Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘pancreatic’ category

The DNA in a human cell undergoes thousands damaging events per day, generated by both external (exogenous) and internal metabolic (endogenous) processes. Unfortunately, some of these changes can generate errors in the transcription of DNA and subsequent translation into proteins necessary for signaling and cellular function. Genomic mutations can also be carried over into future generations of cells, if the mutation is not repaired prior to mitosis.

This DNA damage repair from normal cell cycle activity is a field with a large body of research over the last decade or so. Damage to cellular DNA is ultimately involved in mutagenesis and the development of some cancers.

Clinically, there are a number of different ways that can be utilised to help repair the damaged DNA. One approach that is included in this category is the poly ADP ribose polymerase (PARP) inhibitors, which target the enzyme of the same name. I first wrote about PARPs on PSB way back in 2006 – you can check out the short posts for some basic background information on PARPs (here).  Fast forward to 2014, and another post highlights some of the challenges and issues associated with developing targeted agents, including PARPs.

In 2009, the hot buzzword of the AACR Molecular Targets meeting was ‘synthetic lethality’, a term that is highly relevant to understanding DNA mismatch repair and PARP inhibitors. Hilary Calvert gave a detailed talk on synthetic lethality and PARP inhibition at that meeting, where many attendees, myself included, were struggling to understand quite what he meant.

The lead scientist at KuDos, Dr Mark O’Connor, (note: KuDos was subsequently bought by AstraZeneca) had a nice poster on their PARP inhibitor in development at that very same meeting.  I’ll never forget our animated discusson and his simple analogy of a three-legged coffee table, removing one of the legs to cause instability and falling over as a great metaphor for what happens with synthetic lethality.

To this day, every time the leading British researchers in this field, Profs Hilary Calvert or Alan Ashworth, mention ‘synthetic lethality’, I immediately think of the unstable and wobbly coffee table visual!

Incidentally, the KuDos PARP compound in preclinical development back in 2009 subsequently became olaparib… is now Lynparza, marketed by AstraZeneca, and available on both the US and EU markets for refractory ovarian cancer with germline BRCA mutations. The EU approval is specifically in platinum-sensitive disease.

The Alamo San Antonio TexasSince then, we’ve seen iniparib (Sanofi) fail badly in phase 3 in a poorly designed catch-all study that didn’t screen or test patients with triple negative breast cancer (TNBC) for BRCA mutations (doh!) and three new promising next generation PARP inhibitors emerge – veliparib (AbbVie), rucaparib (Clovis) and talazoparib / BMN 673 (Biomarin).  All three of these have received attention on this blog in the past (check the links).

In this article, we discuss what’s happening with Biomarin’s PARP program based on their latest update at the recent San Antonio Breast Cancer Symposium (SABCS) last month.

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Yesterday, the European Society of Medical Oncology (ESMO) released the abstracts to the poster and poster discussion sessions.  This preview will be quite long by nature of it being the first time we get a look at the topline details behind some of the key sessions and their abstracts for both immunotherapies (especially checkpoint inhibitors) and targeted therapies.  This includes posters and their discussion sessions, plus poster late breaking poster titles.

For reference, you can find the ESMO 2014 poster and poster discussion abstracts can be found here.

In addition, there appears to be some pretty cool presentations in the Special Symposia, which are rather like ASCO scientific symposia and contain a lot of useful information and often strategic ideas about where thought leaders see hot topics going in the future.  This can be very helpful in learning about possibilities for new clinical trials ahead of time. As we focus on the poster highlights today, do check back tomorrow for a detailed look at the scientific symposia.

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Our ASCO 2014 conference coverage continues with more gems from the poster sessions; it’s where we believe you find the promising gems that offer hints of future promise (or not) as the case maybe.

ASCO 2014 General Poster HallSometimes a failure with one agent can help another company design a more optimal trial for their own new product in development, thus moving the field on. Other times, a surprising result can emerge that teaches us something new about the science and increasing our body of knowledge about pathways or biomarkers.

The other thing to understand about phase I trials is that they are generally conducted in the salvage situation where patients are refractory to most current treatments.  The disease burden is high and the patients much sicker than when they were newly diagnosed. What companies are looking for is to characterise the side effect and PK profiles while looking for possible hints of where the agent might be efficacious.  Given that most cancer therapies are given in combination, it’s very rare to see a home run in phase I, especially in solid tumours.

Here are a triplet of interesting posters from small companies looking at moving the needle in solid tumours with early phase I studies:

Companies mentioned: Nucana, OncoMed, Celldex

Agents mentioned: Acelarin, OMP–59R5, varlilumab

Over the last few days, we’ve covered data from the leading checkpoint inhibitors from BMS, Merck and Roche, but what about other agents in development in immuno-oncology? One of the companies that burst on the scene in Chicago at ASCO 2014 with solid data was AstraZeneca with their anti-PD-L1, MEDI4736.

To put progress in context, last year Merck had one single abstract for MK–3475 (pembrolizumab), whereas this year MEDI4736 debuted with 7 abstracts, including several Trials in Progress posters in combination with their anti-CTLA4, tremelimumab, plus some important oral presentations too.

The last morning of the final day of the ASCO conference has not exactly been well attended in past years, especially in Developmental Therapeutics. This year was different – the large hall was jam packed and it was standing room only. I was lucky to get one of the last seats in the front row a good 15–20 mins early!

As we were waiting for the proceedings to start, the Japanese doctor sitting next to me turned and said:

“What do you think of this compound? I’m not expecting much, and they are behind the others already!”

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“Nothing lasts forever, because nothing ever has.”

James Shelley, The Caesura Letters

This year’s annual AACR meeting was so good, we could probably write another 50 posts and still not be done! With ASCO fast approaching, however, it’s almost time to draw it to a close and the final post conference note will be published on Monday.

Today is the penultimate report and focuses on the key highlights that caught my attention in immuno-oncology, which covers the gamut from checkpoint inhibitors, co-stimulants, innate immunotherapy and CAR T cell therapy to bispecific antibody TCRs.

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Andrew Armstrong MD ASCO GUSan Francisco – In the ASCO GU prostate cancer session yesterday morning one of the most interesting presentations was by Andrew J Armstrong, Associate Professor of Medicine and Surgery at the Duke Cancer Institute.

I previously referenced Dr Armstrong’s excellent education presentation at ASCO 2012 in my piece on Xconomy about the emerging challenges of prostate cancer drug development.

He’s a speaker that I particularly enjoy listening to, so my attention was immediately drawn to his presentation at ASCO GU on, “Beyond Enzalutamide and Abiraterone: What’s Next in Androgen Therapy.

Looking at this title, at first glance the question that comes to mind is do we really need new treatments that target the Androgen Receptor (AR), after all we’ve heard this week about the PREVAIL trial with enzalutamide?

Based on Dr Armstrong’s presentation the answer is a resounding yes!

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Cancer immunotherapy was described in the December 20, 2013 issue of Science magazine as their Breakthrough of the Year, but really, we are just scratching the surface of what can be achieved.

We are at beginning of a REVOLUTION in immunotherapy,” said Elizabeth M. Jaffee, MD at the start of American Society of Clinical Oncology GastroIntestinal (ASCO GI) symposium keynote lecture on Immunologic Treatments for GI Cancers.

Elizabeth M Jaffee MD ASCO GI Keynote

Elizabeth M Jaffee, MD

Jaffee likened the revolution in immunotherapy to the same excitement the Beatles brought to music, or the same magnitude of technology advances made by Apple.

Dr Jaffee is the Dana and Albert “Cubby” Broccoli Professor of Oncology at Johns Hopkins, and has developed a number of vaccines including GVAX, which is currently licensed to Aduro Biotech.

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The 2014 ASCO Gastrointestinal (GI) Cancer Symposium takes place in San Francisco from Jan 16-18 and is the second meeting in this year’s oncology conference calendar. GI cancers include oesophageal, gastric, colorectal and pancreatic cancers, as well as hepatocarcinoma or HCC (liver).

You can follow any tweets from ASCO GI using the hashtag #GI14.

This year, the topics that most caught my eye in the program were pancreatic and gastric cancers.

This post provides insights on the key studies that looked interesting to me at this event, based on the schedule available.  The abstracts will be available on January 14th and can be accessed here.

Companies mentioned: Celgene, Lilly, Roche/Genentech, Aduro Biotech
Drugs mentioned:  Abraxane, Gemzar, ramucirumab, Avastin, Herceptin, GVAX


Immuno-oncology is fast becoming one of the hottest topics in cancer research following the approval of the anti-CTLA4 checkpoint antibody, ipilimumab, in advanced melanoma, as well as emerging solid data from anti-PD-1 and PD-L1 antibodies in melanoma, lung and renal cancer at ASCO in June.

The big question on many people’s minds though, is what other checkpoint inhibitors are out there and can they safely be used either as single agents or in combination with the above agents, or even with existing standard of care combinations (chemotherapy and targeted therapies)?

I have long argued that what will really make a difference in this space is combinations and the ability of sponsors to successfully evaluate novel-novel agents in clinical trials. After all, BMS have a huge advantage with ipilimumab and the ability to combine it with their PD-1 or other immunotherapeutics, since their rivals will be greatly hampered by the $120K per person price tag for the commercial drug required as part of clinical trial costs.

This means most companies in this space are looking at other options in the search for better outcomes.

At the AACR-NCI-EORTC Molecular Targets conference in Boston this week, the last day was devoted to two sessions in immune-oncology and one of the plenary sessions included Dr Susan Topalian discussing an update on nivolumab and anti-PD-1/L1 therapies post ASCO. There was also ample opportunity to discuss immunotherapy with the many attendees in the busy poster sessions.

The first immunotherapy session on Weds morning particularly caught my attention and it seems a good opportunity to summarize some of the key observations emerging in this field. Here are my detailed notes from the session, which raise a lot of fascinating questions from the presenters about this field and – more importantly – where it’s going:

Boston – at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics conference today, preclinical data was presented on a first-in-class antibody-drug conjugate (ADC) targeting guanylyl cyclase c (GCC) expression in pancreatic cancer.

Petter Veiby Ph.D presenting at Molecular Targets press briefing Petter Veiby, Ph.D, Global Head of BioTherapeutics, Oncology DDU at Takeda Pharmaceuticals International Co. in Boston, MA took the assembled press corps through data that showed MLN0264 demonstrated antitumor activity in GCC-pancreatic cancer xenograft models.

In drug development, as in life, timing is everything. The recent FDA approval of Celgene’s nab-paclitaxel (Abraxane) has changed the standard of care in pancreatic cancer.

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