Technology | Pharma Strategy Blog

Nanoparticle drug delivery helps reduce tumour metastasis

By MaverickNY on August 23, 2010

Nanotechnology is a topic that fascinates me, ever since hearing some interesting data in pancreatic cancer at the American Association of Cancer Research (AACR) meeting last November on Molecular Targets in Boston.

Someone kindly sent me a paper from PNAS recently (link below), from 2008, which got my attention essentially because:

"Integrin aBv3 is found on a subset of tumor blood vessels where it is associated with angiogenesis and malignant tumor growth. We designed a targeted aBv3 nanoparticle (NP) encapsulating the cytotoxic drug doxorubicin (Dox) for targeted drug delivery to the expressing tumor vasculature."

Now, giving doxorubicin by the normal route of administration results in noticeable weight loss and other side effects when given systemically. Using nanotechnology, a 15-fold increase in anti-metastatic activity without concomitant weight loss, which is very interesting indeed.

The authors noted that integrin could represent an ideal vascular targeting receptor since it is highly expressed on the angiogenic endothelium and expression of this receptor on tumor vessels correlates with disease progression. This was first shown by Gasparini et al., in 1998 (see reference source below).

Meanwhile, in this 2008 study, the researchers used models from renal cell and pancreatic carcinoma to determine the effectiveness of the nanoparticle delivery system. Given that the results appear better with metastatic rather than primary tumour growth, I wondered if anyone was looking at this concept with currently approved drugs for metastatic disease?

A quick search for nanoparticle and cancer in the clinical trials database brought up mostly trials associated with nanoparticle paclitaxel (Abraxane) from Abraxis ($ABII). Of course, one of the challenges here is that in animal research, drugs and nanoparticles can be injected directly into the tumour thus avoiding systemic effects, whereas in human research, nanoparticle drugs are more typically combined with regular drugs and infused as normal.

It was, hover, no surprise to learn earlier this year that Abraxane is looking promising in 2nd line advanced pancreatic cancer as a single agent after failure of gemcitabine-based chemotherapy. At AACR last year, researchers from Mass General showed that Abraxane targets the tumour stroma, depleting it, thereby reducing the impediment to chemotherapy. The Nab-paclitaxel utilises 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 logical target for the drug. Abraxis reported in May that the median overall survival was 7.3 months, which is impressive in a very hard to treat refractory population.

I wonder what the Nab paclitaxel data would look like in front-line treatment in combination with gemcitabine? Or what about using it in advanced renal cancer with any of the half dozen drugs already approved but with limited effectiveness? Would adding a nanoparticle delivery system such as Abraxane to the mix reduce metastasis, deplete the stroma and improve access to the tumour for the anti-angiogenic agents?

Overall, it's an interesting technology concept for improving drug delivery and we're still at relatively early stages of research. Hopefully, we'll hear more about nanotechnology and the broader application of new combination nanoparticles to cancer treatment in the near future. It takes significant investment, creativity in trial design and an intensive yet broad research program to drive results though. Celgene ($CELG) have since bought Abraxis and may be more willing to aggressively invest in the growth of this interesting drug.

I must say that the AACR Molecular Targets and Cancer Therapeutics meeting every November is one of my all time favourites, but it alternates with Europe every other year and will be in Berlin this November, so depending upon my schedule I may not be able to make it this time 🙁

Murphy, E., Majeti, B., Barnes, L., Makale, M., Weis, S., Lutu-Fuga, K., Wrasidlo, W., & Cheresh, D. (2008). From the Cover: Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis Proceedings of the National Academy of Sciences, 105 (27), 9343-9348 DOI: 10.1073/pnas.0803728105

Gasparini G, Brooks PC, Biganzoli E, Vermeulen PB, Bonoldi E, Dirix LY, Ranieri G, Miceli R, & Cheresh DA (1998). Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 4 (11), 2625-34 PMID: 9829725

Patterns of expression of DNA repair genes and relapse from melanoma

By MaverickNY on August 17, 2010

Someone kindly sent me this paper on how gene expression can be used to track insufficient DNA repair, which can lead to relapse in melanoma, making it potentially useful as both a prognostic and predictive biomarker for the disease. Regular readers will notice that I am slowly changing my opinion of gene expression studies as a result of articles like this one :-).

According to the researchers:

"Over-expression of DNA repair genes was shown to be associated with reduced relapse-free survival, thicker tumors and tumors with higher mitotic rate.

Preliminary data are also reported suggesting that DNA repair genes are overexpressed in tumors from patients who do not respond to chemotherapy."

Resistance to treatment is one of the biggest ongoing problems associated with treatment of melanoma, both with approved therapies and also pipeline drugs, so finding ways to detect it earlier (and the reasons why) would potentially help in sequencing with different drugs.

So what was involved in this study, which is the largest gene expression study to date in melanoma? The authors decided to see whether formalin-fixed tissue analysis would be useful:

"Gene expression profiles were identified in samples from two studies (472 tumors). Gene expression data for 502 cancer-related genes from these studies were combined for analysis."

The findings were quite interesting.

Basically, the increased expression of DNA repair genes most strongly predicted relapse, and was associated with thicker tumours. Increased expression of RAD51 was the most predictive of relapse-free survival (RFS). In addition, RAD52 and TOP2A were independent predictors of RFS in the analysis.

The authors concluded:

"Over-expression of DNA repair genes (predominantly those involved in doublestrand break repair) was associated with relapse. These data support the hypothesis that melanoma progression requires maintenance of genetic stability."

In the past, we have discussed synthetic lethality and DNA repair on this blog in breast and ovarian cancers, with respect to PARP inhibitors seeking to repair damaged DNA and prolong survival outcomes. Based on the current analysis, it looks as though a similar approach may be useful in melanoma. This may give clues for future pipeline development of new therapeutics designed to tackle the specific underlying biology of the cancer.

It should be noticed, though, that the results are describing the factors contributing to relapse from chemotherapy (dacarbazine, DTIC) rather than current pipeline drugs in development for melanoma such as PLX-4032 (Roche/Plexxikon) or ipilimumab (BMS).

I would be very interested to see whether the biomarkers identified in this research for chemotherapy would also apply to the targeted therapies. It is possible that they may not, or possibly they could help reverse or repair some of the changes occurring. Either way, finding ways to address the DNA repair may be a fruitful area of study.

Jewell, R., Conway, C., Mitra, A., Randerson-Moor, J., Lobo, S., Nsengimana, J., Harland, M., Marples, M., Edward, S., Cook, M., Powell, B., Boon, A., de Kort, F., Parker, K., Cree, I., Barrett, J., Knowles, M., Bishop, T., & Newton-Bishop, J. (2010). Patterns of Expression of DNA Repair Genes and Relapse from Melanoma Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-10-1521

An experiment on Pharma Strategy Blog

By MaverickNY on August 9, 2010

Over the last couple of months I've had a few grumbles from readers suggesting that the 13pt font was too small on the screen or the blog text in the emails was miniscule.

I've played around with the theme a bit and it seems the default goes from 13pt to 16pt, which for me as a scientist used to reading tiny text in journal papers is a bit like shouting, but we'll see what happens.

Over the next few months you'll see some UI and UX changes as we move from Typepad to WordPress for blog hosting. I've resisted the move some time as I'm one of those people who aren't really interested in the nerdy bits inside the engine, preferring to set up a theme and just blog rather than fiddle with the innards.

Still, we are planning to evolve Pharma Strategy Blog with new services such as monthly newsletters and more extensive cancer reports that you can purchase, in addition to the daily snippets here on the blog. Setting up a commercial service is much easier and more professional in WordPress (WP), so that is pretty much driving the decision to move along with other cool tools such as Disqus and Backtype, which don't play at all well on the Typepad platform.

Converting the posts (over 700 of them along with comments) is not going to be easy by all accounts, especially transferring the precise urls, so you may see some old posts reappear in Twitter or the RSS feed as we convert them from the old Typepad Oncochat url to the Pharma Strategy Blog one before the move to WP. We do appreciate you patience during the transition to our new home.

A number of you have asked how to find old posts.

The Archives section has been added to the right hand column, which is useful if you can remember when (approximate month) it was posted or you can browse for anything interesting. Alternatively, the Lijit search widget on the right works like Google – you just type in what you're looking for and it will produce a list of posts on that specific topic if it has been covered.

If you have any other ideas or suggestions that you would like to see here, please add them in the comments.

Social media is NOT a strategy…

By MaverickNY on August 6, 2010

No, it is not a strategy in and of itself.

It is, however, a useful collection of tools that can be used tactically as part of an overall brand strategy… one element or part of the whole, if you like. To make social media work well you need to integrate it with more traditional approaches that capture the imagination and inspire people.

New (digital) toys on their own will not do much for your brand or ROR, return on relationships. Adding value, will however, make a huge difference. Deep down, we all know this intuitively, but it’s easy to get distracted by shiny lures and forget the basics of marketing.

Joe Chernov and Valerie Maltoni illustrate this conundrum perfectly (see link below for the cartoon source):

Source: Eloqua Blog

If a consultant or agency comes to see you Pharma folks touting “social media strategy” you instantly know they’re a fake and don’t know what they’re talking about ;-).

Isolated tactical execution without a strong focused brand strategy is doomed to failure from the start so avoid that trap.

Think differently.

Pathwork Diagnostics and Novartis to pursue a research partnership

By MaverickNY on July 30, 2010

It was interesting to see my Diagnostics alert feed full of the news that Pathwork Diagnostics and the new Novartis molecular diagnostics group are entering a research partnership.

I first came across Pathwork Dx at ASCO last month when they presented an interesting poster on their tissue of origin gene based expression test to help in the diagnosis of poorly differentiated and metastatic tumours. Clearly, an accurate diagnosis will lead to better optimisation of appropriate therapy and risk assessment/management. The tissue based test has since received approval from the FDA.

According to Pathwork:

"The Tissue of Origin LDT uses a combination of microarray technology and advanced analytics to measure the gene expression patterns (comprising more than 1500 genes) of challenging tumors, including poorly differentiated, undifferentiated, and metastatic cancer. These data are compared with the gene expression patterns of a panel of 15 known tissue types—representing 58 morphologies and covering 90% of solid tumors—in order to identify the tumor."

The tissue test is based on gene arrays using DNA and RNA technology used in research, but with its approval, we will start to see more commercial applications evolve for diagnostic purposes.

More details about the deal and the financial background can be found in the WSJ.

What's interesting here is that:

1) We are seeing more sophisticated technology emerge for both tissue and blood biomarkers, which will hopefully help us improve not only diagnosis but also treatment and monitoring of drug responses over time.

2) More integration and collaborations between manufacturers and diagnostic companies means that the information and knowledge can be shared more easily and quickly rather than being bogged down in silos.

3) The companies that do well with integrating diagnostics into their cancer programs will not only have a huge commercial edge, but it will continue to raise the bar for new competitors and smaller companies in terms of funding and resources.

It's going to be fascinating watching this area of oncology develop.

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Dendreon's sipuleucel-T data from the IMPACT trial shows no surprises

By MaverickNY on July 29, 2010

Yesterday was a travel day but thanks to gippy wifi and a packed day, I didn't have the opportunity to post about some interesting articles on prostate cancer published in the NEJM, which I read and digested on the train up to Boston. Now that the embargo has lifted, we can all talk and write about the data publicly.

Kantoff et al., have reported the full results of the IMPACT trial data for sipuelucel-T (Provenge) from Dendreon (a client), which led to the vaccine being approved by the FDA for the treatment of asymptomatic prostate cancer recently. The results are not new and contain no surprises as they are already well represented in the prescribing information (PI), which are available online for anyone to read and have been presented ad nauseum at recent meetings at the American Urology Association (AUA) and American Society of Clinical Oncology (ASCO).

For those who missed the meetings, the data can be summarised by the following quotes from the article:

"This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group."

"The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group."

"Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache."

What can conclude from this is that the vaccine helped men with asymptomatic prostate cancer live longer without the known significant toxicities seen with chemotherapy such as alopecia (hair loss), severe myelosuppression, neutropenias, anemias, febrile netropenias and infectious complications. That would be a win in most people's books because people want to know whether their relative with cancer will live longer, feel better than they do and have a reasonable quality of life with their families. The price might be a bit of a sticker shock, but insurers seem to be covering it to date without any major hiccups.

The accompanying editorial, however, from Dan Longo, a cancer researcher and Scientific Director, National Institute on Aging, National Institutes of Health in Maryland, was probably well meaning, but rather surprising and a little harsh at times.

Science is about the pursuit of truth and in this case, finding out whether men with an advanced cancer would live longer, which they clearly did, so to grumble about the lack of tumour shrinkage is a little odd. Oncologists have for years focused on this as an indication of response rate through a measurement system known as RECIST although whether the patient lived any longer was somewhat moot. In Longo's editorial, he noted:

"It is hard to understand how the natural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least disease stabilization reflected in a delay in tumor progression."

This is rather old school thinking and as we develop new therapeutic approaches, the end points and surrogate biomarkers may well change.

There have been far too many studies in cancer that showed that traditional chemotherapy could shrink a cancer (great) while toxically poisoning everything in its wake as well (not so great), making many of us wonder whether this was actually a useful approach if survival wasn't impacted. By this, I mean are we measuring the right thing in the first place?

In full disclosure, my own Father passed away from this disease 10 years ago this month, so it possible that I'm biased in my thinking have gone through his experience with him. It was a very stressful time for all of us, him especially, although he held up well and maintained his dignity until the end. Still, I think I would rather know that a new therapy would help a male relative of mine lived longer (improved overall survival) and felt better (less sickness and pain). Then we could all enjoy their last few years together in dignity with quality time than go through the hell that is chemotherapy, which he chose not to do because after many discussions, because if it wasn't going to cure him he saw no point in putting my Mother through that agony.

Sometimes, we need a more humanistic approach to oncology and to remember that these are people's lives we are talking about, not a number on a stat sheet. Tumour shrinkage? "Pshaw, what does that mean?!" was my Dad's cynical reaction. Looking back, he was instinctively right.

Another question that was raised in the editorial was the study design, ie was the control group an ideal one? Well, to be fair the time for input into those issues is during the protocol design stage when many people's input is sought before a trial even begins enrolling. Grouching about it after the event seems a little churlish at best.

Could the control group have experienced some stimulatory effect? Possibly, but then when you look at the data, the survival time is not out of kilter with those from other control groups previously reported versus chemotherapy who mostly received best supportive care, ie usually pain medications and growth factor support. Perhaps had that approach been taken the difference between the control group and the sipuleucel-T group would have been even greater.

"As the authors point out, differences in subsequent treatments (e.g., docetaxel) do not appear to account for the survival differences, but methods for assessing such effects are imperfect. New prognostic variables such as statin use, the duration of the first off-treatment interval, circulating tumor cells (as assessed as EpCAM+CK+CD45− objects), and new prognostic algorithms may need to be accounted for in assessing therapeutic effects."

Well quite, but I'm sure we'll hear more about further meta analyses of the data at some point. There are a number of other vaccines in phase II/III trials and as we learn more about how this therapeutic approach works, which markers to measure and what impact they have on both the immune system and the natural course of the disease, so our scientific and clinical knowledge will improve and hopefully, patient outcomes as well.

Promising phase II data doesn't always translate into significant phase III data, as we have seen more compounds and vaccines than I remember over the years. For now, we have two new therapy options for men with prostate cancer at different stages of the disease, more choice can only be a good thing, as is having a active pipeline for treatment of prostate cancer, offering hope for many that progress is being made after years of stagnation.

{UPDATE: I spotted Adam Feuerstein's (The Street) and Matthew Herper's (Forbes) excellent articles on this topic after writing this blog post, so they are linked for further information and background reading for those interested.

Kantoff, P., Higano, C., Shore, N., Berger, E., Small, E., Penson, D., Redfern, C., Ferrari, A., Dreicer, R., Sims, R., Xu, Y., Frohlich, M., & Schellhammer, P. (2010). Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer New England Journal of Medicine, 363 (5), 411-422 DOI: 10.1056/NEJMoa1001294

Longo, D. (2010). New Therapies for Castration-Resistant Prostate Cancer New England Journal of Medicine, 363 (5), 479-481 DOI: 10.1056/NEJMe1006300

Abnormal Circulating Cells in Lung Cancer Patients: Possible New Technique for Identification

By MaverickNY on July 27, 2010

A while back I wrote about how circulating tumour cells (CTC’s) see here and here, can be used as a potential new surrogate measure for prostate cancer, so it was with great interest that I read an excellent article (free public link courtesy of AACR) on abnormal circulating cells in non-small cell lung cancer (NSCLC) late last week.

Essentially, this new research from three academic institutions (MD Anderson TX, Manchester UK and Baltimore, MD) set out to:

“Determine if a fluorescence in situ hybridization (FISH)–based assay using isolated peripheral blood mononuclear cells (PBMCs) with DNA probes targeting specific sites on chromosomes known to have abnormalities in non–small cell lung cancer (NSCLC) cases could detect circulating genetically abnormal cells (CACs).”

In the recent discussion about fluid-based blood biomarkers, we saw how people could be spared invasive and inconvenient tumour biopsies, which are not always practical in advanced lung cancer, particularly if the patient is elderly or frail. In this study, the researchers demonstrated that detection of circulating epithelial cells (CECs) or CTCs using a simple blood test may assist in early detection of lung cancer at diagnosis and relapse and provide a minimally invasive way to monitor results of therapy.

Now in this study, only a small number of people with NSCLC were evaluated (NSCLC n=59 plus n=29 controls), but they do give us an indication of what could be looked at in larger scale clinical trials (first find your needle in the haystack!) The presence or increased numbers of these circulating abnormal cells confers a poorer prognosis, ie associated with relapse of disease and poorer survival, so the ability to pick them up earlier and more easily would be an advantage clinically.

The approach used in this research was a commonly used technique called fluorescence in situ hybridization (FISH) to detect abnormal circulating cells that have aberrations found in non-small cell lung cancer. FISH detects and quantifies abnormal cells by using dye-labeled DNA probes of cell chromosomes that cause cells with the targeted genetic abnormalities to light up when viewed under a fluorescent microscope.

The researchers chose 12 biomarker probes that target aberrations previously connected to lung cancer to analyze both the controls (people without lung cancer) and people with NSCLC, including both smokers and non-smokers. In the analysis they found the following:

Highly significant differences in the average number of abnormal cells in the bloodstream between patients and controls.
Abnormal cells were significantly associated with disease stage, with cells that contained certain abnormalities increasing significantly as cancer progressed from early to advanced stage disease.
Eight of the biomarkers had a strong overall correlation between abnormal circulating cells and tumors. Chromosomal gain of the EGFR gene in circulating cells was significantly associated with the same gain in tumors, particularly in patients with stage III or stage IV disease.

No doubt work will soon be underway to develop a commercial clinical test based on FISH, which would then be able to be used in the Community Oncology setting, where the majority of patients are treated in the US. Validation in clinical trials will be crucial to this process.

In an MD Anderson news release, the lead author, Ruth Katz, was quoted as saying:

“Blood tests for these circulating tumor cells could be used to diagnose lung cancer earlier, monitor response to therapy and detect residual disease in patients after treatment.”

Source: MD Anderson Cancer Center

Having an easier to use test to monitor responses more accurately to products in development will be particularly useful for pipeline drugs.

References:

Katz, R., He, W., Khanna, A., Fernandez, R., Zaidi, T., Krebs, M., Caraway, N., Zhang, H., Jiang, F., Spitz, M., Blowers, D., Jimenez, C., Mehran, R., Swisher, S., Roth, J., Morris, J., Etzel, C., & El-Zein, R. (2010). Genetically Abnormal Circulating Cells in Lung Cancer Patients: An Antigen-Independent Fluorescence In situ Hybridization-Based Case-Control Study Clinical Cancer Research, 16 (15), 3976-3987 DOI: 10.1158/1078-0432.CCR-09-3358

The growing importance of KRAS in ovarian cancer and its impact on pipelines

By MaverickNY on July 26, 2010

We've heard a lot about the impact of KRAS in colorectal cancer as a useful biomarker for determining whether or not to treat with EGFR therapy, depending on whether the mutation is wild-type or mutated, but now new evidence has emerged for it's possible role in ovarian cancer.

A paper by Ratner et al., from Yale University, looked at the relationship between an increased risk of OC and a KRAS variant.

Overall, the data demonstrated that a variant of the KRAS oncogene was present in 25% of all ovarian cancer patients. The same variant was also found in 61% of ovarian cancer patients with a family history of breast and ovarian cancer. Up until now though, it has proven impossible to tell which women with a strong family history of breast and ovarian cancers would go on to develop the disease. These results therefore offer some new clues in the puzzle.

Related research from another team from the UK, Denmark and US, published last year, looked at tagging single-nucleotide polymorphisms (SNPs) in candidate oncogenes and the susceptibility to ovarian cancer in approx. 1,800 women with invasive ovarian cancer compared with controls (n=3,000). The goal was to identify moderate/low-risk susceptibility alleles of the proto-oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, but no evidence of ovarian cancer association was found with these SNPs. When stratified by
histologic subtype, however, one common variant allele have borderline evidence of association with epithelial ovarian cancer.

What was interesting to me in the latest research from Yale is that all the women in the study had a strong family history of cancer, but only half had known genetic markers of ovarian cancer risk such as BRCA1 or BRCA2 mutations. The results, albeit from a small sample (n=157), suggest that the KRAS variant may offer a more sensitive than currently available.

The Yale group had previously established that the KRAS-variant is not somatic but germline, meaning it is identical in person's normal and tumour tissues, thereby enabling the researchers to collect primarily germline DNA from either blood or saliva, rather than from tumour biopsy samples. This is huge from a patient perspective and physician point of view in terms of ease of use and convenience.

This study is important because ovarian cancer is the single most deadly form of women's cancer and is usually diagnosed in advanced stage disease. Part of the reason is because of the lack of known risk factors or genetic markers of risk. To this end, the authors concluded:

"Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing ovarian cancer, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for hereditary breast and ovarian cancer families without other known genetic abnormalities."

What we now need is validation in large scale clinical trials to determine whether the genetic marker can be used commercially to determine prognostic risk for ovarian cancer earlier. If the results ultimately prove useful in clinical trials, then this finding relating to the KRAS variant may well have important implications for future therapeutic strategies and pipeline development in ovarian cancer as well as for prognostic testing and earlier detection for improved outcomes.

Ratner, E., Lu, L., Boeke, M., Barnett, R., Nallur, S., Chin, L., Pelletier, C., Blitzblau, R., Tassi, R., Paranjape, T., Hui, P., Godwin, A., Yu, H., Risch, H., Rutherford, T., Schwartz, P., Santin, A., Matloff, E., Zelterman, D., Slack, F., & Weidhaas, J. (2010). A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk Cancer Research DOI: 10.1158/0008-5472.CAN-10-0689

Quaye, L., Song, H., Ramus, S., Gentry-Maharaj, A., Høgdall, E., DiCioccio, R., McGuire, V., Wu, A., Van Den Berg, D., Pike, M., Wozniak, E., Doherty, J., Rossing, M., Ness, R., Moysich, K., Høgdall, C., Blaakaer, J., Easton, D., Ponder, B., Jacobs, I., Menon, U., Whittemore, A., Krüger-Kjaer, S., Pearce, C., Pharoah, P., & Gayther, S. (2009). Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer British Journal of Cancer, 100 (6), 993-1001 DOI: 10.1038/sj.bjc.6604947

Chin, L., Ratner, E., Leng, S., Zhai, R., Nallur, S., Babar, I., Muller, R., Straka, E., Su, L., Burki, E., Crowell, R., Patel, R., Kulkarni, T., Homer, R., Zelterman, D., Kidd, K., Zhu, Y., Christiani, D., Belinsky, S., Slack, F., & Weidhaas, J. (2008). A SNP in a let-7 microRNA Complementary Site in the KRAS 3' Untranslated Region Increases Non-Small Cell Lung Cancer Risk Cancer Research, 68 (20), 8535-8540 DOI: 10.1158/0008-5472.CAN-08-2129

Pipeline analysis: Verona Pharma ($VRP) – Asthma and COPD

By MaverickNY on July 22, 2010

The other day as I was clearing out my office of a hideous amount of paper as we continue our quest for a true minimalist and paperless office that is also scanned and searchable as well as being environment friendly, when I came across a tiny scrap of newspaper. Before throwing it out, curious, I wondered what it was about as a large starfish in the centre caught my attention.

It was a clipping from the Mail on Sunday (oops) back in early 2008.

The snippet described how a starfish could potentially point to a new way of developing treatment for asthma. The company involved, Verona Pharma, was headed by Clive Page, a Pharmacology Professor from Kings College London, where I did my Ph.D research in asthma back in the late 80's (hello, Clive!). We met at a fascinating lecture at the Brompton Hospital given by Prof Peter Barnes, I recall. No wonder I tore out the article in the financial section after idly picking up the paper on the Tube, it's like finding old memories in sepia print.

Serendipity is a fine thing sometimes.

Wondering if the company was still going (they were looking for approval for a clinical trial at that time according to the newspaper), I checked them out and was delighted to see they're not only still going strong, but now have 3 products in development and are doing well, including RPL554, the compound mentioned in the clipping.

The late 80's and early 90's were almost a heyday for respiratory research. Many of the University of London respiratory labs (including Kings and the Brompton) were busy doing large scale clinical trials that later led to a new raft of inhibitors as either long-acting beta2-adrenergic agonists eg bronchodilators (salmeterol) or new generation steroidal anti-inflammatories (fluticasone) for treating asthma. There was also a vibrant basic research community at that time looking at phosphodiesterase (PDE) 3 and 4, leukotrienes (LT), prostaglandins, cytokines and thromboxanes as mediators of the inflammatory response.

It was therefore very interesting to me to discover that Verona's lead compound, RPL554, is a mixed phosphodiesterase (PDE) 3 and 4 inhibitor (a bronchodilator and anti-inflammatory compound in a single molecule). Furthermore, it was co-invented by Sir David Jack (former Research Director of Glaxo) who was involved in the development of the inhaled asthma drugs such as salmeterol and fluticasone, among others.

Meanwhile, I was pleased to see on Verona's website that RPL554 has completed a phase I/IIa trial of RPL554, and will watch it's future progress with interest. The company is taking a smart approach to drug development. Rather than putting all their eggs in one pipeline basket,Verona have have several compounds in preclinical development for related areas such as cough and have also identified some marine organisms (hence the starfish in the news clipping), a natural source of novel anti-inflammatory polysaccharide (NAIPS) without unwanted anti-coagulant actions.

It's going to be interesting to watch Verona's development and I hope at least one of the compounds makes it to market because the underlying scientific rationale is solid.

Watch this space!

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