Pharma Strategy Blog

Dual HER2 inhibition improves survival benefit in advanced breast cancer

Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy. 

Blackwell KL, Burstein HJ, Sledge GW, Stein S, Ellis C, Casey M, Baselga J, O'Shaughnessy J

Background: The synergistic interaction of lapatinib combined with trastuzumab was established in HER2-positive preclinical models, hence providing the rationale to evaluate this combination in a clinical setting. Progression-free survival (PFS) from study EGF104900 revealed the combination of lapatinib plus trastuzumab was superior to lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) that progressed on multiple lines of trastuzumab-based therapy. Preliminary data showed a trend in overall survival (OS) favoring the combination therapy; however, data were not mature. Updated OS analyses are reported. 

Methods: Women with HER2-positive MBC progressing on prior trastuzumab-containing regimens were randomized to receive either lapatinib 1500 mg once daily or lapatinib 1000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose). If objective disease progression occurred on or after 4 weeks of lapatinib alone, crossover to the combination arm was permitted. OS was summarized using Kaplan-Meier curves and compared between treatment arms using stratified log-rank tests. Analyses adjusting for baseline prognostic factors and crossover were also performed. 

Results: 296 women were randomized (148 per arm). The median number of prior trastuzumab-containing regimens for MBC treatment was 3. Of the women randomized to lapatinib alone, 52% (77/148) crossed over to the combination arm. At data cut-off for updated OS, 218 deaths (74%) had occurred. Median OS following treatment with lapatinib plus trastuzumab was 60.7 weeks compared with 41.4 weeks for lapatinib alone. A significant improvement in OS was demonstrated with combination therapy compared with lapatinib monotherapy (HR: 0.74; 95% CI: 0.57, 0.97; P=.026). The survival benefit was maintained after adjusting for baseline prognostic factors (HR: 0.71; 95% CI: 0.54, 0.93; P=.012). A trend toward a clinically relevant 25% reduction in risk of death (P=.080) was also observed after adjusting for crossover.

Conclusion: A statistically significant OS benefit was observed in women with heavily pretreated, HER2-positive MBC treated with lapatinib in combination with trastuzumab compared with those treated with lapatinib alone. The actual survival benefit of the combination therapy may be underestimated due to the high frequency of crossover.

Source: SABCS.org

This data from the Sam Antonio Breast Cancer Symposium last month showed that heavily pre-treated patients including prior trastuzumab (Herceptin) who received a combination of two HER-2 inhibitors, trastuzumab and lapatinib (Tykerb) improved their survival by 4.5 months over lapatinib alone:

The EGF104900 study included 296 women and resulted in an overall survival rate of 56% in patients randomized to lapatinib (1,000mg/day) plus trastuzumab compared to 41% in those assigned to lapatinib (1,500mg/day) alone.

Presently, trastuzumab is approved for first treatment of HER-2 positive breast cancer and lapatinib is given in second line once Herceptin fails.  It is interesting that there wasn't a Herceptin only arm, only a lapatinib only arm, but then the patients had previously progressed on trastuzumab therapy.

Previous studies with Herceptin and anthracyclines have shown an increase in cardiotoxicity associated with mainly with doxorubicin.  There was no suggestion of a cardiac safety issue with the HER-2 combination therapy in this study.

Lapatinib and trastuzumab target HER-2 through different mechanisms, which may account for the apparent additive effect in combination.  Previous preclinical and animal studies have suggested synergistic benefits for the combination, including enhanced apoptosis, anti-proliferative effects and downregulation of survivin.

This is the first study to show a survival improvement for any anti-HER2 agent taken beyond first line therapy.  It validates the concept that trastuzumab is an important drug to maintain through disease progression beyond initial therapy in patients who have previously done well on combined chemotherapy and HER-2 regimens before developing disease progression.

#AACR Personalized therapy in lung cancer - part 3

After writing the first two posts in the series, I was much amused to see this tweet in my Twitter stream from one of buddies:

When you've been blogging on science, marketing, PR and cancer topics for several years you begin to wonder if it actually beneficial to anyone, so today's post is dedicated to Miguel in Barcelona for making me smile :-).  If you're on Twitter, please do follow him because he's a great guy and shares a lot of very interesting pharma related links.  Give him some Twitter love!

Today's topic is about a new generation flavanoid, ASA-404, from Novartis.  Of course, under FTC guidelines, I should disclose that as many of you know, I'm a former employee and have also done consulting work for the company, but not on this particular product.

ASA-404 is an interesting agent in phase III development.  It's a vascular disrupting agent (VDA) with a tubulin dependent mechanism of agent.  Unlike taxanes, which target the microtubulin in DNA, this agent is also part anti-angiogenic agent because it selectively disrupts the tumour vasculature with both direct and indirect effects.  In simple terms, I think of it as a kind of hybrid cross between an anti-angiogenic such as bevacizumab (Avastin) and a taxane such as paclitaxel or docetaxel.

Dr Mark McKeage presentation at the AACR lung cancer meeting was focused on the phase II that has been published to date, including a publication in the British Journal of Cancer (see bottom of article). 

The drug was well tolerated in phase I trials, achieving an MTD of 3700 mg/m².

In a phase II trial, paclitaxel and carboplatin (pc) therapy was used as the reference arm, and ASA-404 added to the standard chemotherapy in the other arm to determine if the agent added any extra benefit for newly diagnosed patients with non-small cell lung cancer (NSCLC) with either a squamous or non-squamous histology. They looked at 2 different doses of ASA-404 - 1200mg/m² was used in the randomised comparison with carbo-tax and 1800mg/m² with out the comparator arm but in combination as before. 36 patients were accrued into the reference pc arm, 37 in the lower dose ASA-404 arm and 31 in the higher dose ASA-404 arm.  This gave a total of 104 patients in the pooled phase II study.

Overall, similar rates of adverse events (AE's) were seen in the squamous and non-squamous patients, except for a slight increase in AE's related to blood/lymphatic effects.  No serious AE's associated with vascular effects of bleeding, hemorrhage or hemoptysis were seen.  There was an increase in hematologic toxicities (anemia, neutropenia and thrombocytopenia) but these were not significant and none rose above 20%.  There was no apparent increase in neutropenia related sepsis.

In terms of efficacy and median overall survival, McKey reported:

PCA  vs. PC

14.0 vs. 8.8 mos for 1200mg/m²

14.9                  for 1800mg/m²

Thus we can clearly see that adding ASA-404 to standard carboplatin-paclitaxel therapy improved median overall in frontline NSCLC by 5 months.

Recently, the FDA has approved several therapies in NSCLC in different histologies, due to either issues with side effects (bevacizumab and bleeding issues) or lack of efficacy (pemetrexed), while others such as erlotinib have been shown to be particularly effective in non-smoking female asians with an adenocarcinoma histology, although the approval is not based on histology.

Let's take a look at the ASA-404 histology data:

                Squamous:                Non-Squamous:          Overall:               

                PCA         PC             PCA         PC              PCA          PC

ORR (%)    40.0        14.3          31.7        25.0           34.4          22.2

One third of the patients had a squamous histology, but experienced no bleeding issues seen with VEGF agents.

While the results are higher for those with a squamous histology, there was also a trend towards higher efficacy in the non-squamous patients.  The positive results provided support and evidence for the drug's effectiveness and rationale for beginning the phase III triala, ATTRACT-1 in first line and ATTRACT-2 in second line NSCLC without restriction on histology.

To put the 5 months improvement in median OS with ASA-404 in context, I checked out the PI for other therapies.  Bevacizumab was approved on the basis of 12.3 months vs. 10.3 months, ie a 2 month improvement, while pemetrexed was approved on the basis of non-inferiority when comparing pemetrexed plus cisplatin to gemcitabine plus cisplatin (ie 10.3 months of overall survival in each arm).

The front-line trial has completed accrual and is ongoing, but the ATTRACT-2 trial for patients who have had prior chemotherapy is still enrolling.  You can find it here: ATTRACT-2.

Of course, these are early days yet and positive phase II data does not always translate to phase III success, but they are a hopeful sign of good things to come.  If the data are repeated, it will be good news for patients with NSCLC.  

McKeage, M., Von Pawel, J., Reck, M., Jameson, M., Rosenthal, M., Sullivan, R., Gibbs, D., Mainwaring, P., Serke, M., Lafitte, J., Chouaid, C., Freitag, L., & Quoix, E. (2008). Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer British Journal of Cancer, 99 (12), 2006-2012 DOI: 10.1038/sj.bjc.6604808

ASH09 meeting report: chronic lymphocytic leukemia (CLL)

At the American Society of Clinical Oncology (ASCO) meeting earlier this year, we learned that rituximab added to standard fludarabine plus cyclophosphamide improved overall survival in patients with chronic lymphocytic leukemia (CLL), even in elderly patients of 70 years old.

Six months later, one of the highlights of the American Society of Hematology (ASH) meeting held in a rather cold, wet and windy New Orleans, was updated data presented by the same German CLL Study Group (GCLLSG) confirming the combination of fludarabine, cyclophosphamide and rituximab (FCR) as the current front-line standard of care in chronic lymphocytic leukemia (CLL).

Increased overall survival for CLL patients receiving the combination of fludarabine, cyclophosphamide and rituximab (FCR)

Michael Hallek of the University of Cologne reviewed updated results from the GCLLSG CLL8 study, in which FCR was compared against the combination of fludarabine and cyclophosphamide (FC).   At ASH in 2008, data was presented showing FCR to be superior to FC in terms of response rate and progression free survival (PFS).  This year at ASH, Hallek presented updated data showing that patients in the FCR study arm still had a statistically significant higher overall survival (OS) compared to those receiving FC.

The published abstract shows the OS rate at 37.7 mo was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01).  At the conference, Hallek presented data showing an 87.2% OS in the FCR arm versus 82.5% in the FC arm (P=0.012) at three years for those who achieve a complete response.  There is a clear survival benefit from treatment with FCR as compared to FC, particularly in those patients who have Binet A or B stage disease.

GLLSG phase II trial combining bendamustine with rituximab (BR) in first-line therapy of advanced CLL

The data for this combination suggested that it appears to be safe and effective.  Response rates for BR were similar to those obtained with FCR. However, there were significantly less neutropenias with BR than would be expected with FCR.  This has led the GCLLSG to initiate a protocol (CLL10) comparing FCR against BR in front-line CLL.  The results from this study will show whether the new standard of care in front-line CLL should become bendamustine in combination with rituximab in the future.

In the poster sessions, a number of interesting ones jumped out at me that may be worth looking at in the clinic for the future. 

Lenalidomide (Revlimid) has shown early promise in CLL in the CLL5 AGMT study.  This was a phase I/II study that looked at combining fludarabine with rituximab with escalating doses of lenalidomide.  Although only a small number of evaluable patients (n=6) were available, all 6 patients responded and 3 achieved a complete response.  40% of the patients were dose limited due to skin and vascular toxicities so the protocol was amended to include thrombo-prophylaxis and delayed start of prophylaxis against pneumocystis.  It is too early to tell whether this regimen will reach the prime time but the risk-benefit trade-off may turn out to an issue.

An interesting compound that I have been following for a little while is Trubion's TRU-016, which is a small modular immunopharmaceutical protein (SMIP) being tested in relapsed and rferactory CLL.  It targetes CD37, expressed predominantly on B-cells.  In a phase I study, interim results were presented from CLL patients (n=33), demonstrating a manageable safety profile despite grade 3/4 myelosuppression.  The DLT and MTD had not yet been reached.  Reductions in peripheral lymphocytosis were observed, together with some objective responses in the higher dose cohorts.  hopefully, further data will be available on this novel agent at ASCO in the summer.

Overall, with new monoclonal antibodies in development and the recent approval of ofatumumuab in refractory CLL, it is likely there will be interesting new data and further changes to the standard of care over the next two or three years.  Biomarkers are also slowly emerging in CLL research, and while it is early days yet, it is good to see some attention finally being given some importance in this disease both from a predictive and a prognostic standpoint. 

We can expect some compelling new data in the treatment of CLL, hopefully by ASCO in June 2010. 

Watch this space!

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What's new at AACR on molecular targeting and biomarkers?

At the AACR molecular targeting meeting in Boston, several key presentations have focused on lessons learned from previous kinase studies and using them to help guide future developments.

Charles Sawyers from MSKCC put together a particularly nice presentation looking at the lessons learned from CML and prostate cancer.  He noted that 75% of CML patients respond to imatinib and attain a complete cytogenetic response, with only a small number, 20% relapsing by 5 years. The question is why and what can be done to change this? 

Firstly, the natural course of the disease predicates that mutations will occur as the cancer finds ways to re-activate BCR-ABL in order for the leukemic cells to survive.  New kinase therapies in development now target not only BCR-ABL, but also the other mutations that evolve with time.  Both dasatinib and nilotinib not only have different conformations than imatinib, but also inhibit most of the other mutations that have been recognised to date.  However, neither targets the T315i mutation, but fortunately other compounds in R&D including AP24534, omacetaxine and others do.

Neil Shah from UCLA also made similar points in his talk and emphasised that as more therapies become available for the treatment of CML, so the ability to personalise therapy for each patient based on their particular mutation analysis now exists by choosing a kinase that is sensitive to the mutations arising. This is especially so in CML with a growing number of drugs available either commercially or through clinical trials.  This is great news for patients, because this cancer was once a death sentence but is now a chronic treatable disease that can be kept under control with targeted therapies.

Hilary Calvert from University College London discussed PARP inhibitors, which target the BRCA1 and BRCA2 mutations and also potentiate the effect of some chemotherapy drugs in vivo such as temozolomide.  He covered a number of these interesting agents in development, including olaparib and AG014699, and how tumour shrinkage occurs but drug resistance ultimately ensues due to intragenic deletion activity of BRCA2.  Despite platinum resistance developing in ovarian cancer, however, responses to olaparib have still been seen, so much work still needs to be done in this area to figure out what resistance mechanisms are in play and what strategies can be used to overcome them.  BRCA1 and BRCA2 mutations occur in both breast and ovarian cancers, so these cancers have been the primary targets for the PARP class of drug initially and represent an interesting new approach.

Kapil Bhalla from the Georgia Cancer Center described a novel new approach in breast cancer that made me stop and think.  The cancer cell is always looking for ways to survive and find alternative escape routes to achieve this despite chemotherapeutic drugs targeting it's death through apoptosis. They forced the cancer cell in the mammary fat pad of mice into autophagy, and then pulled the rug away by adding an autophagy inhibitor.  This was achieved by targeting heat shock response protein with panobinostat combined with an autophagy inhibitor, thus allowing apoptosis to continue instead of being inhibited. 

In this novel approach, Dr Bhalla described it succintly as,

"The panobinostat accentuates stress, causes autophagy and sets up the cell to be eliminated by autophagy inhibitors."

It will be interesting to see how this approach translates into humans and if it works, we may see more autophagy inhibitors developed that are tumour specific.

AACR have launched a series of podcasts from the meeting, including one with Charles Sawyers, which you can find here and download to listen to on your MP3 player or computer.  They make for very interesting listening, especially if you were unable to attend the meeting in person.

Continuous learning in Pharma marketing

Many of us in the industry attend annual meetings in our specialty area thus the regular conference season is full of events such as the American Society of Clinical Oncology (ASCO), American Association of Cancer Research (AACR), American Society of Hematology (ASH), American Society of Therapeutic Radiology and Oncology (ASTRO), San Antonio Breast Cancer Symposium (SABCS) etc for just a few of the big American meetings in oncology, to say nothing of their European counterparts or similar meetings in other disease states. 

It's no wonder that with thousands attending these meetings, people (health care professionals and consultants alike!) become overwhelmed by the sheer volume of data and information available.

One of the things I really enjoy though, is the smaller, more intimate meetings either focused on the local needs or around a more specific topic such as an individual cancer (World Lung Congress, Miami Breast Cancer meeting and the International Society for Gastrointestinal Oncology); all are excellent meetings for getting a snapshot around more specialist areas, for example.

However, my favourite little conference outside of ASH, ASCO and AACR is the New York Chemotherapy Foundation Symposium held annually in November at the Marriott Marquis in Times Square.  For those interested, it was started by Dr Ezra Greenspan:

"Dr. Greenspan was the pioneering oncologist who founded The Chemotherapy Foundation in 1968 and the Chemotherapy Foundation Symposium in 1972 in order to bring the new developments in cancer therapeutics to practicing oncologists in the years ahead. His goal was the control and eventual cure of cancer."

Image by Michael McDonough via Flickr

From my perspective, the meeting offers lots of little snapshots and vignettes on the cutting edge data that will impact community medical oncology either now or in the near future.  They invite a lot of the experts running the trials from around the country, so you get a great sense of what's happening in areas you may be less familiar with as the program shows.  In the past, some of the keynote speeches have also been great fun and quite irreverent, which also means you tend to remember the important data better.

The Greenspan meeting is being held at Times Square in NY next week, so I'll be live tweeting key snippets from the event from Tues to Friday under the hashtag #NYCT. 

If anyone is either at the meeting or in NY and wants to meetup for coffee, lunch or dinner for some social networking, do let me know.  You can tweet me @maverickNY and I'll be sure to return your shout out.

Novel use of web 2.0 in Pharma clinical trials

This week has been insanely busy, especially with the 4 day work week, so I haven't had as much time as usual to post some detailed blogs.

Here's something interesting I came across this week, which may provide some food for thought.

One of the challenges of taking drugs to market faster is more rapid enrollment of clinical trials, hence cutting down the time to get the registration trials ready for the FDA or EMEA submission.  One small biotechnology company came up with a novel approach - using the web to effectively provide useful information based on where the sites are and also key words such as TKI or CML resistant etc.  I found the site by searching on the T315i mutation, which is what doctors and patients might also search for if they have CML with that aberration.  

This is what the site looks like:

ChemGenex is an Australian based company, with offices in California, who submitted an NDA this week:

"For the treatment of patients with chronic myeloid leukemia (CML) who have failed treatment with imatinib and who have developed the Bcr-Abl T315I mutation. Imatinib, a tyrosine kinase inhibitor (TKI), is the first-line standard of care for patients with CML."

What's interesting about their site, http://www.tkiresistantcml.com is that when you look at the trials, you can download a map of either of the trials.  The map provides information on where the centres are, who the PI's are and contact details (email and phone numbers) for physicians to call if they have suitable patients eligible for the study:

As you roll over your cursor on the site or the PDF download (see example here), you get a pop up box with the relevant contact information.  Very neat.

These are user friendly ways of communicating relevant information and embracing and extending the knowledge to patients and physicians in a searchable way.

It's good to see companies trying new approaches like this, rather than just sticking the study in the clinicaltrials.gov database and hoping for the best.

New chemotherapy regimen for pediatric NHL

A new study published in the American Journal of Hematology Oncology by the Children's Oncology Group demonstrated that the ABVE-PC regimen provided high efficacy and reduced the cumulative doses of chemotherapy and radiation:

"Between 1997 and 2001, 216 eligible patients younger than 22 years with intermediate- or high-risk HL were treated with ABVE-PC. The median time from the beginning of the first cycle to the end of the third cycle was approximately 8.7 weeks, and time to completion of the fifth cycle was approximately 16 weeks. Rapid early response was documented in 63% of patients. Dose densities were greater than those of the most commonly used regimens, but cumulative doses were significantly lower, especially in the rapid responders."

For years, patients have been treated with the standard of care, ie MOPP or ABVD regimens, but while these approaches lead to excellent survival rates, they often result in long-term effects from toxicity, including infertility, second malignancy, and cardiopulmonary toxicity.    Doctors hope to be able to cure the cancer while reducing the risk of long term effects on patients with the new 6 drug combination, although it will take a while before the true effects are known.  

This new approach consists of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide and while not a walk in the park, as the first four chemotherapies are fairly toxic themselves, it may represent a potential improvement for children with NHL over existing options.

Schwartz, C., Constine, L., Villaluna, D., London, W., Hutchison, R., Sposto, R., Lipshultz, S., Turner, C., deAlarcon, P., & Chauvenet, A. (2009). A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate and high risk Hodgkin lymphoma: the results of P9425 from the Children's Oncology Group Blood DOI: 10.1182/blood-2008-10-184143

Sally Church

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http://www.pharmastrategyblog.com

Twitter: maverickNY Skype: sallychurch

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Update on therapies for malignant melanoma

Someone asked me whether it would be possible to have an update on new therapeutics in melanoma recently and I'm pleased to say there were some interesting data in this difficult to treat cancer at the recent ASCO meeting in Orlando.

Melanona is an immune type cancer but the long held theory that various immune type therapies such as vaccines would work effectively has not yielded significant results, mainly because stimulating the body's immune response to attack the cancer cells has not led to very durable results.  The bedrock of treatment has therefore remained as a stark choice between DTIC, IL-2 or interferon therapy, all of which are severely limited by side effects.

At ASCO this year, a number of new approaches were tried and tested.  These included aflibercept (VEGF-Trap), an anti-angiogenic VEGF inhibitor, intetumumab (CNTO-95), an alpha integrin, ADI-PEG 20 which affects cell metabolism and arginine depletion, sagilipone (ZK-EPO), which affects microtubulin function (similar to ixabepilone), CRO11-vcMMAE, another microtubulin compound and ipilimumab, BMS's CTLA-4 antibody.  This variety of new therapeutics raises a number of interesting questions, including whether the targets are clinically relevant in melanoma and were patients selected appropriately for the studies.

This blog post will focus on the data for VEGF-Trap, intetumumab and ipilumumab.

The VEGF-Trap study (Abstract #9028) looked at patients with stage III or IV melanoma with no prior chemotherapy and no brain mets.  VEGF-Trap is a fusion protein combining the Fc portion of human IgG1 with the principal extracellular ligand binding domains of human VEGFR1 and 2, leading to angiogenesis inhibition.  The phase II study looked at response rate and 4 month PFS.  Aflibercept was given 4mg/kg iv every 2 weeks for 8 weeks.  The stated goal of the trial was to improve median PFS from 2.3 months to 4 months, which corresponds to a PFS rate from 30% to 50%.

41 patients were enrolled and the therapy was shown to be well tolerated with predictable class adverse events including hypertension, GI bleeding and proteinuria.  1 response was seen and a further 20 patients had stable disease.  Early results suggest that a PFS of 6 months, if so the study endpoint will be met.  This is one of many trials exploring anti-angiogenesis therapy in patients with melanoma, either as a single agent or in combination with chemotherapy.

The CNTO 95 study (abstract #9029) looked at a phase II study alone or in combination with dacarbazine in patients with stage IV melanoma with two different dosage arms per treatment.  129 patients were enrolled and the main adverse events seen were cytopenias related to DTIC and uveitis related to intetumumab.

Intetumumab alone (either dose) resulted in a PFS of 1.4 months, DTIC alone was 1.8 months, while intetumumab plus DTIC was 2.5 months.  Overall survival was 9.8, 7.6, 14.0 and 10.9 months respectively.  This study was complicated by the sample size not based on statistical power considerations so it is difficult to draw any conclusions between the four study arms and there is little rational for the combination.  Although the target may be relevant, trials to date have shown little clinical activity.

The most interesting data was on ipiliumumab (abstract #9033), which looked at the effect of the agent on 18 and 24 month survival from 3 phase II trials dosed at 10mg/kg every 3 weeks (plus maintenance therapy Q12W from week 24 in appropriate patients) in advanced melanoma, where survival outcomes are usually poor.  Ipilumumab is a fully humanised monoclonal antibody that targets T-lymphocyte antigen 4 (CTLA-4).  The 3 studies summarised were CA184-008, CA184-022, CA184-007.

The results clearly showed that:

- 12 month survival rates were >47%
- 18 month survival rates were >34%
- 24 month survival rates were >30%

For previously treated patients, 24 month survival rates ranged from 24% to 33%.

Long term survivors included patients with progressive disease according to WHO criteria.

These results are promising but caution must be extended because a significant number of patients were lost to follow-up, which may reduce the reliability of the results.  Ongoing biomarker studies are looking at predicting which patients are most likely to benefit from ipilumumab therapy. 

What did we learn from these trials?  Well, there is an urgent need to define optimal endpoints for melanoma clinical trials in terms of response rate, PFS, OS and survival at 12 months.  It is interesting that over the past 10 years the majority of abstracts have hyped the results in this disease as 'promising' or 'clinically active' regimens and yet very little in the way of new therapies have actually been approved by the FDA.  Based on these data, I suspect it will still be a little while before we see some solid phase III data in malignant melanoma.

Clinical trial results show Denosumab is superior to Zometa in breast cancer patients with bone metastases

Image via Wikipedia

Amgen's recent announcement of phase III trial data showing that it's monoclonal antibody, denosumab was superior to Novartis' Zometa (zoledronic acid) for the treatment of breast cancer patients with bone mestastases is further news that scientifically driven drug development can yield exciting results. 

Denosumab is in essence a targeted therapy like Gleevec, Avastin or Herceptin.  It's development came about from basic research that discovered the cellular control of bone remodelling and regulation of bone density is reglated by the RANK Ligand pathway.

RANK Ligand is a TNF famly member, a protein that is expressed on the sufrace of marrow, stromal cells and osteoblasts (the cells responsible for bone formation). When RANK-L binds with its receptor RANK it stimulates the activity of osteoclasts (cells responsible for bone resorption).  In the body, RANK-L production is naturally regulated by the protein Osteoprotegerin (OPG), which binds with RANK-L thereby preventing it from binding to its receptor, RANK.  When there is insufficient OPG, or too much RANK-L produced, excess bone loss occurs.   This occurs in post-menopausal women or in cancer related bone loss.

Denosumab acts by attaching itself to RANK-L, thereby inhibiting its action. Deprived of RANK-L, osteoclasts cannot form, function or survive.  The result is less bone destruction and bone loss.  Understanding the RANK Ligand pathway has been a breakthrough step in understanding bone biology.

Many cancer patients end up with bone metastases that not only causes pain, but also bone destruction.  Roodman, in a 2004 New England Journal article, proposed the "vicious cycle" hypothesis to explain this: Tumor cells produce parathyroid hormone-related peptide (PTHrP), which stimulates osteoblasts to produce RANK ligand leading to less production (downregulation) of osteoprotegerin (OPG), thereby stimulating osteoclasts to resorb more bone.  At the same time, production of PTHrP promotes tumor growth directly.  Therefore, it should come as no surprise that denosumab would be effective in cancer patients with bone mets and skeletal related events.

What does the future hold for denosumab?  In the postmenopausal osteoporosis market, a once or twice yearly injection is extremely attractive given its ease of use. Compliance is a real issue with bisphosphates such as alendronate or risedronate where a daily pill must be taken.  Many primary care physicians are not set-up to administer an infusion, which is what Novartis' once a year osteoporosis treatment, Reclast requires. 

However, despite impressive clinical data, Amgen does not yet have a home run.  It lacks a large sales force and infrastructure to sell to primary care physicians. Also with generic fosamax (alendronate) available, the cost/benefit trade off is going to be a key factor in uptake.  The cost of denosumab will need to be carefully considered for Amgen to enter this competitive market.  The FDA advisory board meets on August 13 to discuss Amgen's BLA application and consider whether to recommend approval for the treatment and prevention of osteoporosis, and treatment of bone loss in patients undergoing hormone ablation for prostrate and breast cancer.  Given the positive data from the phase III pivotal studies, a positive recommendation is expected with approval by the FDA expected in October. 

For cancer patients, denosumab could become the gold-standard for treatment of bone metastases given its superiority over Novartis' Zometa.  For oncologists, the fact that denosumab only requires an injection while Zometa requires an infusion is less of an issue.  The key to success for oncology drugs is based solely on the data. If the positive results continue, Amgen are likely to take market share from Zometa once approval for the treatment of bone metastases is obtained in 2010 or 2011.

So, my take on this is that denosumab is a real winner for Amgen.  Whether it will capture the market for postmenopausal osteoporosis remains to be seen, but it is an exciting new drug that will benefit cancer patients.  Further data on denosumab can be expected from the September meeting of the American Society of Bone and Mineral Research (ASBMR) in Denver.

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Twitter is a great source for Pharma news alerts: Update on Rezonic

This morning I was browsing through my lifestream, in particular checking out the Pharma and Biotechnology news on Twitter to find out what's significant today, when a tweet from Scrip News made me sit up and pay attention:

Credit for the scoop though, should go to CNBC's Mike Huckman, who broke the news last night:

Whoa, FDA has cancelled the GI meeting to review GSK's Rezonic data?  Wow.  Rezonic, also known as casopitant, is being developed as an NK-1 inhibitor for post-operative nausea and vomiting (PONV) and chemotherapy induced nausea and vomiting (CINV).  It would be the second to market in this class of drugs after Merck's Emend (aprepitant), who I should disclose, are one of my Pharma clients. 

A cancelled FDA meeting usually means significant delays owing to the need for more supporting data.  I checked out the global GSK website, nothing.  Checked out the US website and bingo:

"GlaxoSmithKline (NYSE: GSK) confirmed today that the May 20 FDA Gastrointestinal Advisory Committee meeting for REZONIC® (casopitant) has been cancelled.

GSK is performing additional analysis and is engaging with the FDA to determine appropriate next steps.

The application filed for REZONIC seeks approval for the prevention of chemotherapy-induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV)."

Analysis:

All in all, this is good news for Merck and bad news for GSK: delays in time to market can have a significant impact for both brands.  The timing is also awkward - at the end of the month it's the annual ASCO meeting, so handling negative PR in the form of delays will be all the more acute and embarrassing.  I'm not sure what 'additional analysis' means exactly but that doesn't inspire me with confidence.  Either a drug works effectively or it doesn't.  We'll have to wiat for more information and see what the next steps are.

New developments in chronic lymphocytic leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is a malignant type of cancer that involves white blood cells, or lymphocytes, in the bone marrow and then invades the blood. 

Image via Wikipedia

Approximately 15,000 people are diagnosed with the disease annually in the USA and about 5,000 will die from the disease.  CLL is distinguished from CML, which involves myeloid white blood cells instead of lymphocytes.  In both cases, one of the defining symptoms of the disease is an excess of white blood cells, either of the lymphocytes or myeloid cells.  CLL can either be an excess of T-cell or B-cell lymphocytes, although 90-95% if cases involve B-cells.

Standard treatments for CLL usually includes chemotherapy such as fludarabine, cladribine, chlorumbucil, bendamustine, cyclophosphamide, doxorubicin or vincristine. 

Several of these can be used in combination with monoclonal antibody therapy such as rituximab (Rituxan) or alemtuzumab (Campath), for example, sequential therapy using fludarabine, high-dose cyclophosphamide and rituximab.  Alemtuzumab is often reserved for patients who have not responded to other treatments.

At the recent American Society of Hematology (ASH) meeting, a number of therapies emerged as potential new agents for the treatment of CLL. 

One of these, fostamatinib, was presented in the plenary session. Friedberg described how inhibition of SYK by fostamatinib (R788, Rigel), an oral inhibitor, was well tolerated and demonstrated significant clinical activity.  Trials are also ongoing in other B-cell related diseases such as NHL and rheumatoid arthritis.  Data from the latter are expected in August/September this year and the company will seek a development partner.

Another interesting compound is ofatumumab (Arzerra), a humanised CD20 monoclonal antibody developed by Genmab and GSK similar to Genentech's rituximab.  Phase III results are expected this year in refractory disease (to fludarabine) and front-line CLL.  It is a biosimilar, but interestingly, Genmab prefer to describe it as a 'bio-better' i.e. greater potential efficacy and better safety/immunogenicity profile.  This is a bit of fluff-puff though, because the golden rule of marketing is be first to market or be better, so one would hope that follow-on drugs to market would offer some meaningful differentiation rather than just being a me-too, otherwise why bother?

A number of marketed compounds are also completing trials in CLL in a bid to expand their franchise.  These include lenalidomide (Revlimid) from Celgene, and rituximab (Rituxan) from Genentech.  Lenalidomide data in CLL was presented at ASH.   Most of the CLL patients were elderly, i.e. older than 70 at diagnosis.  The protocol looked at continuous therapy with a starting dose of 5 mg, followed by slow dose escalation.  Results showed an overall response rate of 54%, 40% had stable disease and 6% progressed on therapy.  What was interesting was that 47% achieved a complete response (CR) and 38% a partial response (PR).  Grade 3/4 adverse events included neutropenia/thrombopenia (26%). Infectious complications were seen in 3 patients.  Overall, it looks as though Revlimid may be a reasonable well tolerated and effective drug in this patient population.

Rituximab has proven to be a very effective therapy for NHL in combination with standard chemotherapy (R-CHOP), so there was little surprise that data were positive in front-line and refractory CLL in combination with FC compared to FC alone.  Although there appeared to be a slight increase in adverse events such as febrile neutropenia, infections were manageable and similar in both arms.

There are also a number of compounds in development for CLL that are not yet approved for any indication and most are still far too early in development (phase I or II) to determine whether they will be useful therapies yet or not.  These include ABT-263 (Abbott), cenersen (Eleos), alvocidib (sanof-aventis), ALXN-6000 (Alexion), atacicept (EMD Serono), CAL-101 (Calistoga), CAT-8015 (MedImmune), cell permeation (MaxCyte), CNF-2024 (Biogen Idec), dacetuzumab (Genentech), forodosine (BioCryst), GCS-100 (Prospect), GS-9219 (Gilead), ISF35 (Memgen), lumiliximab (Biogen Idec), MDX-1342 (Medarex), milatuzumab (Immunomedics), obatoclax (Gemin X Biotechnologies), polyphenon E (Polyphenon), PRO-131921 (Genentech), SPC-2996 (Santaris), TRU-016 (Trubion) and motexafin gadolinium (Pharmacyclics). 

Many of these small biotechs are, however, struggling to raise capital in the current economic climate and may struggle to develop the agents effectively unless they re-focus their efforts on the lead candidate.

Perhaps the most interesting compound in development is Allos Therapeutics pralatrexate, an anti-folate, which is expected to be filed for PTCL later this year under the FDA's Fast Track mechanism and is also potentially being developed in CTCL, NHL, NSCLC and transitory cell carcinoma of the urinary tract.  Succesful data in NHL may also suggest a role in CLL, since therapies that are effective in one often work in the other tumour type too because of the role of B-cells and T-cells in the disease.

Cancer cells - a sense of awe and wonder

One of the amazing things about science and biology is coming across amazing photos and microscopic shots like these, before and after treatment of lung cancer from the Government website Ocean Explorer. 

For a moment I was wondering what on earth human cancer cells were doing on an oceanic site, then I realised that they discuss a collection of sponges and sea fauna, which may contain the active ingredients for the development of various cancer therapies.  The active ingredient is isolated and often re-engineered in the laboratory to create a synthetic version that is more viable for the long term health of the planet.

Here's one example using the red sponge, from which lasonolide was isolated in 1999 and is now in development as a potential anti-cancer cytotoxic agent to induce apoptosis (programmed cell death).  By 2004, five potential lasonolide compounds had been isolated.  Last year, some early preclinical results were published on cell adhesion by the NIH - cancer cells need to adhere to enable the tumour mass to develop via angiogenesis.

Efforts to develop a synthetic version of the molecule are currently underway.  One article I came across referred to the potent anti-neoplastic activity of the compound in pancreatic cells lines, which would be a good tumour type to test it in given the high unmet need and poor survival reported with existing therapies either with single agent gemcitabine or in combination with other chemotherapy agents.

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Lipid technology and cancer therapy for GBM

Continuing the recent theme of new and interesting technologies in cancer therapeutics, today’s blog post looks at neolipid technology and examines how a novel Trojan horse strategy might make existing chemotherapy more efficient and effective.

Tumor cells need to consume large amounts of fat to sustain their rapid growth (angiogenesis).  Neolipid technology takes advantage of this by entrapping anti-cancer agents inside liposomes, which are microscopic membrane-like structures created from lipids (fats).  The tumour then eats the liposome and absorbs the anti-cancer agent at the same time.

One company that is looking at this liposome technology is NeoPharm, a small biotechnology company based in Illinois, who are developing a NeoLipid drug delivery system.  Their lead compound in R&D, cintredekin besudotox, is about to enter phase III trials for glioblastoma multiforme (GBM).  While GBM is one of the most common types of malignant brain cancers, it is also one of the most aggressive.  It typically spreads and grows tentacle-like within normal brain tissue, often damaging adjacent tissues as it grows uncontrollably.  The NCI described the agent thus:

"... composed of interleukin-13 (IL13), a pleiotropic immunoregulatory cytokine, linked to a mutated form of pseudomonas exotoxin A; this agent targets and kills tumor cells that express the IL13 receptor (IL13R). The IL13 moiety attaches to the IL13R on the tumor cell membrane, facilitating the entry of the exotoxin. The exotoxin moiety induces caspase-mediated apoptosis of tumor cells via a mechanism involving mitochondrial damage; it also catalyzes the transfer of ADP ribose from nicotinamide adenine dinucleotide (NAD) to elongation factor-2 in eukaryotic cells, thereby inactivating elongation factor 2 and inhibiting protein synthesis."

Over the last 20 years there has been very little improvement in treatment success in GBM and patients often survive only a year or so, despite aggressive surgery, radiation and chemotherapy.  The biggest barrier to treatment is targeting the cancer cells without damaging the normal healthy brain cells.  GBM is also more resistant to treatment than most cancers because few drugs are able to successfully cross the blood-brain barrier. 

How is NeoPharm’s compound cintredekin besudotox different from others that have failed in R&D?  Firstly, it is delivered by micro-infusion into the brain rather than via traditional intravenous infusion, which limits its toxicities elsewhere in the body.  Secondly, it is hoped that the liposomes will be absorbed by the fat hungry tumour, thereby enabling more chemotherapy to reach the intended target where it is most needed.  Thirdly, it targets IL13, which is found on the surface of some cancers.  It will be interesting to see if inhibiting IL13 is critical to the survival of the brain tumour.

This combination of regional and molecular targeting is both novel and fascinating; the results for the ongoing phase III trial will determine whether the scientific approach is a valid one or not.

A genetic cause for neutropenia associated with cancer chemotherapy?

A fascinating article in the New England Journal of Medicine caught my eye this morning basically saying that a genetic cause has been found for severe congenital neutropenia. The German study found that severe congenital neutropenia can arise from mutations in the gene for glucose-6-phosphatase. Studies in five patients from two interrelated families of Middle Eastern descent revealed that all were heterozygous for the same mutation in the gene.

The researchers then looked for it in 104 other patients with severe congenital neutropenia with previously unknown genetic origins. Seven of those patients had distinct mutations affecting both alleles. Several different mutations were found.  None of the patients had mutations in other genes known to cause severe congenital neutropenia. The condition is seen in about one in 200,000 births and involves the lack of functioning neutrophils. 

Depending on the gene responsible, other abnormalities may be present as well, including neurological and cardiovascular defects.  In some cases, only neutrophil development is affected.  The gene encodes part of the catalytic region of the glucose-6-phosphatase enzyme, which is involved in multiple glucose metabolism pathways.

Why does this matter?

Well, one of the complications associated with some chemotherapy regimens or drugs is severe neutropenia where the white blood cell count drops drastically below normal and weakens the patient's ability to recover from the treatment because they cannot fight infections. Standard treatment for cancer related symptoms is often to use a growth stimulating factor called G-CSF such as Neulasta (Amgen). Other conditions may also cause a low white blood count such as Lupus, Malaria, Hepatitis viruses, Rheumatoid Arthritis, Aplastic Anemia, Myelodysplastic Syndromes, Parvovirus and others.

Altogether, defects in six separate genes with a variety of functions, are now known to cause neutropenia and explains why some patients suffer from it and others do not.  In addition to the glucose metabolism enzyme encoded by G6PC3, the other mutations are related to mitochondrial function, cytoskeleton integrity, and G-CSF signaling.  One gene encodes a transcription factor of uncertain function, and still another is for the multifunctional neutrophil elastase enzyme. 

What does this all mean?

Well, if you have a condition which is known to sometimes cause low counts and you have the genetic defect, then those patients would most likely benefit from upfront G-CSF treatment to protect against the potential count drop.  This would ensure the patient has a better chance of doing well and also target the costly medication where it is most likely to be needed. 

That's a win-win solution for everyone.

New simple strategies for enhancing cancer chemotherapy treatment

Patients undergoing treatment for cancer with chemotherapy may often not receive the optimal drug combination or dosing for a number of reasons.  These include debilitating side effects, high interstitial fluid pressure, leaky vessels or the development of tumour resistance. 

In recent years, researchers have started to look at novel ways of making treatment more effective.  On such way is to change the formulation, develop more targeted agents that specifically inhibit the abnormal protein or better sequencing of available therapies.  Some of these have had mixed success as the stories of Gleevec, Tarceva, Iressa and Avastin have shown, albeit in some, but not all patients.

Image via WikipediaLung cancer, or more specifically, non-small cell lung cancer (NSCLC), which affects 80% of lung cases, has a very low response to chemotherapy with only 20% typically experiencing tumour shrinkage and an survival rate on average of 10-16%.  New approaches are desperately needed in this disease as well as basic research underpining greater tumour specificity.  At present, standard chemotherapies used in NSCLC target not only the lung cancer cells but also normal cells, thereby increasing the burden of drug toxicity and reducing the chances of overall success.

An interesting idea that has just been investigated by Taiwanese researchers in NSCLC is the use of a novel peptide to overcome the therapeutic effectiveness of drug delivery:

"We isolated a novel peptide ligand from a phage-displayed peptide library that bound to non-small cell lung cancer (NSCLC) cell lines. The targeting phage bound to several NSCLC cell lines but not to normal cells."

This interesting and specific approach was tested in mice and led to a 5-7 fold increase in the drug accumulation inside the carcinoma.  This should lead to greater chance of apoptosis (cell death) of the cancer cells and thus improved tumour shrinkage.  The authors concluded that:

"The current study suggests that this tumor-specific peptide may be used to create chemotherapies specifically targeting tumor cells in the treatment of NSCLC and to design targeted gene transfer vectors or it may be used one in the diagnosis of this malignancy."

Although the idea is an early one, we may soon see the approach used with existing chemotherapies inclinical trials in the near future.  While there is no guarantee that the mice results will translate to humans, it is certainly an idea worth trying.

 

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