Biotech Strategy Blog

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

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Regenerative medicine – will we be able to rebuild our bodies as we get older?

By on March 9, 2011

The Lancet yesterday published news of the world’s first tissue engineered implant of a urethra (the tube that carries urine out of the body from the bladder).

This research by Atlantida Raya-Rivera and colleagues at the Wake Forest Institute for Regenerative Medicine and Metropolitan Autonomous University in Mexico is another step towards when we may be able to regenerate a wide range of body parts. This would solve many of the donor shortages for livers and kidneys that exist today.

In their paper, Raya-Rivera describe how they took a tissue biopsy from five Mexican boys and by then seeding these cells on a scaffold, grew new urethras. These were subsequently transplanted into the boys (aged 10-14) between 2004-2007.  The results show that the tissue engineered urethras remained functional for up to 6 years, appeared normal within 3 months of implantation and allowed a urine median end maximum urinary flow rate between 16-28 mL/s.  To put this in context, the average urine flow rate of males aged 8-13 is 12mL/s, suggesting that the tissue engineered urethras functioned well.

For those who suffer from complex urethral problems as a result of disease, infection or congenital defects, this research offers the prospect of a new treatment option.  More research is required with a larger sample size to validate the findings, and to confirm that no strictures are seen long-term after reconstruction.

Ongoing research at the Wake Forest Institute of Regenerative Medicine (WFIRM) into engineering human livers, kidneys, pancreatic beta cells and heart valves suggests that, if successful, regenerative medicine will have a major impact on the treatment of future diseases.  I can imagine a world for people with diabetes where new pancreatic insulin producing cells could be engineered and implanted.

The potential to replace non-functional or diseased organs and tissues with a replacement tissue engineered new one (like replacing a car part) will have a tremendous impact on the pharmaceutical and biotechnology industry. Blockbuster drug franchises could disappear overnight.  Regenerative medicine is an exciting area to watch over the next few years.

References

This post was chosen as an Editor's Selection for ResearchBlogging.orgRaya-Rivera, A., Esquiliano, D., Yoo, J., Lopez-Bayghen, E., Soker, S., & Atala, A. (2011). Tissue-engineered autologous urethras for patients who need reconstruction: an observational study The Lancet DOI: 10.1016/S0140-6736(10)62354-9

New artificial retina restores some visual perception and improves autonomy

Detecting a door or a window may not be a big deal for all of us with normal vision, but for those who lose their sight, e.g. through retinitis pigmentosa (RP), a new “artificial retina” now provides hope of a better quality of life.

The Argus™ II Retinal Prosthesis System from California based company Second Sight, has just received CE marking.  This innovative device can now be sold and marketed within Europe, but it remains investigational in the United States. It is the first such device to be approved.

While this blog is mainly focused on the biotechnology industry, I’m very interested in innovation and bringing novel products to market. I also have a personal interest in the ophthalmology market.  Earlier in my career, I spent three years at Alcon working with leading European ophthalmologists on intra-ocular lens clinical trials, including the IDE registration trial for AcrySof®.

In the same way that a cochlear implant does not restore hearing, the “artificial retina” or so-called “bionic eye” from Second Sight is not intended to restore vision, instead it artificially provides electrical signals that it is hoped the brain can learn to interpret as shapes.

The “artificial retina” has three parts, a small video camera worn in a pair of glasses that captures visual images.  This transmits the electronic images to a video processing unit worn by the patient.  Data is then transmitted wirelessly to an implant that is located on top of the retina.

The array of electrodes resting on the retina stimulates those rods and cones that remain functional to generate electrical impulses that are then transmitted down the optic nerve to the brain.  Patients learn to interpret the patterns of light that are generated, and in the process gain some sense of visual perception that improves their daily life.

In an interview broadcast on French radio station, RTL one of the four French patients in the clinical trial, Thierry, talks about how this retinal stimulation device has improved his autonomy and quality of life.

When faced with blindness, any progress is noteworthy and it will be interesting to see the extent to which this technology can be further developed.  I expect that more clinical trial data will be forthcoming at the annual meeting of ARVO (Association for Research in Vision and Ophthalmology) in May.

Update August 23, 2012:  FDA Panel to review whether to recommend of approval of Argus II artificial retina in the United States

The FDA Ophthalmic Devices Panel will review on September 28, 2012 the Humanitarian Device Exemption (HDE) market approval application by Second Sight for its Argus II Retinal Prosthesis System with an indication for patients with severe to profound retinitis pigmentosa (RP) who have bare or no light perception in both eyes.

What is a Humanitarian Device Exemption? 

“An HDE is similar in both form and content to a premarket approval (PMA) application, but is exempt from the effectiveness requirements of a PMA. An HDE application is not required to contain the results of scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose. The application, however, must contain sufficient information for FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury, and that the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment.”  U.S. Food & Drug Administration

Given the lower standard required for a HDE, and the fact that Second Sight obtained a CE mark in Europe, it would be hard to believe the FDA advisory panel will not recommend approval in a patient population that are effectively blind.

However, the FDA guidance also notes that an approval of an HDE, while allowing marketing of the device, does require it’s use to be at facilities where an institutional review board (IRB) has approved the use of the device. If approved for sale in the US, the market for Second Sight will be limited as a result to academic and hospital settings that have an IRB able to provide the necessary oversight and review.

“An approved HDE authorizes marketing of the HUD. However, an HUD may only be used in facilities that have established a local institutional review board (IRB) to supervise clinical testing of devices and after an IRB has approved the use of the device to treat or diagnose the specific disease. The labeling for an HUD must state that the device is an humanitarian use device and that, although the device is authorized by Federal Law, the effectiveness of the device for the specific indication has not been demonstrated.”

For those interested in more information, background material on the HDE application will be available on the FDA website no later than 2 days prior to the September 28 meeting of the Ophthalmic Devices Panel of the Medical Devices Advisory Committee.

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Engrailed-2 (EN2) may be a new biomarker for the early detection of Prostate Cancer

By on March 7, 2011

One of the challenges with cancer is being able to detect the disease early enough for effective treatment. The staging or progression of the cancer at time of diagnosis is correlated with 5 year overall survival (OS) rates. Biomarkers that may be expressed by a cancer are, therefore, potentially useful for diagnosis and monitoring of treatment.

There is an ongoing debate about the effectiveness of prostate specific antigen (PSA) as a biomarker for early detection of Prostate Cancer (PC). As Sally Church on Pharma Strategy Blog discusses, PSA measurements can offer false positives and up to 75% of men have a negative biopsy. There is clearly a need for alternatives to PSA measurements.

In the March 1, 2011 online edition of Clinical Cancer Research (a journal of the American Association for Cancer Research, AACR), Richard Morgan and colleagues from the Postgraduate Medical School at the University of Surrey in Guildford, assessed the potential of the Engrailed-2 (EN2) protein as a prognostic biomarker for PC.

Their research found that EN2 is secreted into the urine of men with PC (92%, n=104), but does not appear in the urine of those without PC (0%, n=11). Presence of EN2 in the urine showed a 66% sensitivity for the detection of PC without a digital rectal exam (DRE) when compared to biopsy findings of those with confirmed PC (54 of 82 men). The specificity of the test is almost 90%, i.e. it can pick out men with prostate cancer versus those without cancer.

Interestingly, there was no correlation between serum PSA levels and the presence or absence of EN2. EN2 is measured in small quantities of unprocessed urine (100μl) by means of a simple enzymatic assay.

The investigators state in their paper that a multicenter clinical trial is planned to investigate whether EN2 measurements can be used as a tool for monitoring disease progression after hormonal treatment, radiotherapy or surgery.

However, despite the promising preliminary results in this paper, it is still too early to say whether EN2 will evolve into a clinically useful predictive biomarker for PC.  The fact that EN2 was secreted in patients with non-PSA secreting PC, raises the possibility that it might have a diagnostic role to play in combination with other biomarkers.

EN2 has also been shown to be an oncogene in breast cancer, so it will be interesting to see if there is any further information presented at the forthcoming AACR annual meeting from April 2 to 6 in Orlando.

I recommend reading Pharma Strategy Blog for further insight on cancer biomarkers.

Unethical Anaesthesia Clinical Research, should all journals require proof of IRB approval before publication?

By on March 6, 2011

BBC health reported this past week on the news that Professor Dr. Joachim Boldt, the former head of anaesthesia at the Klinikum Ludwigishafen hospital in Germany had published 102 papers in leading academic journals without first having obtained ethics committee (EC) or institutitional review board (IRB)  approval for the research.

These studies on patients undergoing surgery or intensive care led to the development of new guidelines for managing the administration of colloids for fluid replacement during surgery. Questions are now being asked about the validity of these scientific findings and whether any fabrication of research data took place.

When Dr Boldt submitted research for publication he indicated that EC/IRB approval had been obtained, a claim that was not checked by any of the journals.  It now appears that EC/IRB approval had not been obtained. Last week the editors of 16 leading publications formally retracted the papers they had published from Dr Boldt.

The news that an anaethetist failed to obtain informed consent or EC/IRB approval for clinical research comes as no surprise to me.

I conducted anaesthesia breathing system research in the early 1990’s in a joint industry/academic partnership program. My research was published in the British Journal of Anaesthesia, who also published several studies from Dr Boldt.

At that time, many of the anaethestists I worked with questioned the need for patient informed consent for research with a new breathing system. They argued the patient would have to use one anyway during the operation, and even if this was a research study it was not necessary. Requiring formal signed informed consent for the clinical trials I did was a novel experience for some of the anaethetists I worked with.

Indeed, if the editors of the journals were to look closely at european clinical research related to medical devices published prior to EC Directives and standards such as EN540, ISO14155 coming into effect, they might find that many researchers did not obtain IRB/EC approval or informed consent for that work.

I think the journal editors are right to condemn the lack of research integrity that took place with Dr Boldt.  All of us in the pharmaceutical, biotechnology and medical device industries who undertake clinical trials to bring new products to market rely on the goodwill of patients to participate in the medical research process.

The news that Dr Boldt did not respect the rights of individuals, and failed to follow the Declaration of Helsinki, the fundamental “Ethical Principles for Medical Research Involving Human Subjects”, published by the World Medical Association, undermines the integrity of the clinical research process for all of us.

Moving forwards, I would suggest that the editors of journals require authors to submit a copy of the EC/IRB approval letter/notification with their manuscripts.  Any form that just requires you to tick a box or sign off to show compliance is open to potential abuse by a very small minority.

All EC/IRB approvals have to be in writing, so this step would not be an onerous burden and would provide some confidence of valid ethics approval, and in the process support the integrity of the clinical trials that we all rely upon.

If you would like to follow this issue in more detail, Ivan Oransky, on his excellent Retraction Watch Blog has been writing about this story since last October.

Letter from San Francisco

I was recently in San Francisco so thought I would continue my theme of writing about biotechnology regions that I visit around the United States.

Growing up in England, I remember listening to the radio broadcasts of the late Alistair Cooke, who from 1946 to 2004 shared his “Letter from America“; the longest running radio programme ever produced.  In the pre-internet era his mixture of anecdotes, insights and reflections reminds me of modern day blogs.

San Francisco remains a favorite city of mine. Fueled by access to venture capital and proximity to major research universities such as Stanford, University of California at Davis, Berkelely & San Francisco, start-up companies continue to thrive in the Bay area. BayBio, Northern California’s Life Science Association runs many excellent events. Their annual conference in April is focused on “Powering Global Innovation.”

The anchor tenant in the San Francisco biotech mall remains Genentech, and no other company in the area has had the same growth trajectory.  What catapults a company forward is a combination of a breakthrough product and ability to capture its value. The licensing deals and acquisitions we see today in the biotechnology industry, to some degree limit the ability of emerging biotech companies to repeat Genentech’s model. Risk sharing, partnering and the desire of venture capitalists for an early return on investment, all limit the ability of a biotech company to make it to the major leagues. In the end, even Genentech ended up being acquired by Roche.

What’s the future in San Francisco? It remains a high cost place to live but with a pool of talent in the entrepreneurial culture of the West Coast. There is also the uncertainty about the California economy and the cost of doing business, which is most likely set to increase.  In some way, my impression is that San Francisco has not quite taken off as a biotechnology city in the same way that Boston and Cambridge has. Feel free to comment if you disagree or have an opinion otherwise.

Allon Therapeutics announces promising preclinical results for davunetide in Parkinson’s Disease

By on February 24, 2011

Earlier this month the Michael J Fox Foundation (MJFF) announced that Vancouver based Allon Therapeutics had been able to improve motor function and brain pathology in a mouse model of Parkinson’s disease (PD).

MJFF funded this research with Allon Therapeutics. The preclinical study results are published in the Journal of Molecular and Cellular Neuroscience.

What makes this data interesting is that it adds further support to the potential efficacy of the company’s lead product, davunetide, in a wide range of neurodegenerative disorders.

Davunetide (AL-108) is a microtubule-interacting peptide based on an eight amino acid sequence, Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln, single letter code NAPVSIPQ (NAP) derived from activity-dependent neuroprotective protein (ADNP). It has been shown to have neuroprotective properties.

Davunetide can be administered by IV or intranasally and crosses the blood/brain barrier. It is effective at promoting neurite growth, restoring transmission between nerve cells and untangling some of the damage seen in neurodegenerative disorders such as Alzheimer’s disease. References to the scientific publications and mechanism of action can be found on the Allon Therapeutics website.

Currently it is being developed for Alzheimer’s disease (AD), schizophrenia cognitive impairment and frontotemporal dementia (FTD). Davunetide is in a phase 3 clinical trial for progressive supranuclear palsy (PSP), a subtype of FTD.

The company’s strategy is to pursue a fast-track to market in a small indication such as PSP. This is makes a lot of sense for a small biotechnology company with limited funding.  Successful approval in PSP will significantly increase the value of the company and improve the terms of any future licensing/partnering deals.

The hope for davunetide is that it will prevent disease progression in disorders such as AD and provide neuroprotective prophylaxisis prior to surgery that carries a high risk of memory loss e.g. heart bypass and coronary artery graft surgery (CABG).

While davunetide may not be a cure for AD, being able to slow down disease progression is something that has considerable value.  Given that new imaging biomarkers are likely to provide the opportunity to detect AD much earlier, the market opportunity for early treatment is set to increase.

Many families and caregivers would welcome a drug that delays further cognitive decline and memory loss in their loved ones.

On the basis of the promising preclinical results, I think we can expect to see further clinical research on davenutide in Parkinson’s Disease.

AB Science – realizing the potential of masitinib in cancer and inflammation

Following on from yesterday’s news that Gilead had acquired Calistoga and CAL-101, another company that is exploring the interface between cancer and inflammation is Paris based AB Science.

Pharma Strategy Blog has an excellent interview with the CEO, Alain Moussy.  AB Science is an emerging French biopharmaceutical company, and I previously wrote about its IPO.

The company has adopted a unique market entry strategy of obtaining approval first in animal health for their tyrosine kinase inhibitor, masitinib.  In 2008, AB Science gained European approval for canine mast cell tumors and in December 2010 FDA approval.

The company recently announced that on February 8, 2011 it had its first US sale of masitinib to vets.

Masitinib is in fact a multi-kinase inhibitor that inhibits wild type and mutant forms of stem cell factor receptor (c-KIT, SCFR), platelet-derived growth factor (PDGFR), fibroblast growth factor 3 (FGFR3) and to a lesser degree, focal adhesion kinase (FAK).

Sally Church on the Pharma Strategy Blog has written about how AB Science’s strategy makes sense – if you look at Pfizer, they obtain more revenue from animal health than they do from oncology.  AB Sciences’ Masivet® in Europe, Kinavet® in the United States competes against Pfizer animal health’s tyrosine kinase inhibitor, Palladia® (toceranib), which also targets mast cell cancer in dogs.

Not only does this growth strategy generate revenue for an early-stage company like AB Science, it also allows the company to build a sales and marketing infrastructure in the United States and Europe while waiting for the results of pivotal phase 3 studies in humans.

The phase 2 clinical trial data for masitinib in combination with gemcitabine in pancreatic cancer were impressive (28% survival at 18 months).  The phase 3 clinical trial results are expected this year.  The clintrials.gov listing shows the date for the estimated primary completion date (Overall Survival) as November 2010 with study completion in November 2011.  Obviously the exact timing depends on how fast subjects were accrued, but I would be surprised if we didn’t see some data presented at ASCO or ESMO, especially if positive.

In terms of targeting inflammation, masitinib is in phase III development for mastocytosis, rheumatoid arthritis (RA) and asthma.  AB Science announced on January 27, 2011 the first patient recruited into their phase 3 study in severe asthma.

The company’s new product development strategy is way ahead of many of its competitors in identifying the links between cancer and inflammation, and choosing to target market opportunities in both areas.

AB Science is an exciting company to watch, and I expect that we will see important new data come out at major scientific meetings this year.

Gilead acquires Calistoga and CAL-101 for $375M

In an acquisition that highlights the importance of cancer and inflammation, Gilead Sciences today announced the acquisition of Seattle based Calistoga Pharmaceuticals for $375M.

Calistoga’s pipeline is focused on the development of PI3 kinase inhibitors for cancer and inflammation. Sally Church on Pharma Strategy Blog has written extensively about “The potential of the PI3K pathway inhibitors in lung cancer”, and discussed Calistoga’s CAL-101 compound and its development for hematological malignancies in her report on “What’s hot at ASH in 2010”.

I encourage you to read (if you already don’t) Sally’s excellent Pharma Strategy Blog for further information on the science and mechanism of action of the PI3K pathway (way beyond my pay grade) and her view on CAL-101’s potential.

Sally will also be at the timely AACR meeting on targeting PI3K/mTOR signaling in cancer that is being held in San Francisco later this week.

What makes CAL-101 interesting to me is its potential in targeting inflammatory mediators. CAL-101 is a first in class PI3K delta specific inhibitor; the delta isoform of phosphoinositide-3 kinase (PI3K) is expressed in leukocytes involved with a variety of inflammatory, autoimmune and hematological cancers. Increasingly I think we will see companies investigating the cross-talk between inflammation and other diseases.

In addition to the upfront payment of $375M, there are potential milestone payments of $225M.  The deal is set to close in the second quarter of 2011.

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Hypoxia and Inflammation: is HIF-1 a target for drug development?

I have a long-standing interest in hypoxia (lack of oxygen). Many years ago while completing my Masters degree in human physiology, I undertook research at the RAF Institute of Aviation Medicine at Farnborough on the effects of mild hypoxia on pilot performance.

So I was interested to read an article in the February 17, 2011 issue of the New England Journal of Medicine (NEJM) on hypoxia and inflammation, and how this influences disease.  Inflammation is one of my blog themes for 2011, and in a previous post, I wrote about how its ubiquitous role has been characterized as one of the “Insights of the Decade”.

In the NEJM article on mechanisms of disease, the authors Holger Eltzschig and Peter Carmeliet discuss the cross-talk between hypoxia and inflammation, and how this is implicated in cancer, infections and inflammatory bowel disease.

A lack of oxygen (hypoxia) is something that humans are acutely aware of.  We are all familiar with the flight/fight response that is designed to increase oxygen delivery to the brain and muscles.  Hypoxia can also lead to an inflammatory response.  The flip side is also true, where there is inflammation there is often local tissue hypoxia. An example of this is in solid tumors where the level of oxygen is considerably lower than in normal tissue.

The link between hypoxia and inflammation is regulated by the hypoxia-inducible transcription factor (HIF) that is activated by hypoxia. HIF has two subunits HIF-α (consisting of HIF-1α and HIF-2α) and HIF-β. The article goes into detail (beyond the scope of this blog post) about the interaction between HIF and the nuclear factor kappa-B (NF-κB ) transcription factor that regulates inflammation.

Elevated levels of HIF-1α and HIF-2α correlate with cancer deaths.  HIF-1 overexpression is associated with tumor growth, vascularization and metastasis. This has led to HIF-1 being evaluated as a target for anti-cancer drugs.

EZN-2968, a novel HIF-1α antagonist is in phase I clinical trials.  It is a joint development of two biopharmaceutical companies, Enzon in New Jersey and Santaris pharma in Denmark.

It will be interesting to see whether targeting hypoxia dependent signaling pathways will enable a clinically significant reduction in the inflammatory response.

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