Biotech Strategy Blog

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

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Pfizer next gen ALK inhibitor PF-06463922 could replace Xalkori

Boston – Preclinical data for PF-06463922 (Pfizer), a next generation ALK inhibitor, with potency for all known Crizotinib ALK resistant mutants and ability to cross the blood brain barrier was presented today at the 2013 International Conference on Molecular Targets and Cancer Therapeutics co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI) and the European Organization for Research and Treatment of Cancer (EORTC).

In addition to being a competitor to other next-generation ALK inhibitors in development such as AP26113 (Ariad), LDK378 (Novartis) and alectinib (Roche/Chugai), PF-06463922 shows activity in both crizotinib-naive and crizotinib-resistant cells, so could end up being a replacement for crizotinib (Xalkori) front-line if clinical results confirm preclinical efficacy.

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ECCO 2013: AZD9291 shows early promise in T790M NSCLC

Amsterdam – Promising preliminary phase 1 data for AstraZeneca’s AZD9291 in T790M+ NSCLC presented today at the European Cancer Congress (ECCO 2013) is good news for lung cancer patients, but a major competitive threat to Clovis Oncology who look like they are now in a race to bring CO-1686 to market in this indication.

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Ibrutinib leads the race to CLL 17p deletion market

Earlier this month, Janssen/Pharmacyclics announced they had submitted a New Drug Application (NDA) for Food & Drug Administration (FDA) approval of ibrutinib, an oral Bruton’s tyrosine kinase inhibitor (BTK) in chronic lymphocytic leukemia (CLL) for the treatment of patients with a deletion of the short arm of chromosome 17 (del17p). Here’s a link to July 10 press release.

The company have requested Priority review; approval later this year or in early 2014 is highly likely given that the agent has also been designated a Breakthrough Therapy by the FDA.

This is great news for CLL patients!

CLL is an incurable disease. It is the most common leukemia in the United States with 15,500 new diagnoses a year.

Chromosomal abnormalities are fairly common in CLL and predict both time to first treatment and overall survival i.e. how long someone will live. Sadly, those with a 17p deletion have the worst outcome and a poor prognosis.

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Orteronel (TAK-700) fails in Advanced Prostate Cancer

Takeda’s orteronel (formerly known as TAK-700) may be on its way to “dog drug heaven” after an interim analysis of the ECM-PC 5 phase 3 clinical trial showed that men with advanced prostate cancer taking the drug did not live significantly longer (HR 0.894, p=0.226) than those taking an inactive placebo.  Here’s a link to the Takeda press release.

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JNJ acquisition of Aragon ARN-509 deals a blow to Medivation

Johnson & Johnson (JNJ) just announced the acquisition of privately-held Aragon Pharmaceuticals and the rights to ARN-509 a second-generation androgen receptor antagonist that will be a future competitor to Medivation’s Xtandi.

The deal, valued at $1billion, with $650M upfront and $350M based on contingent milestone payments, is a blow to Medivation who have been locked in litigation with Aragon and the University of California over ownership of the rights to ARN-509.  Both ARN-509 and Xtandi were developed in the laboratories of Charles Sawyers and Michael Jung at UCLA.

The Aragon acquisition is a sound strategic decision for JNJ, offering them the ability to develop their prostate cancer franchise after Zytiga goes off patent and more importantly, offer a product that at the very least is equivalent to Xtandi, and potentially, may be superior.  ARN-509 will also allow JNJ to compete in earlier stages of prostate cancer with a drug that does not require use of steroids, something that has always been a major problem for Zytiga in the chemotherapy-naïve setting.

JNJ now have a corporate strategy for life post-Zytiga. They have the resources and expertise to fund large phase III clinical trials for ARN-509, not only in prostate cancer, but potentially also in breast cancer.  Aragon being bought out by a big Pharma with deep pockets is a blow to Medivation/Astellas.

What this acquisition also tells us is that Johnson and Johnson lawyers consider the Medivation appeal over intellectual property rights to be weak.  They will no doubt have done considerable due diligence on Medivation’s claims and consider the risk to be low or manageable.

My personal view was that cash-rich Medivation should have acquired Aragon themselves and neutralized the competitive threat rather than pursue a scorched-earth litigation strategy.

The JNJ acquisition of Aragon also suggests that ARN-509 may be perceived as the best in class of the second-generation androgen receptor inhibitors in development. There are others that JNJ could have sought to acquire or licence, including ODM-201 (Orion).  The fact that JNJ chose ARN-509 or a better version of Xtandi is not good news for other companies with AR antagonists in early-stage development.

Medivation are unlikely to feel the competitive threat from ARN-509 in the prostate cancer market for a few years, because registration trials against the current standard of care are needed to show that the drug offers an equivalent or better survival benefit.  ARN-509 will most likely be compared against Zytiga, offering yet another benefit of the deal – the ability to provide free comparator drug in the clinical trials.

The JNJ acquisition is good news for men with advanced prostate cancer who may in 5 years see another new treatment option become available.  It is, however, a blow to Medivation and Astellas who now have a serious competitor to deal with in the future in a space where they may have thought they had a major competitive advantage.

ASCO 2013 Abraxane in pancreatic cancer is a welcome new treatment option

At ASCO 2013 Daniel D. Van Hoff, MD, Physician-In-Chief of the Translational Genomics Research Institute (TGen), presented the data for the phase III pancreatic cancer MPACT trial that compared weekly nab-paclitaxel (Abraxane) plus gemcitabine (Gem) versus gemcitabine alone (ASCO 2013 Abstract 4005).

The results were first presented at the ASCO GI meeting earlier this year, so what’s new here?

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AZD3514 Fails to Live up to Preclinical Promise in CRPC at ASCO 2013

AZD3514 is a novel Selective Androgen Receptor Down-Regulating Drug (SARD) that showed early preclinical promise for the treatment of Castration-Resistant Prostate Cancer (CRPC).

However the development of this drug in advanced prostate cancer has been terminated by AstraZeneca according to Dr Aurelius Omlin, a Clinical Research Fellow at The Royal Marsden Hospital who presented clinical data on AZD3514 at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

I previously wrote about the promising preclinical data for AZD3514 presented by Sarah Loddick at the 2012 annual meeting of the American Association for Cancer Research (AACR) and sometimes drugs when they transition to the clinic just don’t live up to their promise.

That’s what happened here, and it reminds us that testing of drugs on human volunteers remains a key part of drug development despite the inherent risks. (See my post on the TLS deaths on the AbbVie/Genentech ABT-199 CLL dose finding trial)

The results from a first-in-human clinical trial with in men with CRPC were presented by Dr Omlin at ASCO 2013 (abstract 4511). In his oral presentation, he first noted that:

“AZD3514 is a first-in-class, non-steroidal small molecule androgen receptor (AR) down-regulator that inhibits nuclear AR translocation and results in proteasomal AR protein degradation.”

The phase 1 clinical trial to assess safety and tolerability explored doses ranging from 100mg once daily (OD) to 1000mg OD in capsule formulation, and from 1000mg OD to 2000mg taken twice daily (BID) in tablet formulation. A pretty comprehensive range, but……

“Tolerability of AZD3514 was problematic,” said Omlin. “80% of patients had Grade 1-2 Nausea (n=39 out of 49) and 49% Grade 1-2 Vomiting (n=24 out of 49).”  Additionally, grade 1-2 thrombocytopenia was seen in 33% of patients.  There was no dose limiting toxicity reported.

What killed it for AZD3514 was the fact that according to Omlin,

“Nausea and vomiting were characteristic from the very first dose level starting about 30-60 minutes after dosing and lasting for several hours thereafter.”

However, the drug did show activity in CRPC patients with several patients showing PSA declines including one patient with prior abiraterone exposure.  Two patients with soft tissue disease had confirmed responses according to Recist 1.1. There was also evidence of clinical activity from changes in the number of circulating tumor cells.

Industry analyst, David Miller (@BiotechStockRsr) commented on Twitter, while watching the presentation, that he thought it hard to see the drug progressing in development, and he turned out to be correct:

Dr Omlin concluded his presentation by stating that, “the development of this compound by AstraZeneca as a selective androgen receptor down-regulator in mCRPC has been terminated.”

Sometimes promising preclinical data just doesn’t hold up when it moves into human clinical trials. Another AstraZeneca drug with preclinical promise has gone to what Sally Church, PhD (@MaverickNY) refers to as “dog drug heaven.”

ASCO 2013 Pfizer joins race to develop a Herceptin biosimilar with PF-05280014

At the 2013 Annual Meeting of the American Society of Clinical Oncology in Chicago this past weekend, my impression of one of the most popular posters in terms of how fast the poster handouts disappeared (all 100 went in 7 minutes) was a phase 1 trial comparing PF-05280014, a potential biosimilar to trastuzumab (Herceptin) in healthy volunteers (ASCO 2013 Abstract No: 612)

Herceptin is used for the treatment of HER2+ breast cancer, and with global sales of over $5 billion, represents a major source of sales to Roche. However, Roche’s patent for Herceptin is expected to expire in 2014 in the UK, 2015 in Europe and 2019 in the United States, providing an opportunity for other companies to take a significant share of this market away from them.

Roche have long focused on life cycle management with strong patent defense built in to their long term strategic plans. In this case, their approach has been to launch new breast cancer products in the HER2 segment such as pertuzumab (Perjeta), for use in combination with Herceptin, and Kadycla (T-DM1) for advanced breast cancer patients who become treatment resistant to Herceptin. Trials are ongoing in the front-line setting with the goal of replacing Herceptin.

Several companies, including Amgen and Novartis, are looking to develop a biosimilar to Herceptin for the treatment of HER2+ breast cancer, and it now looks like Pfizer is in the race too. A biosimilar product is not a generic “copycat” i.e. a copy of a small molecule chemically synthesized to provide equivalent efficacy. Instead, a biosimilar is a copy of a biological compound such as an antibody or protein produced by living organisms intended to be equivalent to the original product. In general, monoclonal antibodies are much more difficult and complex to re-engineer than a pill or TKI.  This means that the main competitors in the biosimilar market are more likely to be generic offshoots of big Pharma rather than Indian generic companies, since they possess the technology and resources to engineer monoclonal antibodies.

There’s a lot of debate over biosimilars and whether they are truly identical. In the United States, the Biologics Price Competition and Innovation Act (BPCI) contained within the Affordable Care Act provided a regulatory route for biosimilars to be approved by the FDA, so long as they could be clinically shown to be “highly similar.”  Once approved, biosimilars are expected to be interchangeable, i.e. substituted for the original product with the expectation that lower drug prices will be the result. This represents a major competitive threat to Roche’s Herceptin HER2 franchise.

Interestingly at ASCO, Pfizer did not provide a QR code that linked to a PDF copy of their PF-05280014 poster, unlike most of their other posters at the meeting. I expect we will be hearing a lot more about biosimilars in the not too distant future, and the potential importance of this was highlighted by the intense popularity of Pfizer’s poster at the meeting.

Viewers of the ASCO 2013 preview video from Sally Church, PhD will have noted that PF-05280014 was one of her key breast cancer abstracts to watch out. If you haven’t already done so, here’s a link to the Pharma Strategy Blog ASCO 2013 Preview Video (free via sign-up) that is well worth watching.

Update June 5, 2013 5pm.  This post was not intended to be a comprehensive analysis of the biosimilar market and all the players (you have to pay me for that). However, Josh Berlin @BioPharmaJosh kindly pointed out on Twitter that the controversial Korean company Celltrion have filed for approval of their Herceptin biosimilar in Korea. This represents a competitive threat to Roche’s Asian market, and could give other companies a run for their money if they are first to market and file for approval elsewhere.

 

ASCO 2013: Cancer Drug Combinations are The Future

Chicago – At the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Charles L Sawyers, MD, President of the American Association for Cancer Research (AACR) and one of the United States leading cancer researchers, told the 30,000 meeting attendees in the plenary session that we need to get to combination therapy faster in order to overcome cancer drug resistance.

In his Science of Oncology Award lecture entitled “Overcoming Resistance to Cancer Drug Therapy,” he told the audience that drug resistance is universal. It represents one of the key challenges in cancer treatment. A patient may obtain a dramatic response on a new treatment, but as the cancer finds escape routes among the network of cellular signaling pathways, resistance to the drug is acquired and the cancer reappears.

You can read a previous interview with Dr Sawyers on Pharma Strategy Blog.

Daniel O’Day, COO of Roche Pharmaceuticals, referred to Dr Sawyers’ ASCO lecture at a corporate event in Chicago. He told analysts that a key future strategy for Roche will be improving cancer treatment with combinations. The ability to bring effective combinations to market faster will favor large companies such as Roche who have a robust pipeline of cancer drugs in development. You can see Genentech’s perspective on this via a well thought out post from their VP of Clinical Development, Chris Bowden.

The other advantage of a broad robust pipeline for large Pharma is the ability to leverage this strategically and globally as the reimbursement landscape changes. In the HER2 arena, for example, Roche could hold the price of Perjeta while offering discounts to Herceptin, thereby offering a lower price for the combination that might be attractive to purchasers. In Europe, this kind of creative bargaining is becoming more common in the approval process as Health Authorities seek to reduce costs and find more affordable options before giving approval for new drugs in their market.

Dr Sawyers talk was one of the highlights of ASCO 2013 for me.  I captured the essence of his presentation from the many tweets that took place as it was presented. Here’s a link to the Storify.

 

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