Biotech Strategy Blog

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

Posts tagged ‘Clovis’

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 – This week is mostly about business news as pharma and biotech companies congregate around the JP Morgan Healthcare conference.

It’s JPM time!

As of today (January 13th) I think a lot of investor and journalistic observers have probably been rather disappointed with no news of any major M&A activity, as this seen as setting the tone for the year ahead. I don’t personally see things that way because there’s always plenty of interesting small deals, new early funding, new science and even newco’s forming.

Indeed, Allogene already announced a new clinical collaboration with SpringWorks Therapeutics to evaluate their investigational anti-BCMA allogeneic CAR-T cell wherapy with their gamma secretase inhibitor in multiple myeloma.  They clearly see this as one way to address the shedding problems that have led to relapse with BCMA therapies.

As in previous years, we have a rolling live blog each day at JPM to highlight some of the scientific and company findings that emerge during the meeting…

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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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Munchen – ESMO18 is finally here, sadly not at the same time as Oktoberfest!

The last time I was in Munich (for the Triple meeting in 2016 where TLRs and RIG-1 were a thing in early drug development), getting to the conference centre at Messestadt West from the Hilton was an absolute doddle – fast and efficient, as you would expect from the Germans, with only one simple change and little waiting around on chilly platforms.  Getting back in the rush hour was another matter entirely, as one was either over tired or the trains were mostly going out of town not into it, and to add insult to injury it was bitterly (freezing) cold in November.  Yes, I was on a train on the right line, but heading in the wrong direction at least once, sigh.  I blame the distorted announcements squawked in German only, apparently alerting unsuspecting punters of crucial platform changes 😉

For those of you heading to the conference centre by train/subway, look out for the red U2 line, direction Messestadt Ost at the end of the line:

En route to Messestadt Ost at the end of the red U2 line

Meanwhile, on to the crucial business matters… we usually do live running daily blogs at JPM in January and ASCO in June, where they are most popular, there’s a massive amount of news and data and thus well received.

At ESMO this year there is a tremendous amount of data to uncover, review, and discuss, so it seemed like a good opportunity to repeat the experiment, not least because there will be too much information to summarise at the end of each day, plus sleep is always a premium at cancer conferences.

This year will be jam packed with KOL interviews, trial readouts and analysis, commentary and perhaps even the occasional lighthearted whimsy… rock on!

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Part 3 of our series on Gems from the Poster Halls at ESMO continues with a look at another four important combination studies that may be of keen interest to readers.

These include both targeted therapies as well as immunotherapies.

Some of the posters I was originally keen to write about turned out a little unexpectedly with some issues to address i.e. lack of efficacy or unwanted toxicities based on the dosing schedule used and may require tweaking of the dosing, schedule or trial design. Others will unfortunately be destined for dog drug heaven unless a new tumour type offers more promise. Such is the R&D roller coaster that is oncology – sometimes we forget that more compounds fail than make it market.

The good news is that there were plenty of promising approaches that are worthy of writing up and discussing. In the third part of our poster mini-series, we take another deeper dive with a careful look at some new data in Copenhagen.

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After a long lull on the targeted therapies front – outside of EGFR T790M in lung cancer – this year’s ASCO has plenty to be cheerful about with new data across multiple tumour types.  We can’t cover them all here, but more will be discussed in the Daily Live Blogs starting on Saturday.

Which drugs are going to be in roaring back after a quiet period?  Which ones will be having a more muted meeting?

ASCO16 Chicago 4For those of you who are working in the targeting therapy world, take heart, there is a future beyond cancer immunotherapy; it is not the universal panacea and will likely not cure every cancer, at least for now.

There’s still a market opportunity for targeted therapies in cancer, and as we mentioned in yesterday’s ASCO Preview, there is also potential for the combination of targeted therapies with immunotherapies, so long as the combined toxicity is manageable and doesn’t outweigh the benefits.

In this post we’re looking at a selection of targeted therapies in a variety of tumour types. There’s a lot to choose from at ASCO this year.

Here’s a few we think are worth highlighting upfront.

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Beyond the late breaking abstracts and plenary sessions at the European Cancer Conference being held in Vienna, Austria later this month, what other important topics can we expect to hear about?

ECCO 2015 Vienna

We covered the former in the last article on Biotech Strategy Blog, today we turn our attention to the proffered (oral) sessions and what we can learn from those sessions and the expected data that is due to be presented.

There are a number of interesting topics and new data slated for presentation that are worthy of review and highlighting in a What To Watch out For (W2W4) format.

Here’s our take on the potential highlights at the meeting.

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Clovis Oncology RociletinibThe potential of Clovis Oncology’s EGFR inhibitor rociletinib (formerly CO-1686) to treat T790M negative non-small cell lung cancer (NSCLC) was one of the interesting talking points of the recent JP Morgan Healthcare conference in San Francisco (JPM15).

At the JP Morgan Healthcare Conference (JPM15), Clovis presented updated data that shows some efficacy in those NSCLC patients who no longer respond to an EGFR inhibitor, but don’t have a T790M mutation (T790M negative).  Both AstraZeneca’s competitor compound, AZD9291, and rociletinib shown considerable activity in those EFGR resistant patients who develop a T790M mutation and it’s likely they will both soon be approved in this indication, based on the encouraging data seen to date.

However, what is surprising and could be a key differentiation factor for Clovis, is if there is sufficient efficacy in T790M negative patients for use of the drug in this indication.

In this post, we discuss the potential of rociletinib in NSCLC T790M negative patients, whether thought leaders might use the drug in this indication, and delve deeper into the science behind the efficacy seen.

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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/AZN 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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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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