One 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!
Pammolli, 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
The patient advocacy session at the recent 16th Congress of the European Hematology Association in London focused on adherence to cancer treatments, and was filled to capacity, with the many attendees having to watch it from an overflow area.
Dr David Marin, Reader in Onco-Haematology at Imperial College, London presented research published last year in the Journal of Clinical Oncology that dramatically demonstrated how adherence to chronic myeloid leukemia (CML) therapy is the critical factor for achieving molecular responses.
In a study of 87 CML patients taking imatinib (Glivec®/Gleevec®) for a median period of 91 days, Dr Marin showed that no major molecular response (MMR) was observed when adherence was ≤ 80% and no complete molecular responses (CMR) were observed when adherence was ≤ 90%. The graphical figure that he presented from his paper, dramatically shows how missing only a few doses of drug can have a major impact on outcome:
Although the work by Marin and colleagues at the Hammersmith Hospital was undertaken with CML patients taking imatinib, the paper notes that adherence problems
“may apply equally to patients receiving second-generation tyrosine kinase inhibitors.”
Imatinib is the only TKI approved in the UK, thus that’s the only one available for studies there to date.
What made this data so compelling was the study rationale that used an electronic pill container, the medical event monitoring system (MEMS™) from the Aardex Group. This product contains a microchip that records the date and time it is opened.
Dr Marin’s study showed that “lack of adherence is underestimated by conventional methods.” Self-reporting of adherence and pill counts are inaccurate compared to electronic data capture using MEMS (study subjects were unaware of the micro-chip in the pill bottle).
When psychologists at the Hammersmith Hospital subsequently interviewed patients who missed doses of drug, they found intentional and non-intentional adherence reasons.
A few excepts of patient quotes from Dr Marin’s presentation:
“Oh I can’t be bothered tonight, it’s not going to kill me [to miss a dose]”
“I thought there was no way I was going [on holiday] and being tired.”
“And sometimes you just forget”
“[the pharmacy] had no medication for me, so I went for nearly a week with no medication.”
Other speakers in the excellent patient advocacy session chaired by Jana Pelouchová (European Cancer Patient Coalition, Czech Republic) and Jan Geissler (CML Advocates Network, Germany) included Giora Sharf (Israeli CML patient’s Organization and CML Advocates Network, Israel) and Professor Rudolf Schoberberger (Medical University of Vienna, Austria).
Professor Schoberberger focused on the impact of drug packaging on compliance, particularly in elderly patients, and presented compelling research on how “child-proof” equals “age-proof.” Sally Church in her video blog from EHA also discusses the patient advocacy session and how pharma/biotech companies could improve drug packaging.
The issue of adherence is a personal choice that every patient taking a chronic therapy makes. However, as Sally notes on Pharma Strategy Blog more patient and physician education is needed so that patients know there may be dramatic consequences from missing only a few doses per month.
Not only may adherence have a major impact on patient outcome, but as one questioner from France pointed out at the end of the EHA patient advocacy session, “for a statistician it is a nightmare.” Poor adherence in clinical trials “means that the true effect of a drug is not well known. Efficacy may be under-estimated if adherence is low.”
More monitoring of adherence in clinical trials through the use of MEMS technology may, therefore, be necessary to ensure that clinical trial data shows the true efficacy and adverse event profile of a drug.
I hope that the European Hematology Association (EHA) will make a webcast of this informative patient advocacy session publicly available online as it raised issues of considerable importance to patients, physicians and biotech/pharma companies alike.
Marin, D., Bazeos, A., Mahon, F., Eliasson, L., Milojkovic, D., Bua, M., Apperley, J., Szydlo, R., Desai, R., Kozlowski, K., Paliompeis, C., Latham, V., Foroni, L., Molimard, M., Reid, A., Rezvani, K., de Lavallade, H., Guallar, C., Goldman, J., & Khorashad, J. (2010). Adherence Is the Critical Factor for Achieving Molecular Responses in Patients With Chronic Myeloid Leukemia Who Achieve Complete Cytogenetic Responses on Imatinib Journal of Clinical Oncology, 28 (14), 2381-2388 DOI: 10.1200/JCO.2009.26.3087
The VC funding from Third Rock Ventures to the Boston/Cambridge based company is reported to be the largest early-stage funding for a New England life sciences start-up.
What makes this exciting news? First it adds to the growing reputation of Boston/Cambridge as a hot-spot for cancer research. Blueprint Medicines will be focused on translational medicine and the development of new kinase inhibitors for the treatment of cancer.
Secondly, it confirms what is taught at business school, that investors back management expertise and their belief in the entrepreneurs ability to execute. In the case of Blueprint Medicines the scientific co-founders are Dr Nicholas Lyndon and Dr Brian Druker, who were instrumental in the development of imatinib (Gleevec/Glivec), a tyrosine kinase inhibitor that revolutionized the treatment of chronic myeloid leukemia (CML).
Blueprint Medicines is a company to watch for the future and Biotech Strategy Blog wishes it well in the quest for personalized medicine and more effective cancer treatments.
The launch of the company in Boston/Cambridge adds to my view that Boston is emerging as the premier biotech region on the East Coast for start-ups interested in oncology and translational medicine.
I recently attended the annual meeting of the American Society of Hematology (ASH) in Orlando so thought I would share my general impressions (in no particular order):
Convention Center Food was Poor:
The food at the Orange County Convention Center reminded me of an airport – desperate choices, poor quality and overpriced. As for no Starbucks or decent coffee shop, civilization has yet to reach Orlando! The Peabody hotel across the road had coffee shops that offered a $3 single espresso shot, but they ran out of pods on the Monday morning – faced with the overwhelming demand that seems to have not been anticipated! Memo to Starbucks – look into a convention center franchise.
Cramming all the science in one day doesn’t work:
People go to a meeting such as ASH for many reasons – networking, business development, education, investigator meetings, but in the end, it is a scientific meeting. The meeting ran from Saturday to Tuesday, yet nearly all the oral scientific program (biology and therapy) was crammed into one day of simultaneous sessions on the Monday – tough if you wanted to cover a product or pathway that targeted multiple therapeutic areas, many of which ran at the same time.
The Poster hall was like a graveyard:
You can tell I didn’t think this was a great meeting. Every time I went into the aircraft like hangar where the posters were housed, I ended up chilled to the bone. It certainly didn’t encourage spending much time there, and I was disappointed that a surprisingly high number of presenters did not attend the poster presentation receptions, when they were supposed to be available to answer questions. Nobody seemed to check if anybody showed up, to me the whole point of a poster is being able to discuss it.
Why not publish the slides from the oral science presentations?
ASH, unlike ASCO does not make the slides of oral scientific presentations available online, so if you didn’t make notes, or break the rules (and risk being ejected) by taking an illegal picture on your phone or camera, then you missed it. Abstracts are often submitted months in advance before the final data is analyzed, so by not making the slides available after the meeting, science to me is being hampered especially given the overlap of sessions on the Monday. If an abstract is presented and published, the scientific information should be available to be shared. Isn’t that what science is about? ASCO have it right, their virtual meeting program is outstanding.
Hospitality lives on – but only if you are an international doctor:
US doctors attending their annual meeting, are warned not to accept a free cup of coffee at an exhibitor booth if their state or employer prohibits the acceptance of such “gifts”, while foreign physician attendees are wined and dined. You see signs for hospitality centers for European doctors or desks in hotels for company sponsored groups of foreign doctors – hard to believe there’s ethically not something wrong with these double standards.
A lack of quality educational materials:
While the free pen and notepad have long since gone the way of the dinosaur, this year there was noticeably fewer educational material to take away. The debate as to whether doctors should pay for their own CME continues, but I do think many in the industry miss the opportunity by not providing educational material on the science, pathways and mechanism of action of new products.
The “Super Friday” is still alive:
Multiple industry sponsored satellite symposia (AKA “Super Friday” sessions) took place before ASH, with several at the Peabody Hotel. I have to say the food at the one I attended on personalized medicine was excellent, one of my best meals in Orlando. They are not cheap to run: not only do 800-1000 people get fed, but a hotel room with audio-visual equipment has to be hired, a panel of experts are paid to talk about a topic, and many of the attendees come away with a glossy brochure. Could this money be better spent elsewhere? ASH has a large education component to it, and it was interesting to note that what the ASH education program committee chose as important topics to talk about and what the industry chose, were pretty different. That is perhaps not surprising – after all if you choose the topic of the satellite symposia and it’s of relevance to your product, indirectly you are trying to influence prescribing behavior, otherwise why else would you fund it? There is no such thing as a free lunch or dinner.
Multiple Myeloma was a hot topic:
There was a lot of interest in clinical trial results in MM. The use of a maintenance therapy, and attempt to turn this into a chronic disease was a widely discussed topic, however many old drugs such as thalidomide have nasty side effect profiles such as peripheral neuropathy, while newer drugs such as lenalidomide are expensive but appear to only incrementally increase survival. Results from multiple combinations of drugs and induction therapies were presented, I was left with the impression that although there is progress, there is still no major breakthrough in this disease area.
Nobody wants to talk about cost effectiveness:
The 800 lb gorilla in the room for hematology/oncology is the comparative effectiveness of one treatment versus another i.e. it’s cost/benefit, yet nobody wants to talk about it. Take for example the treatment of CML, should you treat with imatinib (Gleevec) which has outstanding long-term survival data over several years thanks to the IRIS trial, or use a second-generation tyrosine kinase inhibitor (TKI) such as dasatinib or nilotinib that is around twice the price, more potent and slightly more effective but obviously we don’t yet know if it improves 5 or 10 year survival yet over imatinib. Nobody wanted to talk about price – physicians currently live in an ivory tower.