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American Urology Association AUA 2010 annual meeting

By MaverickNY on May 25, 2010

On Friday, I'm heading off to the annual American Urology Association (AUA) meeting in San Francisco and looking forward to catching up on the hot topics in prostate and renal cancers.

It promises to be a good meeting this year with lots of new data expected from a number of marketed products, newly approved products and of course, products in development.

I'll be tweeting snippets from the meeting under the hashtag #AUA2010 as some attendees are already actively using that one. Unfortunately, #AUA already seems to be used for something else, which is a shame as those extra 4 characters make a huge difference on Twitter!

More to follow at the meeting, where I'll summarise some of the key findings over the weekend as they are published.

If you're attending the event and would like to meet up, please contact me either via email or via Twitter - it's always fun to meet people in real life!

Photo Credit: Alain Picard

The lull before the Dendreon storm?

By MaverickNY on April 29, 2010

Today's post is going to be relatively short as I'm knee deep (literally) reviewing poster handouts from the recent AACR meeting, but while reading translational medicine data I came across a poster on sipuleucel-T basically explaining that it engages the immune system and activates or stimulates priming of T-cells in asymptomatic disease.

Like many out there I'm quietly wondering what will happen tomorrow with Dendreon's PDUFA date due on Saturday May 1st. We can reasonably assume a response on sipuleucel-T (Provenge) might be forthcoming on either Friday or Monday.

Given the gap in available treatments between castration resistance (CRPC) and stage IV metastatic disease, I'm hoping Provenge receives approval on the basis of the four month survival advantage after a somewhat rocky path along the journey. Approval could well kick off what may well turn out to be a new era, with other therapies also in late stage development, namely OrthoBiotech/Cougar's abiraterone and Medivation/Astellas' MDV3100, which are both seeking to test their efficacy and safety and in phase III trials for CRPC.

Non-approval could well be a disaster for a company who has invested so much into immunotherapy as their lead product, investors will likely be very unhappy and Monday could turn into a blood bath. I'm more inclined to be positive though, and my educated guess is that approval will be forthcoming given Dendreon met the pre-defined FDA targets.

We shall see.

{UPDATE: The FDA officially approved Dendreon's Provenge today 29-4-10, see comments below for FDA links and materials including the PI.}

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New developments in castration resistant prostate cancer – MDV3100

By MaverickNY on April 15, 2010

Last night I received an alert from Medivation announcing that an article would be published in today's online The Lancet regarding their prostate cancer agent, MDV3100. Sure enough, here's the article:

Although the trial is an early phase I/II study, encouraging antitumour effects were reported in 140 men, of whom 65 were chemotherapy naïve. Time to disease progression (TTP) was 47 weeks, which is decent considering the men in the study were all castration resistant and likely had advanced disease.

Obviously, it is too early to tell yet quite what Medivation and Astellas have here, but to put things in context, docetaxel (Taxotere), was approved for hormone refractory prostate cancer (HRPC) with prednisone in androgen independent (hormone refractory) metastatic prostate cancer with a median overall survival of 18.9 months (approx. 85 weeks) in a large phase III trial.

We must also remember that in another more recent trial, it was demonstrated that men who received cabazitaxel (sanofi-aventis' follow on taxane to docetaxel) lived a median of 15.1 months (68 weeks), compared with 12.7 months (57 weeks) for those who receive mitoxantrone, a difference that was statistically significant.

That said, the side effect profile of chemotherapy is certainly not benign, with significant risk of myelosuppression and infectious complications.

However, what was encouraging about the Medivation trial was early Kaplan Meier response curves, which demonstrated those men who had no previous chemotherapy generally did better than those who received it in terms of both PSA and radiological progression.

At the AACR Molecular Targets meeting last November, Charles Sawyers gave a keynote talk on prostate cancer and looked at the various opportunities for investigating new therapeutics in clinical trials for prostate cancer. He suggested that circulating tumour cells (CTCs) might be a more useful marker for disease status than PSA. In The Lancet study, the authors noted that:

"We recorded early post-treatment conversions from unfavourable to favourable in 75% of patients not exposed to chemotherapy and in 37% of those who were exposed. Decreases in PSA were generally associated with parallel falls (or no progression) in CTCs, but this finding was not consistent, suggesting that these measures assess different aspects of the malignant process. PSA decreases might in some cases be an indicator of the mechanism of action of MDV3100 as an androgen-receptor antagonist rather than an actual antitumour effect. However, the benefit of MDV3100 on several assessments, including CTCs and radiological time to progression, suggest that MDV3100 does have a true antitumour effect."

The other interesting observation that Sawyers made was that traditionally, early prostate disease is treated with oral hormonal therapies and once castration resistance sets in, the patient is referred to an oncologist for consideration of chemotherapeutic options. With the advent of new therapies with different MOAs in development such as MDV3100, abiraterone (Cougar/J&J) and Provenge (Dendreon), the lives of men with prostate cancer can potentially be extended further before stage IV metastases sets in.

At AACR last November, Sawyers also discussed the importance of androgen receptor signalling in the disease (previously discussed here with simple models) and the data from this trial seem to bear out his elegant theory. I'd like to see more analysis though and learn whether those men who had AR amplified prostate cancer did better on MDV3100 than those who did not?

All in all, this is an exciting time for men with prostate cancer. Dendreon's Provenge may well be the first new drug that fits between the hormonal therapies and chemotherapy, since the FDA PDUFA date is May 1st, although since that is a Saturday, we may well here the Go/No Go news on Friday 30th April.

In the meantime, the annual AACR meeting in DC this weekend can't come soon enough!

Scher, H., Beer, T., Higano, C., Anand, A., Taplin, M., Efstathiou, E., Rathkopf, D., Shelkey, J., Yu, E., & Alumkal, J. (2010). Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study The Lancet DOI: 10.1016/S0140-6736(10)60172-9

Update on Prostate Cancer therapies

By MaverickNY on February 2, 2010

It's been a while since I took a look at what's happening in the prostate cancer arena, but it seems a good time after the recent flurry on lung and colorectal cancers, especially as it's Groundhog Day :-).

There are three particular agents that I'm interested in:

MDV3100 (Medivation/Astellas)
Abiraterone (Cougar Biotech/J&J)
Provenge (Dendreon)

I'm going to spend most of this post talking about the first two, as much has been said on Dendreon already.

Dendreon filed their amended BLA on November, and the FDA have given a PDUFA date of 1 May 2010. The data from 512 patients showed an improvement of 4 months survival for Provenge over placebo, meeting the FDA's threshold.

We have, however, no idea how the vaccine would have done compared to standard chemotherapy such as docetaxel plus prednisone, and therein lies the rub. Normally, in oncology trials we compare the standard of care with and without the new agent or compare the standard therapy to a different regimen. Placebo controlled trials have not done well with ODAC and the FDA, as J&J, Vion and Genzyme all learned with placebo controlled trials in elderly AML patients.

Regular readers of Pharma Strategy Blog will know I'm not a big fan of either placebo trials in cancer or vaccines, so we'll wait and see what the FDA decide. My expectation is that it will receive approval this time round having jumped through the extra hoops.

Cougar Biotech and J&J are developing abiraterone in advanced prostate cancer. A phase III trial in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer began enrolling this month.

It's estimated to complete in April 2014 and the primary endpoint is overall survival, but initial results should be available in April 2011 for progression free survival at 12 months from what I can see, so perhaps there will be some data around ASCO in 2011. Based on that data I can't see a filing much before the 2nd half of 2011 at the very earliest, possibly not until 2014.

Looking at J&J's analyst presentations, I found the following timeline for their pipeline:

Now, many drugs are lumped together in the 2011 timeframe across 3 columns. It isn't clear whether each column represents 2011, 2012 and 2013 or it's a random list of drugs that will be filed in that period. Either way, it's hard to see abiraterone getting accelerated approval so my assumption for now is abiraterone will be filed in 2013, with approval in 2014.

It's not going to be a fast development: Cougar is very inexperienced and J&J are relatively weak and slow in oncology.

The asymptomatic nature of the patients will also complicate things because it's a high risk study that may not show much in the end. If it works, great! That said, I'm not sure how well the results will fare in what looks like a fluffy trial design comparing abiraterone plus prednisone to placebo plus prednisone. Patients are specifically excluded if they have received prior chemotherapy. Well then, why not compare abiraterone to docetaxel, which is the current standard of care in castration-resistant disease, given that this is a front-line trial?

Recently, at the AACR Molecular Targets meeting in Boston, I had the pleasure of listening to a most excellent talk from Dr Charles Sawyers (MSKCC), one of may favourite researchers. He covered a lot of ground on the lessons learned in targeted agents, principally in CML and prostate cancer.

With regards to prostate cancer, he showed a graphic similar to this one (from Medivation):

Clearly, there are a number of opportunities to explore for the development of new drugs for the disease after hormome therapy ceases to work. This is where traditional drug development for chemotherapies typically starts.

What was interesting about Sawyers talk is his discussion about the androgen receptor (AR) and whether or not it is important in castration resistant disease.

Previously, AR was thought to be irrelevant in this situation because it is not expressed in 2 common prostate cancer cell lines, but Sawyers argued cogently that this shows a failure to appreciate the potency of inhibition because AR is restored through PSA production. Several reasons have been evaluated for this, including AR amplification, mutation and alternative pathways among others. AR is also overexpressed in castration resistant xenograph models, and can confer castration resistance.

What followed was an elegant discourse showing that MDV3100 is distinct from bicalutamide, whereby it has a greater affinity, binds AR selectively, without displaying agonism in AR overexpressing cells and has more potent antagonistic activity.

In the end, Sawyers argued that what was important was not AR overexpression per se, but AR amplification because prostate cancer cells with natural AR amplification are more sensitive to AR knockdown than AR single copy prostate cancer. Minor AR knockdown is sufficient to inhibit growth of AR amplified disease. All of this leads us logically to an important question:

Are AR amplified prostate cancers a different (and important) patient subtype?

Clinical trials with MDV3100 have demonstrated that at least half of prostate cancer patients remain AR dependent, suggesting that this is indeed the case. Clearly, if you can keep patients hormone sensitive or at least responding to therapies using different approaches, then the opportunity to delay time to metastasis and late stage disease may well exist with these novel approaches.

Time will tell.

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What's hot in oncology? A review of 2009 and predictions for 2010

By MaverickNY on December 18, 2009

Back in February, I took a big picture look at some of the cancer drugs in development that might be reviewed by the FDA for approval in 2009.

You can see the review here.

Of the eight drugs that were highlighted in the post, all were discussed by ODAC, so that was a positive sign. Five (Afinitor in RCC, Folotyn and Istodax in t-cell lymphomas, pazopanib in RCC and Arzerra in CLL) all passed the final hurdle, receiving a positive FDA opinion, while others (clofarabine, trabectedin and denosumab) were less lucky and issues associated with the filings are still being discussed. The EU CHMP has issued a positive opinion for Prolia (denosumab) but the FDA seem less convinced so far and issued a complete response letter requesting further information before giving approval. Amgen seem confident of addressing these issues, so we may well seen a green light soon.

While Genzyme and Amgen should be able to resolve the concerns successfully and will likely obtain FDA approval in 2010, J&J may well be left at the altar again with Yondelis. The drug was approved in Europe for soft tissue sarcomas, but approval in ovarian cancer is being sought in the US and ODAC had major issues with the trials and the risk-benefit trade-off. Time will tell what will happen in 2010.

AstraZeneca have not had a lot of luck with their pipeline since the infamous Iressa troubles. This year, they withdrew their filing for Zactima, a combination VEGF/EGFR inhibitor with limited efficacy over existing therapies. It will be interesting to see if they rebound in 2010.

The most promising robust oncology pipelines at the moment are probably those of Roche/Genentech, Novartis and Pfizer. Merck, BMS and GSK also have some interesting solid bets in their pipelines, but are not renowned for their speed of R&D and marketing in oncology compared to the other three, who are much more aggressive and focused in their resources and efforts.

W2W4 (what to watch for) in 2010?

That's the big question I'm getting in my email bag this month.

2010 is going to be an interesting year for CML patients, who will see a lot of new activity. ChemGenex filed omacetaxine for T315i mutations and treatment in patients who had failed existing TKI therapy. They have an ODAC in February and based on the data presented at ASH this month, I think they have a good chance of approval.

Novartis and BMS are both expected to submit an NDA to both the FDA and EMEA for approval of nilotinib and dasatinib respectively, in newly diagnosed CML. The nilotinib data was presented at ASH and clearly showed a 12 month efficacy benefit over imatinib, the current standard of care. We are still awaiting the dasatinib vs. imatinib data, hopefully it will be presented at either ASCO or EHA. My guess is that we may well see approvals for both drugs in the front-line setting in 2010.

The biggest challenge both companies may well have though, is not getting approval per se from the EMEA, but rather getting past NICE in the UK given the disparity in price with imatinib, when 60-70% of patients do well on the drug and attain a complete cytogenetic response at 18 months. Currently, NICE has declined to approve the second generation TKI's even in the relapse/refractory/resistance setting, so that does not augur well for the frontline setting.

Genzyme will likely have data from randomised trials with clofarabine in elderly AML in 2010, which means that approval may well be possible if the data is positive.

Cell Therapeutics presented data at ASH on pixantrone in 3rd line NHL, with evidence of activity. This drug will be another candidate for approval and the ODAC is currently scheduled for April, according to the company.

Ariad, a biotech based in Boston, have two promising agents in development. Ridaforolimus is an mTOR being developed in soft tissue sarcomas with Merck in the second line setting. I think this agent is promising, but the placebo controlled trial design in a heterogeneous disease where some subsets respond well to therapy and some are insensitive makes me nervous what the final phase III results will bring. In such an allcomers trial, you run the risk that the responders will be drowned out by the non-responders. Of course, screening out subsets in a fairly uncommon disease makes for slower accrual and time to market so the risk is a high one. What I do know is that KOL's I spoke to who participated in the trial noted that those patients who did respond tended to do very well in a heavily pretreated setting. We should know by ASCO whether Ariad's big play paid off or not.

Ariad also have a interesting agent in development for CMl, which targets the T315i mutation, currently a gap not met by the current TKI's approved on the market. Given my interest in CML, this is a new agent worth following. The early phase I data presented by Dr Cortes from MD Anderson at ASH this month looked very encouraging indeed.

Dendreon's Provenge is always a controversial topic on this blog. I'm not going to make any predictions about the vaccine this time other than to say it will be fascinating to see what happens next year! It's been somewhat of a roller coaster ride so far and I suspect that trend will continue in 2010.

J&J and Cougar's abiraterone may have enough data in prostate cancer by ASCO mid year to determine if they have enough evidence for a filing too. If so, it could be an interesting year in prostate cancer given very little new therapies have made any headway in the middle to advanced settings in extending hormone sensitivity and delaying time to progression to metastases. If either of these drugs can achieve that lofty goal, it will be very good news indeed.

Medivation also have a novel compound (MDV-3100) in much earlier development, so while the others test the regulatory waters, we can see how the new partnership evolves with Astellas.

Two other compounds I'm watching are Novartis' Antisoma compound, ASA404, in lung cancer and ipilimumab in melanoma and prostate cancer from BMS. Both of these agents have shown early signs of efficacy, so data at ASCO may well tell us whether they look like showing real promise or turning into duds.

This year saw the evolution into the limelight from the PARP inhibitors, most noticeably sanofi-aventis and BiPar's BSI-201 in triple negative breast cancer and AstraZeneca and KuDos's AZD2281 in BRCA1 and 2 mutated cancers such as breast and ovarian. I'm really looking forward to seeing the latest data at ASCO in June 2010 after following their progress at ASCO and AACR this year.

So of all the new pipeline drugs mentioned in this post, what is particularly compelling? I'm probably most excited by the PARP inhibitors and ASA-404, all of which have a real chance to stand out from the crowd. We'll see this time next year whether that turns out to be a good prediction or not!

Further updates of interesting compounds in development will continue o
n this blog next year.

Of course, if anyone has any other favourites they're following in oncology, please add them in the comments or drop me an email. We'd love to hear what others think.

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