Biotech Strategy Blog

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

Posts tagged ‘Cystic Fibrosis’

White House Washington DC BIO 2011 Convention © Pieter DroppertOne of the sessions at BIO 2011 in Washington DC that I hope to make if my travel plans permit, is the Monday afternoon session on “What is the Future for Innovative Medicines in Our Industry’s Pipeline?”

The June issue of Nature Reviews “Drug Discovery” attempts to answer this question by looking back at what happened to the R&D projects involving 28,000 compounds investigated since 1990.

Fabio Pammolli and colleagues analyzed the Pharmaceutical Industry Database (PhID) maintained by the IMT (Institutions, Markets, Technologies) in Lucca, Italy.

In their Drug Discovery article entitled “The productivity crisis in pharmaceutical R&D,” they reach a number of conclusions, some of which are:

  • Output of new drugs has not matched investment in R&D
  • Therapeutic innovation has become more challenging and complex
  • Decline in R&D productivity is associated with investments in R&D areas where risk of failure is high
  • There is no evidence of any R&D productivity differences between United States and Europe.

The authors analyzed R&D investment decisions by looking at the potential pay-off for an R&D project (probability of market launch multiplied by potential market value) and the expected Probability of Success (POS) in reaching the market based on the average success rate of compounds with the same pathology.

What I found interesting in their paper was the fact that many of the therapeutic areas with the highest percentage of R&D projects had the lowest average POS e.g. cancer drugs (antineoplastic and immunomodulating agents) had the lowest POS (1.8%) and the highest share of total projects (21.77% from 1990 to 1999, increasing to 29.77% from 2000-2007).  The 1.8% average probability of success can be contrasted with 4.19% for musculoskeletal system drugs and 6.64% for dermatologicals.

The authors argue that the data shows a shift towards therapeutic markets with a lower POS. What are the reasons for this? Possible explanations include:

  • Orphan drug development incentives: legislation that provides incentives to undertake drug development for rare diseases (orphan drugs) has led to a shift towards these targets, which by definition have smaller markets.
  • Development of drugs for chronic diseases e.g. Alzheimer’s disease: Collectively these have a POS of 6.88% compared to the acute disease average POS of 8.77%.  85.80% of R&D projects from 2000-2007 were within this category.
  • More research targeting lethal diseases such as cancer and infectious disease, which have an average POS of 5.54% compared to non-lethal diseases, average POS of 9.72%.

The authors conclude from this research that:

“R&D investments tend to focus on new therapeutic targets, which are characterized by high uncertainty and difficulty, but lower post-launch competition.”

This article offers some interesting retrospective analysis, but I am concerned that they may have underestimated the market potential for many rare disease areas where market size cannot properly be quantified.

As Novartis showed with imatinib (Gleevec®/Glivec®), it is possible to build a blockbuster out of a very small, rare market (only 4,500 – 5,000 new diagnoses of CML per year in the United States), creating a new market segment and moving the leukemia from a certain death sentence to a chronic disease that can be easily managed with targeted therapy.

The focus of many biotechnology and biopharmaceutical companies on orphan drug development has been shown to be a valid strategy by Genzyme and others.  Proving you can bring a product to market and obtain some revenue is likely to stimulate more company investment rather than less.

In the run up to BIO 2011 several companies have highlighted their orphan drug strategy, including Oklahoma City based Selexys Pharmaceuticals who announced news about SelG1 in Sickle Cell Disease and Lamellar Biomedical from Glasgow with LMS-611 for Cystic Fibrosis.

I am looking forward to learning more at BIO on how industry experts view the future for innovation within the sector.  Also whether the orphan drug strategy that many biotech companies are now following will pay off given the lower probability of success in rare indications.

All in all, the 2011 BIO international convention is set to be an interesting and informative meeting.  Business cards, comfortable shoes and camera/video – I’m ready!

ResearchBlogging.orgPammolli, F., Magazzini, L., & Riccaboni, M. (2011). The productivity crisis in pharmaceutical R&D Nature Reviews Drug Discovery, 10 (6), 428-438 DOI: 10.1038/nrd3405

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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Thanks to Adam Feuerstein of TheStreet for breaking the news this morning, that shares in Inspire Pharmaceuticals (NASDAQ: ISPH) have plunged following the announcement of negative data from the phase 3, TIGER-2 clinical trial for denufosol in cystic fibrosis.

According to the Chief Medical Officer at Inspire Pharma: “The analysis of the primary endpoint, key secondary endpoints and select subgroup populations in TIGER-2 indicates an absence of meaningful treatment benefit in this patient population.

I wrote a blog post last week about denufosol and the hope that this drug offered to cystic fibrosis patients despite the uncertainty about its clinical effectiveness.

The latest data is disappointing and a major setback to Inspire Pharma. It highlights the risk/reward situation that many emerging biotechnology companies face with new product development, the hope that they will make it to market, coupled with the reality that many will fail.

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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