Biotech Strategy Blog

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

Posts from the ‘Regulatory’ category

Juno Therapeutics LogoThis morning we heard that Juno Therapeutics have registered their plans with the SEC for an Initial Public Offering (IPO), highlighting the desire of the VC investors to generate a fast turnaround on their money before a multi-center trial of their CAR-T cell therapy has even started!

One of the challenges with CAR-T cell therapy is despite some stunning results, particularly in pediatric ALL, it remains an experimental one with toxicities that have to been managed. Adult patients, who are extremely sick, have died on trials. If I was at the end of the line faced with certain death, I’d probably roll the dice and take an experimental therapy, but CAR-T cell therapy does have challenges that need to be addressed.

Indeed at the Society for Immunotherapy of Cancer (SITC) meeting last week, one of the Hot Topic sessions that took place after the conference formally ended was in managing the toxicities associated with chimeric antigen receptor T cell (CAR-T) therapy.

Of particular concern for all CAR-T cell therapies in development is severe cytokine release syndrome (sCRS), which requires treatment in hospital intensive care.

Cytokine release syndrome (CRS) involves fevers, hypotension, hypoxia and even neurological toxicities. It’s been known for some time to be a challenging side effect of CAR-T therapy. We first wrote about it at ASH 2012.

As Novartis, Juno and Kite all look towards multi-center registration trials, the identification of patients at risk of severe CRS (sCRS) and the management of this in very sick, often end stage patients remains a real challenge, especially given that we don’t fully know what causes it to occur in some patients, but not others. Patient deaths due to sCRS are not good news on any clinical trial, and even less so when it’s a novel therapy in development.

IFDA Logon the first part of his interview, Dr Jenkins shared with Biotech Strategy Blog the FDA perspective on what constitutes a breakthrough drug? Given he is one of the senior managers at the FDA and sits on the committee that decides whether to grant or deny a company’s breakthrough therapy request, his opinion counts.

In the second and final part of the interview, Dr Jenkins discusses the advantages and benefits of the Breakthrough Therapy designation, as well as some of the challenges the agency faces in administering it.

Receiving a breakthrough designation is no guarantee of FDA approval. Drisapersen (GSK/Prosena), a drug for the treatment of Duchenne muscular dystrophy failed a phase III trial in September, despite having received a breakthrough therapy designation in late June.

In this respect, the breakthrough therapy designation is no different from other expedited pathways such as accelerated approval, fast-track or priority review: you still have to generate clinical trial data from a registration trial that supports the initial promise shown.

What then, does the breakthrough therapy designation mean for cancer drug development? Subscribers can read below the second part of the interview with John Jenkins MD, Director, Office of New Drugs, Center for Drug Evaluation and Research at the FDA:

The FDA approval earlier this week of ibrutinib (Imbruvica) for the treatment of mantle cell lymphoma (MCL), and the recent approval of GA101 / obinutuzumab (Gazyva), for previously untreated chronic lymphocytic leukemia (CLL) is good news for patients.

The forthcoming annual meeting of the American Society of Hematology (ASH) in New Orleans (Dec 7 – 10, 2013) is set to be an exciting event with the launch of new products to treat blood cancers.

Both ibrutinib in MCL and obinutuzumab were granted “breakthrough therapy” designation (BTD) from the FDA. Over the past several months I have been researching what a BTD may mean for cancer drug development.

The catchy “breakthrough” title has given companies and the FDA a noticeable bonanza of good PR, but there’s been a paucity of critical analysis by the media. I have yet to see a convincing argument that that there was a compelling need for a new approval pathway for cancer drugs, or that innovative and breakthrough cancer drugs such as imatinib (Glivec/Gleevec) and crizotinib (Xalkori) could have got to market any faster.

One of the key FDA decision makers is John K. Jenkins, MD, Director, Office of New Drugs in the Center for Drug Evaluation and Research (CDER); he’s Richard Pazdur’s boss. I had the privilege to conduct a phone interview with him over the summer.

In my first post from this interview, subscribers to Premium Content will obtain Dr Jenkins’ perspective on what constitutes a breakthrough? If you are an investor you want to try and predict what may be a “breakthrough” before it becomes one…

As we herald in a New Year, it is time to reflect a little on the past year. 2012 was, to paraphrase Professor Bertrand Tombal’s quote about prostate cancer drug development, “a Grand Cru year” for the United States Food & Drug Administration (FDA) with 39 new molecular entitites (NMEs) approved. This is the highest approval number in the last 10 years, beating the previous high of 36 obtained in 2004. Reuters report it is a 16 year high.FDA 2012 New Molecular Entity NME Approvals Biotech Strategy Blog

Unfortunately, I don’t think can we can draw many conclusions about the state of drug development innovation from this 2012 high.

The FDA in their 2011 report on novel new drugs note that “the number of NMEs approved over time has not been substantially increasing.”

To me, the overall picture looks pretty flat. There’s bound to be variation between years as a result of timing differences with some regulatory submissions obtaining priority review, while others do not.  Some companies can take longer than others to close a clinical trial database and prepare a dossier.  We also have to factor in that some clinical trials may end earlier than expected, if the data is positive.

Regulatory approval is the result of innovation that started several years ago. It only represents the point at which you have a safe and efficaceous product that can be sold to the public. The number of approvals in any given year is not a surrogate benchmark for the state of current innovation.

Given it typically takes several years to bring a new product to market, what we are looking at today is the result of research done 5-10 years ago. It is, however, interesting to note that of the 39 NME approvals in 2012, one-third (13) were cancer related.FDA 2012 Cancer Related Approvals Biotech Strategy Blog

A key driver of innovation in this area is the increased knowledge we have of cancer biology.

In my view, investors will continue to support companies that develop new products with:

  • a clear scientific rationale as to why their mechanism of action may impact the disease
  • a focused clinical development plan that through use of biomarkers and diagnostics targets those most likely to respond
  • a market opportunity worth going after in what is increasingly a competitive landscape

2012 was a “grand cru year” for the FDA. I look forward to what 2013 may bring and to learning more about the new products in development that may make a difference to the lives of patients.

Happy New Year!


The decision expected this Thursday by the Supreme Court of the United States on the constitutionality of the Patient Protection and Affordable Care Act (PPACA) may impact the development and approval of biosimilars.

US Capitol Photo Credit Pieter DroppertPart of the PPACA signed into law by President Obama on March 23, 2010 was the Biologics Price Competition & Innovation Act (BPCI).

This amended the Public Health Service Act (PHS) to create a pathway under section 351(k) for the licensing of biological products that are “interchangeable” or “biosimilar” to an FDA-licensed product.

In addition, to a licensing pathway, the regulatory framework introduced “exclusivity” periods that prevented approval of a 351(k) application until 12 years after the first license of the reference product. I doubt very much that Congress will want to have to negotiate exclusivity provisions again.

I am not a regulatory expert, but my understanding is that if the Court declares the PPACA unconstitutional in its entirety, the BPCI would be lost too.

At the risk of venturing an opinion, I don’t think the Court will want to cause collateral damage to uncontroversial parts of the PPACA such as the BPCI, but it is something to watch out for this Thursday.

Many commentators think it likely the Court will uphold certain parts of the PPACA and invalidate other provisions. This was the approach the Court followed in a decision earlier this week on Arizona Immigration Law (Arizona v. United States).

However, until a decision is published by the Court, nobody knows.  Thursday is set to be a landmark day whatever the Court decides.

Update June 28, 2012

In a 5:4 opinion, the Supreme Court has upheld several provisions of the Patient Protection and Affordable Care Act (PPACA). The Court did not rule the PPACA unconstitutional in its entirety which was the only way the biosimilars provisions would have been lost. Therefore, from a biosimilar regulatory perspective, nothing has changed as a result of today’s decision – the exclusivity and approval pathway are maintained. This is good news for the biotechnology industry.

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Abiraterone Acetate Pre-Chemotherapy ASCO 2012Men with advanced prostate cancer want to know “if I take this drug, will I live longer?” Unfortunately, for abiraterone acetate (Zytiga®) in the pre-chemotherapy setting i.e for asymptomatic or mildly symptomatic men, doctors will only be able to say, “maybe” and tell the patient there is a strong trend towards an overall survival (OS) advantage.

You can read my Xconomy article published yesterday, on why I think it was a mistake for the abiraterone acetate COU-AA-302 trial (302 trial) in chemotherapy-naïve (pre-chemo) men to be stopped early.  The results were presented on Saturday at the American Society of Clinical Oncology (ASCO) meeting in Chicago.

Understanding the Lan-DeMets alpha spending function with O’Brien-Fleming boundary based on number of death events observed is challenging for non-experts.

However, the bottom line is that the 302 trial failed to meet the pre-specified hazard ratio for stopping early, and by so doing it failed to meet one of its co-primary endpoints. This is disappointing because the trial most likely only needed another 92 deaths to occur before it would have reached significance, and this would have occurred in a matter of months.

The co-primary endpoint of radiographic progression free survival (rPFS) was, however, met in the 302 trial. Whether rPFS reflects tangible clinical benefit is unknown.  The FDA have (to my knowledge) not approved a prostate cancer drug on the basis of rPFS , overall survival remains the regulatory standard.

I also learnt for the first time at ASCO about the problem of bone flare in patients receiving abiraterone. Charles Ryan, MD who presented the 302 data, discussed this is an ASCO educational session on prostate cancer imaging.

Bone scan flare is a spurious, “worsening” bone scan in the context of clinical response that reflects increased intensity of lesions, not new lesions.  In other words a brighter image on a bone scan may not represent disease progression.

In a previously published study, Dr Ryan showed a 43% incidence (10/23) of bone flare with abiraterone.  He advised attendees at the ASCO 2012 educational session to “look for, and CONFIRM new lesions before calling progression based solely on bone scans.”

Although the rPFS data for the COU-AA-302 trial was read centrally, and is therefore presumed to be more reliable as a result, I would have welcomed more discussion on the extent rPFS correlates with survival following the COU-AA-302 data presentation at ASCO.  I expect the Oncologic Drugs Advisory Committee (ODAC) will vigorously discuss this in more detail when Johnson & Johnson seek a pre-chemotherapy indication for abiraterone based on the COU-AA-302 data.

Bearing in mind overall survival has been the de facto standard in advanced prostate cancer, it will be interesting to see how the FDA and ODAC will view what is essentially a failed trial with a non-significant OS.  Will precedent be broken, opening the floodgates for future sponsor submissions based on PFS?

Update January 24 2013: FDA & EMA approve Zytiga Pre-Chemo in CRPC

With little fanfare and no ODAC, the FDA issued a press release on December 10, 2012 announcing that abiraterone acetate (Zytiga) had received approval “to treat men with late-stage (metastatic) castration-resistant prostate cancer prior to receiving chemotherapy.”

The press release states: “The FDA reviewed Zytiga’s application for this new indication under the agency’s priority review program. The program provides for an expedited six-month review for drugs that may offer major advances in treatment or provide a treatment when no adequate therapy exists.

The fact that there was an unmet need for prostate cancer treatments prior to chemotherapy was clearly key to their decision making. The press release notes that “patients who received Zytiga had a median overall survival of 35.3 months compared with 30.1 months for those receiving the placebo.”

However, the FDA in their carefully worded press release make no mention of the fact that the difference of 5.2 months in median overall survival failed to reach the pre-specified value for statistical significance.

In other words, although JNJ have expanded the label for abiraterone to include the pre-chemo indication, they cannot make the claim that taking abiraterone prior to chemotherapy definitely results in men living longer (overall survival). All we can say is that the data was trending towards a statistically significant overall survival advantage. To many this may seem academic, but overall survival remains the benchmark that drives cancer drug development and by which treatment effectiveness is judged.

As I noted in my post from ASCO 2012 for Xconomy, most likely statistical significance for overall survival would have been reached in a few months, which is why I and others thought the trial had been stopped too early. I would be surprised if other companies follow JNJ’s strategy, and expect Medivation will seek to show a significant overall survival advantage for enzalatumide (Xtandi) in their pre-chemotherapy PREVAIL trial.

Johnson & Johnson announced on January 11, 2013 that abiraterone has also received approval in the European Union for the pre-chemotherapy prostate cancer indication following a positive recommendation from the Committee for Medical Products for Human Use (CHMP) of the European Medicines Agency (EMA).

It will be interesting to see if there is any new data in the updated interim analysis for the COU-AA-302 trial (abiraterone pre-chemo) that will be presented at the 2013 ASCO Genitourinary Cancers (ASCO GU) symposium in Orlando next month.


A standing room only audience at the recent annual meeting of the American Association for Cancer Research (AACR) heard from several distinguished speakers on what the future of cancer drug therapy is likely to look like: combinations of novel cancer agents.

This AACR session was one of the highlights of the meeting and would have merited from being part of the plenary program.

Jeffrey Engelman from MGH persuasively presented on why we need combination therapies to overcome resistance. He noted that:

  • Most cancers are not sensitive to currently available single-agent therapies
  • Even when sensitive to single-agent therapies, cancers develop resistance, often necessitating combinations

One of the challenges of this approach will be “identifying effective combinations,” he said.

Roy Herbst from Yale, presented on some of the practical challenges involved with the early phase testing of two drugs, and challenged the audience with a critical question:

“Do we possess the necessary translational tools that will help us identify the right drug combinations, ratios and schedules with the right patient?”

Stuart Lutzker from Genentech described their experiences of clinical trials with rational drug combination of trastuzumab and pertuzumab for HER2+ breast cancer.  He concluded that:

“Rational drug combinations have begun to yield exciting Phase III results and should be preferred over empiric drug combinations.”

The Pharma Strategy Blog video interview with Gordon Mills from ECCO/ESMO 2011 in Stockholm offers some interesting insights into how MD Anderson are helping to facilitate academia-industry combination trials with novel compounds from different companies in order to achieve more rational drug design and improve outcomes for people with cancer.

If two or more novel cancer drugs are required to interrupt key pathways or to avoid adaptive resistance, what does this mean for the regulatory strategy?

Janet Woodcock addressed some of these challenges in her AACR presentation, and discussed how the:

“FDA would not want to approve a combination regimen with two new agents unless each contributed to the effect.”

Draft guidance on “Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination” was published by the Agency in December 2010. Click here for a PDF copy.

The document gives examples of a number of different phase II trial designs that can be used to demonstrate the contribution each drug makes to the combination, and the additive effect seen.

As an example, if each drug in a combination has activity and can be administered individually then the guidance document suggests a multi-arm phase II trial may be needed that compares the impact of either drug alone versus the combination and standard of care.  An adaptive trial may also be used if appropriate.

Dr Woodcock noted that future cancer drug development is likely to include increasing use of combinations, adaptive trials to evaluate various drug and diagnostic combinations and increasing attention to the use of novel biomarkers.

The message I took home from the AACR annual meeting is that the future of cancer therapy is in combinations, and we can expect more clinical trials with two unapproved agents (novel-novel combinations) in the future.


Prostate cancer is the second leading cause of cancer death in men, so it was good news this morning when Medivation & Astellas issued a press release that showed positive data from the phase 3 AFFIRM trial for MDV3100.

MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo.

MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

To put the 4.8 month survival advantage in context, this compares favorably with 3.9 months for abiraterone (Hazard Ratio =0.646), in the COU-AA-301 trial.

Positive data was expected given the sound scientific rationale behind MDV3100 and the preliminary data (abstract 4501) presented at the ASCO annual meeting this year. J Clin Oncol 29: 2011 (suppl; abstr 4501).

The drug has a high affinity for the androgen receptor (AR) that is highly expressed on prostate cancer cells.  You can read an excellent interview on Pharma Strategy Blog with Charles Sawyers, who was one of the co-inventors.

MDV3011 blocks the androgen receptor (AR) from moving into the nucleus and activating growth genes and is a more complete inhibitor of AR than bicalutamide.

One hot topic of conversation at ASCO was the potential to combine MDV3100 (androgen receptor blocker) with abiraterone acetate (Zytiga) (androgen synthesis inhibitor), thereby shutting down upstream and downstream activity of the driving receptor in advanced prostate cancer.  The scientific rationale for this appears sound, so it is likely that a combination clinical trial may well be done to test this hypothesis at some point in the future.

MDV3100 has a significant advantage over abiraterone acetate (Zytiga) in that concomitant steroids are not required. Daily steroids have their side effects.  Urologists in particular will be attracted to MDV3100 and its ease of use.

Clinical trials in prostate cancer are ongoing with a multitude of new emerging therapies including TAK-700, Cabozantinib (XL184), radium-223 chloride (Alpharadin), BPX-101, Prostvac-VF, ipilumumab, Custirsen (OGX-011), dasatinib (Sprycel), lenalidomide (Revlimid) and ARN-509 to name but a few.

It is a therapeutic area with a lot going on after very little activity for a decade. The positive interim data for MDV3100 announced today is good news for prostate cancer patients, and we await presentation of the data next year.

Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012, so US approval could be possible later next year.

Although I had to leave BIO 2011 early due to illness, I did shoot some video during the time I was at the meeting, and have now put this together into a short 2 minute video that you can watch below.

This post wraps up my coverage of the 2011 BIO international convention in Washington DC. Next week, I’ll be writing more about innovative science and new products in the pipeline that have caught my attention.

A happy holiday weekend to everyone in North America.

Bevacizumab (Avastin®) should be withdrawn for metastatic breast cancer. That is the unequivocal recommendation of the Oncology Drugs Advisory Committee (ODAC) yesterday.

Despite the passionate patient advocacy in favor of continued approval, withdrawal is the right decision and it is hard to see the FDA overruling ODAC, given the safety issues such as bowel perforations and relative lack of efficacy.  The patient advocacy at this week’s public hearing was fundamentally biased, those who died early and who received no treatment benefit are not alive to stand up and share their experiences.

The bottom line is that Genentech were unable to identify the sub-set of patients who might benefit from the drug.  They simply did not have the data, and the reality is that treating all potential HER2- patients in the hope of finding the few who might respond is not a rational drug development or marketing strategy, especially when those that don’t respond may do worse on the drug.

Personalized medicine requires a thorough understanding of the science and molecular biology of a disease.  Pfizer recently showed an excellent example of this with crizotinib that targets ALK mutations in non small cell lung cancer (NSCLC).

It is disappointing that a scientifically orientated company such as Genentech would continue to try and push Avastin in Breast Cancer when the data is clearly unconvincing to ODAC.   But, if we look at how Genentech approached the Lucentis v Off-label Avastin issue in AMD, with a 40x higher cost for using Lucentis, then what we see is that commercial decisions, and maximization of profit has become more important than doing what’s right for patients.

BIO 2011 Presentation Personalized Medicine Payment Sessions

This is a flawed long-term strategy in my opinion. Society cannot afford to pay for treatments that don’t work in many patients or pay for treatments that are excessively priced. We are already seeing “pay for results” being introduced in Europe, notably England and Italy where payors are reimbursing companies only for those patients that respond.

Personalized medicine is the future. This requires targeted therapies that are aimed at patients who we can predict will have a good chance of responding based on our understanding of mutations, molecular biology and biomarkers.

Avastin in metastatic breast cancer is not an example of personalized medicine and should be withdrawn from the market for this indication.

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