Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘ipilimumab’

Evidence for role of microRNA in Melanoma

By on July 16, 2010

Twitter is great for highlighting interesting journal articles, as I found when Edward Winstead from the NIH shared this paper from PLOSone on the importance of microRNA in melanoma in his Twitter stream (thanks, Ted!).

image from en.wikipedia.orgThere has been a lot of interest in melanoma lately, with the rise of a couple of interesting new compounds targeting different mutations or kinases including CTLA4 by ipilimumab (BMS) and B-RAF by PLX-4032 (Plexxikon/Roche).  

You can see some of the recent data I've blogged about here, here and here.  

At the moment, we're waiting for the new data from PLX-4032 at a melanoma conference later this year and BMS may be filing their phase III data in ipilimumab by the end of this year after some promising reactions to the data presented last month in the plenary session at ASCO.  In addition, GSK also have some compounds in earlier development that are generating interest.

How does the new data in PLOSone connect with melanoma?

Well, it's an aggressive and highly malignant cancer and scientists have long wondered how melanoma cells travel from primary tumours on the surface of the skin to the brain, liver and lungs, where they become more aggressive, resistant to therapy, and deadly. This ultimately makes treatment and control of the disease very challenging.

In Feb 2009, an article in PNAS (see reference below) suggested that the culprit might be a short strand of RNA called microRNA (miRNA) that is over-expressed in metastatic melanoma cell lines and tissues. It is also known that the Microphthalmia associated transcription factor (Mitf) is an important regulator in melanocyte development and has been shown to be involved in melanoma progression.
The new data reported in PLOSone this month takes our understanding a little further and shows that microRNAs are also involved in regulating Mitf in melanoma cells. 

The authors concluded that:

"miR-148 and miR-137 present an additional level of regulating Mitf expression in melanocytes and melanoma cells. Loss of this regulation, either by mutations or by shortening of the 3′UTR sequence, is therefore a likely factor in melanoma formation and/or progression."

What this means is that the microRNA's involved may offer new therapeutic targets in order to either reduce the development of resistance or aggressive progression and metastasis (ie spread of melanoma) to other organs. In order words, future research may involve the addition of microRNA therapy to optimise outcomes.

For now, microRNA is very much a research on the rise but it won't be long before we start seeing the first RNA based therapies in the clinic based on a solid scientific research rationale.  As our understanding of the complex biology improves, so does the chances of developing a multi-factorial strategy to combat the devastating disease.

For those of you interested in this exciting field, I'll cover a more basic primer on microRNA and RNA therapeutics in development in a future blog post.

Photo Credit: Wikipedia

ResearchBlogging.org
Haflidadóttir, B., Bergsteinsdóttir, K., Praetorius, C., & Steingrímsson, E. (2010). miR-148 Regulates Mitf in Melanoma Cells PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011574

Segura, M., Hanniford, D., Menendez, S., Reavie, L., Zou, X., Alvarez-Diaz, S., Zakrzewski, J., Blochin, E., Rose, A., Bogunovic, D., Polsky, D., Wei, J., Lee, P., Belitskaya-Levy, I., Bhardwaj, N., Osman, I., & Hernando, E. (2009). Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor Proceedings of the National Academy of Sciences, 106 (6), 1814-1819 DOI: 10.1073/pnas.0808263106

#AUA2010: new perspectives and learnings in prostate cancer

By on June 2, 2010

It's been an interesting time here in San Francisco at the American Urology Association (AUA) meeting. Mostly, I've attended prostate cancer sessions to get both a breadth and depth perception of what's going on this cancer type.  

My focus is very much therapeutic development, so here are three key trends that I've noticed at the 2010 AUA meeting:

  1. PSA is not a brilliant biomarker, but it's all we have for now.
  2. Androgen ablation is not permanent.
  3. Immunotherapy is a hot new topic.

What alternatives are there to PSA?

An abstract today from the Colorado Cancer Center suggested that PCA3 may offer a urine based genetic assay for detection of prostate cancer in men with elevated levels of PSA. PSA can offer false positive results and up to 75% men with prostate cancer have a negative biopsy. This new approach sounds promising. PCA3 is overexpressed in more than 90 percent of prostate cancers and the gene overexpression is specific to prostate cancer.  It has been linked to more accurate prediction of positive biopsies compared to PSA, and it is easy to test in urine samples following a digital rectal exam of the prostate.

Presumably it may turn out to be more accurate than PSA and perhaps offer a better way to detect either the actual disease earlier or more aggressive disease earlier.  The test was developed by GenProbe and is not yet approved by the FDA, but a new test to watch out for.

Androgen ablation therapies are not particular effective

Often times, testosterone levels rise above the minimum castrate level after about a year.  Ultimately, more effective androgen receptor antagonists are needed, hence the significant interest in this meeting in abiraterone and MDV3100, two new antagonists in phase III development.  Long term use of androgen deprivation is also inevitably associated with side effects, which have not been well appreciated until recently.

The approval of Provenge gives hope that survival can be extended without drastic side effects

Pharma companies in the oncology space would do well to realise that sick people with cancer don't want to be reminded of such and most certainly do not want a 'relationship' with a brand.  This is not Nike or a FMCG brand offering coupons and offers.  What most people do want is less side effects and better efficacy without having to trade them off.  

Now that we have a proof of concept poster child in Provenge in a solid tumour, we can also see that it may ultimately offer a way to combine newer hormonal therapies with a vaccine to offer men a more effective tool against their disease, delaying the time not only to progression, but also to metastases and chemotherapy.

Other immunotherapies are also being evaluated in prostate cancer, including ipilimumab (BMS), an anti-CTLA4 inhibitor and ProstVac, a cancer vaccine.  More on ipilimumab in another blog post but having had a few queries as to what ProstVac is, here's my basic take on it.

ProstVac differs from Provenge in that it requires 7 infusions over a 6 month period as opposed to 3 within the first month.  My understanding is that it is a sequentially dosed combination of two different Poxviruses which each encode prostate specific antigen (PSA) plus three immune enhancing co-stimulatory molecules, B7.1, ICAM-1, and Lfa-3 (TRICOM). The first Poxvirus is Vaccinia-PSA-TRICOM, which is replication competent and is good for immune priming. The second Poxvirus is Fowlpox-PSA-TRICOM, a non-replicating virus, which is good for repetitive immune boosting.  In some ways, it seeks to achieve the same end as Provenge (T-cell stimulation) but via a slightly different approach.

What's next?

More on prostate cancer at the American Society of Clinical Oncology (ASCO) meeting next week!

1 Comment

ASCO 2010 Preview #1

By on May 11, 2010

It's only 3 weeks to go to the Annual ASCO meeting in Chicago so I thought it would be a good time to kick off the annual preview of key data.  One of the things that sets the tone of the meeting is which abstracts are in the plenary session.  Sometimes I don't attend the session if it looks arcane, but this year looks really interesting and worthwhile attending.

The selected abstracts comprise the following:

#LBA1: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or Fallopian tube cancer (FTC): A Gynecologic Oncology Group study.

#2: Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC).

#3: Clinical activity of the oral ALK inhibitor, PF-02341066, in ALK-positive patients with non-small cell lung cancer (NSCLC).

#4: A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma.

Now, three of these trials promise some excitement.  The one I'm surprised about is the French Intergroup study looking at a taxane plus platinum in lung cancer.  In case anyone is wondering, the trial (link) states that:

"It thus seemed to us justified to compare a standard arm, the vinorelbine or the gemcitabine (with the choice of the center) in monotherapy with an experimental arm, association carboplatine + paclitaxel."

Carboplatin plus paclitaxel (with or without bevacizumab) is pretty much standard as first-line treatment for non-small cell lung cancer (NSCLC), so now we know that the doublet is likely more effective than single agent gemcitabine or navelbine in the elderly too, but for me all four are old drugs, likely available as generics and it's all an iteration of what we mostly know already.  I'm particularly interested in new and exciting agents that are coming through or new indications or more recent drugs as we see them expand their utility.

The results are no doubt important, but plenary important?  It could
have well led off an oral lung cancer session and received attention at
Best of ASCO perhaps, but for me, the plenary sessions should be
about groundbreaking new therapies or indications, which the other three
clearly are.

Still, the Korean study in ALK-positive people with NSCLC really gets my attention because we've only heard about a US study in the past, so seeing how this evolves Globally is vitally important.  Pfizer have done a nice job speeding this agent, PF-02341066 (crizotinib), through development having recognised the significance of the rearrangements and then invested significant resources to moving it forward.  They should be commended for that and I sincerely hope the results continue to be positive. 

What is also nice is that I've come across a few new ALK inhibitors at AACR and elsewhere that may work in patients where crivotinib stopped working, perhaps as a reult of new mutations.  This is an exciting area of research, even if it just affects a small subset of patients.  Cancer is a heterogeneous disease so researching and identifying different subtypes that can be then targeted with new therapeutics is critical.

After excitedly listening to the BMS R&D Day, I was expecting that ipilimumab might have a chance of a plenary with the melanoma data because the example they gave just took your breath away – this is what we all live for in cancer research – something that really makes a difference to the disease and makes you go, "oh wow!"  You can read more about that commentary here.  Roche and Plexxikon also have a promising compound in development (PLX4032) that targets BRAF.  At Roche's R&D Day, they noted that they planned to present the phase II data later this year at a melanoma meeting.  That's how the timing rolls sometimes.

The bevacizumab (Avastin) data in ovarian cancer was previously announced by Roche earlier this year to be positive, so this is excellent news for women with ovarian cancer.  I really look forward to seeing the results in full.  What's particularly important about this trial is that it is the first positive phase III study of an anti-angiogenic therapy in advanced ovarian cancer.  I think Judah Folkman would be mightily pleased with the progress of angiogenesis inhibitors such as Avastin so far, if he could see them.  It's all too easy to forget the visionaries in research and focus on the results.

For some reason, ovarian cancer always seems to be the poor cousin to breast and lung cancers and regimens that work in either tend to dribble down to ovarian cancer years later, but all three share many similar regimens.

From tomorrow, I'll start an ASCO series taking a look at some of the bionic biotechs with interesting data and a review of some of the big cancers and the potentially interesting data that may be worth highlighting and checking out.

5 Comments

Ipilimumab from BMS looks like an interesting new melanoma drug

By on March 5, 2010

It's been a frantic week on the work front and today was no different, but I wanted to highlight a really interesting slide from the BMS pipeline presentation yesterday afternoon.

Here's one of the slides Elliot Sigal, President of R&D, showed from one of the ipilimumab trials.  More data may be available at ASCO if the submitted abstract is accepted, but for now, even though it's only an n of 1, a picture tells a thousand words:

Picture 29
Source: BMS

After all the recent good news about malignant melanoma, hopefully at least one of these promising agents will make it to market in the not too distant future, offering people suffering with the condition a glimmer of hope.  I sincerely hope the CTLA4 results turn out to be durable.

In the meantime, we can all wonder until June, when the annual ASCO meeting will held.

 

2 Comments
error: Content is protected !!