Biotech Strategy Blog

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

Posts tagged ‘GSK’

Recently, PARP inhibitors have been back in the news for several reasons, including the publication of the olaparib (AstraZenca/Merck) advanced mCRPC data in the New England Journal of Medicine from the phase 3 PROfound trial and the announcement regarding achievement of the key secondary endpoint of overall survival. As Dr José Baselga quite rightly noted, this is very good news indeed because:

“Overall survival in metastatic castration-resistant prostate cancer has remained extremely challenging to achieve.”

We’ve rather more trial misses in this disease setting than successes from various therapies over the last few years including ipilimumab, PROSTVAC, alisertib, and atezolizumab, to name a few off the top of my head.

Related to mCRPC, let’s also not forget the upcoming PDUFA date later this month for Clovis’s rucaparib in the very same indication.

Not to be outdone on the PARP front, just a few days GSK received FDA approval for niraparib as first-line monotherapy maintenance therapy for women with platinum-responsive advanced ovarian cancer – regardless of biomarker status – based on the phase 3 PRIMA study presented at ESMO last year and simultaneously published in the NEJM. Recall that the majority of women (51%) had homologous-recombination deficiency (HRD) and this subset saw the greatest benefit.

Flying high in the DDR space?

We have now seen clinical benefit in the PARP inhibitors in four tumour types driven by DNA damage repair (DDR) deficiencies, namely ovarian, breast, pancreatic, and prostate cancers.

How do we go about extending the concept of DDR in terms of the biology of other tumour types?

A number of related pathway targets have been investigated, including ATM/ATR, Chk1, Wee–1 and others, with mixed success.

It’s not the nature of oncology R&D to stand still, however; what if we could turn things on their head and think creatively about the problems still to be addressed?

One particular new company to the PARP space is doing just that… so what are they doing and what’s different about their approach?

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San Francisco – the 2020 JP Morgan Healthcare conference is now in full swing, and we’re continuing our coverage with another rolling blog that provides review and analysis of company presentations, deals, and plans for the coming year.

Some of the companies featured in yesterday’s commentary were: BMS, Incyte, Novartis, Deciphera, Allogene, Nektar, Seattle Genetics, Mirati, and Clovis.

While our focus on BSB is mainly writing about the science driving innovation and new product development, especially in oncology and immunology, it’s good to hear what companies are looking to accomplish in the coming year and then put that in context.

Cancer drug development, whether it be with targeted therapies or immuno-oncology remains a fast moving and continually evolving field, and one you have to keep your finger on the pulse of if you don’t want to be left behind.

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What do cancer drug development and Sherlock Holmes have in common?

The simple answer is that sometimes you can gain insights by looking at what did not happen.

Will belantamab mafadotin stand out in the crowded BCMA space?

In 1892 Sir Arthur Conan Doyle wrote a short story about the disappearance of a famous racehorse the night before a race. What was curious about the incident was that there was no barking from the watchdog when you might otherwise have expected it, suggesting the dog knew the thief…

Can we follow the same inductive reasoning when it comes to cancer drug development? Are there things we would expect to see, but don’t? If so, what inferences can we draw from them?

In this post we’re taking a closer look at the latest data for GSK2857916 (now belantamab mafadotin), which in many ways was “the dog that didn’t bark” at ASH19.

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Who’s King of the PARP castle?

After yesterday’s review and expert commentary on the phase 3 PROfound trial presented in the Presidential Session at ESMO 2019, we’re continuing our look at PARP inhibitors in advanced prostate cancer.

Perhaps surprisingly, there were a lot of insights to be found in the posters that were presented and discussed at the meeting for other PARPs in clinical development.

How do these stack up against olaparib? We’re not fans of cross-trial comparisons as they always come with a mandatory health warning, but if you want to consider the emerging landscape, it is important to be aware of the different patient populations, lines of therapy, and details of the trial designs.

For additional perspective at ESMO19, we spoke to a European prostate cancer expert who kindly talked about his clinical practice and also offered insights into a PARP clinical trial he and colleagues presented in Barcelona.

Who will be King of the PARP castle in advanced prostate cancer?

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With the Jounce-Celgene announcement that the ICOS agonist, JTX–2011, is being returned and new priorities being pursued there is much to consider. There are quite a few nuances to this story to consider beyond the obvious that BMS already have an ICOS stimulating molecule.

Here we put together a synopsis and some commentary in looking at several relevant targets of interest in the context of the broader landscapes that are evolving.

Are Jounce left high and dry with this latest development or is there still a future in ICOS agonism?

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One of my favourite areas to follow in oncology research is Developmental Therapeutics, whether they be targeted, genomic, epigenetic or immune therapies. At some point, even currently approved products started off life in this category, either in preclinical research or in early phase 1 trials.

It’s almost like a primordial soup from which future pipelines spring.

Following these initial approaches over time can be useful in many ways – you can pick up new trends and emerging drugs earlier than most, and can also step back to see a broader picture of the landscape as it evolves.

While there are no formal developmental therapeutics sessions at the American Society for Hematology (ASH) annual meeting per se, that doesn’t stop the intrepid scientist from creating their own selection, in fact it’s a lot more fun this way!

That’s exactly what I’ve attempted here…

Be warned though, this year, the mix is much more complex and intriguing with a lot of interesting and, in some cases, novel targets to explore and consider, including the deeper and tricky protein-protein ones to hit, which are now receiving more attention as researchers find more creative and indirect ways to tackle the problem.

Our second ASH 2017 Preview goes deep into what for many BSB readers will be intriguing, yet for others… completely unknown.

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Dr Bernie Fox (@BernardAFox) is a man on a mission to #FinishCancer, a Twitter hashtag he uses to reflect his vision.

A cancer immunotherapy rockstar, Bernard A Fox, PhD, is the Harder Family Endowed Chair for Cancer Research at Providence Center Center and Chief of the Laboratory of Molecular and Tumor Immunology at the Earle A. Chiles Research Institute in Portland, Oregon.

Fox is also a past president of the Society for Immunotherapy of Cancer (SITC) and CEO of UbiVac, a biotechnology company focused on therapeutic cancer vaccines.

Readers of the Blog and Novel Targets Podcast listeners will recall we had the privilege to interview Dr Fox back at the American Association for Cancer Research (AACR) annual meeting in New Orleans in 2016: “AACR Cancer Immunotherapy Insights from Dr Bernard Fox.”

Fast forward 18 months… it is now time for a detailed update on this issue, as a few interesting events have since come to light in this niche with Genentech/Roche abandoning development of their OX40 agonist, coupled with several new publications from different labs suggesting that concurrent administration of an anti-OX40 antibody with an anti-PD1 antibody attenuated the effect of anti-OX40 and resulted in poor treatment outcomes in mouse models.

Dr Fox kindly spoke to Biotech Strategy Blog about some of the key learnings from this research, where he sees the future potential for OX40, and what his vision for cancer immunotherapy is.

Here’s a short clip from the fireside chat…

 

He’s definitely a man on a mission to #FinishCancer!

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The BET Bromodomain market is a meaty epigenetics topic we have followed for several years now, including a look at the space back in 2013 on the old Pharma Strategy Blog (Link). The last update on this was ironically at AACR last year when we discussed MYC and bromodomains (Link).

Nawlins Mardi GrasIn a remarkable tale of two cities in real life, two companies we discussed in those posts – Constellation Pharma and Tensha Therapeutics – have had markedly different fortunes since then. Roche decided to end their collaboration with the former and went on to acquire the latter instead.

Since we first wrote about bromodomains and BET inhibitors, the niche has exploded in a wildly stunning way… More drugs in the pipeline, more tumour targets being explored, and even novel combinations being evaluated preclinically for synergistic or additive effects. Even I was surprised by how competitive this niche has become based on the offerings at AACR this year.

With all the wealth of new data at the AACR annual meeting and also some other recent presentations I’ve attended elsewhere, it’s time for a more in-depth look at the BET/Bromodomain landscape.

Who are the new players, which tumour targets are now being evaluated, which combinations might be useful?

A word to the wise – this is neither a nerdy science post nor a comprehensive literature review – instead we take a look at the emerging landscape from a new product development perspective.

Science has been absolutely critical to success in all of the cancer therapeutics from targeted therapies to immunotherapies that have emerged in the last decade.

It really doesn’t matter whether you come from a marketing and commercial organisation or the investment community – if you want to make great decisions, you need to understand the basics of the science underpinning the R&D, where the strengths and weaknesses are. The alternative is play Roulette and put everything on Black 11 as a euphemism for whichever company/product/target you have an interest in.

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British Javelin TrainIt’s Day 6 of our Countdown to the AACR 2016 annual meeting in New Orleans. We’re at the halfway, 6 posts written and 6 more to go!  Then it will be daily Live blogs from the meeting.

There’s a lot of cancer immunotherapy at AACR this year, so after yesterday’s post on GITR we’re continuing our mini-series with a look at another immune agonist.

Today, we’re moving onto OX40 (CD134) as a novel immuno-target. Regular readers will know that we’ve been following this target for some time.

Immune agonists such as GITR, OX40, CD40, CD27 and 4-1BB help to rev up T cells. As Dr Tom Gajewski (Chicago) told us last year, in an interview published on the blog and excerpted in Episode 6 of the Novel Targets Podcast: Stepping on the Gas:

…there are inhibitory receptors on activated T cells that are involved with shutting immune responses down. There are also activating receptors that help to rev up those T cells. You might question whether you can push an activator and block an inhibitor, and maybe get a good anti-tumor response going as well.

When we drive a car, we both lift our foot off the break and we step on the accelerator. We have really beautiful data in animals that that this is exactly the case, that if you hit one of those strong positive regulators, and block just one of the negative regulators, you can have complete disappearance of the tumors in mice.

Several of those positive agonistic antibodies against costimulatory receptors are in the clinic. One of them is anti-OX40 that a couple of groups have in the clinic. We’re working with Genentech, that has one of those agents in phase I.

What does the OX40 competitive landscape look like?

In those post we’ve provided commentary on some of the new products in development from companies and highlighted a surprising number of abstracts that you’ll want to watch out for at AACR 2016 if you’re on the cancer immunotherapy track.

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Ovarian cancer is an often neglected area in cancer drug development and historically has often been one of the last solid tumours to be evaluated as part of a life cycle management program. There are a number of reasons for this, but recently that situation has begun to change as our knowledge of the underlying biology improves and new agents are developed that target the particular oncogenic aberrations.

It is a tumour type that ranks 5th in cancer deaths amongst women and accounts for more deaths than any other gynaecologic cancer. Indeed, in 2014 nearly 22,000 women are estimated to be diagnosed with this cancer in the U.S. and approx. 14,000 will likely die from the disease.

Earlier this month the FDA approved bevacizumab (Avastin) in combination with chemotherapy (paclitaxel plus pegylated liposomal doxorubicin or topetecan) for the treatment of platinum-resistant, recurrent epithelial ovarian cancer (EOC), fallopian tube, or primary peritoneal cancer who have received no more than two prior therapies. The approval was based on the phase 3 AURELIA trial (n=361), which demonstrated an improvement in median progression free survival (PFS) of 6.8 vs. 3.4 months (HR 0.38, P<0.0001). This means that the women in the trial saw a 62% reduction in the risk of their symptoms worsening compared to chemotherapy alone.

Surprisingly, this advance represented the first new treatment option in this setting for 15 years!

The good news is that beyond Avastin, there are a number of other promising agents in development for ovarian cancer. At this year’s EORTC-AACR-NCI Molecular Targets meeting held in Barcelona, new data was presented on several such compounds that are well worth highlighting.

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