Lymphoma | Pharma Strategy Blog

The relationship between radioactivity, leukemias and lymphomas

By MaverickNY on March 14, 2011

Ohayo gozaimasu! Like many people this weekend, I have been following the twin earthquake and tsunami disaster in Northern Japan with a great sense of sadness after hearing that thousnads of people have died. If you haven’t already seen it, pictures of Japan before and after the tsunami devastation are an astonishing testament to the power of nature. Coming so soon after the harrowing pictures of the massacres in Libya, it certainly feels like a violent world at the moment.

It is interesting to follow the news on Twitter in real time, generally much more useful (bar some hype and silliness from some people) than CNN and other News outlets who struggled to get to grips with timely information. I was, however, disheartened to see that the engineers at Fukushima had no choice but to resort to venting the gases and also pumping in borax and sea water into the reactor chamber. They needed to do this to try and cool the reactors down, reducing pressure, thus try to prevent explosions (and noxious radioactivity escaping into the atmosphere) or even worse, a core meltdown.

One source of accurate information was the Nuclear Energy Institute, who provided regular, factual updates on their website and pictures to explain what was going on with the Fukushima Boiling Water Reactors or BWR in short (you can see where the NY Times and others got their pictures from, for example):

Source: Nuclear Energy Institute

Social Media is useful for collating information from local people in Japan, such as this brief but alarming video from Fukushima courtesy of Japanese tv of one of the explosions at the nuclear plant:

There was some great commentary on Twitter from nuclear professionals such as Arclight, who spent most of his weekend monitoring the situation and answering anxious people’s questions about what was going on. In times like these, accurate information rather than speculation is more more helpful and reassuring.

It is, however, decay heat that creates challenges, ie heat that has been stored in the rods and is expelled rapidly if they are not cooled sufficiently or exposed to air, thereby creating hot steam and pressure. The NY Times has an excellent simplified graphic that explains how nuclear reactors work for those interested.

The problem is that high levels of radioactivity in the sea or air is never a good thing for life around it. Years ago, there was a hugh debate (that’s an understatement) about the increased incidence of leukaemia and lymphomas in children around the Sellafield nuclear plant in Cumbria, UK, with different groups arguing for and against it (see references below as a snapshot).

The argument about cause and effect doesn’t seem to have been settled either way judging from various epidemiology studies and intense papers/letters to journals such as the BMJ over the past few decades. Still, I’m sure most of us would probably agree that exposure to direct prolonged radiation from the sea or air is, intuitively, probably not a good thing in the long run. Strontium, for example, one of the chemicals produced as a by product in nuclear reactors, tends to build up in teeth and bones, and may well be an irritant that can cause mutations over time.

What is clear, is that once sea water is pumped into a reactor, it is essentially dead and can never be used again, necessitating a massive clean up operation that may well take years to effect. If anyone can do it efficiently and effectively, it is probably the Japanese with their superb engineering and sadly, experience from the Hiroshima clean up after the Second World War.

This morning, the availability of clean air, food and water took on an entirely different meaning. In the meantime, my thoughts are sincerely with the Japanese people in their hour of need.

References:

Gardner, M., Snee, M., Hall, A., Powell, C., Downes, S., & Terrell, J. (1990). Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. BMJ, 300 (6722), 423-429 DOI: 10.1136/bmj.300.6722.423

Gardner MJ, Hall AJ, Snee MP, Downes S, Powell CA, & Terrell JD (1990). Methods and basic data of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. BMJ (Clinical research ed.), 300 (6722), 429-34 PMID: 2107893

Roman E, Watson A, Beral V, Buckle S, Bull D, Baker K, Ryder H, & Barton C (1993). Case-control study of leukaemia and non-Hodgkin’s lymphoma among children aged 0-4 years living in west Berkshire and north Hampshire health districts. BMJ (Clinical research ed.), 306 (6878), 615-21 PMID: 8461811

Watson GM (1991). Leukaemia and paternal radiation exposure. The Medical journal of Australia, 154 (7), 483-7 PMID: 2005848

Draper GJ, Little MP, Sorahan T, Kinlen LJ, Bunch KJ, Conquest AJ, Kendall GM, Kneale GW, Lancashire RJ, Muirhead CR, O’Connor CM, & Vincent TJ (1997). Cancer in the offspring of radiation workers: a record linkage study. BMJ (Clinical research ed.), 315 (7117), 1181-8 PMID: 9393219

Highlights and lowlights from the ASH meeting #ASH2010

By MaverickNY on December 14, 2010

Since the pre-ASH review of what might be hot at the conference, a few people have written to me asking for a rundown on my highlights from the recent hematology and breast cancer conferences. In the end, I only made it ASH in person, but followed the tweets and news that flowed out of the AACR SABCS meeting, which will post either later today or tomorrow.

Here are a few observations that struck me from ASH. There were some genuine highlights from this meeting, both in lymphomas and leukemias:

Rituximab (Roche) was the only clinical abstract selected for the plenary session this year. I loved Dr Anas Younes’ summary of this data on his Facebook Page:

“Clearly, early treatment with rituximab improved the progression free survival and time to next therapy. It is too early to see any effect on survival. My guess is that watch and wait will disappear as patients and doctors will start recommending early use of rituximab instead of watch and worry!”

The results are therefore potentially practice changing and it’s good to see positive data in a difficult to treat subset.

Ponatinib (Ariad), a third generation tyrosine kinase inhibitor (TKI) had excellent phase I data in relapsed/refractory chronic myeloid leukemia (CML), both with and without the T315I mutation. The phase II trial (PACE) is now enrolling and it is my hope that patients who find the existing TKIs fail or develop the T315I mutation will have a new therapeutic option in the not too distant future if the results continue to hold up.

Brentuximab vedotoxin (Seattle Genetics and Millennium) was the real star at ASH this year though. We’ve covered some background on the blog here. Basically, it’s a novel conjugate consisting of a monoclonal antibody with a chemotherapy molecule bolted on. The data in Hodgkin Lymphoma (HL) was absolutely stunning and a nice follow up to the article published in the NEJM by Dr Anas Younes et al., earlier this year. The companies have since announced that they intend to file with the FDA in early 2011, so perhaps we might see this exciting agent approved in the second half of next year.

Unfortunately, there were also some disappointing lowlights:

Lenalidomide (Celgene) had some interesting data in several phases of multiple myeloma, but what shocked many observers was the results of the MM-015 trial. This was the third study to suggest that there may be a risk for secondary cancers with Revlimid. Previously, the data emanated from the IFM and CALGB cooperative studies, but this was the first company sponsored trial that may be considered a registration study.

Clearly, the trend is not good news at all, although it is known that:

Alkylating treatment for AML and NHL run the risk of secondary cancers later in life
The literature suggests that all three cancers have a higher risk of secondary cancers developing, which may or may not be drug related.

In the light of all this, the myeloma finding with Revlimid is not entirely surprising but one can see why investors panicked and sold off stock after the data was announced. Of note though is that patients in the maintenance arm (MPR-R), however, will clearly receive more exposure to the drug than those in the MPR arm, potentially exposing them to a slightly higher risk.

Bosutinib (Pfizer) is a 2nd generation TKI in phase III development for newly diagnosed CML. Much of the expectation surrounding this agent was whether is would be superior to imatinib (Gleevec) in terms of efficacy in the same way that nilotinib (Novartis) and dasatinib (BMS). Both have proven to deliver earlier and deeper responses than imatinib, albeit with the caveat that we won’t know whether survival and overall outcomes will be better until the 5-10 year data is available. There was also some suggestion from Pfizer evolving over the last year that bosutinib might also be cleaner given that it only inhibits BCR-ABL and Src and not other off-target kinases such as PDGF. Unfortunately, that turned out to be a complete misnomer.

Dr Carlos Gambacorti-Passerini (Milan) did an excellent job trying to put a positive spin on the data, but this was a resoundingly negative trial. The primary endpoint of confirmed complete cytogenetic response (CCyR) at 12 months in the intent to treat (ITT) population was not met, although the secondary endpoint of major molecular response (MMR) was met. The side effect profile was particularly disappointing with a lot of diarrhoea, nausea and vomiting being frequent and most unwelcome side effects, which are very similar to chemotherapy. Much of the goal of targeted therapy is to hit the cancer cells for six while leaving normal cells largely alone. Chemotherapy is highly untargeted and hits everything in it’s wake, leaving people well aware that they are undergoing treatment for cancer rather than living with a chronic condition. Sometimes a disconnect between scientific theory and reality happens.

Pfizer announced at the meeting that they plan on pursuing an EU filing, but would hold discussions with the FDA about the relapsed/refractory setting, suggesting they will not file in the US for newly diagnosed CML, unless the FDA do a U-turn on the secondary (MMR) endpoint. The chances of that are rather slim, I suspect. I’m not entirely sure how the filing might be suitable for the EMA and not the FDA, unless the primary endpoints agreed with the Health Authorities were different. That said, given the good choices already available to people with CML, bosutinib is not going to appeal to many, I’m afraid. Certainly the CML KOLs I spoke to at the meeting were largely unenthusiastic about the agent.

Like many of the attendees, the thing most remembered from Orlando will be the bitter cold, both outside and in the presentation halls! Overall, it was really a rather quiet meeting this year, except for the excellent data in brentuximab.

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Highlights of #ASH2010 – Day 1

By MaverickNY on December 5, 2010

Yesterday was an unusually quiet day at the conference, with no formal oral abstract sessions, although there were various educational symposia running in a number of topics. Depending on what’s happening in the particular disease and who is presenting, sometimes these can be exciting when the deep thinkers present the data in an interesting way and advance the field by asking the audience to consider things more strategically.

This year, there was no new data or ideas expounded in the sessions I chose, they were basically a run through of the old data with a couple of slides at the end listing a few compounds that are in development. The pipeline in for hematologic malignancies is gradually gaining more attention from Pharma, which is great news, although they are probably a lot less crowded than the main solid tumours.

The Leukemia press briefing was informative and a number of abstracts were selected for discussion. All of the presenters did an excellent job of summarising their data, which is embargoed until after the Plenary or Oral sessions on Sunday and Monday.

The leukemia highlights comprised:

Dr Fielding: imatinib in Ph+ pediatric ALL
Dr Rosti: nilotinib in Ph+ early phase adult CML
Dr Cortes: ponatinib in advanced phase CML
Anna Jankowska and Prof Maciejewski: TET2 mutations in myeloid malignancies

I will write more about the data after the embargoes have been lifted.

A number of people were tweeting snippets from the meeting and quite a few bots were posting various press releases. There are a number of tools out there for showing the big picture around conferences and hashtags, which we’ve shared in the past on this blog. The latest one I came across was shared by Greg Mathews (@chimoose) who kindly put this TPS (tweet positioning system) dashboard together:

Screen shot 2010-12-05 at 7.03.11 AM

You can check it out for yourselves by clicking on the tool link here.

The Highlights of the Day for me weren’t any of the education sessions, but rather took on a more human element, ie catching up with Twitter buddies in person. It is always nice to chat with the excellent Jan Geissler (@jangeissler), who was diagnosed with CML in his late twenties and now does sterling work in CML advocacy and Silja Chouquet (@whydotpharma), who also used to work at Novartis like myself, but we never met until afterwards. I love this photo taken during the conversation:

203139505 Later in the poster session, I tracked down Michael Becker (@mdbpartners) at the Semafore poster he was hosting for SF1126, a dual PI3-kinase-mTOR inhibitor being investigated in a phase I trial for B-cell malignancies. Michael and I have been exchanging tweets during and after conferences for some time now but never actually met in person, so it was great to finally put the face to the Tweeter, so to speak. A great guy!

Here he is at the SF1126 poster:

203149060 If you’re not watching Semafore and another PI3-kinase company, Calistoga, that I mentioned in my What’s Hot at ASH 2010 post, then check them out as they both have novel and interesting compounds that may be eventually licensed by pharma or biotech companies. You can also read more about the background behind PI3-kinase as a valid cancer target here.

American Society of Hematology meeting #ASH2010

By MaverickNY on December 3, 2010

The annual American Society of Hematology (ASH) meeting has come around all too quickly this year and starts today in Orlando.

I’ll be tweeting snippets from the event (wifi permitting) and also curating the tweets from the event below for those following remotely, based on the official Twitter hashtag #ASH2010, as well as other likely ones that may be in use.

The ASH organisers have a Twitter account (@ASH_Hematology), if anyone is interested in following them. They seem pretty helpful and responsive.

If you have any questions about the scientific presentations at the meeting, do feel free to tweet me or add them in the comments below. I’ll do my best to answer them or find someone who can.

Dr Anas Younes (@dranasyounes), a lymphoma specialist from MD Anderson, will also be tweeting and he has posted some of his top abstracts on his awesome Facebook page – check it out here.

To follow the meeting tweets, click on the play button below. The event runs through from Friday 3rd until Tuesday 7th.

What’s Hot at ASH in 2010?

By MaverickNY on December 2, 2010

Here’s my 2010 list of a few pipeline and approved products that I’ll be watching out for at the upcoming American Society of Hematology (ASH) meeting , which begins tomorrow and runs over the weekend. Some of them will not the expected hot ‘news’ items so beloved of the medical media who often seem to delight in over-hyping things.

Saturday and Sunday typically embrace the posters, education and plenary sessions, while Monday and Tuesday heralds the oral sessions.

In no particular order, and by no means extensive, these are agents I personally find interesting and worth checking out at the meeting:

1. ARRY-520 (Array Biopharma)

There is still no cure for multiple myeloma, although a wealth of new therapies and combinations has definitely improved survival and outcomes for this disease. It is always good to look out for new agents in development in the relapsed/refractory setting.

ARRY-520 is interesting because it’s a kinesin spindle protein (KSP) inhibitor. KSP is required for cell cycle progression through mitosis and inhibition of KSP has been shown to induce mitotic arrest and cell death, in a similar fashion to taxanes and vinca alkaloids. The company has a number of small molecule compounds in development for cancer:

Source: Array Biopharma

ARRY-520 has been researched specifically in hematologic models such as myeloma, so this will a poster I’ll be looking out for.

What I love about this compound:
While ARRY-520 may target the spindle like taxanes, it appears to do so without the associated peripheral neuropathy and hair loss.

2. SGN-35/brentuximab vedotin (Seattle Genetics/Millennium):

I wrote about the recent promising data from the NEJM by Dr Anas Younes and colleagues. At ASH the same group are presenting on SGN-35 in relapsed/refractory Hodgkin Lymphoma including adverse events and ORR (Mon 6th, 7am) and another group is looking at the agent in Anaplastic Large Cell Lymphomas (Tues 7th, 7.30am) where they will be presenting data on complete remissions.

What I love about this compound:
The concept of a monoclonal antibody combined with chemotherapy as a drug conjugate is an exciting new disruptive biotechnology with a lot of promise.

3. CAL-101 (Calistoga)

Most (but not all) of the other PI3-kinase inhibitors in development seem to have been focusing primarily on solid tumours with mixed results to date. There is also a potential role for the delta form of PI3 kinase inhibitors in B-cell signalling, which encompasses Non Hodgkins Lymphoma (NHL), Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL). Calistoga have been looking at CAL-101 specifically in hematologic malignancies and 7 abstracts are being presented this year either alone or in combination.

What I love about this compound:
When everybody zigs, zag.

4. Crizotinib (Pfizer)

This year, we’ve all heard a lot about ALK rearrangements in non-small cell lung cancer (NSCLC), but such translocations also occur in anaplastic large cell lymphoma (ALCL). It would be most logical to see if crizotinib has any effect in these people with this uncommon form of lymphoma, so I’m looking forward to seeing what the data looks like in the poster session on Sunday evening. I’m expecting/hoping it will show some positive signs in this particular subset who are chemorefractory.

What I love about this agent:
It’s highly and specifically targeted to ALK, a constitutively active translocation (and occasional mutation) that appears to be driving some lung cancer, lymphoma and other rarer cancer subsets.

5. Imatinib/nilotinib (Novartis)

How low should you go? It is now clear from the evidence that people living with CML who attain a major molecular response (MMR) are less likely to relapse than those with a complete cytogenetic response (CCyR).

Ten years ago, the expected life span was only 3-4 years. Imatinib has dramatically shifted the paradigm for the treatment of CML, with people having a realistic goal of living for at least a decade after diagnosis with early chronic phase disease. It is likely that the baton will soon pass to the new second generation TKIs such as nilotinib and dasatinib, which can help achieve an earlier response into the ‘safe haven’ zone. They typically all achieve 90% response rates, but differ in their side effect profiles owing to the additional targets they inhibit.

It will be interesting to see what new data will be presented at this meeting in the annual IRIS trial update and other presentations in several sessions on Monday 6th.

What I love about this drug:
You can’t keep an old warhorse down!

6. Ponatinib (Ariad):

None of the TKIs currently approved for CML target the rare T315I mutation, which ponatinib does target, based on preclinical data. Initial phase I data in the relapsed/refractory setting including T315I mutations is due to be presented in Orlando in the oral session (Monday 6th, 8:15am).

What I love about this compound:
Resistance to all of the TKIs is not that common in CML, but I do think it would be good to have an option for those who find themselves in that unfortunate situation.

7. Rituximab (Roche/Genentech):

Most of the plenary presentations on Sunday afternoon are scientifically focused this year, but there is some preliminary clinical data on rituximab in follicular lymphoma (FL).

The randomised trial from the UK looks at rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky FL. The reason for this is that patients with asymptomatic, advanced stage, follicular lymphoma have shown no benefit of immediate chemotherapy when compared with a watchful-waiting approach, so chemotherapy is typically deferred until disease progression. Rituximab (when used with the CHOP chemotherapy regimen) has become the standard of care for NHL, so looking at it’s activity in another lymphoma subset makes sense.

What I love about this compound:
Anything that significantly delays disease progression without the side effects of chemotherapy would be a welcome addition to treatment options in FL.

8. Concomitant VEGF and MEK inhibition

There are a couple of novel approaches looking at new combinations at the ASH meeting. Thoughtful research studies can often inform us about a potential new approach that might be worthwhile considering in the clinic. One such example I came across was dual VEGF and MEK inhibition in pediatric 11q23 AML. In AML, it has been found that simultaneous activation of these pathways results in a poor prognosis, so this would be a logical therapeutic combination to consider in appropriate children. Chromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene at locus 11q23 are also associated with a poor outcome. These translocations represent approx. 15-20% of pediatric AML.

What I love about this concept:
As a result of the preclinical research, future studies looking at a VEGF-MEK combination are now being planned in pediatric AML and will be worth watching out for.

9. Panobinostat and everolimus (Novartis)

Believe it or not, I was actually trying very hard to avoid selecting another Novartis drug or combination, but they have a very broad portfolio in oncology and lots of interesting early data coming out. The reasoning behind this combination is that mTOR and deacetylase (DAC) inhibitors have demonstrated single agent activity in patients with relapsed and refractory lymphoma. Synergy between DAC inhibitors and mTOR inhibitors has also been observed in lymphoma cell lines in vitro. This is a phase I dose finding trial, so the results will be preliminary, but we should see whether the promise is possible from the early signals.

What I love about this concept:
HDAC and mTOR is a highly logical combination to explore in lymphomas based on the preclinical research to date.

10. TET2 mutations in myeloid malignancies

In case you’re thinking this might be a bit obscure, this presentation actually kicks off the Plenary session on Sunday and I have to say that it’s cool to see a Masters student present some really cool research.

“TET2 mutations are frequently found across broad spectrum of myeloid malignancies but how these mutations contribute to diseases is still unknown.”

I’m not going to spoil the presentation, but what I suspect they may have is a new therapeutic target in myeloid malignancies based on a mutation that occurs through epigenetic changes.

To check out some other top lists, take a look at Dr Anas Younes Facebook page, where he has posted his top 10 lymphoma clinical abstracts. I haven’t seen any other 10 ten abstracts for ASH yet, so we may well be the first two to stick our necks over the parapet 🙂

Disclosures:

– I own no stock in any of these companies (perhaps I should!)
– I’m a former employee of Novartis who worked on imatinib and my company has done consulting work for them.

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American Society of Hematology Meeting 2010

By MaverickNY on November 18, 2010

I’m currently wading through the ASH abstracts on leukemia, lymphomas and myeloma and probably won’t have time to put out a substantial post today. The meeting is only two weeks away, how time flies!

You can search and check out this year’s abstracts and schedule online here.

This year, I’m actually doing ASH in Orlando and then the San Antonio Breast Cancer Meeting back to back, what was I thinking? The good news is that the annual Hot Topics and pipeline posts for both events will appear here on the blog soon.

If there are any ASH abstracts on targeted therapies that you would particularly like discussed in a future post, please feel free to add your suggestions/requests in the comments below.

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Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas

By MaverickNY on November 4, 2010

This morning I was delighted to see that one of my favourite medical doctors on Twitter, Dr Anas Younes from MD Anderson, has published a paper in the New England Journal of Medicine on a clinical trial of a promising new agent in development for a particular type of lymphoma.

Dr Younes is very active in social media on Twitter and Facebook and has garnered quite a following of lymphoma patients interested in learning about new treatments for the disease. This also means that patients and caregivers following him are able to find out about new clinical trials as they open up. MD Anderson Cancer Center probably has access to more clinical trials across all tumour types than any other cancer center, offering lots of options for cancer patients to receive novel therapies that may help their condition. Another benefit of a physician being involved with social media is that awareness of the trials will reach more people this way and hence probably accrue faster.

What’s new in Hodgkins Lymphoma?

Before we discuss the NEJM paper, the other side of social media is that MD Anderson also use it to communicate the results of their trials on the Institution website and Dr Younes also has a nice video for patients, explaining how the drug works, about the trial and the results that they found.

Now, this was a phase I trial so normally we wouldn’t expect to see too much from an efficacy standpoint, as the main goal of these studies is to assess the range of toxicities and determine the maximum tolerated dose (MTD) for phase II trials, which look at the efficacy signal in more detail.

That said, what Dr Younes and his colleagues found was quite impressive responses in a disease that has not seen much in the way of new treatments for more than a decade.

It should be noted that the agent targets CD30 antigen that is expressed on Hodgkin Lymphoma and anaplastic large-cell lymphoma (ALCL) cells. Previous attempts to target the CD30 antigen with monoclonal-based therapies have shown minimal activity. What’s different about this new agent is that it is an antibody-drug conjugate (ADC), with an anti-CD30 monoclonal antibody linked to monomethyl auristatin E (MMAE), an anti-cancer agent.

The drug they were evaluating, brentuximab vedotin (SGN-35), from a partnership between Seattle Genetics and Millennium, elicited complete responses (CR) or partial responses (PR) in 38% of the patients with Hodgkin Lymphoma (HL). In the NEJM article it boldly stated that:

“The median duration of response was at least 9.7 months. Tumor regression was observed in 36 of 42 patients who could be evaluated (86%).”

Looking at the data in the article, what was amazing was that there were 17 objective responses (38%), 11 of which (25%) were complete remissions, which essentially means disappearance of all evidence of the disease. In addition, CT scans showed that 36 of 42 (86%) of evaluable patients saw their tumours shrink.

What’s next?

Overall, I think these very promising results raise hopes that the phase II trial will also produce positive results at the American Society of Hematology (ASH) in December, which will be really great news for patients with Hodgkin Lymphoma.

If the phase II results also look positive, then we can probably expect Seattle Genetics and Millennium to file in the first half of 2011.

Younes, A., Bartlett, N., Leonard, J., Kennedy, D., Lynch, C., Sievers, E., & Forero-Torres, A. (2010). Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas New England Journal of Medicine, 363 (19), 1812-1821 DOI: 10.1056/NEJMoa1002965

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Aggregating the EHA 2010 tweets

By MaverickNY on June 8, 2010

After the success of the American Society of Clinical Oncology (ASCO) Twitter aggregation, with over 250 readers over the course of the weekend, I thought it would be fun to repeat the experiment for the European Hematology Association (EHA) meeting in Barcelona this weekend. The tweet volume is likely to be significantly less tough, with fewer people tweeting from the event.

Most of the topics I'm interested in will be on leukemias, lymphomas and myeloma, so if you are interested in these cancers, you can follow the feed below. I've aggregated two hashtags, #EHA10 and #EHA2010.

Additionally, Dr Anas Younes from MD Anderson Cancer Center will also be attending and following his tweet stream may also be instructive, especially if you are interested in his specialty, lymphomas.

<a href="http://www.coveritlive.com/mobile.php/option=com_mobile/task=viewaltcast/altcast_code=e5f2b0bbde" >EHA 2010 Barcelona</a>

Do feel free to join in remotely in the back channel and add links, comments or ask questions if you feel so inclined. The more the merrier!

I'm particularly looking forward to the Patient Advocacy symposium chaired by Jan Geissler, an awesome guy who just happens to have CML. While the science and clinical data are important, it's also critical to hear and learn from the advocacy viewpoint.

On the healthcare (#hcsmeu) front, I'm also hoping to meet fellow Twitter buddies, Miguel and Angel for an impromptu tweetup of #hcsmeuES. If you're on Twitter and interested in healthcare, check them all out, all three are great gentlemen I would highly recommend!

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The molecular genetics of aggressive B-cell lymphomas

By MaverickNY on April 15, 2010

As many readers here on PSB know, I've not been a big fan of genome-wide molecular profiling, preferring an oncogene addiction approach to drug development and targeted cancer therapies. However, every once in a while something comes along that stops you in your tracks and makes you think differently.

This morning I was reading the latest copy of the New England Journal of Medicine over coffee and was fascinated by a review article by Drs Lenz and Staudt at the NCI on the molecular genetics of diffuse large-B-cell lymphomas (DLBCL), which account for 30-40% of newly diagnosed lymphomas.

As the review article points out, it is well know that different subsets of diffuse large-b-cell lymphomas are associated with different overall survival rates after initial anthracycline based therapy. For example, it is more favourable in people with PMBL and the GCB subytype but less favourable in those with the ABC subtype. R-CHOP therapy has improved survival in people with ABC, but the cure rates are still lower than those with the GCB subtype. Gene expression signatures can help identify the subtypes and predict survival rates:

Source: NEJM

Current therapeutic treatment with chemotherapy has made headway in improved survival, but in order to make further headway, new approaches are very much needed. Targeted therapies have now begun to expand clinical trial options.

The article talks about numerous pathways, but I particularly liked this one, which details the Nuclear Factor kB (NFkB) signalling pathways in normal and malignant lymphocytes:

Source: NEJM

Essentially, signalling is initiated when a SRC family kinase ( SFK) phosphorylates tyrosines in the immunoreceptor tyrosine-based activation motifs (ITAMs) on B-cell subunits. SYK is then recruited to the ITAMs through the SH2 domains and becomes active. Many of you will remember SYK inhibition from previous posts on Rigel's fostamatinib, a SYK inhibitor. I think Celgene also mentioned a SYK inhibitor in early development at their recent R&D Day, although the Rigel-AZ is further ahead but more erratic in it's results, at least in immune disorders. A more recent paper in Blood looked promising in NHL and CLL, though. Companies are clearly starting to look at specific inhibitors in the downstream pathway for lymphomas and chronic lymphocytic leukemia.

What's interesting about the cartoon above is that you can also see that phosphatidylinositol-3-kinase (PI3-kinase) is activated in parallel, activating the mTOR pathway. These two targets are getting a lot of attention from Pharma in the clinic, especially in leukemias and lymphomas, and we may well see more of their latest development at AACR next week and ASCO in June. Exelixis and their partner, sanofi-aventis (a client), for example, have already announced 12 abstracts at ASCO, including 6 on their PI3K and mTOR inhibitors, but they are focusing on lung cancer, a much more difficult carcinoma, rather than NHL, where there is a strong rationale.

It's good see new treatment modalities being tested in leukemias and lymphomas and not just solid tumours, where most companies inevitably focus due to the larger population sizes. That said, the challenge in lymphoma is going to be identifying rational combinations that kill lymphoma cells synergistically. As we learn more about the underlying biology of the disease, targets and biomarkers, so more effective and less toxic solutions may evolve.

Lenz, G., & Staudt, L. (2010). Aggressive Lymphomas New England Journal of Medicine, 362 (15), 1417-1429 DOI: 10.1056/NEJMra0807082

Friedberg, J., Sharman, J., Sweetenham, J., Johnston, P., Vose, J., LaCasce, A., Schaefer-Cutillo, J., De Vos, S., Sinha, R., Leonard, J., Cripe, L., Gregory, S., Sterba, M., Lowe, A., Levy, R., & Shipp, M. (2009). Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia Blood, 115 (13), 2578-2585 DOI: 10.1182/blood-2009-08-236471

An overview of Roche's oncology pipeline

By MaverickNY on March 26, 2010

At last weeks investor meeting held by Roche in downtown Wall Street, the Board reviewed the pipeline opportunities in a number of areas. Earlier this week I wrote about the non-oncology pipeline and today will form an overview of the cancer drugs in development.

One of the things that Roche is renowned for is life cycle management. They do this better than many in the industry in my opinion and it makes an enormous difference not only to continuity, but also long term revenues and performance. Too many companies take a short term view and do not think ahead to the future. This is a big mistake. Perhaps they get bogged down in classic silos or management do not see it as a priority, but it does make a difference.

Why?

Well, for starters, think about the basics of marketing. It is much easier to sell new products to existing customers than it is to sell existing products to new customers and even harder to sell new products to completely new customers.

Thus life cycle management is a smart strategy and done well, enhances the experience for everyone involved whether employees or investors. I only wish more companies paid closer attention to this important aspect of Pharma marketing.

The other thing I like about Roche's approach to R&D is rigorous and strong proof of concept studies (usually in phase II). Between Roche and Genentech, they both do this particularly well in oncology, it seems to be their signature. This partly explains why they mostly end up with a continuous wall of data across several products including trastuzumab (Herceptin), rituximab (Rituxan) and bevacizumab (Avastin). Of course, negative trials do occur but overall, they seem to have more positive trials than not. This partly explains why they have fewer phase III flops than say, Pfizer, because they spend the time in phase II working things out rather than rushing aggressively ahead on the basis of early evidence.

So what did we learn from the pipeline presentations last week?

There are late stage oncology products in development that look promising.

One example is trastuzumab-DM1, which is basically modified Herceptin with a potent cell killing agent, DM1, bolted on. The goal is to improve the action of Herceptin in metastatic breast cancer, and at the same time invetigate whether the xenograft data in a variety of cancers (breast, ovarian, lymphoma and prostate) with an armed antibody is an effective strategy in people. Recent phase II data from the San Antonio Breast Cancer Symposium in heavily treated women with metastatic breast cancer look encouraging. Phase III trials have already begun and if all goes well, filing is currently anticipated by 2012.

Also potentially strengthening the breast cancer franchise is pertuzumab, a monoclonal antibody that targets HER2. Early phase I trials in several cancer types produced so-so results, but more recent phase II data in breast (combined with Herceptin) and ovarian cancer (in combination with gemcitabine) published this month in JCO look interesting.

Perhaps the most exciting compound though, is PLX4032/RG7204, a BRAF inhibitor being evaluated in malignant melanoma. Currently available data suggests survival is improved by 6 months so the big question is what causes resistance to develop and how this can be overcome. Data on this compound is expected at ASCO, where many are keen to see how it stacks up with ipilimumab (BMS).

In hematologic malignancies, GA101 or galiximab is being evaluated in non-Hodgkin's Lymphoma (NHL) and chronic lymphocytic leukemia (CLL). It appears to target a different part of the CD20 isotope than rituximab and this may increase it's efficacy. Phase III trials began in 4Q09 thus it will be a little while before we see some results. There is clearly an unmet medical need in the 3rd line refractory disease for more tolerable agents and rituximab is very much the bedrock of treatment for both across multiple lines of therapy either alone or in combination with chemotherapy. A similar agent will likely have good take up with the right approach.

Genentech are investigating various new and improved approaches to angiogenesis, but these are in much earlier development and the bar is very high with bevacizumab (Avastin), even for the company who manufacture it. The list of anti-angiogenesis compounds that didn't make it to market is very long indeed.

I've left the best to last, as hedgehog (Hh) signalling is one of my favourite pathways – it always reminds me of the cheerful cartoon character, Sonic the Hedgehog. RG3616, licensed from Curis, is currently in phase II trials for advanced basal cell carcinoma and trials are also underway for medulloblastoma. If interested, you can find out more about the pathway and the science here.

Overall, the oncology pipeline has a nice mix of follow on compounds to strengthen life cycle management with a raft of monoclonal antibodies with different targets in new cancer types. Such a strategy should reduce risk and drive the future bottom line if the promise delivers in phase III trials.

Baselga, J., Gelmon, K., Verma, S., Wardley, A., Conte, P., Miles, D., Bianchi, G., Cortes, J., McNally, V., Ross, G., Fumoleau, P., & Gianni, L. (2010). Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy Journal of Clinical Oncology, 28 (7), 1138-1144 DOI: 10.1200/JCO.2009.24.2024

Makhija, S., Amler, L., Glenn, D., Ueland, F., Gold, M., Dizon, D., Paton, V., Lin, C., Januario, T., Ng, K., Strauss, A., Kelsey, S., Sliwkowski, M., & Matulonis, U. (2009). Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer Journal of Clinical Oncology, 28 (7), 1215-1223 DOI: 10.1200/JCO.2009.22.3354