin, and RNA shearing. Epitomics, located in Burlingame, California, offers custom antibody services for use in epigenetics research. Li Fang, Project Manager of Custom Antibody Services at Epitomics, said that Abcam is buying the company. Abcam is a supplier of antibodies,proteins, kits and reagents.

Spotlight on New Medtech Firms at the 12th BIO Investor Forum Meeting in SF

Palace Hotel, 12th Annual BIO Investor Forum meeting in San Francisco Oct 8-9, 2013.  According to David Thorcirus, the host of the opening meeting, this year’s BIO Investor Forum had about 700 attendees, 900 one-on-one partnering meetings and had a 30% increase in attendees compared to last year. The meeting focus is about small companies seeking funding or commercial partners. Of the 120 presenting companies, about 2/3 were private and about 1/3 were public stock firms.

Small Company Presentations Of Note.

  I found four new interesting medtech firms that were worth a first look.

1. Nano3D Biosciences (n3D) is new company run by Glonco Souza, the President and CSO.  The company is a spin-off of Rice University and the MD Anderson Cancer Center in Texas.  n3D’s mission is to develop the “Bio-Assembler” technology. They said it is a big paradigm shift in the developing of complex 3D tissue models.  They do this by levitating cells in dish. The Bio-Assembler (TM) is a nnao shuttle refill.  The product is covered by patent IP.

They get in-vivo -like results.  They claim to have the fastest 3D cell-based assay. It can produce results overnight vs. in 10 days. n3D uses Apple iPod Touch 4G mobile devices as computer controllers.

The “Magnetic Levitation Grows Realistic Lung Tissue…” in a headline in Science Magazine. The company uses ten Apple iPod Touch mobile devices for its compute platform.  Souza said that the limitation of existing 3D tools and assays for a small company. So far, n3D has raised $2.3 million.  Souza said that the investor exit strategy is to sell itself to a large company.  The firm is looking for customers, partners and investors.  Souza said that they currently need $600,000 in new funding.

2.Another new company, Nanofiber Solutions creates poly-nanofiber structures.  Ross Kayula, CEO, said that they place cells in fiber and look normal (cancer cells).  Their plates replace 2D plates. Their idea is similar to those of Nano 3D Biosciences.

The CEO said that their scaffold for implants prevents rejection and scarring in a trachea.  Their idea is a platform technology for organ regeneration — as implantable products.  Product status: Trachea in clinical trials; Other products are in pre-clinicals.

Ross said that IP is their largest cost and said that they need to raise a VC-backed seed-funding round of about $2 million.

3. iNanoBio is a new firm based in Tempe, Az. The company develops nanoscale sensors for combining nanoscale and diagnostics.  iNnaoBio seeks $7.5 million in a VC funding series.  The company is developing ultrafast next generation sequencing technology over the past nine months. The initial phase of their development is to make kinase activity high throughput screening. The CEO said that their technology is ultra fast an will sequence DNA in just fifteen minutes for about $200. They expect to target clinical applications using nanopore diagnostic technology. iNanoBio will make nanowire sensors attached to a nanopore to detect DNA in one pass at high speed. The firm is involved in an NIH program to develop their platform technology. The technology provides real-time detection of kinase proteins when compared to competing technologies from Thermo, Life Technologies, DiscoverX or others. The CEO said that their next step is to integrate microfluidics.  The manufacturing process is the same as in making semiconductor chips on a six-inch wafer. They can make a 1×3-inch slide with 10,000 wells to make an alpha-p53 assay. Their future n-MEDD product lines include: 1. Kinase chip assays, 2. Inhibitor discovery assay, 3. Target-ID assays for phenotypic screens. A key value is the real time kinetic results.  They are talking with Big Phama companies about their technology. iNanoBio plans to seek series A and B funding from VC firms.  The n-MEDD system development beta product is being shipped to customers.  They are developing a prototype genome sequencing device.

4. Metactive Medical is a medical device company run by CEO, Nicholas Franano MD.  He is the former founder of Proteon Therapeutics. The firm is developing two vascular repair products. Nicholas said that their first product involves a device for treating cereberal aneurisms that have a narrow neck. He said that cereberal aneurisms impact about 4% of the population. A rupture of an aneurism produces a hemorragic stroke which is often fatal. Patients usually have very bad headache symptom prior to an aneurism occurring. If they can detect the aneurism in time, the Dr. uses a catheter to put a coil of wire into the ball of the aneurism. The wire coiling procedure is the standard of care for treating cerebral aneurisms. This is a $500 million market segment. Dr. Franano said that wire coiling procedure is delicate, difficult and takes about two hours to complete.  He said that doctors need about two years training to perform this procedure. Unfortunately, about 3-5% of the aneurisms are punctured by dosctors. Each coil costs about $1,000 and some aneurisms require up to twenty wire coils.

Metactive Medical is developing a better device, the Ball Stent which is attached to a microcatheter. The Ball Stent is guided up to and into the ball of the aneurism. When activated, the end of the stent expands and fills the ball of the aneurism. A wire seals off the bloodflow from the artery at the neck of the aneurism. The procedure takes about twenty minutes. The company tested the idea in a pilot study in dogs by testing an 8mm Ball Stent. The successful procedure delivers a permanent treatment. The FDA classify would the Ball Stent as Class-2 Device and would require a 510K filing application. The second product is vacular device to repair peripheral artery occlusion.  This is a $50 to $75 million market. The Firm’s device deploys a ballon that repairs the artery wall. Dr. Franano estinmated that the market for the Ball Stent is $1 billion and the peripheral artery occlusion device market is $100 million.  He said that the company would sell itself for $200-250 million to a buyer or develop its products further. I asked when might the Ball Stent likely reach the market and Dr. Franano said that, if developed, it could reach Europe by 2020.

Using Stem Cells and HCA to Discover Drugs.

San Francisco — Fairmont Hotel January 10, 2013.  While taking a break from my reportage of the JP Morgan Healthcare Conference and the Biotech Showcase 2013, it came to my attention that I should checkout the CHI meeting at the Fairmont Hotel.  Cambridge Healthtech Institute’s High-Content Analysis meeting was winding down its meeting so I was able to briefly see the exhibits and see a few minutes of a session about HCA in stem cells.

Mark Mercola , PhD. gave a talk called HCS to Discover Drugs for Heart Failure.  Dr. Mercola is Director, Muscle Development and Regeneration Program Sanford Burnham Medical Research Institute

Mercola talked was about studying cardiomyocytes with instrument based iPS disease models.  He used the KIC (kinetic imagery cytometry) instrument from VALA Sciences, Inc. to run his disease-in-a-dish screening assay that put iPS cells in dishes to then analyze and identify miRNAs that target heart failure.  His goal is to try to restore the calcium channel in heart failure.

He said that miRNA are efficient to target multiple proteins. He noted that this process to discover a drug is better than with direct targeting.  Dr. Mercola said that he developed a target sensor screen. He looked at 900 miRNA and picked the eGFP miRNA.  He picked the conserved human miRNA and used the best ten.  He checked each sample with the KIC instrument. Mercola created an anti-mir to target miRNA in cardiomyocytes. The in vitro experiments helped identify the in-vitro move to in-vivo.  He simulated heart failure by squeezing the rat aorta to create heart failure over next 3 months.  He said that the increased pressure in the heart leads to fibrosis.

After the talk. I spoke with several exhibitors including Eugene Cho from VALA Sciences, Inc.  The  CHI meeting had about 300 attendees.

Diagnostic Companies Speak About Challenges With Pharma Partners at IBC Event

On August 6, 2012, I attended the IBC Life Sciences’ Drug & Diagnostic Development Conference at the Westin San Francisco Market Street Hotel.  The three-day conference consisted of four ‘summits’ that included the Future of Rx/Dx Summit, the Clinical Biomarkers and New Frontiers in Cancer Summit, the Next-Gen Sequencing Summit, and the Antibody-Drug Conjugates, Bispecfics and Empowered Antibodies Summit.  I decided to focus on the Future of Rx/Dx Summit business track.  A number of the presentations discussed the many challenges and success factors that go into developing companion diagnostics (CDx), which companies need to consider when developing a CDx.

Tips to Navigate Rx/Dx Co-Development

Patrick Goody, Divisional Vice President, R&D at Abbott Molecular brought up a number of important guidelines during his case study presentation, “Co-development of Diagnostics and Therapeutics: Abbott/Pfizer Crizotinib.”  Crizotinib (Xalkori) is Pfizer’s personalized medicine that targets a type of late stage non-small cell lung cancer (NSCLC).  Abbott Molecular developed the FDA required EML4-ALK fusion companion molecular test that enables physicians to select the sub-group of patients that would benefit from using crizotinib.

He said in order to be successful, the partners need to “capitalize on their collective strengths and establish good chemistry.”  He believes that good “communication is key.”  Other important factors include “coordination of drug/IVD submissions as well as commercial execution and worldwide distribution.”  Goody emphasized that pharmas should get involved with a diagnostic partner early. This point was mentioned in other presentations as well.  He also said that there must be business incentives for both partners.

Ron Mazumber, Global Head, Research and Product Development, at Janssen Diagnostics spoke of the “Challenges and Opportunities/Solutions of CDx in Pharma” during his presentation.  Some of the main challenges include the “complex regulatory landscape, PMA process/expectations, and variability of testing.”  He offered some solutions such as “repurposing an existing 510 (k) cleared product, bridging studies, use of CTCs (circulating tumor cells), and multiple partners/platforms.”  Mazumber said the “ideal scenario is to start at Phase 3 with an IUO (investigational use only).”

Panel Discusses Rx/Dx Business Ideas

I also attended the panel discussion about “Emerging Commercialization, Collaboration and Business Models for Rx and Dx.”  One of the major themes of the discussion was that diagnostic companies need to continue to drive the value of their product.  Panelist Michael Pellini, President and CEO, at Foundation Medicine, said, “it’s all about education.”  Another panelist, Ron Andrews, President, Medical Sciences, at Life Technologies said, “We are venturing into a more complex world.”  He said “a lot more goes into a diagnostic nowadays than even five years ago.”  To the question posed by moderator Alexis Borisy, Partner, at Third Rock Ventures, “Do Pharmas ever pay diagnostic companies big fat royalties?”  “No, pharmas are not paying diagnostic companies big fat royalties,” said panelist Ron Mazumder at Janssen.”  However he did say, “pharmas are starting to recognize value but it is still a sticky issue.”  Andrews said “there are tons of therapeutics that have been shelved that might have value if the right diagnostic is developed.”  Panelist Pellini said that he “dreams of a fat royalty if they enter into a relationship with a pharma company and salvage a drug with a diagnostic.”  “They should share revenue downstream if they add enough value,” he added.

Circulating Tumor Cells Emerging as a Hot Topic In Cancer Research

While visiting CHI’s Molecular Medicine Tri-Conference back on February 20th at the Moscone Convention Center, in  San Francisco, I had a chance to walk around the exhibit hall and talk with some of the people working at their trade show booths.

I spoke with Sally Hall, who was working at the Transgenomic, Inc. booth, and asked her, “What are some of the hot topics at the show?.” She said that it seems that this year, a hot topic at the CHI MMTC is about circulating tumor cells (CTCs).  Sally said that “this year there are about twenty companies working in this field.”

I mentioned that I noticed that the number of conference talks about CTCs at the CHI MMTC had grown over the last three years.  She agreed that she had seen increased research activity in the CTC field.

As I understand it, when cancer tumors reach a certain size or age, some of the cells break off and migrate through pores in the walls of  blood vessels and circulate in the blood stream as CTCs. The CTCs may remain dormant for months or years in the circulatory system before migrating through pores in the blood vessels to spread to other organs or tissues.

Scientists are using CTCs as a new type of biomarker.  Several research tools and technology companies have developed technology platforms to identify, isolate or characterize CTCs.

Some companies are working to develop a platform that utilizes CTCs as basis for a future personalized diagnostic.  Researchers might someday develop blood  tests that can accurately identify specific kinds of cancer tumors long before they spread to other organs.  Blood test based companion diagnostics might be developed using CTCs in concert with targeted medicines to kill tumor cells before a cancer tumor has a chance to spread.

On the other side of the exhibit hall, I spent a few moments to see a talk from the founder of Rarecells, Inc.who discussed their progress in developing a CTC-based diagnostic method that they called ISET.  I was impressed by their concept. The table below lists a few of the commercial companies working in CTCs.  Whereas the CTC field is an emerging niche market today, it may be too soon to tell what the size and shape that this market might take.

Selected companies working in CTCs

Application Company Comment
Clinical Use of CTCs Fluxion Biosciences, Inc. IsoFlux system for  analyzing CTCs
Clinical Use of CTCs On-Q-ity, Inc. Microfluidic system for selecting CTCs
Clinical Use of CTCs BioCept, Inc. OncoCEE™ Platform for capture and detecting CTCs for molecular analysis
Clinical Use of CTCs Rarecells, Inc. ISET, a diagnostic method for isolation and immuno-molecular characterization of CTCs
CTCs in Clinical Trials Johnson and Johnson, Oncology Biomarkers Liquid biopsy – the use of CTCs in clinical trials as prognostic and predictive markers.
Novel Technologies ScreenCell, Inc. A mini device to isolate rare circulating tumor cells (CTCs).
Novel Technologies Advanced Cell Diagnostics, Inc. The CTCscope platform for detection and character-ization of CTCs
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