Biotech Strategy Blog

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

Posts from the ‘FDA’ 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.

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One area that is finally seeing a lot more research results of late is neo-adjuvant therapy in breast cancer, i.e. therapeutic intervention prior to surgery.

The main advantages of neo-adjuvant over adjuvant therapy are:

  1. If it works, then the therapy allows the margins to shrink prior to surgery, potentially making the tumour easier to excise
  2. If therapy works prior to surgery, you know what will likely be effective post surgery, whereas in adjuvant treatment after surgery, this is unknown.

One of the leading trials for neoadjuvant breast cancer was the ISPY2 (Investigation of Serial studies to Predict Your therapeutic response with imaging and molecular analysis 2) study.  I wrote about it in more detail at the time it was launched on Pharma Strategy Blog, if you need more information. Basically, the study is based on a complex adaptive conjoint design in neoadjuvant breast cancer, so over time, additional arms were added to the study (there were originally four) while others were removed. In this way, the investigators can find the best therapies for each tumour subtype (HER2+/1, ER+/- or triple negative) based on the responses and biomarkers.

One element of neoadjuvant trials is figuring out what the most valid and meaningful endpoints are. In metastatic breast cancer (MBC), for example, we tend to see the primary and secondary endpoints being focused around the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). These endpoints are rarely used in neoadjuvant trials though, because:

a) the goals of therapy are different and
b) patients are expected to live much longer with earlier stage disease so other outcomes such as DFS or EFS are often used

Given these factors, the FDA recently brought out new guidelines suggesting that pCR improvement would be a useful surrogate marker and predictor of survival endpoints. One example they used was HER2 disease and the ISPY2 model where drugs ‘graduate’ based on their performance over time. This is why the current ISPY2 trial is recruiting different arms than the original study setup. The first two therapies were considered to have ‘graduated’ from the trial with data (triggered 60–120 patients are enrolled) late 2013, i.e. AbbVie’s veliparib, a PARP inhibitor, and Puma’s neratinib, a pan-HER/ErbB inhibitor.

Veliparib was considered to have graduated in the triple negative signature. Initial veliparib data was presented at SABCS in December (see our analysis, commentary and update of this study data here). The neratinib data has yet to be presented at a medical conference, although the company have announced an oral presentation at AACR in 3 weeks time.

That said, neratinib and neoadjuvant therapy, in general, was discussed by several participants at last week’s Miami Breast Cancer Conference (MBCC).

For those interested in my thoughts and analysis, you can sign in or sign up below:

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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:

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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…

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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.

Subscribers can login to read more or you can purchase access by clicking on the blue icon at the end of the post.

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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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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.

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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.

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The phase 3 ALSYMPCA prostate cancer trial results for radium-223 chloride (Alpharadin) were presented at the recent ECCO ESMO ESTRO 2011 European Multidisciplinary Cancer Congress in Stockholm. This was the highlight of the meeting for me.

There was also exciting data in Breast Cancer (BOLERO-2) that you can read more about on Pharma Strategy Blog.

Alpharadin from Norwegian company, Algeta, is the first new treatment for advanced prostate cancer that not only prolongs overall survival (OS) but delays time to first skeletal related event (SRE) in metastatic castration resistant prostate cancer patients.

Leading physicians at the meeting believe that it will be “practice changing.

The Alpharadin data may also have an impact on other bone targeted agents in development for prostate cancer such as cabozantinib (XL184).

Sally Church, PhD (who writes the Pharma Strategy Blog) is quoted by “The Street” as saying that “Alpharadin raises the bar for Exelixis. They have to produce overall survival data now.” Overall Survival (OS) remains the primary regulatory endpoint in prostate cancer drug development.

Prostate cancer experts Johann de Bono and Cora Sternberg also mentioned, in presentations at the Stockholm meeting, that in the future it will be increasingly difficult to do placebo controlled trials in Prostate Cancer given the new treatment options available.

Alpharadin is not yet approved in Europe or the USA, but is on fast track for approval by the FDA in 2012.

Chris Parker (Royal Marsden Hospital) presented the Alpharadin ALSYMPCA trial data as a late breaking abstract in the presidential session at ECCO ESMO 2011. He also conducted a media briefing that I was fortunate to video.

You can watch this below. In it he explains how radium-223 choloride works and why he (and others) believe this may change the standard of care for prostate cancer patients with bone metastases. It is well worth watching!

 

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