Genentech | Pharma Strategy Blog

FDA rejects the Roche Immunogen T-DM1 accelerated approval filing

By MaverickNY on August 27, 2010

Interesting news arrived in my email box this morning:

"Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the U.S. Food and Drug Administration (FDA) issued a Refuse to File letter for accelerated approval for the company’s trastuzumab-DM1 (T-DM1) Biologics License Application (BLA). As planned Roche will continue with its ongoing Phase III EMILIA registration study. Roche will continue to work with the FDA and expects a global regulatory submission of T-DM1 mid 2012.

The BLA submitted in July 2010 requested accelerated approval for T-DM1 based on the results of a single-arm Phase II study, which showed T-DM1 shrank tumors in one-third of women with advanced HER2 positive breast cancer, who had received on average seven prior medicines, including two HER2 targeted agents."

There was a lot of excitement around the initial phase II results (one third of the women experienced tumour shrinkage, for example). Yet, to much surprise, the application was rejected:

"In their review of the BLA, FDA stated the T-DM1 trials did not meet the standard for accelerated approval because all available treatment choices approved for metastatic breast cancer, regardless of HER2 status, had not been exhausted in the study population."

At first reading of the press release, my thoughts centred around:

How could the FDA possibly reject such an application?
Was an SPA agreed up front?

The first question is easy to be indignant about, but what criteria were used for the trial and what does the data actually show?

Looking at the available clinical trials for T-DM1, this one looks most likely as 100 patients were required and the inclusion criteria stated:

HER2-positive disease
Metastatic breast cancer
Disease progression on the last chemotherapy regimen received in the metastatic setting
Prior treatment with an anthracycline, trastuzumab, a taxane, lapatinib, and capecitabine in the neoadjuvant, adjuvant, locally advanced, or metastatic setting and prior treatment with at least two lines of therapy (a line of therapy can be a combination of two agents or single-agent chemotherapy) in the metastatic setting
At least two lines of anti-HER2 therapy must have been given in the metastatic setting as monotherapy or combined with chemotherapy or hormonal therapy. The HER2-targeted agent can include trastuzumab, lapatinib, or an investigational agent with HER2-inhibitory activity.

There are only two approved treatments for HER2-positive breast cancer, trastuzumab and lapatinib, plus others in clinical trials, eg pertuzumab, which was also allowed as one of the prior therapies. All patients appear to have been refractory to at least two of these drugs, most likely trastuzumab and lapatinib.

The prior chemotherapies included anthracyclines, taxanes and capecitabine, which is quite heavy pre-treatment and includes all of the considered standards of care for several lines of therapy. Indeed, the results of the trial presented at the San Antonio Breast Cancer Symposium last December showed that the average number of prior treatments in the metastatic setting was 7.

The others that could be used in the treatment of breast cancer include nab-paclitaxel (Abraxane), which I'm assuming would be covered in the taxane group and ixabepilone (Ixempra), an epothilone approved in by the FDA for metastatic breast cancer following progression on a taxane and anthracyclines, with or without capecitabine.

Ixabepilone is not a taxane or an anthracycline and therefore technically not covered in the inclusion criteria as a prior therapy, although some of the women would likely have received it, but not all. It is, however, a taxane-like compound in that it targets the microtubules, as described in the PI:

"Ixabepilone is a semi-synthetic analog of epothilone B. Ixabepilone binds directly to B-tubulin subunits on microtubules, leading to suppression of microtubule dynamics. Ixabepilone suppresses the dynamic instability of aB-II and aB-III microtubules."

If that was the criteria for rejecting the trial as not truly refractory in a very heavily pre-treated setting, I would be surprised. It's a bit of a technicality and nit-picking. Ixabepilone is not a commonly preferred treatment at all and BMS reported very low sales in 2009. Most US physicians appear to prefer the well established taxanes such as paclitaxel, docetaxel and nab-paclitaxel rather than a synthetic taxane-like agent and probably consider it as a last resort. It is used as a standalone therapy in the refractory/salvage setting.

However, we're talking about a potential indication for a targeted agent that inhibits HER2 dimerization not a chemotherapy, so I would have thought that most of the important bases were covered by including the most common chemotherapies, trastuzumab and lapatinib in the inclusion criteria.

With regards to the latter question, Twitter chat this morning suggested that no, an SPA wasn't formally agreed upon, but Roche held discussions with the FDA that led them to file for accelerated approval. Thanks to Adam Feuerstein of The Street for being the first to answer that question.

My general opinion is that if you have an agreed Special Protocol Assessment (SPA) and meet the defined targets, it's much easier to move forward and gain approval. If you don't, things may turn into a crapshoot and it can go either way. And that seems to be what has happened here.

The other factor that comes into play in this discussion is the ongoing discussion of the accelerated approval for Avastin in metastatic breast cancer and the overwhelming negative ODAC opinion last month. That will not have helped, although one would like to think it shouldn't influence any decision making at the FDA. We would probably be naive to think otherwise given the full protocol included PFS rather than OS as the endpoint.

To be fair, Roche appear to be addressing this issue, in their announcement this morning:

"Roche will amend the Phase III randomized EMILIA study in order to rigorously evaluate overall survival in addition to progression-free survival and will submit data from EMILIA to support a global regulatory submission in mid 2012."

Overall, I think it's a disappointing decision by the FDA given the heavily pre-treated population and lack of options for women who are refractory to both trastuzumab and lapatinib. Chemotherapy has not been shown to be particularly effective in HER2 disease, and by then the women generally have a poor prognosis. When you look again at the SABCS data, you find an objective response rate (ORR) of approximately 30% and a clinical benefit rate of around 40%, which is quite startling in a heavily pre-treated group.

Meanwhile, for now we'll have to wait another two years to see what the survival data looks like. That's a rather long time for women who have failed Herceptin and Tykerb to wait for a drug that appears to have significant activity.

{UPDATE: I posted this analysis in a hurry, uncaffeinated, and in a rush to head out to a meeting. Of course, one remembers later that SPA's apply to phase III not phase II trials, so a formal agreement wouldn't apply here. Thanks also to the two people who gently reminded me of this. Usually though, there are some discussions with FDA around the trial design for accelerated review. Essentially, in layman terms, it means patients are refractory to existing treatments for the disease concerned. Note that Roche, in their press release defined it as, "Consideration by the FDA for accelerated approval requires recognition of a defined patient population of unmet need (a life-threatening disease with limited treatment choices)." It looks like the FDA are applying it more strictly to ALL therapies, although the number of women who might have taken ixabepilone AND be HER2-positive will likely be miniscule. I would still maintain that refractory to all available HER2 therapies and most chemotherapies apply for the majority in this case.}

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Somatic mutations and pathway alterations in cancer

By MaverickNY on August 5, 2010

"The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics."

So began today's journal article from a letter to Nature (link below) from scientists at Genentech. They went on to state that they have looked at:

"The identification of 2,576 somatic mutations across 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes.

Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets.

Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for Ga subunits in multiple cancer types."

The goal of this type of analysis is to look for patterns and alterations associated with disease and try to figure out which are potentially druggable targets for drug development. The researchers went on to note:

"Our study represents a substantial expansion of the knowledge base of cancer somatic mutations. Of the 845 genes with proteinaltering mutations identified in this study, 361 (43%), including 13 significantly mutated genes like TLR4, SPOP and NRG3, have not previously been reported."

That's great news. Of course, it should be noticed that theory is one thing, but until a pipeline compound enters into clinical trials and we see the results of extensive studies, we won't know whether the target is truly a relevant one in human cancers or not.

Not all mutations may occur in every person though, as we have seen in lung cancer where some people might have an EGFR mutation, some an ALK mutation and so on. The secret to this approach is to start documenting the likely targets and go looking to see how many exist, which ones might be a critical driver and which ones are merely passengers.

Clearly though, it does help to have an idea of what the needles in the haystack might look light before going hunting for them to increase the chances of success.

Photo Credit: Yellow Book

Kan, Z., Jaiswal, B., Stinson, J., Janakiraman, V., Bhatt, D., Stern, H., Yue, P., Haverty, P., Bourgon, R., Zheng, J., Moorhead, M., Chaudhuri, S., Tomsho, L., Peters, B., Pujara, K., Cordes, S., Davis, D., Carlton, V., Yuan, W., Li, L., Wang, W., Eigenbrot, C., Kaminker, J., Eberhard, D., Waring, P., Schuster, S., Modrusan, Z., Zhang, Z., Stokoe, D., de Sauvage, F., Faham, M., & Seshagiri, S. (2010). Diverse somatic mutation patterns and pathway alterations in human cancers Nature DOI: 10.1038/nature09208

Time for FDA and ODAC to decide on Avastin in breast cancer

By MaverickNY on July 20, 2010

Today I will be out of the office at client meetings, but many of you will be wondering what will happen at the FDA ODAC briefing meeting, which will be discussing the bevacizumab (Avastin) data in breast cancer this morning. You can take a look at the briefing documents here.

Background

Avastin was approved to much fanfare because it was basically shown to shrink tumours quite dramatically and the early magnitude of the PFS data suggested benefit in favour of adding Avastin to chemotherapy. According to the FDA, full approval would be thus debated once the final survival data were available:

“As a condition of the accelerated approval, Genentech was required to submit data from two ongoing, placebo-controlled trials (AVADO and RIBBON1) to provide verification of the treatment effect on PFS and to provide additional information on the effects on overall survival.”

According to the FDA documents:

“The addition of bevacizumab to paclitaxel resulted in a 52% increase in progression-free survival (HR 0.48, 95% CI 0.39, 0.61; p< 0.0001) with an observed 5.5-month difference in median PFS, based on an independent radiographic review.

There was no significant difference in overall survival, a secondary endpoint, between the two treatment arms. The tumor response rate was higher with bevacizumab plus paclitaxel as compared to paclitaxel alone (48.9% versus 22.2%).”

Breast cancer was one of the early tumour types that Genentech tested the drug in but despite promising phase II data, the phase III study was negative and thus they decided to go back to the drawing board with the statisticians and investigate the drugs safety and efficacy in another large scale phase III trial. Meanwhile, colon cancer overtook breast cancer and became the first approved indication for Avastin instead.

Fast forward to 2010.

The data from AVADO and RIBBON1 is now available in the FDA briefing documents. Here is a quick synopsis from each. I confess that I found the FDA summary of the data a little confusing, but the tables tell the picture more easily and have included the efficacy data tables from the briefing documents, where appropriate.

AVADO

This study comprised a double-blind, placebo-controlled, three-arm trial of:

docetaxel plus placebo
docetaxel plus bevacizumab 7.5mg/kg
docetaxel plus bevacizumab 15 mg/kg

with all therapies given on a standard three-weekly schedule.

A total of 736 patients with HER-2 neu negative tumors who had not received prior chemotherapy for metastatic breast cancer were enrolled.

Overall the data was summarised as follows:

Source: FDA (pdf link)

The OS Kaplan-Meier curve for the AVADO study looks like this – you can see that they cross over just coming up to two years:

Source: FDA (pdf link)

The FDA went on to describe the tolerability data as thus:

“Safety data showed an increase of grade 3-5 adverse events, serious adverse events and study drug discontinuation with the addition of bevacizumab to docetaxel. More patients in the bevacizumab-containing arms required interruption/dose reduction or discontinuation of docetaxel due to an adverse event.”

RIBBON1

This was a double-blind, randomized, parallel group study conducted in people with metastatic or locally recurrent HER2-neu negative adenocarcinoma of the breast, who had not received prior chemotherapy for their advanced or metastatic cancer. A total of 1237 patients were randomized (2:1) to receive anthracycline or taxane-based chemotherapy (n=622) or capecitabine (n=615) in combination with either bevacizumab or placebo.

The efficacy data looks like this:

Source: FDA (pdf link)

The FDA also summarised the side effect profile:

“Overall, the incidence of grade 3-5 AEs and serious AEs were almost twice as high in the bevacizumab arms compared to placebo arms in both cohorts. In the taxane/anthracycline cohort, taxane subgroup, there was slightly more deaths in the bevacizumab containing arm than placebo arm (49.8 % versus 43.1 %).

The vast majority of the deaths were attributed to breast cancer. Adverse events known to be caused by bevacizumab were, as expected, increased in the bevacizumab containing arms in both cohorts. The most common AEs associated with bevacizumab were hypertension, bleeding/hemorrhage and febrile neutropenia.”

Essentially though, the incidence of AEs is not significantly different than currently described in the prescribing information.

Overall Conclusions:

In the summing up to the ODAC committee, the FDA briefing document declares:

“AVADO and RIBBON 1 are well conducted, double-blinded trials. The magnitude of the improvement in PFS observed in these two studies failed to confirm the magnitude of PFS improvement observed in the E2100 trial, the basis for the accelerated approval.

The magnitude of treatment effect is clinically important because it is really a measure of delaying symptoms from tumor progression, which has to be weighed against drug toxicity that is present for the duration of treatment.”

The short answer is that the overall survival data suggested hazard ratios favoring the placebo arms in the AVADO study and the taxane/anthracycline cohort of the RIBBON1 study. This is important, because it raises the issue of risk:benefit because the women are being exposed to significant toxic side effects with no impact on overall survival.

What next?

Looking at the data from the two trials objectively, it is hard to justify treating women with newly diagnosed breast cancer with Avastin, when they would appear to live longer and have less side effects with chemotherapy alone. The PFS effect seen in E2100 has not been confirmed at all.

Ultimately, I think Roche/Genentech would have a much better case to argue to the FDA and public if they had a biomarker to determine which patients are likely to do better on bevacizumab therapy, just as erlotinib works better in lung cancer patients who are EGFR mutation positive.

I wonder what ODAC will decide?

My educated guess is that one of two scenarios might happen:

Approval remains, but modify the PI language similarly to Iressa to indicate that there is no overall survival advantage associated with adding Avastin to chemotherapy in breast cancer.
Withdrawal of breast cancer indication for Avastin.

Technically, logic would suggest the latter option is more likely given the rules governing accelerated approval, but these panels are a notorious minefield sometimes, very hard to predict and the FDA doesn’t always follow their advice, as the original approval for Avastin in breast cancer demonstrated!

What do you think?

{UPDATE: My educated guess was correct – ODAC voted 12-1 to withdraw Avastin from the market. The big question now is what will the FDA decide?}

{UPDATE 2: FDA decided to hold a public hearing, now scheduled for Weds June 29th, 2011}

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PI3-kinase (PI3K): a hot topic in cancer research

By MaverickNY on July 19, 2010

Recently at a couple of scientific cancer meetings, American Urology Association (AUA) and American Society of Clinical Oncology (ASCO), Frank McCormick described a fascinating talk about how a wac-a-mole approach to figuring out how the phosphatidylinositol 3′-kinase (PI3-kinase or PI3K) pathway could be targeted effectively with therapeutics. The reason for research in this area is PI3K has been shown to play a major role in proliferation and survival in a wide variety of human cancers, thus making is a potential target for therapeutic intervention.

I’ve been following this target for a couple of years now and data is now starting to emerge that’s worth discussing on a broader scale, given the implications. Here’s a quick snapshot of the PI3K pathway and related pathways:

Source: Workman et al., Nature

As many of us well know, however, simply targeting one element of an aberrant pathway can lead to cross-talk and feedback loops as the cancer tries to maintain the signals important for it’s survival, so a more cunning approach is needed whereby the escape routes are closed off one by one by targeting different kinases as well as PI3K.

McCormick’s talk was a fascinating lecture that basically went through multiple pathways explaining, ‘well we tried X and this happened, so we tried blocking Y as well and this happened…’ kind of approach in a very logical and systematic fashion. Eventually, all options will be explored and a new paradigm might emerge.

It was therefore with great interest that I read a series of new papers in AACR’s journal, Clinical Cancer Research (see references below) over the weekend on both the pathway itself, and also new data with targeted PI3K agents in both breast and renal cancers.

The Data so far:

Miron et al., looked at PI3K mutations in in situ and invasive breast carcinomas and reported:

“This is the first study to show that PIK3CA mutation is a relatively early event in breast tumorigenesis preceding invasion because the frequency of PIK3CA mutations was the same in pure DCIS as in DCIS adjacent to IDC and in IDC.”

Given the frequency of mutations was the same for the 3 groups they studied (pure ductal carcinoma in situ (DCIS), DCIS adjacent to invasive carcinoma, and invasive ductal breast carcinomas), the data suggest that the PI3K mutation may play a greater role in breast tumor initiation than in invasive progression.

If this is the case, targeting PI3K early, for example in neoadjuvant therapy, may have a positive beneficial effect.

In the O’Brien paper, the researchers looked for predictive biomarkers of sensitivity to Roche/Genentech’s PI3Ki, GDC-0941 in preclinical models of breast cancer:

“We found that models harboring mutations in PIK3CA, amplification of human epidermal growth factor receptor 2, or dual alterations in two pathway components were exquisitely sensitive to the antitumor effects of GDC-0941. We found that several models that do not harbor these alterations also showed sensitivity, suggesting a need for additional diagnostic markers.”

Identifying suitable biomarkers in preclinical studies, such as the HER2 amplification and the PIK3CA mutation (but not PTEN deficiency) previously identified in other studies and now validated in O’Brien et al’s GDC-0941 study, will hopefully help in better design of future clinical studies. They also noted that decreased ERBB3 expression in PIK3CA mutant cell lines, and ERBB3 expression was increased in response to treatment with a PI3K inhibitor, suggesting that ERBB3 expression levels might be used as a biomarker for high activation of PI3K signaling and increased sensitivity to PI3K inhibitors. This kind of rigourous approach would potentially enable selecting which people are most likely to respond up front to the agent, rather than exposing those who are unlikely to get a response to additional toxicities and side effects.

In a well written editorial, Turke and Engelman, also emphasised that:

“A novel expression profile was developed to identify other breast cancers sensitive to PI3K inhibitors. These expression studies highlighted feedback networks connecting TORC1, PI3K, and mitogen-activated protein kinase (MAPK) pathways, and underscored the potential for combination therapies.”

They also went on to observe:

“It will be interesting to determine if PI3K inhibitors induce substantial apoptosis in vitro and tumor regressions in vivo in these cancer models (without HER2 amplification or PIK3CA mutation). Of course, it will be crucial to assess biomarkers identified in laboratory studies in clinical samples from patients who respond to PI3K inhibitors. Neo-adjuvant trials in breast cancer patients can be leveraged to address these translational goals, because they correlate clinical efficacy and pathologic signs of response (e.g., changes in Ki67 levels and induction of caspase cleavage) with the presence of potential biomarkers.”

In another study, Cho et al., looked at the effects of a dual PI3-Kinase/mTOR Inhibitor
NVP-BEZ235 compared with rapamycin in renal cancer (RCC) with BEZ235 (Novartis). The proof of concept for mTOR has already been shown clinically with the approval of two drugs in this indication, temsirolimus (Pfizer) and everolimus (Novartis):

“These agents induce only modest tumor regression and extend progression-free survival only a few months in most patients.”

The big question here is whether targeting PI3K as well as mTOR would have any extra beneficial effects? The results demonstrated that dual inhibition of PI3K/mTOR with BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone. If reproduced in the clinic, this may offer a new and more effective approach to treatment of the disease.

The Future:

The PI3-kinase field is particularly interesting, with several companies snapping up PI3K inhibitors including sanofi-aventis (from Exelixis) and more recently, Infinity (from Intellikine). Other oncology companies already have some in their pipeline, such as Novartis (BEZ235) and Roche/Genentech (from Piramed). Meanwhile, smaller biotechs such as Semafore and Calistoga also have some promising early phase compounds in development. Some of these compounds target PI3-kinase alone, while others target PI3K and mTOR.

This is not going to be a straightforward approach to targeting cancer and identifying biomarkers along the way will be key, as well working out the best combinations that might make a more effective therapeutic approach than single agent activity. Figuring out when best to test these agents (early or late) will also be critical. The I-SPY breast cancer trials have already led the way in creating protocols for testing novel agents in the neoadjuvant setting in breast cancer, and it may well be that PI3K inhibitors would be a good class to test in this setting based on the new evidence from Miron et al’s study.

What is particularly interesting to me is that PI3K signalling may also have a role to play in asthma and COPD (the area I did my doctoral research in) rather than just cancer. Now that would be really fascinating as the biochemical and molecular biology overlap have long been suspected, but very little research has really evolved this way. Part of that is due to drug manufacturer silos and the inability to effectively spearhead cross-therapeutic research.

It will be fascinating to watch how the PI3K data shakes out in practice over the next few years.

What do you think?

O’Brien, C., Wallin, J., Sampath, D., GuhaThakurta, D., Savage, H., Punnoose, E., Guan, J., Berry, L., Prior, W., Amler, L., Belvin, M., Friedman, L., & Lackner, M. (2010). Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models Clinical Cancer Research, 16 (14), 3670-3683 DOI: 10.1158/1078-0432.CCR-09-2828

Turke, A., & Engelman, J. (2010). PIKing the Right Patient Clinical Cancer Research, 16 (14), 3523-3525 DOI: 10.1158/1078-0432.CCR-10-1201

Miron, A., Varadi, M., Carrasco, D., Li, H., Luongo, L., Kim, H., Park, S., Cho, E., Lewis, G., Kehoe, S., Iglehart, J., Dillon, D., Allred, D., Macconaill, L., Gelman, R., & Polyak, K. (2010). PIK3CA Mutations in In situ and Invasive Breast Carcinomas Cancer Research, 70 (14), 5674-5678 DOI: 10.1158/0008-5472.CAN-08-2660

Cho, D., Cohen, M., Panka, D., Collins, M., Ghebremichael, M., Atkins, M., Signoretti, S., & Mier, J. (2010). The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma Clinical Cancer Research, 16 (14), 3628-3638 DOI: 10.1158/1078-0432.CCR-09-3022

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Gefitinib or Chemotherapy for Non–Small Cell Lung Cancer with Mutated EGFR

By MaverickNY on June 28, 2010

AstraZeneca's Gefitinib (Iressa) has had a bit of a chequered history since it's fast track approval by the the Japanese Health Authority in 2002 and the FDA in 2003 for non-small cell lung cancer (NSCLC). However, since the phase III trials did not appear to generate a significant overall survival advantage, it has been available in the US, Canada and Switzerland under strict labelling restrictions based on the ISEL study since 2005. A patient assistance program is available for suitable patients in the US:

"In the light of positive survival data with other agents including another oral EGFR inhibitor, physicians should use other treatment options in advanced non-small cell lung cancer patient populations who have received one or two prior chemotherapy and are refractory or intolerant to their most recent regimen."

Source: US Iressa PI

The IPASS study (IRESSA Pan-ASia Study) subsequently demonstrated superiority of gefitinib's efficacy over doublet chemotherapy in EGFR mutation positive patients in 2008. In Europe, this led to gefitinib being finally approved for the treatment of adults with locally advanced or metastatic NSCLC with activating mutations of EGFR-TK across all lines of therapy in 2009.

The latest data, from the North-East Japan Study Group, published in this weekend's NEJM, showed some interesting new results in a study of 239 newly diagnosed Asian patients with NSCLC and EGFR mutations when they compared standard chemotherapy of carboplatin plus paclitaxel to gefitinib as a single agent.

Essentially, in this front-line setting, treatment with the EGFR tyrosine kinase inhibitor gefitinib resulted in progression-free survival (PFS) that was twice as long as treatment with standard chemotherapy, ie PFS of 10.8 months in the gefitinib group compared with 5.4 months in the chemotherapy group. Response rates were also improved in the gefitinib arm compared to chemotherapy (73.7% vs. 30.7%). Side effects were as expected for the two treatments (rash and elevated aminotransferase in the gefinib group and neutropenia, anemia, loss of appetite and neuropathy in the chemotherapy group).

However, the median overall survival (OS) of 30.5 months vs 23.6 months was not significantly different between the two groups.

It is clear from both IPASS and the NE Japan studies that in a select sub-population of lung cancer patients, patients could elect to receive biologic therapy such as gefitinib rather than chemotherapy and have a reasonable quality of life.

However, given the lack of over survival benefit with Iressa but has been demonstrated with Tarceva (erlotinib) in other studies, I'm not sure where this leaves AstraZeneca. It is unlikely that the restrictions on the US or Canadian approvals will change as a result of this study.

Why Tarceva led to a survival benefit in EGFR mutated NSCLC and Iressa does not is still unclear at this stage.

Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T, & North-East Japan Study Group (2010). Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. The New England journal of medicine, 362 (25), 2380-8 PMID: 20573926

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ASCO 2010 Preview #2: PI3K and mTOR inhibitors

By MaverickNY on May 12, 2010

One of the interesting things about scientific conferences such as AACR and ASCO is that everyone looks at the same data differently as if it were through a kaleidoscope.

Brand marketers focus on their competition by tumour type or disease, scientists look at specific mechanisms or pathways, investors look at particular companies and so on.

Someone asked me the other day how I analyse the data. I hadn't really thought about it much until then, but on reflection what I'm interested in is trends and how research evolves from a big picture science view so that means I look at pathways like a true biochemist. This also teaches us where the gaps are and what opportunities may arise in the future. It's not exactly rocket science, but it is a useful approach sometimes.

Image via Wikipedia

One of the clear trends emerging at AACR the other week is that dual inhibition of both the PI3K-mTOR and RAS-ERK pathways may be necessary in some cancers such as melanoma to reduce cross-talk, feedback and feedforward loops, drug resistance and loss of PTEN gain of function, just as one might also target IGF-1R and EGFR to reduce cross-talk and add in another inhibitor, eg MEK or AKT.

Given the increasingly critical role of MEK and AKT in various combinations in the future to reduce the potential for drug resistance occurring, this bodes well for a host of companies. I wasn't, therefore, surprised to see Novartis snap up Array's MEK inhibitor (ARRY-162) given they already have an mTOR on the market (everolimus, Afinitor), two PI3-kinases in development and others including a RAS inhibitor. Having a MEK inhibitor as well may therefore give them a lot of flexibility with different combinations in multiple cancer types if this approach pans out.

Merck are also following a similar approach with their mTOR inhibitor, ridaforolimus, which they have finally grabbed commercial control of from their partner, Ariad. Let's not forget they also have an AKT inhibitor, dalotuzumab and a MEKi through their partnership with AstraZeneca to play with too.

This is all good news for several biotech companies though, if some big Pharma companies start catching onto the trend and realise they need may a PI3K-mTOR inhibitor and a MEK or AKT inhibitor to stock up in their pipeline before the field gets too crowded.

Which companies might have new and interesting data in this area?

Well, Keryx and Aeterna Zentaris, Semafore, Calistoga, Intellikine and a few others all have PI3K inhibitors in development, while Exelixis have a deal in place with sanofi-aventis for XL147 and XL765 and Roche/Genentech have a pan-PI3K inhibitor, GDC-0941. Novartis have two (BEZ235 and BKM120). Some of these compounds are single PI3K inhibitors and some are dual inhibitors of PI3K-mTOR.

Looking at the ASCO abstract titles, Exelixis appear to have the most abstracts in this area this year, so it will be interesting to see what sort of data they have across a range of different tumour models and early phase I results in solid and hematologic malignancies, with a variety of different combinations.

One session I'm really looking forward to at this year's ASCO is a Clinical Science Symposium entitled, "Paths for Clinical Development of PI3K Inhibition" with some of the heavyweights in the field such as Neil Rosen (MSKCC), Skip Burris (Sarah Cannon), Jose Baselga (Spain) and Carlos Arteaga (Vanderbilt). Arteaga is presenting a talk in that session entitled, "Next steps in clinical development of PI3K inhibitors?"

More later on this blog after the posters and the data become available at the meeting.

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BIO 2010: A place for new biotech deals emerging?

By MaverickNY on May 6, 2010

I've been following the annual Biotechnology Industry Organisation (BIO) Conference being held in Chicago remotely on Twitter (check out the hashtag #BIO2010) while busy with client work this week and secretly thanking my lucky stars that I'm office bound and not whinging about sore feet myself as McCormick Place has hard floors and miles of corridors! Much of the lifestream seems to be a lot of moaning about the limited/almost non media access to the keynotes and grumbling about the general lack of social media savvy of the organisation. No surprises there.

Still, in a world where life seems to be increasingly on 24/7, this interesting little snippet from the San Francisco Business Times was much more revealing:

"Big drug makers are ready to make a deal.

With some facing a multibillion-dollar patent cliff and others just trying to expand their focus, big biotech and pharmaceutical companies are reaching out to capture potential products from other companies.

That played out at the recent Biotechnology Industry Organization convention in Chicago. While smaller, privately held companies continued to dominate the number of 15-minute pitches, South San Francisco-based biotech biggie Genentech Inc. and German goliath Bayer Schering Pharma AG also spun out appeals to smaller companies to sell out or partner up.
The list of big companies taking time slots to make similar pitches included the likes of Pfizer, Merck AstraZeneca, Eli Lilly and GlaxoSmithKline."

It's a few weeks post AACR and a month before the run-up to ASCO, also oddly in Chicago, and thus companies interested in oncology will have been evaluating the latest AACR data and thinking about whether or not to make a move before the competition do.

Of course, with many companies facing a potential perfect storm of patent cliffs and a shortfall in the in-house pipelines over the next few years, everyone is desperately hunting for 'breakthroughs'. These are never a sure fire thing and are very hard to predict.

Increased activity and competition for licensing deals also means good news for the little companies as supply and demand may well drive prices up. It will certainly be interesting to see who pounces over the next few weeks and many investors will be scanning their crystal balls hard for clues.

Who do you think will be snapped up?

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An overview of Roche's oncology pipeline

By MaverickNY on March 26, 2010

At last weeks investor meeting held by Roche in downtown Wall Street, the Board reviewed the pipeline opportunities in a number of areas. Earlier this week I wrote about the non-oncology pipeline and today will form an overview of the cancer drugs in development.

One of the things that Roche is renowned for is life cycle management. They do this better than many in the industry in my opinion and it makes an enormous difference not only to continuity, but also long term revenues and performance. Too many companies take a short term view and do not think ahead to the future. This is a big mistake. Perhaps they get bogged down in classic silos or management do not see it as a priority, but it does make a difference.

Why?

Well, for starters, think about the basics of marketing. It is much easier to sell new products to existing customers than it is to sell existing products to new customers and even harder to sell new products to completely new customers.

Thus life cycle management is a smart strategy and done well, enhances the experience for everyone involved whether employees or investors. I only wish more companies paid closer attention to this important aspect of Pharma marketing.

The other thing I like about Roche's approach to R&D is rigorous and strong proof of concept studies (usually in phase II). Between Roche and Genentech, they both do this particularly well in oncology, it seems to be their signature. This partly explains why they mostly end up with a continuous wall of data across several products including trastuzumab (Herceptin), rituximab (Rituxan) and bevacizumab (Avastin). Of course, negative trials do occur but overall, they seem to have more positive trials than not. This partly explains why they have fewer phase III flops than say, Pfizer, because they spend the time in phase II working things out rather than rushing aggressively ahead on the basis of early evidence.

So what did we learn from the pipeline presentations last week?

There are late stage oncology products in development that look promising.

One example is trastuzumab-DM1, which is basically modified Herceptin with a potent cell killing agent, DM1, bolted on. The goal is to improve the action of Herceptin in metastatic breast cancer, and at the same time invetigate whether the xenograft data in a variety of cancers (breast, ovarian, lymphoma and prostate) with an armed antibody is an effective strategy in people. Recent phase II data from the San Antonio Breast Cancer Symposium in heavily treated women with metastatic breast cancer look encouraging. Phase III trials have already begun and if all goes well, filing is currently anticipated by 2012.

Also potentially strengthening the breast cancer franchise is pertuzumab, a monoclonal antibody that targets HER2. Early phase I trials in several cancer types produced so-so results, but more recent phase II data in breast (combined with Herceptin) and ovarian cancer (in combination with gemcitabine) published this month in JCO look interesting.

Perhaps the most exciting compound though, is PLX4032/RG7204, a BRAF inhibitor being evaluated in malignant melanoma. Currently available data suggests survival is improved by 6 months so the big question is what causes resistance to develop and how this can be overcome. Data on this compound is expected at ASCO, where many are keen to see how it stacks up with ipilimumab (BMS).

In hematologic malignancies, GA101 or galiximab is being evaluated in non-Hodgkin's Lymphoma (NHL) and chronic lymphocytic leukemia (CLL). It appears to target a different part of the CD20 isotope than rituximab and this may increase it's efficacy. Phase III trials began in 4Q09 thus it will be a little while before we see some results. There is clearly an unmet medical need in the 3rd line refractory disease for more tolerable agents and rituximab is very much the bedrock of treatment for both across multiple lines of therapy either alone or in combination with chemotherapy. A similar agent will likely have good take up with the right approach.

Genentech are investigating various new and improved approaches to angiogenesis, but these are in much earlier development and the bar is very high with bevacizumab (Avastin), even for the company who manufacture it. The list of anti-angiogenesis compounds that didn't make it to market is very long indeed.

I've left the best to last, as hedgehog (Hh) signalling is one of my favourite pathways – it always reminds me of the cheerful cartoon character, Sonic the Hedgehog. RG3616, licensed from Curis, is currently in phase II trials for advanced basal cell carcinoma and trials are also underway for medulloblastoma. If interested, you can find out more about the pathway and the science here.

Overall, the oncology pipeline has a nice mix of follow on compounds to strengthen life cycle management with a raft of monoclonal antibodies with different targets in new cancer types. Such a strategy should reduce risk and drive the future bottom line if the promise delivers in phase III trials.

Baselga, J., Gelmon, K., Verma, S., Wardley, A., Conte, P., Miles, D., Bianchi, G., Cortes, J., McNally, V., Ross, G., Fumoleau, P., & Gianni, L. (2010). Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy Journal of Clinical Oncology, 28 (7), 1138-1144 DOI: 10.1200/JCO.2009.24.2024

Makhija, S., Amler, L., Glenn, D., Ueland, F., Gold, M., Dizon, D., Paton, V., Lin, C., Januario, T., Ng, K., Strauss, A., Kelsey, S., Sliwkowski, M., & Matulonis, U. (2009). Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer Journal of Clinical Oncology, 28 (7), 1215-1223 DOI: 10.1200/JCO.2009.22.3354

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Thoughts on the Roche non-oncology pipeline

By MaverickNY on March 24, 2010

Last Thursday, I attended the Roche Investor meeting in Wall Street, live-tweeted it using the hashtag #RocheIR and enjoyed an interesting event packed full with lots of information to digest.

Luckily, I bumped into an old colleague from Sandoz UK days and was delighted to learn that he is now Global Head of Regulatory at Roche. Of course, if you spend a day out of the office, you pay for it severely the next day with an even bigger pile of emails, client requests, RFPs and telecons to catch up on >.<

In fact, I was so busy, I didn't have time to post a blog about Thursdays event on Friday, but I did manage to interview Dr. Laura Esserman, the breast cancer surgeon at UCSF behind the fascinating I-SPY2 project that we discussed last week. More on that tomorrow.

The next two days of blogs will cover two reports on the Roche pipeline (non-oncology and oncology) and Dr. Esserman's unique perspective on getting the I-SPY2 project up and running, she has certainly made a difference shaking things up and challenging people's approach to drug development in a short space of time.

Let's begin with the non-oncology agents in Roche's pipeline.

Granted I normally write more about oncology, hematology and immunology here, but my background in Pharma started in more humble beginnings as a sales rep in the statin market, where we were also looking to differentiate ourselves by being an attractive option for people with diabetes, who have a much higher risk from long term CV mortality.

I was therefore very interested to see where Roche were going with this approach fifteen years later because we never had much success with it, despite Marketing thinking it looked to be an attractive opportunity no one was exploring. However, the undoubted long risk of earlier mortality and morbidity is subsumed to more urgent and immediate needs such as getting sugar levels under control and insulin levels regulated. Adding yet another drug into the mix complicates things for physicians considerably. Plus taking oral drugs over time also results in long term compliance issues, which may impact outcomes negatively.

Dalcetrapib is being developed for dyslipidemia and cardiovascular high risk patients. The first trial looks at artherosclerotic disease progression, lipid profile and biomarker profile and long-term safety profile of dalcetrapib in people with established coronary artery disease compared to placebo.

The primary endpoints include:

Nominal change from baseline to study end in coronary percent atheroma volume (PAV) of the target coronary artery assessed by IVUS.
Rate of change from baseline to study end in carotid intima-media thickness (CIMT) using B-mode ultrasound

The second trial is looking at the potential of dalcetrapib to reduce cardiovascular morbidity and mortality in stable coronary heart disease patients with recent Acute Coronary Syndrome (ACS) and evaluate the long term safety profile of the drug, again, compared to placebo.

The primary endpoint is defined as:

Time to first occurrence of any component of the composite cardiovascular event (cardiovascular mortality and morbidity)

These two phase III trials are currently recruiting people with coronary artery disease, so we won't know the results for quite a while, probably over the next 2-3 years. Such large scale trials are very expensive and time consuming to conduct. For all the the noise about statins reducing cholesterol, I sometimes wonder what impact they actually have on long term mortality and morbidity. Do they lead to any meaningful clinical change in outcomes, ie improved survival, rather than just lowering cholesterol per se?

Roche also have two drugs in development for type II diabetes, both of which are tongue twisters: taspoglutide, a new GLP-1 drug for Type 2 diabetes, and aleglitazar, for cardiovascular high risk in diabetes. The diabetes market is suddenly getting very crowded with numerous insulin, syringes, pens, pumps, and oral therapies all available.

Thus as a marketer, I'm wondering how new products into these segments differentiate themselves from existing therapies in this competitive disease? It's one thing to claim blockbuster potential, but quite another to capture the heart and minds of the physicians prescribing yet another me-too in a crowded existing market segment.

The $64M blockbuster question in diabetes for BMS's Onglyza, in the DPP-4 segment, rapidly turned into a spectacular $4M flop in the launch year. The inhaled insulins such as those from Pfizer and Mannkind were either withdrawn or struggle to make it to market. Two precautionary tales of humility in the diabetes market if there ever were some.

How Roche develop and differentiate taspoglutide and aleglitazar from existing segment leaders will therefore be an interesting process to watch. For now, we can sit back and wait for the various clinical trials to complete and see how the agents stack up. The phase III trials were initiated for aleglitazar were initiated in 1Q10, taspoglutide initial phase III results were released in 4Q09 and further results are expected in 2010. The results for dalcetrapib will not be available for a few years given the enrollment is just starting.

Two other non-oncology drugs in development include RG1678, a GLY-T1 inhibitor, for treatment of the negative symptoms of schizophrenia. The initial phase II results were positive last year and phase III trials are planned for 2010.

Ocrelizumab is a humanised CD20 monoclonal antibody similar to rituximab. The phase III trials were negative in rheumatoid arthritis and lupus, despite the agent being developed to reduce the development of drug neutralizing antibodies and infusion reactions. Recent studies, however, established that the safety risk associated with ocrelizumab outweighed the benefits and Roche disclosed that several patients died from infections so the development in RA and lupus was promptly suspended. Meanwhile, ocrelizumab is also being developed for the treatment of people with multiple sclerosis and a Go/No Go decision for the phase III development is expected this year.

Given the focus on five main disease areas including oncology, virology, immunology, metabolism and CNS, it is good to see new agents being developed in the metabolism and CNS areas after the long term focus on oncology with Genentech lately. How well they will do in the long run compared to the oncology pipeline, only time will tell.

Bench to Bedside: How can we speed up cancer drugs to the clinic?

By MaverickNY on March 18, 2010

After yesterday's post about the I-SPY trials in neoadjuvant therapy for breast cancer and how they may speed up the process of bringing new innovative cancer drugs to the clinic faster, I was reflecting on my own experiences with imatinib (Gleevec).

The Philadelphia Chromosome was first identified in 1960 by Nowell and Hungerford. Gleevec was finally approved by the FDA in May 2001, 41 years later.

Between 1999, when I arrived in the US and working in New Product Development at Novartis until 2001 when Gleevec was launched, I attended scientific meetings including AACR, ASH and ASCO. Often, Dr Judah Folkman, a scientific researcher from Harvard, would talk about angiogenesis and hypothesised that was the principal mechanism by which tumours grew. I listened to his ideas many times because I was curious and found the concept both fascinating and intuitive. There was a long line of drugs that failed to work though, and every meeting seemed to bring yet more negative results.

Now, Folkman first advanced the angiogenesis theory in 1971 in the New England Journal of Medicine, but it wasn't until 2002, when bevacizumab (Avastin), a VEGF inhibitor that prevented angiogenesis from happening, was finally approved for the treatment of colon cancer. At that point you go, 'oh wow' and realise that Folkman's theory was indeed proven correct.

Thus a tale of two incredible cancer drugs that both took a relatively long time to evolve from scientific idea to effective treatment in people with cancer. Or perhaps they were actually relatively 'quick' compared to others, but why it takes this long is something we can surely do better at.

Last night I was researching ideas for drug development and innovation since the concept of bench to bedside fascinates me and came across this enlightening video from a lunchtime talk that Dr Susan Desmond-Hellmann gave last year at UCSF. Oddly, she seems to have trodden similar thought processes and asked why and how can we speed things up as well.

The short lecture is well worth listening to for those interested in drug development – the good doctor explains the bench to bedside concept far better than I:

Sources for scholars and clinical scientists:

The NEJM doesn't appear to go back beyond 1993 online, but the original reference to Folkman's article is at:

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.

A more recent one from 1995, which provides an update is available online at: NEJM

Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘Genentech’

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AVADO

RIBBON1

Overall Conclusions:

What next?

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An overview of Roche's oncology pipeline

Thoughts on the Roche non-oncology pipeline

Bench to Bedside: How can we speed up cancer drugs to the clinic?