I did a double take at my inbox alerts this morning as things have been rather quiet of late in the Pharma and Biotech world. You can read the financial aspects of the deal in Celgene's press release.
While the timing might be a little bit of a surprise, the strategic acquisition is not and makes a lot of commercial sense for Celgene. There are a number of reasons for my thinking here:
It continues to build out of hematology with the beginnings of a solid tumour franchise since Abraxane is approved for breast cancer and has trials ongoing in pancreatic, lung, melanoma and bladder cancers.
The patent life for Abraxane is something like 2023, much longer than lenalidomide (Revlimid) and with few near term opportunities in the oncology pipeline, this adds extra protection.
Abraxane, while more expensive than generic paclitaxel, has probably been underfunded in clinical development and marketing efforts to date, so Celgene's thorough and aggressive approach may well kick start things, especially as they have cash to do so.
Buying Abraxis gives them access to nanotechnology, which I think will become more important in the future as an improved drug delivery system.
Late last year, while at the AACR Molecular Targets meeting in Boston, I wrote about nanoparticle technology and how it appears to offer a chance of improved outcomes in pancreatic cancer using Abraxane. The concept described by the researchers at Mass General was solid and promising, as was the early phase I data. Sometimes, it's not just about drug A being better or more potent than drug B, but the science and thinking behind solving a problem is elegant and well thought out. This was one of those cases. A couple of Phase II trials have so far yielded early but promising results in a devastating disease. The latest results, reported by the Abraxis in May this year, look encouraging so far.
Of course, most oncology specialists will know that melanoma, pancreatic and lung cancers as probably three of the four toughest cancers to get positive results in from phase III trials (the fourth is glioblastoma), but if any of them actually pan out with a significant difference in overall survival and FDA approval, then Celgene will have another winner on it's hands. I say 'if' because the road to approval and cancer drug development is littered with promising phase II studies that flopped or were sadly cancelled for futility in phase III.
Time will tell if this was a good acquisition or not, but for now, it's early but promising. That's ultimately both the lure and the heartache that is oncology.
The cause of pancreatic cancer is still unknown, although there are risk factors involved, such as increased exposure to tobacco smoke and a family history of the disease. It is usually detected late when advanced stage disease has set in because most patients are asymptomatic for a long period and then it is too late. This raises the question of how can we learn and understand more about the biology of the disease as well as develop early warning signs via biomarkers used in screening?
It was therefore fascinating to be browsing through the latest edition of the New England Journal of Medicine over coffee this morning to discover an article on the medical progress in pancreatic cancer while simultaneously noticing an item on a new potential biomarker for the disease in Twitter! The NEJM review hasn't been published online yet, so I'll add the reference later.
Essentially, the NEJM article reviewed the biology of what we know of pancreatic cancer so far:
Results from successive accumulation of gene mutations (average of 23 per tumour)
Most patients with malignant disease carry 4 or more mutations (eg KRAS, CDKN2A, TP53, DPC4)
It's extremely heterogeneous (more difficult to treat)
Formation of dense tumour stroma (dermoplastic reaction)
It is poorly vascularised (due to stellate cells and activation of TGFβ1, PDGF and FGFR)
Poor prognosis and treatment resistance has been conferred by the presence of cyclooxegenase-2 and PGFR, VEGF, SPARC and Hedgehog overexpression to name a few
The poor vascularisation of the tumour may well explain why anti-angiogenic therapies have not yielded promising results in the clinic to date.
Treating advanced cancer is always more difficult than earlier cancers in the neoadjuvant and adjuvant settings. The big challenge with pancreatic cancer to date, though, has been finding useful biomarkers for earlier detection, which would most likely impact outcomes for the disease. According to the NEJM article:
"The overall 5-year survival rate among patients with pancreatic cancer is <5%."
That's a pitiful number that needs to change.
There are a number of agents in the clinic for the treatment of advanced pancreatic cancer including inhibitors of SPARC, MEK, Mucin-1, IGF-1R, Hedgehog, PDGF and FGFR, Src, RAS, JAK-STAT and TNFα, for example.
Many of these agents are looking at single agent studies or in combination with the current standard of care, gemcitabine, itself with limited effectiveness. It is, therefore, quite hard to imagine that blocking one pathway alone is likely to be the panacea for such a hard to treat and highly complex cancer, as the graphic to the left shows (click to see the detail).
Meanwhile, progress may be possible on the detection front. Goicoechea et al. reported in PLoSONE that a type of protein called "palladin" is produced in large amounts in groups of cells in the stroma surrounding pancreatic tumours, known as the 'tumour nest'. By measuring the levels of palladin in patient samples, doctors could have an improved way to screen for the disease, potentially detecting it earlier than current tests.
However, I say potentially, because these findings while interesting, need to be validated in large scale phase III clinical trials before we can really be certain of their long term validity. Nevertheless, it is a promising start for a devastating disease.
If there was one cancer that would hugely benefit from better earlier detection and diagnosis, it's pancreatic cancer. We need more cowbell. That is all.
Goicoechea, S., Bednarski, B., Stack, C., Cowan, D., Volmar, K., Thorne, L., Cukierman, E., Rustgi, A., Brentnall, T., Hwang, R., McCulloch, C., Yeh, J., Bentrem, D., Hochwald, S., Hingorani, S., Kim, H., & Otey, C. (2010). Isoform-Specific Upregulation of Palladin in Human and Murine Pancreas Tumors PLoS ONE, 5 (4) DOI: 10.1371/journal.pone.0010347
There are a lot of clinical trials out there right with tyrosine kinase inhibitors; unfortunately many will fail because they were rushed into phase II or III trials without thinking through all the options. There are, however, some smart companies out there who do think.
What was noticeable at AACR this year, was the surfeit of posters and presentations regarding logical combinations designed to eliminate escape routes and hence resistance. For example, cross-talk is a common problem between ligands, eg IGF-1R and EGFR, so combining the two may reduce the problem but that isn't the whole story.
Feedback loops also exist, so targeting PI3-kinase alone is less likely to be effective than targeting both PI3-kinase and mTOR. Neal Rosen from MSKCC showed some interesting data to this effect and argued cogently that oncogenes tend to lead to constitutive negative feedback. He also noted that the BRAF mutation predicts for sensitivity to MEKi, for example. Michael Korn also discussed the feedback activation loop between the RAS-ERK and PI3K pathways and how the inhibition of autophagy (where cells self digest themselves) can enhance apoptosis and the anti-tumour effect with smart combinations.
Targeting both MEK and AKT may therefore also have more effect than either alone, as you can see in the chart below:
In a recent trial reported at the the ASCO GI meeting in January, Merck described an elegant design where IGF-1R, EGFR and AKT inhibitors were all combined to target advanced pancreatic cancer, with promising early results. I thought this was a prescient approach at the time, since it clearly sought to eliminate both cross-talk and feedback, so it was interesting to see numerous researchers advocating similar approaches in different tumour types based on the overexpression profiles at AACR last week. The design is based on rational biochemistry, which regular PSB readers will know I'm a big fan of, rather than randomly adding a kinase inhibitor to whatever is the standard chemotherapy of the day in a haphazard blunderbuss approach.
There are a number of MEKi and AKTi inhibitors out there (I counted nearly a dozen last time I checked), as well as a plethora of PI3-kinase and mTOR inhibitors, either alone or in combination. Merck and AstraZeneca announced an interesting deal earlier this year to jointly pursue research with their AKT (MK-2206) and MEK (AZD6244) inhibitors. This collaboration makes a lot of sense biochemically. Novartis (a client) have one of a broadest kinase pipelines in the industry and just added to it prior to AACR in a deal with Array BioPharma to license their MEK inhibitors, of which ARRY-162 is the lead candidate.
The compounds that ultimately win the race may not necessarily be the ones furthest ahead in clinical trials right now, but the ones with the smartest clinical trial designs to eliminate some of the issues associated with kinase inhibition - cross-talk, feedback, feed-forward loops and additional mutations.
MEKi and AKTi are two of my favourite kinase approaches right now because they offer the flexibility to add to existing TKI's such as erlotinib, sorafenib or everolimus, for example, potentially improving the outcomes further in a variety of different cancers, never mind the future combination possibilities. It's going to be a very interesting and hot area to watch in the near future, that's for sure.
If you have any thoughts or questions on this fascinating topic, please do add them in the comments below.
An interesting article has been published in the latest New England journal describing how the addition of a cisplatin to gemcitabine improved survival by two months in biliary tract cancer. Currently, there is no standard treatment for this rare disease, so a solid phase III trial (ABC-02) represents an important step forward for treatment.
Biliary tract cancers are tumours that develop in the gallbladder and bile ducts. Those that develop in the bile duct within the liver are known as cholangiocarcinomas. Approx. 6500 new cases of gallbladder carcinoma are diagnosed each year in the US. Interestingly, chronic inflammation appears to be a common aetiologic factor in the disease development. There has been a rise in incidence of the cancer in recent years, which may possibly be attributable to the association between liver disease and increasing hepatitis C virus infections.
Although there are no standards, gemcitabine has been the bedrock of palliation therapy for the disease based on the experience in pancreatic cancer. The earlier ABC-01 phase II trial suggested a benefit in adding a platinum to gemcitabine.
In the current ABC-02 phase III trial, the median overall survival with the combination was 11.7 months and 8.1 months in the gemcitabine alone group, a significant improvement of 3.6 months.
As a result, the combination of cisplatin and gemcitabine is likely to become the new standard of care for the treatment of biliary tract cancer. As we learn more about the science and biology underlying the disease, further improvements may be possible with the addition of targeted agents.
Reference Valle, J., Wasan, H., Palmer, D., Cunningham, D., Anthoney, A., Maraveyas, A., Madhusudan, S., Iveson, T., Hughes, S., Pereira, S., Roughton, M., Bridgewater, J., & , . (2010). Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer New England Journal of Medicine, 362 (14), 1273-1281 DOI: 10.1056/NEJMoa0908721
West, J., Wood, H., Logan, R., Quinn, M., & Aithal, G. (2006). Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001 British Journal of Cancer, 94 (11), 1751-1758 DOI: 10.1038/sj.bjc.6603127
El-Serag HB, Engels EA, Landgren O, Chiao E, Henderson L, Amaratunge HC, & Giordano TP (2009). Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: A population-based study of U.S. veterans. Hepatology (Baltimore, Md.), 49 (1), 116-23 PMID: 19085911
It's been a busy week on the road here at Icarus and today and tomorrow are no exception, so finding time to blog is a little more challenging.
Yesterday, I got back from a biomarker symposium in Princeton to find that my Twitter and almost everything else Pharma related were full of Genvec'sannouncement that their phase III trial for TNFerade was being discontinued in pancreatic cancer.
It's not really a drug, more an experimental gene therapy, that according to Genvec:
"Acts as an adenovector, or DNA carrier, which contains the gene for tumour necrosis factor-alpha (TNFα), an immune system protein. It is directly injected into the tumour. After administration, TNFerade stimulates the production of TNFα in the tumour."
The abandonment of the trial isn't really big news though, as the drug previously failed in melanoma and other cancers, despite the magic words, "promising phase II data." Let's face it, pancreatic cancer is also probably one of the toughest nuts to crack out there in the oncology world. Sadly, it was doomed to failure from the beginning; I would have been more surprised had it actually worked.
Genvec have a raft of other trials that are either currently enrolling people with various cancers or have recently finished enrollment; I wonder what the fate of the overall program will be given the repeated negative results?
At the beginning of this month many pharma and biotech pundits smiled at the 'beware the Ides of March' quips on Twitter, but by the end of March they seem much more accurate than one may realise!
Looking back through the months posts, there were several spectacular phase III flops from Pfizer and Roche, Roche's ocrelizumab and AstraZeneca's cediranib bit the dust, the ODAC meeting on 22nd was brutal for Cell Therapeutics and ChemGenex with neither getting approved, Antisoma's ASA404 crashed on Monday, Merck KGaA are reviewing the EU cardiac data for Erbitux, which may also have implications for BMS and ImClone in the US. Yikes, I could go on...
Let's hope that April and May bring more positive news to talk about.
Recently, I noticed that oncology companies are in the news for raising new financing or even announcing IPO's, and wondered if that was an anomaly after the credit shutdown following the Wall St crisis. In general, my perception was that they seemed to be down overall. To find out more, I checked out the VC funding statistics at OnBioVC:
Surprisingly, oncology dominates the market at the moment, with the latest data being available from 3Q09: nearly one-third were from oncology alone during that period. According to the report, they represented:
"... a diverse therapeutic approach; from small molecules targeting the inhibition of receptor tyrosine kinase to HDAC to metallo-enzymes to PI3K and mTOR, as well as a variety of mAb’s and therapeutic vaccines."
In more terms, though, the aggregated dollars raised per sector is significantly down over the same period in 2008:
But overall, the total number of financings for Biotech are up, thanks to a strong growth in the medical device sector, although the biopharma sector is down slightly:
Last October, Auxilium received proceeds, net of offering expenses and underwriting discounts and commissions, of approximately $115.7 million. The company closed its previously announced public offering of 3,000,000 shares of common stock at a price of $34.50 per share.
Meanwhile, last week was a busy one.
Firstly, Ironwood raised $188M from their IPO in one of the biggest deals of the decade (more than Eyetech's $150M in 2004) by selling over 16M of shares at a price of $11.25. It was, however, perceived to be a discount price, because their SEC filings in November hoped for a higher target of $14-16/share. As a friend commented last week, "Well, $188M isn't chump change!"
Secondly, Reuters reported that the private French Biotech company, AB Science,
"is preparing for a 50 million euro ($70 million) initial public offering next month in a move that could make it France's first biotech stock exchange listing since mid-2008."
What's interesting about AB Science is that the company have yet to officially announce or confirm the date of the IPO, although they made clear their intent to pursue one in 1Q10 when we interviewed Alain Moussy, the CEO, in October.
The company has an interesting KIT inhibitor on the market in Europe, masitinib, for mastocytosis in dogs and is now developing the drug in pancreatic cancer for humans. In order to fund the phase III trials, more financing is needed so the IPO is clearly a sign that the company is going places.
This week heralds the annual BIO CEO meeting in New York, where there will doubt be a lot of interesting discussions and presentations going on. The schedule is packed with a quite a few oncology focused companies, so more news will be covered on this blog later this week as details emerge. Sadly, I will miss the event, as I'll be at the ePharma meeting in Philadelphia. More on that tomorrow!
A Pharma friend who regularly reads this blog attended the ASCO GI meeting last weekend and phoned me to say that cancer is indeed getting much more complex. She was also highly amused at the buzzword bingo post from the AACR Molecular Targets meeting:
"Well, I just thought you might like to know that the latest buzzword bingo is 'cross-talk'"
Funnily enough, I was writing a report on cross-talk at the very moment she called. Cross-talk occurs when two powerful signaling pathways interact, leading to interactive processes between them downstream of the original receptors.
Another Pharma buddy sent me the slides from a presentation on the Merck IGF-1R inhibitor, MK-0646, phase I results of which were reported in pancreatic cancer. One of the focus of the presentation was 'cross-talk' according to the abstract:
"Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/Akt pathways mediate resistance to anti-EGFR agents such as erlotinib. IGF-1R + EGFR antagonists result in synergistic antitumor activity in preclinical pancreatic cancer models."
When you actually look at the pathways involved, you can see that things are indeed very complex and cross-talk is not surprising, as Pollak et al., showed in 2004:
This means that inhibiting the IGF-1R pathway alone with a inhibitor such as Pfizer's figitumumab or Merck's MK-0646 is unlikely to be effective because cross-talk between the receptor and AKT/mTOR or MEK pathways may well have an impact and lead to an escape route for the cancer cells to continue surviving. For this reason, we can see that the recent futility reported in the figitumumab lung cancer trial is not completely surprising. However, combining the drug with an AKT or MEK inhibitor may well yield better results.
In the Merck study, the majority of patients had an objective response or stable disease when the IGF-1R inhibitor was combined with erlotinib, an EGFR inhibitor. Cross-talk between IGF-1R and EGFR has been shown in preclinical models of pancreatic cancer.
These early results are promising for the compound, but much work is still needed to determine suitable predictive biomarkers and ideal combinations/sequencing before moving forward into a phase III trial.
Pollak, M., Schernhammer, E., & Hankinson, S. (2004). Insulin-like growth factors and neoplasia Nature Reviews Cancer, 4 (7), 505-518 DOI: 10.1038/nrc1387
One of the great things about travelling to scientific conferences around the world, is catching up with old friends, meeting new people, learning new things and also seeing some wonderful sights when least expected.
Here's a quick shot I took at dusk on my 3G iPhone took walking from
the bus stop to the hotel I was staying in for the recent AACR meeting
on molecular origins in lung cancer.
It was nice to get out at the end
of the day for some fresh air, but the sunset was certainly an added bonus and a heartening welcome after the chill of the East coast winter!
Some meetings you can get a decent flavour of what's going on from the press releases and reports coming out from good science writers, reporters and analysts such as Brooke Wang, Kerri Wachter, Mike Huckman and Roxanne Nelson. You can't attend every conference, but you can trust in a few good men (and women) to tell the stories in a straightforward and accurate way.
After a while, I can tell who is actually reporting live from the meeting and who is just rehashing a press release or media briefing - the quality of the reporting and analysis shines through beyond mere data repetition :>}.
One of the biggest things I personally gain from being on the spot is the chance to interact with key opinion leaders and ask them questions. Of course, you can do this by email or phone too, assuming you can track them down in a timely fashion, but checking the nuances on the spot is extremely valuable both for greater understanding and immediacy.
Right now, I'm following the ASCOGastrointestinal Cancer Symposium from Fort Lauderdale on Twitter via the #GICaSymp hashtag. Kerri is tweeting and reporting from there and several Pharma buddies are also attending and sending updates by email. I'm particularly keen to hear what Dr Eric van Cutsem has to say in his update about KRAS and biomarkers from the CRYSTAL trial in colorectal cancer.
"Researchers have developed a novel immunoassay for detecting early-stage pancreatic cancer that identifies and quantifies blood levels of the PAM4 protein – a unique antigen present in almost 90 percent of pancreatic cancers and precancers."
Wow, that little snippet from the ASCO press releases from the Gastrointestinal symposium in Florida woke me up while sipping coffee this morning!
The reason is that pancreatic cancer is an insidious disease and most patients are diagnosed late, usually in stage IV when there is little that can be done to successfully attentuate the cancer. For years, researchers have struggled with ways of detecting the cancer earlier when treatments are more likely to be effective without confusing cancer from pancreatitis.
Approximately 7% of pancreatic cancer cases are detected at an
early stage, before the cancer has spread to other parts of the body.
The survival rate for early stage pancreatic cancer is around 20%, compared with just 1.8% for those diagnosed when the disease has metastasized.
The PAM4 antibody, also called clivatuzumab, from Immunomedics ($IMMU) used in the assay reacts with a protein produced by pancreatic cancer cells. It appears that the protein is not detectable in normal pancreatic cells and is rarely detected in pancreatitis (inflammation of the pancreas), making it potentially highly specific for pancreatic cancer.
The researchers evaluated an immunoassay for the PAM4 protein in 68 patients who had pancreatic cancer surgery and 19 healthy controls. They found that the test was 62% sensitive for detecting stage 1 pancreatic cancer (disease confined to the pancreas), 86% sensitive for stage 2 disease (disease which has spread to nearby organs) and 91% sensitive for stage 3/4 cancers (local and distant spread). Overall, the assay was 81% sensitive for detecting all stages of pancreatic cancer; while not perfect, it would represent an enormous improvement on current detection rates.
The obvious next step is to validate the test on a larger scale with more patients to determine if it has utility as a diagnostic tool to detect people at risk for pancreatic cancer such as patients with a history of tobacco use, or those with genetic or other medical factors on a yearly basis, to enhance the chance of early detection.
The investigators also suggested that the clivatuzumab antibody may also prove useful for treating the disease by acting as a carrier for agents (such as radioactive isotopes labelled with Y90) that can target and kill cancer cells, but this idea is pure supposition at present and as yet, unproven. Immunonomedics have a phase I trial ongoing with clivatuzumab in pancreatic cancer
At the ASCO GI symposium there was, however, some interesting new data in the treatment of pancreatic cancer as Pfizer announced the final results from a randomized Phase III
trial of sunitinib (Sutent) in patients with advanced pancreatic
neuroendocrine tumors, a type of cancer which originates in the
hormone-producing area of the pancreas.
Sunitinib appeared to more than double the
time the patients with lived without
disease progression compared with patients treated with placebo; results showed that median progression-free survival (PFS) was 11.4
months in patients treated with sunitinib compared with 5.5 months in
patients treated in the placebo arm. Overall survival was also prolonged.
Adverse events were similar to those observed in other sunitinib
studies.
The sunitinib results are particularly interesting, not only because they improve survival beyond the six months typically seen with the disease, but also because other VEGF inhibitors such as bevacizumab (Avastin) previously did not appear to be effective in slowing the disease. Sunitinib, though, is a multi-kinase inhibitor that also targets other pathways other than VEGF, including c-KIT, PDGF, FLT3 and RET, suggesting that dual inhibition of perhaps VEGF and PDGF is necessary in this disease.
On the basis of these results, Pfizer filed supplemental applications
for approval in pancreatic neuroendocrine tumours with the US, EU and
Canadian authorities, so help for patients may well be coming sooner than expected.
Pancreatic cancer is a devastating disease with a generally poor prognosis, largely because it is usually detected in late stage disease where chemotherapy options generally have a limited effect. Typically response rates with gemcitabine are around 5%, with advanced patients living around 5-6 months on average. Erlotinib, an EGFR inhibitor, is also approved in the USA for treatment of the disease, but the therapy only adds approximately two weeks to survival. Many doublets and triplets have been tried and tested over the last 10 years, with little impact on survival. It was, therefore, exciting to see some young researchers presenting interesting and novel strategies at AACR this week to try and evade the resistance inherent in the disease.
Recently, Nab-paclitaxel (abraxane) has been granted orphan drug status in pancreatic and melanoma cancers. The rationale for using Nab-paclitaxel in pancreatic cancer is that it appears to weaken the stroma surrounding the tumour and also synergistically increases the effect of gemcitabine, the standard of care for the treatment of late stage disease when surgery is not an option.
Anirban Maitra presented a poster which showed how Abraxane targets the tumour stroma, depleting it, thereby reducing the impediment to chemotherapy. The Nab-paclitaxel works by utilising endogenous albumin pathways via binding of the albumin to secreted proetin acid rich in cysteine or SPARC. Interestingly, pancreatic cancer is known to overexpress SPARC and therefore offers a target for the drug.
In a Phase I/II trial presented earlier this year at ASCO by Daniel van Hoff, the median PFS with the combination was 6.9 months, and median OS was 10.3 months. To put this in context, gemcitabine alone usually gives an OS of around 5 months, so adding Abraxane doubled the overall survival, which is a lot in pancreatic cancer. Dr Maitra's research showed that this doubling of response occurred because there was a 3.5 fold increase in the amount of gemcitabine delivered in the tumour after the depletion of the stromal layer by Nab-paclitaxel.
This research therefore offers a fascinating insight into how other treatments could also be used in combination with Abraxane to potentially improve overall survival in this disease.
Two of the other interesting ideas came from a research group at the Massachusetts General Hospital here in Boston. The first one, presented by Tayyaba Hassan, took an out of box approach to rethink how to get a drug that has shown some modest efficacy in pancreatic cancer, bevacizumab, inside the cell. The drug is a VEGF inhibitor that typically acts on VEGF outside or on the ligand on the cell surface. It has limited efficacy in mopping up the VEGF this way, because getting past the stromal layer, as Dr Maira showed, severely limits drug access.
Hassan and her group decided to find a way to get the drug inside the cell to see if that would mop up more VEGF and induce a more durable response. They created a nanotechnology based delivery device to simultaneously deliver the bevacizumab and an FDA approved light activated chemical in the tumour cells in a mouse model. Photodynamic therapy (PDT) has been shown previously to improve treatment outcomes in pancreatic cancer. However, in clinical trials where standard chemotherapy was combined with bevacizumab, there was no benefit in survival. The theory was that perhaps not enough chemotherapy or monoclonal antibody therapy was getting through to mop up the VEGF and induce apoptosis in the pancreatic cells.
The results were highly interesting.
In the mice models, the nanotechnology device (nanocell) successfully delivered bevacizumab to the tumour cells and improved the acute response in the mice compared with those treated with bevacizumab alone. The combination with PDT was associated with even greater improvements.
The nanocell also delivered enough bevacizumab to cause a 2 fold reduction in metastasis to the lungs, liver and lymph nodes.
Phase I trials are due to begin in humans and the results will be eagerly awaited. If successful, the nanotechnology concept will offer a new and creative paradigm for delivering cancer drugs to the right place at the right time with greater effectiveness and less toxicity.
Prakash Rai and his colleagues at the MGH also looked at the possibilities with nanotechnology by combining it with photodynamic therapy (PDT) to simultaneously target the EGFR and MET pathway using cetuximab and PHA-665752:
The goal behind the approach was to reduce cross-talk and escape routes for the cancer cell, attacking several pathways at once is one way to do this. The end result is drug delivered more effectively inside the tumour cell and ultimately, a reduction in the tumour burden. It will interesting to see if there is a reduction in metastasis and overall survival.
This novel approach could potentially be applied to other drug combinations and tumour types and offers a new targeted method of getting larger amounts of drug inside the cancer cell, where it can do more damage.
As announced last week, this is the first in a series of interviews with people who make a difference in the Pharma, Biotechnology and medical world.
Alain Moussy is CEO of AB Science, an emerging French biotechnology company. As previously reported on this blog, AB Science gained EMEA approval in 2008 for its novel tyrosine kinase, masitinib, in dog mast cell cancer. This product was launched to vets throughout Europe earlier this year and is awaiting FDA approval. Masitinib is also in phase 3 human clinical trials in GIST, mastocytosis and pancreatic cancer for which the EMEA has granted orphan drug status.
Pharma Strategy Blog: Could you tell us about yourself and how you came to start AB Science in 2001?
Alain Moussy: I met a great team of researchers and physicians, and we decided to build a company around tyrosine kinase inhibitors for oncology and other diseases. Compared to big pharmaceutical companies, our goal has been to come up with the safest tyrosine kinase inhibitors, and the first one we have is now available in dogs and we hope will go all the way in humans both in oncology and outside oncology.
Pharma Strategy Blog: Why did you start off with a drug for dogs?
Alain Moussy: We think that that dog is a fantastic scientific platform for humans and is also a shorter time to develop, so you can go to the market earlier, which is good when you don’t have any revenues.
Pharma Strategy Blog: What is your vision for AB Science?
Alain Moussy: This business is about making drugs that really make a difference for patients. Pharmaceutical companies, however, have the constraints of having to make a return for the benefit of their shareholders, and so 90% of the time they develop a drug that is not that effective but is safe. This generates revenue that sustains their sales force and high cost structure. We at AB Science are here to make new drugs that radically change the life of patients by surviving more in cancer, or reducing symptoms in chronic inflammatory disorders. Our vision is to make new drugs that make a difference.
Pharma Strategy Blog: Many biotechs have pursued alliances or partnerships with large pharma companies, why has AB Science publicly said it has no interest in this?
Alain Moussy: Biotechs are owned by venture capitalists, who have a 5 to 7 year cycle to make money, but the cycle of drug development is 10-12 years, so in the middle of the cycle they have to sell where the risk is not too high. Typically, venture capitalists do not care whether the product ends up being approved or not. Most biotechs end up following this strategy because they are owned by VC firms. AB Science is owned by entrepreneurs, and we have chosen to dedicate our life to developing products that make a difference. We have to stay independent, because if we try to make money in the middle of the drug development cycle, then we will just select drugs that we can sell to a big pharma, and this is not what we want. What we want is stability for the long-term to have time to take the necessary risks to make the right products. We take a lot of risks everyday because it is the only way to find the right drug. We don’t think we need to partner with anybody because we know how to develop our drugs and that is what we did in dogs.
Pharma Strategy Blog: How do you feel about going up against large companies such as Pfizer?
Alain Moussy: In dogs, we obtained the first approval in Europe for a drug to treat cancer in animals, ahead of Pfizer Animal Health. We are competing against them, and we will see who has the best product. Pfizer based their regulatory submission on a clinical trial with only a 6-week end point, while we have follow-up data after 150 weeks showing a significant increase in survival. We think our product is very specific and safer and that based on the data, it offers a greater benefit/risk.
The other important thing to note is that last year Pfizer spent $10 billion in R&D with no new chemical entity registered, and AB Science had one. It does not cost $1B to develop a new drug, as that is the cost of failure integrated into debt. If you go to a very severe disease with the right product, you can do it even if you are small.
Pharma Strategy Blog: How have sales of masitinib for dogs gone in Europe?
Alain Moussy: Sales are picking up and because they like the drug, orders are repeating. That is the sign of a good drug. The profit generated by the veterinary business, although limited, will be invested back in R&D.
Pharma Strategy Blog: Where do you hope to go after Europe?
Alain Moussy: The United States is the next target for dogs and we are very close to registration. Besides that there is Canada, Australia, South Africa, South America and Japan. There are a dozen or so countries that are of interest for dogs.
Pharma Strategy Blog: When is approval likely in humans?
Alain Moussy: In humans, we don’t expect approval before end of 2011, with sales in early 2012. If our phase 3 trials are positive, we will register in the US and Europe at the same time. The earliest approval will be in pancreatic cancer. GIST is a long-term play because it is difficult to recruit.
Pharma Strategy Blog: Where do you see masitinib being used in humans, will it compete against existing products?
Alain Moussy: In pancreatic cancer, the positioning of our product is in addition to gemcitabine. In vitro masitinib has been shown to reverse resistance of pancreatic tumor cell lines to gemcitabine. Our product is unique in its ability to resensitize the pancreatic cell line that has become resistant to gemcitabine.
In phase 2, the survival rate at 18 months was 28% with no difference between metastatic tumors and locally advanced. From an analysis of 45 other studies, the current survival rate at 18 months is 6-8% in metastatic, non-resectable tumors. In our study, 28% survived. This is a major difference, but sometimes phase 2 data is not replicated in phase 3, but that is the magnitude of the hope we are carrying. Many large companies have failed in pancreatic cancer, so if we succeed this will be big news for us and for pancreatic cancer patients who, unfortunately, die rapidly.
Masitinib is able to resensitize other cell lines with other chemotherapies, so it has a generalist mechanism of action that can be used in many cancers, so we are doing clinical trials in e.g. prostate, CRC, NSCLC, breast, and multiple myeloma. We get very good results in-vitro, which we hope to replicate in-vivo in humans and dogs. This is why masitinib is fascinating in oncology.
In the GIST indication, we will not compete against sunitinib since our product is not positioned in resistance to imatinib, but we will compete directly against imatinib. Our phase 3 trial is head to head against Glivec/Gleevec. We will see what results we have at the end.
Pharma Strategy Blog: Les Echos published a report earlier this year that you planned an IPO in early 2010, is that still planned?
Alain Moussy: The market for IPOs was closed, but is re-opening. AB Science is a candidate for an IPO next year and we will do that in Europe, not in America. We plan to use the money we gain from an IPO to invest in clinical trials. The IPO will take place before we know the results of our phase 3 trials, so I hope that people will in invest in the hope of what masitinib may be able to do.
Pharma Strategy Blog: What are your plans post IPO?
We hope post IPO to deliver positive results in one of our phase 3 trials, which would allow us to register the drug in humans. If that happens then since it is a specialty business product sold to hospitals and not general physicians, it is likely we will keep ownership and distribute the product ourselves, which means we will make high margins in markets that are worth billions. In that case, it is likely AB Science will become big, which we are not today.
Pharma Strategy Blog: Does AB Science have other products in the pipeline other than masitinib?
Alain Moussy: We have a platform of new products, which have not been developed yet. In order to keep control of the company, we have limited the amount of money we have raised so far. After the IPO we will invest in developing these new products.
Our approach is to invest in one compound at a time, because if you have multiple indications with one compound you have economies of scale. If our development cost for one compound in multiple indications is roughly €200M in man, this would be €800M if instead we had one compound per indication. So our strategy of one compound for multiple indications, which some people think is risky, saves us €600M.
Pharma Strategy Blog: Do you have to spend a lot of time with your institutional investors explaining your strategy?
Alain Moussy: We have refused many venture capitalists because they did not share our strategy. We selected the shareholders of AB Science on the basis of sharing the long-term strategy of the company. There is no conflict with them because they agreed at the beginning to give us the time and independence to develop drugs that change the lives of people.
Pharma Strategy Blog: Finally, looking back on your experiences over the past eight years, what advice would you give to other biotech entrepreneurs who wish to follow you?
Alain Moussy: Coming from the retail industry at Carrefour, I was totally ignorant of the difficulties. Bringing a drug to market is an incredibly challenging, difficult and positive job helping save people’s lives and there is nothing better that I could have done in my life. Science needs entrepreneurs because science needs to take risks. The lesson of entrepreneurship is when you do believe in something, you should not try to measure the effort but just do it and that is what we are doing.
ABT-737 is a BH3 mimetic compound and Bcl-2 family protein inhibitor from Abbott Labs being tested in various oncologic indications. It has also been shown to potentiate TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells.
Malignant melanoma is resistant to almost all conventional forms of chemotherapy. Recent evidence suggests that anti-apoptotic proteins of the Bcl-2 family are overexpressed in melanoma and may contribute to melanoma's striking resistance to apoptosis. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xl and Bcl-w, has demonstrated efficacy in several forms of leukemia, lymphoma as well as solid tumors. However, overexpression of Mcl-1, a frequent observance in melanoma, is known to confer ABT-737 resistance.
Methodology/Principal Findings
Here we report that knockdown of Mcl-1 greatly reduces cell viability in combination with ABT-737 in six different melanoma cell lines. We demonstrate that the cytotoxic effect of this combination treatment is due to apoptotic cell death involving not only caspase-9 activation but also activation of caspase-8, caspase-10 and Bid, which are normally associated with the extrinsic pathway of apoptosis. Caspase-8 (and caspase-10) activation is abrogated by inhibition of caspase-9 but not by inhibitors of the death receptor pathways. Furthermore, while caspase-8/-10 activity is required for the full induction of cell death with treatment, the death receptor pathways are not. Finally, we demonstrate that basal levels of caspase-8 and Bid correlate with treatment sensitivity.
Conclusions/Significance
Our findings suggest that the combination of ABT-737 and Mcl-1 knockdown represents a promising, new treatment strategy for malignant melanoma. We also report a death receptor-independent role for extrinsic pathway proteins in treatment response and suggest that caspase-8 and Bid may represent potential markers of treatment sensitivity.
This was a stunner via a tweet from the Roswell Park Cancer Institute yesterday. Of course, I clicked on the link because my suspicion was that it wouldn't be the most common O blood that is linked to pancreatic cancer, and no, I don't have blood group O. A little voyeuristic, perhaps, but sometimes curiousity literally kills the cat.
What was interesting about the link was that it came from the NCI, a well respected institution in the US, which was reporting on a study that has just been published in Nature Genetics confirming epidemiology studies on stomach and other GI cancers going back to the 1950's. It's not new? How come we haven't heard much about this fascinating story then? That's the trouble with science, a lot of great stuff gets lost in the river of noise in daily life and finding the good snippets can be like searching for needles in a haystack, to mix metaphors.
Previously, we have heard that a high fat diet, alcohol and heavy smoking have all been linked with the disease, but that isn't always the case as Prof Randy Pausch and these incredible patient stories have shown.
"The researchers discovered that genetic variation in a region of chromosome 9 that contains the gene for ABO blood type was associated with pancreatic cancer risk. Individuals with the variant that results in blood types A, B, or AB were at an increased risk of pancreatic cancer, compared to those with the variant for blood type O. This finding is consistent with previous research, some of it dating back to the 1950s and 1960s, that had shown increased risks of gastric and pancreatic cancer among individuals of the A and B blood groups (i.e., blood types A, B, and AB). The latest results provide a genetic basis for those earlier observations."
So what does that mean from a scientific basis? The NIH continued:
"A person's blood type depends on which form or forms of the ABO gene they inherit from their parents. The protein produced by the ABO gene determines the type of carbohydrates (complex sugars) that are present on the surface of red blood cells and other cells, including cells of the pancreas. The proteins encoded by the A and B forms of the gene transfer different carbohydrates onto the cell surfaces to make A and B blood types. The O form encodes a protein that is unable to transfer carbohydrates. Studies by other researchers have shown that ABO protein encoding in pancreatic tumor cells is different than in normal pancreatic cells."
Most pancreatic cancers are diagnosed late, ie in stage IV, meaning that the prognosis and long term survival is poor but these new findings may help enable earlier detection of the disease. The researchers performed arrived at their conclusions by conducting a genome-wide association study (GWAS). In a GWAS, researchers analyze common variants, called single-nucleotide polymorphisms (SNPs), in the genomes of people with disease and in a control group (people without the disease).
The team genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. They also conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components.
The end result?
They were able to identify several SNPs on the long arm of chromosome
9 that were associated with pancreatic cancer risk and mapped to the
ABO gene.
Still, the big questions in my mind are:
a) Why do people with blood group O appear to have a lower risk? What protective effect is at play?
b) How can we use the knowledge of higher risk factors in blood groups A, B and AB to screen and diagnose pancreatic patients earlier? Would the spittoon type tests offered by commercial genetic testing companies such as 23andme help with this at all?
It's all very well science finding new relationships and genetic associations with disease, but it would be very sad indeed if we went another 50 years with no improvement in early detection and mortality associated with the fatal disease.
Amundadottir, L., Kraft, P., Stolzenberg-Solomon, R., Fuchs, C., Petersen, G., Arslan, A., Bueno-de-Mesquita, H., Gross, M., Helzlsouer, K., Jacobs, E., LaCroix, A., Zheng, W., Albanes, D., Bamlet, W., Berg, C., Berrino, F., Bingham, S., Buring, J., Bracci, P., Canzian, F., Clavel-Chapelon, F., Clipp, S., Cotterchio, M., de Andrade, M., Duell, E., Fox Jr, J., Gallinger, S., Gaziano, J., Giovannucci, E., Goggins, M., González, C., Hallmans, G., Hankinson, S., Hassan, M., Holly, E., Hunter, D., Hutchinson, A., Jackson, R., Jacobs, K., Jenab, M., Kaaks, R., Klein, A., Kooperberg, C., Kurtz, R., Li, D., Lynch, S., Mandelson, M., McWilliams, R., Mendelsohn, J., Michaud, D., Olson, S., Overvad, K., Patel, A., Peeters, P., Rajkovic, A., Riboli, E., Risch, H., Shu, X., Thomas, G., Tobias, G., Trichopoulos, D., Van Den Eeden, S., Virtamo, J., Wactawski-Wende, J., Wolpin, B., Yu, H., Yu, K., Zeleniuch-Jacquotte, A., Chanock, S., Hartge, P., & Hoover, R. (2009). Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer Nature Genetics DOI: 10.1038/ng.429
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This blog is published by: Sally Church, PhD of Icarus Consultants, Inc. The contents of this blog are the intellectual property of the author and all rights are reserved. No commercial use, copying or distribution is permitted without the author's express permission.
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