Biotech Strategy Blog

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

Posts tagged ‘Market Opportunity’

Nanotechnology is set to have a major impact on drug development and new products for the diagnosis and treatment of cancer.  Research from UCSF and Northwestern University published earlier this year in “Science Translational Medicine” shows this potential.

Edward Chow and colleagues describe how binding the cancer chemotherapy doxorubicin (DOX) to carbon nanoparticles 2-8nm in diameter in the form of a diamond, “nanodiamond” (ND), improved drug efficacy and overcame drug resistance.  Although this pre-clinical animal research has not yet been confirmed in humans, it raises the possibility of more efficient chemotherapies and the hope of increased survival rates as a result.

The conclusion from this research is that nanodiamonds may be a viable drug delivery platform for small molecules, proteins and nucleic acids. This technology could have an application in wide range of diseases.

Why is nanoparticle-mediated drug delivery more effective? The paper suggests one reason is that the nanodiamond-doxorubicin complex (NDX) allows for a more gradual release of DOX, allowing for increased tumor retention and increased circulation time.

It’s important to note that the NDX complex does not specifically target the drug efflux pumps, such as MDR1 and ABCG2 transporter proteins, responsible for chemoresistance. Instead the NDX complex appears to overcome drug resistance passively by the way DOX is released from the nanodiamond.

This research shows that taking old drugs and combining them with new drug delivery technology may offer therapeutic benefits.  The authors conclude that this research, “serves as a promising foundation for continued NDX development and potential clinical application.”

If successful in humans, it will translate into new product development and market opportunities for emerging biotechnology and biopharmaceutical companies.


ResearchBlogging.orgChow, E., Zhang, X., Chen, M., Lam, R., Robinson, E., Huang, H., Schaffer, D., Osawa, E., Goga, A., & Ho, D. (2011). Nanodiamond Therapeutic Delivery Agents Mediate Enhanced Chemoresistant Tumor Treatment Science Translational Medicine, 3 (73), 73-73 DOI: 10.1126/scitranslmed.3001713

I’m off to a conference in Orlando today, so thought it might be interesting to follow-up on my previous post about the emerging medical device/biotechnology cluster around Austin, Texas to think about what’s happening in Central Florida.

Orlando is most well-known for Disney and theme parks, and major conferences (see my post on attending the ASH annual meeting in Orlando last year). However, the opening of a new medical school, children’s hospital and medical research institute will undoubtedly lead to biotechnology and biomedical companies considering start-ups in the surrounding area.

Florida, like Texas, offers no personal taxation and Orlando is also well connected for flight connections throughout the country.

Orlando, in my opinion, is further behind Austin, and to some degree all cities with a medical school, in it’s attempt to drive research and innovation.  Whether Central Florida can establish a critical mass of companies and sufficient industry talent is the challenge, especially as multiple regions across the United States are also competing for biotechnology $.

However, even if Orlando does not become a major biotechnology cluster, it is more likely to become a major center for clinical and biomedical research.

In April 2009, the La Jolla based Sanford-Burnham Medical Research Institute opened a new research facility at Lake Nona in Orlando.  It is home to 900 scientists undertaking R&D on drug discovery, stem cells, nanomedicine and translational research.

One of research areas it is focusing on is diabetes and obesity, or diabesity as it is rapidly becoming known, an area that is rapidly reaching pandemic proportions in the United States. A symposium on Frontiers in Biomedical Science: Metabolic Networks and Disease Signatures will be held on March 11.

Luke Timmerman’s post on Xconomy about the Institute and the $50M gift it received last year to change its name is well worth a read.  In another post, he also raises the question of whether biotechnology companies can make money going after diabesity, notwithstanding the market opportunity? Need and market opportunity don’t always translate into valid targets for drug development, especially when many of the issues to do with diabetes and obesity relate to lifestyle and food content.

The Sanford-Burnham Medical Research Institute is the cornerstone of a cluster of bio-medical research companies and healthcare institutions, including the M.D. Anderson Orlando Cancer Research Institute, the new University of Central Florida (UCF) College of Medicine that opened in 2009, and Nemours Children’s Hospital that will open in 2012.

I think it will take several years before we can see if a significant biotechnology cluster grows up around these research and medical institutions.  Whether Central Florida and Orlando can grow into a leading biotechnology region remains to be seen.

That is the interesting question that struck me after reading Sam Kean’s informative article in the February 4 edition of Science.  Ten years on from the sequencing of the Human Genome, the patenting of human genetic information presents unique challenges at the interface of science, law and innovation.

Researchers have obtained patents for isolating different sections of DNA that occur naturally in our bodies.  Whether this should be permitted is still open to debate. Currently, diagnostic companies who want to launch a new cancer test face the challenge that patents now cover many genes.

The Science article cites start-up Foundation Medicine in Cambridge, MA who estimated the cost of investigating possible patent infringement for a new diagnostic test at $35M, a cost that exceeded the company’s $25M of VC funding.

Add in the costs of any royalties or licensing fees and the issue of prior patents is now a nightmare for any diagnostics company.  It is simply not practical to license every gene that may be implicated in a multifactorial disease such as diabetes.  Pre-existing patents have become a barrier to market entry.

As the Science article reports, gene patents cover not only very small snips of DNA, as short as 15 nucleotides, but can prohibit the sequencing of associated DNA. Companies such as 23andMe that sequence an individual’s genome to test for the presence of certain genes may be violating patent rights of others.

What’s more so called “method” patents cover the linking of a gene sequence with a specific medical condition.

As advances in personalized medicine continue, there is a need to balance the competing interests of protecting scientific discovery and rewarding innovation, while at the same time allowing access to human genetic information that many think should be “free to all men and reserved exclusively to none.” Quotation from Bilski v. Kappos, 130 S.Ct. 3218, 3225 (2010)

A law suit currently on appeal to the US Court of Appeals for the Federal Circuit may lead to a change in the current practices of the US Patent & Trademark Office.  The American Association of Pathologists and others have challenged several patents relating to the breast cancer genes BRCA1 and BRAC2 held by Myriad Genetics and the University of Utah Research Foundation.

BRCA1 and BRCA2 genes are associated with an increased risk of breast and ovarian cancer.  The US district court for the Southern District of New York in a surprise decision by Judge Robert Sweet, invalidated Myriad’s patents.  The New York Times article about the case has a link to the Judge’s 156 page opinion.  The decision that isolated but otherwise unaltered DNA should not be patentable is now being appealed by Myriad.

In their legal brief, arguing for the decision to be upheld, the United States Government states:

“The fact that a particular segment of the human genome codes for the BRCA1 protein in a human cell, for example, rather than for adrenaline or insulin or nothing at all, is not within the power of science to alter. Such basic natural relationships may not be the subject of a patent.”

If the District Court’s decision is upheld on appeal, it would represent a fundamental policy shift on what patents can be obtained for human genetic information. Such a decision would prevent Myriad from charging royalties and exclusivity for the genetic testing of BRCA1 and potentially invalidate similar types of patents. Depending on your point of view this will either harm the biotechnology industry or increase the market opportunities.

Given the stakes involved, it is likely the Myriad case will end up being considered by the United States Supreme Court, and what they may decide is anyone’s guess.

To read more in-depth analysis about the Myriad case and the legal issues involved with the patenting of genomic information, I strongly recommend the “Genomics Law Report”, a blog written by Dan Vorhaus and others.

Ten years after the human genome was sequenced we are still working out the intellectual property rights. The question as to whether companies should be allowed to patent unaltered human genes is one that will be answered in the not too distant future.

Following on from my recent blog post on emerging treatments in osteoporosis, one of new approaches in development is the inhibition of cathepsin-K.

Cathepsin-K inhibition is a novel approach to osteoporosis treatment and Merck’s odanacatib is leading the way in this new class of drugs. It is currently in phase III development, with 16,716 subjects enrolled (NCT00529373).

Cathepsins are lysosomal proteases. Cathepsin K (Cat-K) is a cysteine protease that plays an important role in the function of osteoclasts (the cells responsible for bone destruction). Cat-K acts to degrade bone collagen. By inhibiting it, the removal of bone matrix proteins by osteoclasts is reduced.

However, Cat-K inhibitors such as odanacatib do not kill off the osteoclast, but allow it to still produce chemokines and growth factors such as WNT that are responsible for the effective function of osteoblasts (the cells responsible for bone formation).

The net result is that Cat-K inhibitors reduce bone resorption.

Phase II clinical trial results for odanacatib presented at the American Society of Bone and Mineral Research (ASBMR) annual meeting last year (abstract #1247),  showed an increase in spine and hip bone mineral density (BMD) after four years of follow-up, suggesting that odanacatib use leads to increased bone strength. As reported by Merck in their press release:

In postmenopausal women who received odanacatib 50 mg weekly for four years (N=13), an increase in BMD of 2.8 percent at the lumbar, and 2.7 percent at the hip were demonstrated between years three and four of treatment. Over four years of treatment, these women had increases in lumbar spine (10.7 percent) and hip (8.3 percent) BMD from baseline.

If you are looking for further information on the science, the February 2011 issue of “The Journal of Bone and Mineral Research” has several papers on odanacatib, osteocytes and cathepsin K inhibitors.

Merck has 16,716 subjects enrolled in their phase III trial for odanacatib, and July 2012 is indicated as the date when data will be available for the primary end-point of reduction in fracture risk over the three year treatment period.  We can expect the phase III results shortly after that, and if positive, an FDA approval could be expected in 2013.

The development of odanacatib by Merck is clearly a strategy to combat generic alendronate, which has eroded Merck’s market share and profits for Fosamax.  Both odanacatib and generic alendronate, are once weekly doses. The timeline for a product launch for odanacatib appears to be in the late 2013/2014 period, and I am sure further clarity on this will appear from Merck nearer the time.

The challenge for odanacatib is that by 2015, analysts estimate that Amgen’s RANKL inhibitor denosumab will be a blockbuster (more than $1 billion in sales) and sales of parathyroid hormone analogues will have tripled to $1.4 billion.

Although the market opportunity in osteoporosis is likely to grow given the aging population around the world, it remains to be seen how the cost/benefit of odanacatib will stack up against the competition, and whether Merck can capitalize on this.

As an update to this morning’s blog post that mentioned Vertex’s VX-770, the company have just announced their key business objectives for 2011.  Further information will be included in the presentation by Vertex at the JP Morgan Healthcare conference scheduled for later today.

The news in Cystic Fibrosis is that if the phase 3 clinical trial data is positive the NDA for VX-770 is expected in the second half of 2011.  The following are the relevant sections from the press release:

Cystic Fibrosis: Phase 3 Registration Program for VX-770 Nears Completion

VX-770 NDA Submission Planned for Second Half of 2011

  • Three trials of the novel cystic fibrosis transmembrane conductance regulator protein (CFTR) potentiator VX-770 are fully enrolled and ongoing as part of a global Phase 3 registration program focused on patients with the G551D mutation. The G551D mutation is present in approximately four percent of people with CF.
  • The first Phase 3 data for VX-770 are expected in the first quarter of 2011 and will come from the Phase 3 STRIVE trial in people aged 12 and older with at least one copy of the G551D mutation. Data from the Phase 2 DISCOVER trial, which was primarily a safety study that enrolled people aged 12 and older with two copies of the F508del mutation, are also expected in the first quarter of 2011.
  • Data from the Phase 3 ENVISION trial in people aged six to 11 with at least one copy of the G551D mutation are expected in mid-2011.
  • If positive, the results from the Phase 3 program for VX-770 could support the submission of an NDA for VX-770 in the second half of 2011.

In addition, Vertex announced that they expected interim data in the first half of 2011 from the phase 2 trial that combines VX-770 with VX-809:

Combination of Two CFTR Modulators for the Treatment of People with the Most Common Mutation of Cystic Fibrosis

  • Vertex is conducting a Phase 2a clinical trial to evaluate multiple combination regimens of its lead CFTR Modulators – VX-770, a CFTR potentiator, and VX-809, a CFTR corrector – in people with the most common mutation of CF, known as F508del. Enrollment is ongoing in Part One of the trial, which is designed to evaluate VX-809 (200 mg), or placebo, dosed alone for 14 days and in combination with VX-770 (150 mg or 250 mg), or placebo, for 7 days. Vertex expects to obtain interim data from Part One of the trial in the first half of 2011.

2011 looks to be an interesting year for Cystic Fibrosis and it is certainly positive to see biotechnology companies such as Vertex developing new products for this debilitating illness.

One of the exciting things about the biotechnology industry is its ability to innovate and translate developments in basic science into potential new drugs.

I previously wrote about denufosol in cystic fibrosis (CF), a disease that affects about 30,000 people in the United States and 70,000 worldwide.  The disease is characterized by the accumulation of mucus that leads to bacterial overgrowth and chronic lung infections. Mucus cannot be removed from the lung in CF due to abnormal mucociliary transport resulting from impaired epithelial chloride secretion and sodium hyperabsorption.  This is now known to be due to defective cystic fibrosis transmembrane regulator (CFTR) protein. A good overview of this can be found in the 2006 New England Journal of Medicine Editorial by Felix Ratjen, “Restoring Airway Surface Liquid in Cystic Fibrosis.”

A good overview of the pipeline of new drugs in development for CF can be found on the Cystic Fibrosis Foundation web site.  Vertex in particular has two drugs  (VX-809, VX-770) in late stage development that are cystic fibrosis transmembrane conductance regulators, aimed at increasing CFTR function.  Phase 3 registration data for VX-770 is expected in the first half of 2011. I look forward to writing about the results.

Recently, a team from Johns Hopkins led by Neeraj Vij published a paper in the January 2011 issue of Journal of Immunology on the “Critical Modifier Role of Membrane-Cystic Fibrosis Transmembrane Conductance Regulator-Dependent Ceramide Signaling in Lung Injury & Emphysema.”

The researchers found that lung damage in mice was associated with changes in the amount of CFTR in the cell surface membrane.  Decreases in the amount of CFTR were associated with increased ceramide, a trigger of inflammation of cell-death. Or as the the paper describes it:

“CFTR expression inversely correlates with severity of emphysema and ceramide accumulation in chronic obstructive pulmonary disease subjects compared with control subjects.”

The emergence of inflammation as a key role in chronic disease was the subject of a previous blog post about diabetes, so is interesting to see another area where it is involved.

This basic research shows that developing drugs that target CFTR and mediate ceramide may have an important role to play in the treatment of emphysema, a chronic obstructive pulmonary disease (COPD) that affects 2 million Americans.  Translational medicine that can take basic science and apply it to clinical practice is key to the long term success of the biotechnology industry.

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Inspire Pharmaceuticals (NASDAQ:ISPH), a North Carolina based biopharmaceutical company that focuses on products for ophthalmic and pulmonary diseases, recently announced positive results from their phase 3 trial (TIGER-1) of denufosol tetrasodium in patients with Cystic Fibrosis (CF).

Cystic Fibrosis is a genetic disorder that can lead to death as a result of pulmonary complications from airway obstruction, bronchial thickening and accumulation of mucous.  Lung function tests are widely used in the diagnosis, treatment and management of patients with CF.  Measurement of FEV1 (Forced Expiratory Volume in 1 second) is regarded as the best predicator of mortality.  As the disease progresses and the lungs become more obstructed, FEV1 decreases.

Inspire Pharma’s denufosol is an ion-channel regulator that helps keep the airways moist and helps mucous removal in CF patients.  It increases chloride secretion via calcium-activated chloride  channels (CaCCs), inhibits sodium absorption via epithelial sodium channels (ENaCs) and stimulates ciliary beat frequency.  Conveniently for patients, it is being developed as an inhaled drug delivered direct to the lungs by nebulizer.

The phase 3 clinical trial data presented by Dr Frank Accurso at the Annual North American Cystic Fibrosis Conference, and in the paper published in the American Journal of Respiratory and Critical Care Medicine (AJRCCM), showed an improvement in lung function after 24 weeks in patients with mild CF who received daily denusofol by means of a nebulizer.  The primary efficacy endpoint was a change in FEV1:

Source: October 21, 2010 presentation by Frank J. Accurso M.D. to North American Cystic Fibrosis Conference.  Available at Inspire Pharma.

Dr Accurso and his colleagues reported that the results demonstrated:

“Mean change from baseline to Week 24 endpoint in expiratory volume at 1 second (primary efficacy endpoint) was 0.048 L for denufosol (n=178) and 0.003 L for placebo (n=174; P=0.047).”

Despite the significant improvement in FEV1, there was no significant difference between the denufosol and placebo arms in the time to progression to first pulmonary exacerbation, suggesting that its long-term clinical effectiveness remains uncertain.

Source: October 21, 2010 presentation by Frank J. Accurso M.D. to North American Cystic Fibrosis Conference.  Available at Inspire Pharma.

Notwithstanding, these results do offer hope to patients with mild symptoms of Cystic Fibrosis.  Early treatment to maintain lung function may delay the onset of more severe physiological changes and the need for more radical treatment options such as a heart/lung transplant.

Thanks to BBC Health for writing about this topic and giving me the idea for this post.

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A company I have been watching for a while is Philadelphia based Avid Radiopharmaceuticals, now a wholly owned subsidiary of Lilly. They have a novel imaging biomarker, florebetapir (18F-AV-45) in development for the detection of Alzheimer’s disease.

In a press release last week, Lilly announced that the FDA had assigned a priority review to the marketing application of florebetapir. The Peripheral and Central Nervous System Drugs Advisory Committee of the FDA meet on January 20, 2011.

Bayer have a competitor product in development, forebetapen (BAY 94-9172). Both florebetapir and florebetapen are 18F radiolabelled imaging biomarkers that bind to amyloid plaque in the brain.  When used in conjunction with a Positron Emission Tomography (PET) scan, they enable the accumulation of amyloid that occurs in Alzhemeir’s disease to be visualized.

Phase 3 trial results for florebetapir published earlier this year showed that the brain amyloid burden seen in the PET scans positively correlated with the plaques seen in autoposies of the same patients.  Proof that what the imaging biomarker shows is an accurate representation of the underlying pathology.

What makes the use of florebetapen and florebetapir interesting is that it is already common practice to use imaging tracers with PET scans. Fluorodeoxyyglucose (FDG) is widely used in the diagnosis, staging and treatment of oncology patients as a result of its ability to show the intense glucose uptake that occurs with most cancers.

Both Avid and Bayer products are most likely to be approved based on the clinical data presented to date.  It will be interesting to see the prices that they intend to charge.

As for the market opportunity, they are likely to have a role to play in the early diagnosis of patients with mild cognitive impairment, since at present it is difficult to diagnose these patients and differentiate Alzheimer’s disease from other forms of dementia.  Most likely, models will be developed that look for a correlation between accumulation of amyloid plaque and decline in cognitive function, from which a probability of developing Alzheimer’s disease can be calculated.

Imaging biomarkers are likely to place an increasingly important role in the development of new products by biotechnology companies and in the design of clinical trial endpoints.

Uveal melanoma is a common cancer of the eye that involves the iris, ciliary body and choroid.  It is a disease that hits 2000 people per year in the United States and is common in those over 50.  Standard treatment involves removal of the eye or radiotherapy. There is an unmet need for systemic drug therapy.

Mutations in the BRAF gene (a member of the Raf family that encodes a serine/threonine protein kinase) have been found in many skin melanomas.  In 80% of the cases, a single point mutation in exon 15 (T1799A) has been shown to occur.  Some new agents in development such as PLX4032, ipilumumab, GSK2118436 have shown promise in advanced skin melanoma, but research suggests that BRAF may not be the key to Uveal melanoma.

Henriquez et al, in a paper published in Investigative Ophthalmology & Visual Science showed that the T1799A BRAF mutation was only present in 9 of 19 iris melanoma tissue samples, but only in one case of uveal melanoma, suggesting differences in the genetic and clinical differences between the two.

Recently, two papers have been published that provide new insight into this intraocular cancer. In the December 2, 2010 issue of the New England Journal of Medicine, Van Raamsdonk et al, found mutations of either the GNAQ or GNA11 gene to be present in 83% of uveal melanomas that were sequenced (n=713).

Harbour et al, in the December 3, 2010 issue of Science reported findings of a frequent mutation of BAP1 in metastasizing uveal melanomas. They found that in 26 of 31 (84%) of uveal melanoma tumors they examined, there was a mutation of BAP1, the gene encoding BRCA1 associated protein 1 (BAP1) on chromose 3p21.1. The results published in Science, “implicate loss of BAP1 in uveal melanoma metastasis and suggest that BAP1 pathway may be a valuable therapeutic target.”

The data suggests that there may be multiple pathways involved in uveal melanoma.  It is promising to see translational medicine in action, with scientists seeking to understand the molecular basis of a disease so that targeted therapies can be developed.  Uveal melanoma only strikes a relatively small number of patients, but if a highly effective drug can be developed, this could be a market opportunity worth pursuing.

This week’s New England Journal of Medicine (NEJM) has an interesting paper (Teriparatide and Osseous Regeneration in the Oral Cavity) that caught my attention on the use of teriparatide (Eli Lilly, Forteo®) in patients with chronic peridontitis, a disease that affects one in five American adults.  The total market for periodontitis services and products is estimated to grow at 6.4% to 2016, when it will be worth $1,937 m.

Teriparatide is a recombinant form of parathyroid hormone (PTH) consisting of amino acids 1-34, and is used for the treatment of osteoporosis.  In the body, PTH is the hormone that regulates the level of calcium in the blood.  Low blood calcium causes increased PTH release. The use of teriparatide has been limited by the FDA due to the risk of osteosarcoma from long-term exposure.  However, what makes it an interesting compound is its ability to stimulate osteoblasts to build bone, which is why the results from the NEJM on peridontitis are perhaps not that surprising.

As Andrew Gray in his NEJM editorial comments, because teriparatide activates bone remodelling it may have a role to play in the management of osteonecrosis of the jaw (ONJ). ONJ is a particularly nasty side effect that many breast, multiple myeloma and prostate cancer patients experience following any dental work.

Badros et al, point out in their Journal of Clinical Oncology (JCO) paper, that bone disease effects 70% of multiple myeloma patients, many of whom take a bisphosphonate such as zoledronic acid (Novartis, Zometa®) to reduce the risk of skeletal related events (SRE). Unfortunately, a few patients subsequently end up with ONJ as a serious side effect! Clinical trial results showed that ONJ occurred with a similar frequency in breast cancer patients taking denosumab (Amgen, Prolia®) as compared to zoledronic acid.

One only has to read the patient commentary available on online forums such as to realize the debilitating effect that ONJ has, not to mention the severe morbidity because of lack of delayed diagnosis and lack of effective treatments.

It is unclear whether the positive results from the NEJM in peridontitis will lead to clinical trials for the treatment of ONJ in cancer patients.  Although there is an unmet need, the market is small. In the meantime, I expect that doctors will be using teriparatide off-label to treat severe ONJ, which is less than ideal.

One biotech company banking on continued interest in Forteo® is Zelos Therapeutics, whose CEO, Dr Brian MacDonald is a fellow alumni of the University of Sheffield.  Zelos have a nasal spray formulation of teriparatide (ZT-034), which they hope will be equivalent to Ely Lilly’s product (that requires a daily injection).

Source: Zelos Therapeutics. In a press release earlier this year, Dr MacDonald commented:

“We believe that formulation of teriparatide as a nasal spray with comparable efficacy and safety to Forteo represents a simple, convenient approach to dosing that will make PTH therapy a better option for many more patients.”

Zelos’ product is currently in early stage clinical trials, so it will be interesting to see how this develops. The NDA is planned for 2012.  It is certainly a valid strategy for emerging biotechnology companies to take an existing marketed product and use a new drug delivery mechanism such as Aegis Therapeutics’ Intravail® drug delivery technology to expand the market.

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