Biotech Strategy Blog

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

Posts tagged ‘BioMarin’

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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PARP inhibitors have had a chequered history as anti-cancer agents from the lows of the failed iniparib (Sanofi) phase 3 trial in triple negative breast cancer (TNBC) and olaparib (AstraZeneca) in ovarian cancer to the highs of the initial waterfall plots for BMN673 (Biomarin) in BRCA-positive breast and ovarian cancers and a successful graduation from the ISPY2 trial in the triple negative signature for veliparib (AbbVie). In between those two extremes, there has been a lot of uncertainty.

ASCO 2014 Poster HallAt ASCO this year, there was a decent crop of new combination data in both posters and oral sessions looking at various PARP inhibitors in breast or high grade serous ovarian cancer with either chemotherapy (typically platinum-based) or targeted therapies such as PI3K (BKM120) or VEGF (cediranib).

Another new development, which was hinted at from previous AACR conference notes was the potential to explore Biomarin’s BMN673 in lung cancer, specifically metastatic small-cell lung cancer (SCLC) and germline BRCA-mutation carrier cancer patients in a poster for a phase 1 dose finding trial.

Wainberg et al., concluded that:

“BMN 673 has antitumor activity in patients with advanced previously treated SCLC and significant activity in patients with gBRCA mut ovarian and breast cancer.”

Emphasis the authors.

For today’s article, we’re taking a slightly different approach. Rather than analyse the clinical data, I wanted to explore physician sentiments around PARP inhibitors and they thought about this class of drug. Is there still traction here or has the rise of immuno-oncology wiped out interest in targeted agents?

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Whew, having just finished the American Society of Hematology (ASH) meeting, we run on to the breast cancer symposium in San Antonio (SABCS), making for a very busy week of data deluge!  Our Post ASH analysis will also run concurrently for a few days.

There are also a number of interesting areas to look out for in terms of interesting breast cancer developments.

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Companies: Roche, GSK, AbbVie, AstraZeneca, Novartis, Lilly
Drugs: Herceptin, Avastin, Perjeta, Tykerb, veliparib, olaparib, BKM120, ramucirumab, PD-1, PD-L1

Here’s a quick preview of some of the landmark data emerging from this conference, some positive, some negative.

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Boston: Fallowing on from yesterday’s post about learnings from the AACR-NCI-EORTC conference in immuno-oncology, today’s post focuses on learnings from non-immune R&D, namely monoclonal antibodies and TKIs.

We know that cancer is a very complex topic and that adaptive resistance is increasingly a huge focus, but where are the new developments in this area and what can we learn from them in order to improve outcomes?

Another key area to consider is therapeutic index, that is are we shutting down enough of an oncogenic target’s activity in order to ensure efficacy? We’ve seen this in the anti-angiogenesis field, for example, where many VEGF inhibitors failed before bevacizumab (Avastin) finally cracked the nut in colorectal cancer and shifted the needle in terms of improving overall survival. We are now seeing this happen in other areas too, which will be covered below.

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This morning in Amsterdam brought some interesting breast and ovarian cancer presentations that I thought deserved a quick recap.

One is potentially practice changing in HER2 breast cancer and the other is a new product in development (Biomarin’s BMN 673) that is worth watching out for:

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In my final post from the 2013 annual meeting of the American Association for Cancer Research (AACR), I wanted to share some more reflections from my time in the poster sessions. It’s certainly not all mice, and test tubes, and there were some interesting data from biotechnology companies to consider.

Sometimes the data presented is completely new, other times if you are following a product or company you can see the next stage of development and track progress. AACR posters are often not available if you don’t attend the meeting.

Additionally companies use AACR to showcase potential early licensing opportunities and new targets, so like Bitcoins a few nuggets can be mined from the meeting.  Here are a few examples of what the AACR poster sessions had to offer from a biotech perspective.

Gilead $GILD – Following a new combination

At the 2012 American Society of Hematology (ASH) annual meeting in Atlanta last year, Russell Burke and colleagues from the Knight Cancer Institute at OHSU (Brian Druker’s lab) presented a poster (abstract 3876) on the rational for Combining idelalisib (GS-1101/CAL-101), a PI3 kinase delta (PI3Kδ) inhibitor and a novel highly selective Spleen tyrosine kinase (Syk) inhibitor, GS-9973. In their abstract they noted that,

Simultaneous inhibition of multiple pathways downstream of the BCR [B-cell receptor] has the potential to result in a synergistic response that may overcome the resistance observed with single compound use” 

Furthermore, they also demonstrated that,

both PI3Kδ and Syk inhibition reduces CLL survival” and that “combination therapy targeting both PI3Kd and Syk may provide a novel treatment approach, especially in patients with poor risk disease that may not respond optimally to single agents.”

This year at the AACR annual meeting, a Gilead poster (abstract  26) evaluated the safety, pharmacokinetics and pharmacodynamics of this combination in female healthy subjects.  The poster concluded:

  • Co-administration of GS-9973 with idelalisib displayed markedly higher PD effect vs. either agent alone.
  • Overall, GS-9973 and idelalisib were well tolerated when administered in combination or alone.
  • Phase 2 studies in B cell hematologic malignancies evaluating GS-9973 + idelalisib are ongoing.

We will most likely have to wait to ASH meeting later this year in New Orleans to see what the clinical benefit of this combination is, but you can see how you can follow progress from a poster at ASH, to a poster at AACR and then a phase II or III clinical trial presentation at ASH or ASCO in the future.

Ariad $ARIA – a new potential target for ponatinib?

Ponatinib (Iclusig) is a multi-targeted tyrosine kinase inhibitor (TKI) of several targets including Bcr-Abl, FGFR, ALK and RET.  Several posters were presented at AACR last week.  In one that caught my attention (abstract 2084), Ariad researchers showed it is a highly potent inhibitor of activated variants of RET Kinase, which is often dysregulated in medullary thyroid cancer (MTC) and non-small cell lung cancer (NSCLC).

Vandetanib ($AZN) and cabozantinib ($EXEL) are other multi-kinase inhibitors that received FDA approval in the last year or two for MTC, albeit in different lines of therapy, so the activity of other TKI’s in MTC should not come as a surprise.

The Ariad poster demonstrated the preclinical activity of ponatinib over other TKI’s in variants of RET in MTC and NSCLC.  The poster concluded:

These results provide strong support for the clinical evaluation of ponatinib in patients with RET-driven cancers.”

From a scientific rational the above statement makes sense, but from a commercial perspective it’s more questionable if this were the lead indication.  However, it could make strategic sense to add on small niche indications for a compound that is generating its primary revenue elsewhere.

The challenge is that the medullary thyroid cancer market is not large especially in the relapse setting, as Exelisis have found, plus the tumour is a slow growing one.  While NSCLC sounds promising, the number of NSCLC patients with RET is small (~1%).

This means it will most likely require the screening hundreds of patients to find one patient with RET into a clinical trial, assuming they are willing and meet the inclusion criteria.  This is likely to be an expensive and time-consuming process, so the commercial rational will need to be carefully considered.

BioMarin $BMRN – a prostate cancer licensing opportunity or a “dead donkey”?

Companies also use posters at AACR to showcase potential licensing opportunities and one example I came across was BioMarin’s poster (abstract 2049) for BMN860 a novel CYP17 inhibitor.  Based on some limited preclinical data that showed BMN860 to be more potent than abiraterone acetate (Zytiga), the company are seeking to license out their compound.

Interestingly, the BioMarin poster showed no data comparing BMN860 to other second-generation CYP17 inhibitors such as TAK-700 (orteronel), and the presenter admitted they had no plans to do further preclinical work on it themselves.

Given the costs of bringing a new prostate cancer drug to market and the uncertainty of the market opportunity in the face of generic abiraterone and competition from other CYP17 inhibitors far head in development, it’s hard to see the commercial opportunity for BMN860.

If you are a Pharma BDL professional looking to in-license a novel CYP17 inhibitor, then BioMarin do have one on offer.  However, for those used to British vernacular, it struck me as a “dead donkey” being too little too late to really capitalise on the market opportunity.

This is the end of my coverage of AACR 2013.  I am looking forward to the AACR-EORTC-NCI Molecular Targets and Cancer Therapeutics meeting in Boston later this year.  Given the focus of Boston biotech on cancer drug development, I expect this to be a high quality meeting.

If you are interested in more coverage from AACR 2013, I encourage you to check out Pharma Strategy Blog, which will have some in-depth pieces in the coming days.

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