Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘biology’

“The problem at the moment is that it takes $1bn [£600m] to get a drug to market and 15 years or more. That is the justification for the pharmaceutical industry charging high prices.

If on the other hand by the time you get to phase 2 you know exactly which patients it is going to work on, you only put those patients through and instead of 10% you get an 80% response rate.

You get a licence on the basis of the data and don’t have to go to phase 3 (a trial involving thousands of people). That saves vast sums of money and years of development. What that does to the business model is it means you can justify charging lower prices because it cost a lot less in the first place.

If we get this right, it changes the entire dynamics of the business model of the pharmaceutical industry.”

Source Harpal Kumar, the chief executive of Cancer Research UK (CRUK) via The Guardian

A UK friend kindly sent me this article today and provocatively asked me what I thought. Hmmm, a very interesting, meaty and relevant topic indeed.  Here goes…

Will this change the way we do business in cancer research?

The theory behind this statement by CRUK is that if we develop more targeted drugs to fewer patients and generate higher response rates e.g. 70-80% in a specific biologic subset, instead of say, 10% in a broader population, then the costs of development will come down and thus the treatment cost of the disease will ultimately lower.

Not so fast!

The reality might actually be different, and here’s why:

  1. For this to happen you need more translational research, biomarkers and companion diagnostics.
  2. The cost of researching and developing the targets is quite high.
  3. While clinical development costs might be lower with fewer large scale trials, the costs of iterative phase II trials will go up and the available pool of patients for commercialization is now much lower e.g. 5% of patients with the ALK translocation in lung cancer not 100% of all available relapsed patients.
  4. In order to maintain revenues, it is basic economics 101 that smaller patient niches will equal higher costs.

If you are not convinced of the last point, take a look at the costs of treating rare diseases or small subsets of patients.

Some good examples exist in the hematology space include:

  1. Alexion’s Soliris (eculizumab),which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This is a rare hematologic disorder that affects approx. 8,000 to 10,000 people in North America and Europe. The cost is something like $400K per annum.
  2. Genzyme’s Fabrazyme (agalsidase beta) for the treatment of Fabry Disease, another rare hematologic condition, this time an inherited metabolic defect that affects 1 in every 40-50,000 people in the US. Fabrazyme lowers the amount of a substance called globotriaosylceramide (GL-3), which builds up in cells lining the blood vessels of the kidney and certain other cells. It’s very effective, but certainly not inexpensive at around $160K per annum.

What is the likely impact of the changing research paradigm?

Both of the above patient pool sizes are not out of the realm of reality for a comparison with oncology.

In the old model, clinical trials tended to involve more allcomer trials, i.e. patients with a particular tumor type (e.g. non-small cell lung cancer), stage of disease (metastatic) and line of therapy (frontline, relapsed or refractory).

In the new world order, things are changing in clinical trials already:

  1. Roche’s Zelboraf (vemurafenib) was recently approved in metastatic melanoma in patients with the BRAF V600E mutation, reducing the available pool who might respond by 50%. It was launched last week with a price tag of around $56.4K for an average of 6 months treatment.
  2. Crizotinib (Xalkori) is being evaluated in patients with NSCLC who have the ALK translocation and have failed prior therapy. That’s a tiny subset of patients. Patients with this aberration make up maybe 4-7% of the total NSCLC pool. Imagine how small the target population will be for other ALK inhibitors in crizotinib refractory disease?!
  3. The cost of funding and finding biomarkers that predict response is a huge undertaking.  Genentech have no doubt spent many millions looking for a predictive biomarker for Avastin, so far to little avail.

Of course, there are plenty of other exciting targets with small subsets being evaluated in the clinic, but there are several factors to consider:

  1. Small subsets = fewer patients = higher cost.
  2. Will combination strategies be affected by the cumulative costs that will inevitably result? e.g. Yervoy + Zelboraf in metastatic melanoma potential treatment cost = $170-180K if the studies are successful in showing that survival is improved.
  3. Since Dendreon’s Provenge ($93K) was recently given the green light by the CMS, the costs of new targeted entrants is creeping up over the $100K watershed marknot down, viz Yervoy ($120K) and Adcetris (~108K), for example.

In conclusion…

I admire the chutzpah of CRUK, but disagree with some of their conclusions, which I think are rather naive.

Today, I will go on record here and declare that I believe specialised treatment based on the underlying biology will ultimately cost more, not less, in the long run in terms of research and development, diagnostics/biomarkers and treatment costs of ever smaller subsets.

However, I have no doubt we will ultimately see better results clinically with this more scientific approach but this will come at a cost.  While that’s great news for patients and caregivers, it is not so great for the payers, Government or investors, because higher risks and R&D costs will inevitably equate to more failures and this drives higher costs in a spiral fashion.  Ultimately, those costs will trickle down to all of us in the form of higher co-pays and more expensive medical plans to cover the payers margins.  Success has to be paid for somewhere down the line.

And the constant refrain from everyone in Pharma of “let’s do more with less” will increase.

It’s a vicious cycle of unsustainability, with no end in sight.

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We discuss the pathogenesis of cancer quite a bit on this blog, but today I wanted to take a look at immune disorders, specifically, systemic lupus erythematosus (SLE) or lupus for short.

Lupus is an autoimmune disease characterised by often widespread multi-organ inflammation, although the skin, kidney, and joints are often affected.  The main reason behind this phenomenon is the inability of the immune system to discriminate between self-antigens and foreign ones.

Historically, the immune component of the disease has resulted in use of immunosuppressants to try and tamp down the inflammatory cascade, but these can have severe side effects in what is essentially a chronic condition.  Three papers have appeared in Science Translational Medicine this month suggesting the possibility of new combination strategies that target specific aspects of SLE pathogenesis (see references).

In his commentary on the papers, Craft noted that two of the papers address one of the key questions that has been baffling sciences for decades:

“What are the steps that lead to neutrophil activation in SLE, what are the consequences of this activation, and how do these physiological consequences further inform us about self-antigen–driven autoreactivity in SLE?”

Lande et al., (2011) and Garcia-Romo et al., (2011) both found that:

“Neutrophils from patients with SLE are activated by IFN-α, with release of neutrophil extracellular traps (NETs) that contain unwound DNA, and antimicrobial peptides.”

Taken together, the two groups make a compelling case for an important role of neutrophils in triggering interferon-alpha (IFN-a) production in lupus pathogenesis and inflammation.  Garcia-Romo and colleagues research went further, finding that lupus generated neutrophils died upon exposure to anti-ribonucleoprotein antibodies, suggesting a potential clinical intervention strategy.

Duffau et al., (2011) took a different approach to the underlying biology of the disease. They looked at CD154, which has also been shown to critical given the modest success with some patients treated with a CD154 antibody, leading to a reduction in disease activity.  They found that in vitro, activated platelets enhanced IFN-a secretion by immune complex–stimulated plasmacytoid dendritic cells through a CD154-CD40 interaction.

The researchers concluded that:

“These data identify platelet activation as an important contributor to SLE pathogenesis and suggest that this process and its sequelae may provide a new therapeutic target.”

 

Clinical Progress

Recently, the FDA approved Human Genome Sciences monoclonal antibody, belimumab (Benlysta), for the treatment of lupus.  Belimumab is interesting because it blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells.  The drug does not bind B cells directly, but by binding BLyS, it inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

This new therapy is given as a intravenous infusion over one hour.  The recommended dosage regimen is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter for maintenance treatment.

In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with belimumab compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving belimumab) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. However, when looking at serious infections, they occurred in 6.0% of patients treated with belimumab and in 5.2% of patients who received placebo, which is quite comparable.

Benlysta is being co-marketed with GSK in the US and it will be interesting to see how well the therapy does, given that is immunosuppressive and not recommended for patients with chronic infections.

In the long run, however, it will also be interesting to see whether the field advances with new developments in the pipeline as a result of the three papers discussed in this post. Clinical trials have mostly yielded disappointing results so far, but it is possible that with a better understanding of the precise immune cascade and sequelae, we may be able to devise better combination and sequencing strategies that benefit lupus patients in the near future.

References:

ResearchBlogging.orgCraft, J. (2011). Dissecting the Immune Cell Mayhem That Drives Lupus Pathogenesis Science Translational Medicine, 3 (73), 73-73 DOI: 10.1126/scitranslmed.3002138

Lande, R., Ganguly, D., Facchinetti, V., Frasca, L., Conrad, C., Gregorio, J., Meller, S., Chamilos, G., Sebasigari, R., Riccieri, V., Bassett, R., Amuro, H., Fukuhara, S., Ito, T., Liu, Y., & Gilliet, M. (2011). Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA-Peptide Complexes in Systemic Lupus Erythematosus Science Translational Medicine, 3 (73), 73-73 DOI: 10.1126/scitranslmed.3001180

Garcia-Romo, G., Caielli, S., Vega, B., Connolly, J., Allantaz, F., Xu, Z., Punaro, M., Baisch, J., Guiducci, C., Coffman, R., Barrat, F., Banchereau, J., & Pascual, V. (2011). Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus Erythematosus Science Translational Medicine, 3 (73), 73-73 DOI: 10.1126/scitranslmed.3001201

Duffau, P., Seneschal, J., Nicco, C., Richez, C., Lazaro, E., Douchet, I., Bordes, C., Viallard, J., Goulvestre, C., Pellegrin, J., Weil, B., Moreau, J., Batteux, F., & Blanco, P. (2010). Platelet CD154 Potentiates Interferon-  Secretion by Plasmacytoid Dendritic Cells in Systemic Lupus Erythematosus Science Translational Medicine, 2 (47), 47-47 DOI: 10.1126/scitranslmed.3001001

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Writing this many articles certainly wasn’t one of my goals when I first started blogging about the science behind cancer, 100 seemed like the north face of the Eiger at the time! I’m not sure how many of you have been with me since the first few posts, but this seems a great opportunity to thank everyone for dropping by and reading, whether it’s your first time or you’ve been a regular for a while. All the comments and emails received have been very much appreciated.

Earlier this month, I put up a one question poll asking what sort of content you wanted to read more about and here are the results (accessed on Jan 18th):

The most popular requests were for more reviews of companies (27%), interviews with thought leaders (20%), with a fifth of those voting saying the mix was about right.  The poll is still running for those of you who missed and want your vote to count.  I’ll be re-running it later in the year to keep tabs on what readers want to see here on the blog.

The conference meeting insights will be rolling out in the newsletter, which will go out to subscribers by email occasionally.  If you haven’t signed up yet, you can add your name and email in the signup box in the right hand margin.

Over the next few days I plan on posting an interview with Dr Michael Kastan of St Judes who did a lot of stellar work on p53 and a review of Mirna Therapeutics, who have an interesting microRNA platform.

If anyone would like to suggest thought leaders or companies they would like to hear more about, please do add them in the comments below.

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The last quarter of the year is always a busy one on the conference circuit in oncology, particularly in December with the annual ASH and the SABCS meetings back to back. We almost always need the Holidays after that just to recover! 

Here's my schedule for the next few weeks:

Colorectal2010_325x180Oct 20th: Xconomy, 'War on Cancer', Boston hosted by Millennium

Oct 27-30th: AACR colorectal cancer biology and therapy symposium, Philadelphia

2010Signiture2

Nov 8-13th: Greenspan Chemotherapy Foundation Symposium, Marriott Marquis Times Square, NY

All three meetings look particularly interesting this year, with a big focus on biology and new product development.

While Pharma is facing some big patent cliffs over the next two years, there are a lot of interesting new compounds coming along in the pipeline in phase I/II right now. Hopefully, some of these will make it through to regulatory filing in a few years time.

If you are around at these meetings, do stop and say hello – it's always good to meet readers in person, however briefly. If you haven't put any of these in your diary, do check them out!

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