Pharma Strategy Blog

BioSante announce positive data from GVAX leukemia vaccine in CML

This morning the newswires (HT Mike Huckman) are full of the BioSante (formerly Cell Genesys) news on their leukemia vaccine, GVAX, which is being tested to see whether it is a viable approach for eradication of minimal residual disease. Accordingly, BioSante announced:

"Positive results of a human clinical study that show that its GVAX Leukemia vaccine may be able to reduce or eliminate the last remaining cancer cells in some chronic myeloid leukemia (CML) patients taking the drug Gleevec (imatinib mesylate). All patients enrolled in the trial used Gleevec for at least one year and still had cancer cells present. The study was conducted by researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, led by Hyam Levitsky, M.D., professor of oncology, medicine and urology at the Cancer Center. The research was funded by the National Institutes of Health."

Currently standard of care for CML is daily treatment with an oral tyrosine kinase inhibitor (TKI), imatinib (Gleevec), with the option of two second generation TKI's nilotinib (Tasigna) and dasatinib (Sprycel) being available if the imatinib fails.  All three of these drugs are effective at inhibiting the enzyme associated with the gene BCR-ABL, which occurs in every CML patient and essentially shut off production of the excess white blood cells so that the cells stop growing and eventually die.

There are various degrees of response with TKIs and at the American Society of Hematology meeting in December, Tim Hughes from Adelaide presented the concept of a safe haven as you can see from the chart below:

Source: Dr Tim Hughes, Adelaide, Australia

Obviously, the deeper the response, the more likely a patient would attain a major molecular response (MMR) and provide a safe haven from treatment relapse.

The important question then becomes one of how low should one go in order to 

• Optimise treatment response and 
• Provide enough protection without increasing side effects?

Going back to the quote at the top of the post about GVAX, we can see that the researchers goal was to eliminate minimal residual disease (MRD) and kill all detectable cancer cells below what is currently possible with TKI therapy.  

In the article published in Cancer Clinical Research (free PDF download courtesy of AACR), it seems that according to the researchers

"Thirteen patients had a progressive decline in disease burden, 8 of whom had increasing disease burden before vaccination. Twelve patients achieved their lowest tumor burden measurements to date following vaccine, including seven subjects who became PCR-undetectable."

Now while this is very good news to hear that it can be accomplished, the numbers are very small and we don't have any data whatsoever yet to prove that achieving the nirvana of MMR is actually necessary for the majority of CML patients. None, nada, zilch.  We also do not have any idea from the article how durable the vaccine results will be yet as there may be an attenuation of response over time.

We do know from the IRIS updates that newly diagnosed people with CML now have a much longer life expectancy of around 7+ years on average when treated with imatinib.  Stem cell transplants are curative in some patients, but that decision is fraught with a risk-benefit trade-off of 20% procedure related mortality and the risk of graft-versus-host disease and other long term complications afterwards.

In conclusion: 

It will be interesting to see what impact this vaccine will have in the long term in terms of improved survival for people living with CML and whether future research will demonstrate a clear need to eliminate minimal residual disease below what is currently possible.  These are promising results and I look forward to seeing more data over the next few years as the answers evolve.  The ultimate goal is always to find a cure but whether this approach will help achieve that remains to be seen.

Smith, B., Kasamon, Y., Kowalski, J., Gocke, C., Murphy, K., Miller, C., Garrett-Mayer, E., Tsai, H., Qin, L., Chia, C., Biedrzycki, B., Harding, T., Tu, G., Jones, R., Hege, K., & Levitsky, H. (2010). K562/GM-CSF Immunotherapy Reduces Tumor Burden in Chronic Myeloid Leukemia Patients with Residual Disease on Imatinib Mesylate Clinical Cancer Research, 16 (1), 338-347 DOI: 10.1158/1078-0432.CCR-09-2046

Abbott makes some waves in Pharma

While listening to last week's presentation by BMS on their pipeline, one slide in particular caught my attention:

Source: BMS

Now, it wasn't the fact that BMS were second in their table of Total Shareholder Return (TSR) that was interesting to me, but that Abbott were first, and by a long way, according to the chart above.  Of course, shareholder return is only one measure of performance and says nothing at all about putting customers and patients first, but that is another story/blog.

Recently, Abbott has been in the news with the acquisition of Solvay, a generics company, which added $3B to their revenues and last night it was announced that the company are also acquiring Facet Biotech, which was being pursued by Biogen Idec.  The Biogen deal clearly fell apart after the company declined to raise their offer beyond $17.50/share.  Abbott offered $27/share and thus a white knight was found.  Interestingly, the Facet CEO, Faheem Hasnain, is a former employee of Biogen Idec.  

The acquisition is a hot one, so to speak, and many of us in the industry have been speculating in vain on who the partner might be, so you would think that going on CNBC's Pharma's Market with Mike Huckman would be a nice coup for a small company.  I thought it was odd though, to see that they seem a little publicity shy, as this tweet shows the company's rather gauche immaturity:

 

What do Abbott get from acquiring Facet?

Well, first we need to think about where Abbott is coming from.  Most companies with either build on existing platforms and franchises or add new products in areas where they want to expand.  Abbott is probably best known for it's immunology franchise, with adalimumab (Humira), its TNF inhibitor for rheumatoid arthritis and psoriasis. 

Several companies, including Abbott and BMS, have embarked on a race to develop the next generation of Hepatitic C drugs and vaccines.  Infectious diseases are not something that are going away fast, so this is seen as an attractive market segment by many.

Looking at the Facet acquisition, the pipeline is thus interesting because they have also been developing monoclonal antibodies but in different diseases including immunology and cancer. The lead compound is daclizumab, which is in phase II development for multiple sclerosis in partnership with... Biogen Idec. Facet own the exclusive rights to the asthma indication though.

There are also several anticancer antibodies such as volocizumab (solid tumours) and elotuzumab (multiple myeloma) in Facet's R&D.  Oncology is an area where Abbott has been relatively weak, although they have some interesting compounds in development for liquid and solid malignancies. In 2009, a joint venture with TAP was concluded, adding Lupron, one of the best selling drugs for hormone-sensitive prostate cancer to the portfolio of currently marketed products.  

Abbott may well see topline growth from it's cancer franchise in the future... if the pipeline products from their own labs or Facet's deliver.  If those from Facet fail, Biogen Idec will be breathing a sigh of relief that their offer was turned down.  

Such is life on the Pharma roller coaster.

Roche's ocrelizumab and AstraZeneca's cediranib bite the dust

This week kicked off with some interesting emails and alerts in my inbox.

You may well be wondering what on earth rheumatoid arthritis and colorectal cancer have in common.  The answer is that yet more agents in development have bitten the dust.

Firstly, it seems that Roche and Biogen Idec have announced that they are suspending the development of their humanised anti-CD20 monoclonal antibody, ocrelizumab, for treatment of rheumatoid arthritis (RA) and Lupus. 

This follows a recommendation of the independent Data and Safety Monitoring Board (DSMB) based on their assessment of the studies in RA. The review detected an infection related safety signal which included serious and opportunistic infections, some of which were fatal.

According to the Roche press release:

"As previously announced, the FILM study in MTX-naïve RA patients was placed on clinical hold following an assessment of benefit to risk in this specific RA patient population.  In addition, the BELONG study in lupus nephritis patients was previously halted due to serious and opportunistic infection signals."

The trials in multiple sclerosis appear to be ongoing.  Their other CD20 antibody, rituximab, has been on the market for several years for the treatment of cancers such as non-Hodgkins Lymphoma (NHL) and more recently, chronic lymphocytic leukemia (CLL).  There have been no safety issues with this product.

Oddly, the second agent that flopped today went up against Roche's Avastin and was found to fall short of the required hurdle in a large phase III trial.  AstraZeneca's cediranib (Recentin), is a oral small molecule VEGF inhibitor that was being evaluated for the treatment of colorectal cancer (CRC).

According to AstraZeneca's press release this morning:

"This study, HORIZON III, assessed the efficacy of cediranib compared with bevacizumab, both in combination with chemotherapy.  Clinical activity was observed in the cediranib arm of the study and there was no statistically significant difference between treatment arms on the efficacy endpoints examined.  However, the efficacy did not meet the pre-specified criteria for the primary endpoint of non-inferiority in progression-free survival."

Ouch!

However, these results are not entirely surprising given the previous failure of Novartis' vatalanib in CRC, another small molecule inhibitor, in phase III trials for colorectal cancer.  There may well be some quirk in the mechanism of action in colorectal cancer that preferentially allows monoclonal antibodies to work more effectively than small molecules.  The half life, dosing schedules or inhibiting the ligand differently could all play a crucial part in the process.

For AstraZeneca, though, their run of bad luck in oncology continues with Iressa, Zactima and now Recentin all struggling to make a major impact.

Photo Credit: Kiragon

Merck and Schering Plough's new robust pipeline

"Merck's newly integrated pipeline follows a comprehensive prioritization process that closely examined all compounds in development at both companies prior to the merger. Candidates were prioritized based on a series of criteria, including potential for impact on human health, molecular characteristics, stage of development, probability of success and commercial potential.   

The new combined pipeline is composed of small molecules, vaccines and biologics targeting a broad range of unmet medical needs including: atherosclerosis and thrombosis, cancer, diabetes, hepatitis C infection, insomnia, and schizophrenia. 

Merck's pipeline is particularly strong in therapeutic areas in which both companies have long-established research programs, such as cardiovascular disease and infectious diseases; Merck has eight investigational medicines in each of these two categories."

Source: Merck

Yesterday, Merck announced the results of their pipeline evaluation and prioritisation following the recent merger with Schering Plough.  There are 19 projects in phase III development across all therapy areas.  Although the two key areas for both companies were the same (cardiovascular and infectious diseases), there was little overlap, so the combined company now has 8 compounds in each area to manage.

What was interesting to me though, was what would happen in oncology where there was some overlap?

It now seems that Merck's IGF-1R inhibitor, dalotuzumab, which is in phase II development, has been selected as the lead cancer candidate.  This is good news for those interested in the IGF-1R pathway after recent events that saw Roche handing back R1507 to Genmab and Pfizer's figitumumab hitting some roadblocks in newly diagnosed non-small cell lung cancer.  

We know that adding an EGFR inhibitor reduces cross-talk between EGFR and IGF1R and including either an AKT or mTOR inhibitor may also reduce opportunities for resistance developing.  Merck recently presented data at the ASCO GI meeting in pancreatic cancer with several drugs in combination, including metformin to reduce the hyperglycemia effect.  The scientists and clinicians did a nice job thinking some of the issues through and managing the effects considering the side effect issues seen with figitumumab.

Of course, the co-development of the mTOR, ridoforolimus, continues in conjunction with Ariad and new data from the phase III trials in soft tissue sarcoma is eagerly anticipated by many at ASCO in June.

In my view, the most interesting cancer agents that Merck has are probably in phase I, time will tell what happens to those.

AstraZeneca license rights Rigel's R788 (fostamatinib) in RA

That sure was a hot alert sitting in my inbox this morning.

In looking carefully at the AstraZeneca ($AZN) press release, it seems that the details are as follows:

Much of the focus in the news is on the RA indication, although AstraZeneca do not have a franchise in this area.  All of their inflammation products on the market have been in the respiratory, not immunology, area as far as I can remember, making them an odd choice for a partner.  Still, AZ have had a few flops recently (Iressa being a spectacular one in oncology) and with a weak pipeline, they are desperate for some near term success to drive revenues sooner rather than later.  The recent announcement that 8,000 jobs will be cut is indicative of much cost cutting is going on.

Previously, we have discussed the Rigel RA data when the initial phase IIb data was disappointing and failed to meet at least one primary endpoint according to Rigel's press release last July.  This raised alarm bells in many Pharma licensing departments and significantly raised the risk for fostamatinib in RA.

That said, the data for fostamatinib in chronic lymphocytic leukemia (CLL), are much more promising as discussed post ASCO last year.  The agent is a SYK inhibitor and updated results presented by Dr Friedberg et al., at ASH in December confirmed that the data is still holding up.

All of the analyst news seems to be rehashes of the joint press release focusing on RA, which of course, is a much bigger, but higher risk, indication than CLL.  In looking at the Rigel pipeline, fostamatinib was the last product seeking a partner:

My assumption is that AstraZeneca will also be taking up the options on all of the indications for R788, including the oncology ones and not just RA from Rigel.

It may well be that in the final analysis, the CLL data will turn out to be more solid than the RA data if the phase II trials are anything to go by, but time will tell.  The good thing is that AZ have an oncology franchise, albeit not in hematologic malignancies.

Related articles by Zemanta

• AstraZeneca set to cut 8,000 jobs (news.bbc.co.uk)
• US FDA Approves New Indication for Crestor (Rosuvastatin Calcium) (worldpharmanews.com)

Novel therapies could improve potency of existing AIDS treatments

"The beauty and mystery of life extends down to the molecular level. 

The more we see, the more we can appreciate the wonder of our own nature."

Prof Arthur Olson, Scripps Institute

Every now and then, something lands in my Google Reader that makes me stop and gasp, or at least eagerly look a little more closely. Today's head turner was:

"Scripps Research scientists find two compounds that lay the foundation for a new class of AIDS drug"

Whoa! On more careful examination, it seems that a team of scientists at The Scripps Research Institute really has identified two compounds that act on novel binding sites for an enzyme used by the human immunodeficiency virus (HIV), the virus that causes AIDS. The discovery apparently lays the foundation for the development of a new class of anti-HIV drugs to enhance existing therapies, treat drug-resistant strains of the disease, and slow the evolution of drug resistance in the virus.

I've written about AIDS and HIV previously and how the disease evades treatment in the past, but if this new finding holds true, we could potentially have a new approach that will add to the current pool of treatment regimens that slow down the path to drug resistance and improve patient outcomes.

Current HIV-protease drugs mimic the shape of certain regions of the HIV protein chain, known as the "cleavage sites" and bind to the active site in the hollow center of protease.  Once this site is blocked by the drug, the protease is disabled, and HIV cannot make new infectious particles.  Protease drugs therefore impede the spread of the HIV infection to other cells within a patient.

The researchers decided to look at drug-resistant strains of the virus.  They then conducted computer simulations of the movement of a particularly nasty multi-drug-resistant mutant strain of HIV (V82F/I84V) to see what happened and if they could learn from it.

The results showed that the flaps of the drug-resistant protease molecule tended to be open more often than their counterparts and they were also more flexible. While the anti-HIV drugs still fit into the active site binding pocket, more energy was needed to close the flaps than the drugs could muster.  The drugs wouldn't stay in the binding site and the pocket remained available for the HIV protein chain, which was still able to close the flaps and go on to create new infectious particles.

We can now see that a new type of drug might be able to bind to alternate sites on the sides of the protease, restraining the flaps from their ends and providing the current anti-HIV drugs enough help to close the flaps and disable the protease. Instead of blocking the protease's active site, these compounds would be "allosteric fragments" ie small molecule building blocks that shift the dynamics of the molecule, allowing a different conformation or shape.

How are these two compounds different from currently approved drugs for HIV?

Well, in plain English, current treatments target HIV protease, however, the two new agents in development are small chemical units or "fragments," which bind with the two specific parts of the molecule where they identified resistance occurring.

Essentially, this approach is an important proof-of-concept that the protease molecule has two non-active site binding pockets or 'allosteric sites', which can be exploited as a powerful new strategy to combat drug-resistance in HIV.

Overall, there is a long way to go yet, including extensive clinical trials to determine the safety and efficacy of the compounds, but in theory, with this approach, future drugs incorporating the fragments' novel structural elements may offer new angles that can be exploited biochemically.

Take a look at a beautiful picture of the HIV complex, courtesy of the Scripps Institute, which was created by Dr Stefano Forli, Ph.D:

Once you have finished comtemplating, please re-read the quote at the top of the post. The more we understand about the science and biology of disease, the more awed I feel.

You can also check out the Scripps Fight AIDS at Home page if you want to learn more.

Perryman, A., Zhang, Q., Soutter, H., Rosenfeld, R., McRee, D., Olson, A., Elder, J., & David Stout, C. (2010). Fragment-Based Screen against HIV Protease Chemical Biology & Drug Design, 75 (3), 257-268 DOI: 10.1111/j.1747-0285.2009.00943.x

Biotech and Pharma news - Genentech, Amgen, GSK and Merck

This week is going to be a busy one in the Icarus office with several client strategy reports to finish and many Pharma companies reporting 3Q earnings and plans for making year end targets.

Image via Wikipedia

Meanwhile, on the Biotech front, Genentech and Amgen are reviewing their letters from the FDA on rituximab in moderate to severe rheumatoid arthritis (RA) who no longer respond to methotrexate (and other DMARDs) and denosumab for the treatment and prevention of postmenopausal osteoporosis, respectively.

Neither letters are a big surprise.  The FDA has declined to support the approval of rituximab in rheumatoid arthritis owing to the incidence of a rare, but fatal adverse event, known as progessive multifocal leukeoencephalopathy (PML).  According to Genentech:

"PML is a usually fatal brain disease caused by the reactivation of a common virus called the JC virus. Although the incidence of PML in RA patients treated with Rituxan is rare (as of today, three reports out of approximately 100,000 patients), there are no known reliable PML treatments."

Amgen have an entirely different kettle of fish on their hands, however.  The FDA were expected to get back to the company this month and last week there were rumours circulating about potential delays in the approval due to the FDA's backlog and other reasons.  However, they have indeed sent a complete response letter, requesting further information be provided, including:

"The Complete Response Letter related to the Prolia applications requested several items, including further information on the design of Amgen's previously submitted post-marketing surveillance program. This letter does not require additional pre-marketing clinical trials to complete the review of the treatment indication. The FDA has requested a new clinical program to support approval of Prolia for the prevention of postmenopausal osteoporosis indication.

The FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) is necessary for Prolia and must include a medication guide, a communication plan, and a timetable for submission of assessments of the REMS. The FDA acknowledged receipt of Amgen's previously submitted proposed REMS materials. The FDA has also requested all updated safety data related to Prolia."

Amgen had clearly anticipated the need for a REMS in pre-submitting some materials, so this application will likely lead to full approval in the near future.  Whether the company has the sales muscle to compete in a highly competitive mass market segment with primary care doctors instead of specialists such as medical oncologists is a whole different ball game though.

At the other end of the spectrum, GSK have received approval to market their HPV vaccine for prevention of cervical cancer, Cervarix, a competitor to Merck's Gardasil, which ironically, just received approval for the treatment of genital warts in boys, a new indication in addition to the one already held for the prevention of cervical cancer in girls.  The Merck vaccine inhibits several additional HPV types compared to the GSK one, but whether this is significant or not is unclear.  Either way, physicians and patients now have a choice and this can only be a good thing, although there will likely not be any difference in the manufacturer's prices of the two vaccines.

{UPDATE:}

Amgen announced that they have also received a complete response letter for the BLA for Prolia in the treatment and prevention of bone loss due to hormone ablation therapy (HALT) in breast and prostate cancer patients.  In a press release, the company stated:

"The Complete Response Letter on the Prolia HALT applications requested additional information regarding the safety of Prolia in patients with breast cancer receiving aromatase inhibitor therapy and patients with prostate cancer receiving androgen deprivation therapy. Specifically, the FDA has requested results from additional adequate and well-controlled clinical trials demonstrating that Prolia has no detrimental effects on either time-to-disease progression or overall survival."

This second letter requesting data from additional clinical trials will likely significantly delay approval for the cancer indication.

Related articles by Zemanta

• Amgen's bone drug gets delayed by the FDA, and Wall Street isn't surprised (dailyfinance.com)
• F.D.A. Says No, for Now, to an Amgen Bone Drug (nytimes.com)
• FDA Approves Gardasil Vaccine for Boys, Cervarix for Girls (blogs.wsj.com)

Nerve Growth Factor: an interesting new treatment approach for glaucoma

A recent paper published in the Proceedings of the National Academy of Sciences  by scientists from the University of Rome has shown that the administration of nerve growth factor (NGF) stabilizes or reduces the damage to the optic nerve caused by the raised intra-ocular pressure (IOP) associated with glaucoma. 

Glaucoma is an eye disease that is the world’s leading cause of blindness affecting 77 million people around the world and causes irreversible damage to vision.  An easy to use eye drop that stabilizes or reduces damage to retinal ganglion cells and the optic nerve cells offers exciting potential and is research that will be watched closely by companies with an ophthalmology portfolio.

NGF was discovered by Stanley Cohen and Rita Levi-Montalcini, who received the 1986 Nobel Prize in Physiology.  NGF may have a neuroprotective and repair function within the body, which could explain its ability to stabilize nerve damage caused by raised IOP. 

In the paper published by Bonini and Levi-Monalcini they administered eye drops with NGF to rats and three human subjects.  This caused an reduction in retinal ganglion cell death in the rats, and the patients who received NGF had improvements in their visual field and visual acuity. 

The data is extremely promising, but in view of the small subject numbers and the fact that rat models do not always translate into humans, more extensive clinical trials data are needed to validate it as a potential new treatment. 

Hopefully more data will be available for presentation at the ARVO (Association for Research in Vision and Ophthalmology) annual meeting in May next year.

Lambiase, A., Aloe, L., Centofanti, M., Parisi, V., Mantelli, F., Colafrancesco, V., Manni, G., Bucci, M., Bonini, S., & Levi-Montalcini, R. (2009). Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0906678106

Sofroniew MV, Howe CL, & Mobley WC (2001). Nerve growth factor signaling, neuroprotection, and neural repair. Annual review of neuroscience, 24, 1217-81 PMID: 11520933

Related articles by Zemanta

• Eye drops 'may reverse glaucoma' (news.bbc.co.uk)

Around the horn in Pharma

The last week or so has brought a variety of news in the Pharma world from good, bad to just plain old ugly. 

BMS's purchase of Medarex is an interesting one; time will tell what happens with the existing licensing deals and whether the pipeline, including ipilimumab pans out or not.  It certainly seems like shark infested waters at the moment, with an eat or be eaten strategy evolving in Pharma and Biotech.

The other week we posted a snapshort of denosumab, a RANK-L inhibitor being tested for the treatment of breast cancer patients with bone mestastases.  Yesterday, Amgen announced a deal with GSK to promote the monoclonal antibody denosumab for postmenopausal osteoporosis (PMO) in Europe, Australia, New Zealand and Mexico once the product is approved.  Amgen will commercialize the drug for PMO and oncology in North America and for all oncology indications in Europe and specified markets.  Seems like a good deal at first sight - Amgen get increased commercialisation in areas where they are weak and GSK get to add another source of revenue in regions where they are strong.

The news that Rigel's fostamatinib has failed to meet it's primary endpoint in a rheumatoid arthritis trial is disappointing.  The company announced:

"The TASKi3 Phase 2b clinical trial in rheumatoid arthritis (RA) patients who had failed to respond to at least one biologic treatment, the group treated with R788 (fostamatinib disodium) did not report significantly higher ACR 20, ACR 50, ACR 70 and DAS28 response rates than the placebo group at three months, and therefore, the trial failed to meet its efficacy endpoints."

The results for the placebo group were unusually high and so this cancelled out any possible chance of showing a statistical difference with the fostamatinib group.  Very unfortunate, but it happens.  It is possible that there was a carryover effect from the biologics taken as first-line therapy if the washout period was too short or the patients were poorly monitored, but who knows?  My guess is that we will see further trials in this area given the promising signs, perhaps a phase III trial or testing in other imunologic indications such as lupus and B-cell lymphomas.  It's unlikely to be the last of R788, but it is a major commercial setback for Rigel and significantly delays fostamatinib's time to market.

Image via Wikipedia

Meanwhile in Europe, the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA), has adopted a negative opinion for the use of Erbitux® (cetuximab) in combination with platinum-based chemotherapy for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, advanced or metastatic non-small cell lung cancer (NSCLC).  The submission was based on the recent FLEX trial reported at ASCO last month.

Merck Serono is apparently considering an appeal, claiming that Erbitux is the first and only new targeted compound in clinical development in more than 10 years that increases overall survival in a NSCLC patient population including all histologies.  Clearly they would like the CHMP to reconsider its decision. 

The EMEA stated their reasons for rejecting the application as thus:

"The CHMP was concerned that the benefits of adding Erbitux to standard platinum-based
chemotherapy were modest in terms of survival times, and that the medicine did not have a convincing effect on how long patients lived without their cancer getting worse. Severe side effects were seen in some lung cancer patients who received Erbitux - these were similar to the side effects seen in patients treated with Erbitux for other types of cancer.

At that point in time, the CHMP was of the opinion that the benefits of Erbitux in the treatment of non-small cell lung cancer did not outweigh its risks. Hence, the CHMP recommended that the change  the marketing authorisation be refused."

If I recall from the FLEX data presented at ASCO last month, the overall survival was something like 11.3 vs. 10.1 months, a gain of about 1 month for a very significant cost, with not insignificant side effects, including a very nasty rash in some patients.  Put in this context, the CHMP clearly had doubts about the efficacy:side effect:cost benefit.  No doubt there will be a lot of noise around this decision over the next few weeks, but the decision is hardly surprising given the marginal improvement in lung cancer.

A wild month so far, for sure.  I wonder what next week will bring?

Related articles by Zemanta

• Amgen, GSK to Launch Joint Sales Attack for Bone Drug (blogs.wsj.com)
• Bristol-Myers buyout of Medarex (dailyfinance.com)
• Clinical trial results show Denosumab is superior to Zometa in breast cancer patients with bone metastases (pharmastrategyblog.com)
• Erbitux FLEX trial improves survival in advanced lung cancer (pharmastrategyblog.com)

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.

Zymo Genetics IL-21 shrinks malignant melanoma

Image via Wikipedia

There are three cancers that make my heart sink when someone calls asking for information on them; pancreatic, advanced lung cancer and malignant melanoma.  Why?  Because patients typically have a poor prognosis and don't do very well.  It's a sharp reminder that for all the good news out there, we still have a long way to go for thousands of cancer patients.

My interest was thus piqued when I found a press release this week from Zymo Genetics suggesting that it's agent in development for malignant melanoma, IL-21, appears to shrink the tumour.  You can read more about it here.

IL-21 or Interleukin-21 is a cytokine.  Within the body, endogenous IL-21 is a potent regulator of key classes of immune cells, including cytotoxic T lymphocyte cells and natural killer cells, which play critical roles in eliminating malignant and virally infected cells from the body.  IL-21 also is important in boosting antibody response. 

 

The combined biologic actions of IL-21 suggest that it may be an effective immunotherapy in the treatment of cancer, either alone or in combination with other anti-cancer drugs.  The preclinical and early clinical trial data suggest that IL-21 could potentially be better tolerated and more efficacious than other currently marketed immunotherapies for cancer, such as interleukin-2 (IL-2) and interferon-alpha.

What of the data then?  Well, essentially, the company reported that:

"Interleukin 21 (IL-21) demonstrated an impressive overall response rate in the treatment of metastatic melanoma. In interim Phase 2 results from 24 patients, 29 percent showed a partial response, with an additional 33 percent of patients showing stable disease in this difficult to treat disease."

The compound, which they are looking to outlicense, also demonstrated that to date, 7 of the 24 patients (29%) had a partial response (5 confirmed by RECIST criteria).  Eight patients (33%) had stable disease.  The most common adverse events reported were mild or moderate fatigue and rash.

Two cancers in particular that are immune sensitive include melanoma and renal cell carcinoma, so it was no surprise to learn that Zymo Genetics are testing recombinant IL-21 in combination with Nexavar® in a Phase 2 clinical trial in patients with metastatic renal cell carcinoma, as well as a Phase 2 clinical trial in collaboration with the National Cancer Institute of Canada to test IL-21 as a single agent in patients with metastatic melanoma.

It will be interesting to see how this novel approach pans out with further research.

Related articles by Zemanta

• Zymo Melanoma Drug Shrinks Tumors (seattlepi.com)
• ZymoGenetics Takes Back Full Rights to Cancer Drug Candidate (xconomy.com)

Stem cell tranplants and HIV

This week's New England Journal of Medicine has an interesting case report on a man who was having an allogeneic stem cell transplant to treat his acute myeloid leukemia (AML), but also happened to be HIV positive.  The transplant team theorised that:

"Infection with the human immunodeficiency virus type 1 (HIV-1) requires the presence of a CD4 receptor and a chemokine receptor, principally chemokine receptor 5 (CCR5)."

They therefore took this into consideration and specifically chose a donor who had a naturally occurring gene mutation that confers resistance to HIV.  The mutation, CCR5 delta32, occurs naturally in 1-3% of the European population.

Two years after the transplant, the patient is alive, well and seemingly free of HIV still. 

This procedure, while offering some early encouragement, is not going to be a panacea for all patients, mainly because of the mortality associated with ablation (wiping out) of a person's immune cells rendering them susceptible to fatal infection.  20% of SCT patients die from the procedure alone, so it is a very risky one indeed.

Jay Levy from UCSF wrote an accompanying editorial in which in he noted:

"Therapeutic targeting of CCR5 could delay the onset of disease and reduce the cost and toxicity of antiretroviral therapy, as it has in this patient for nearly 2 years. This case places further emphasis on gene therapies and treatments directed at blocking the CCR5 receptor with decoy drugs. Maraviroc, a recently approved CCR5 inhibitor, has had some success, but it must be administered along with other antiretroviral medications."

In the past, there were several attempts to control HIV-1 infection by means of allogeneic stem cell transplantation without regard to the donor's CCR5 delta32 status, but these efforts were not successful.  This fascinating study demonstrated the critical role CCR5 plays in maintaining HIV-1 infection and the need to consider it in treatment with SCT for HIV-1.

Source:

Gero Hütter, Daniel Nowak, Maximilian Mossner, Susanne Ganepola, Arne Müßig, Kristina Allers, Thomas Schneider, Jörg Hofmann, Claudia Kücherer, Olga Blau, Igor W. Blau, Wolf K. Hofmann, Eckhard Thiel (2009). Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation New England Journal of Medicine, 360 (7), 692-698

Stem cells and multiple sclerosis

"For the first time, some of the disability associated with the early stages of multiple sclerosis appears to have been reversed.  The treatment works by resetting patients' immune systems using their own stem cells."

New Scientist

Well, that paragraph certainly caught my eye this morning in the news, thanks to a friend for sending the link over. 

My initial thoughts were two fold - I liked the idea that stem cell technology might possibly help people with MS since I have several friends who suffer from the debilitating condition, but it tempered by the phrase 'resetting patients immune systems'.  Regular readers of this blog will be familiar with the disastrous TGN 1412 trial at Northwick Park, which has been covered here previously see here and here.  That study warned of the dangers of stimulating a normal immune system in homeostasis.

Let's take a look at multiple sclerosis though.  It's an autoimmune disease where the fatty myelin sheath, which wraps around nerve cells and speeds up their rate of transmission, is attacked by the body's own immune system.

Previous efforts with stem cells have tried to reverse that process with no success.  The researchers decided that perhaps waiting until advanced disease when neuro-regeneration had set in was the problem.  The next logical approach was to therefore look at early stage disease before the body is under attack.

21 people with early relapsing-remitting MS who had not responded to treatment with the standard drug, interferon beta, after six months received an autologous stem cell transplant (aSCT).  The patients had stem cells removed from their bone marrow, then receive chemotherapy to destroy all existing immune cells in the body, before re-injecting the stem cells.  The stem cells then developed into naïve immune cells that do not see myelin as alien, and hence do not attack it.

Three years later, 17 of the patients had improved by at least one point on a standard disability scale, while none of the patients had deteriorated.  The study has just been published in The Lancet Neurology.

The authors concluded that:

"Non-myeloablative autologous haemopoietic stem cell transplantation in patients with relapsing-remitting MS reverses neurological deficits, but these results need to be confirmed in a randomised trial."

I have to say that realising the patients received a stem cell transplant rather than some immune stimulant reassured me greatly.  However, SCT is not a walk in the park - it is a known curative treatment for some forms of leukemia, but because it involves wiping out all the existing white blood cells, it weakens the patient and some die because they are unable to fight infection.

Interestingly, the patients received alemtuzumab as part of their SCT regimen, similarly to the Cambridge patients reported in the Guardian article highlighted below.  Alemtuzumab is a monoclonal antibody approved for the treatment of leukemia, but it became a candidate for MS when it was realised that it dampens the immune system.

Larger scale trials are still needed to confirm the initial results, but so far it looks a promising approach for the treatment of early stage MS.

Sources: R BURT, Y LOH, B COHEN, D STEFOSKY, R BALABANOV, G KATSAMAKIS, Y OYAMA, E RUSSELL, J STERN, P MURARO (2009). Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study The Lancet Neurology DOI: 10.1016/S1474-4422(09)70017-1

Related articles by Zemanta

• Major step towards treating multiple sclerosis as trials show drug reverses effects of disease

On politics, stem cells and Geron Corp

Image via Wikipedia

The outgoing Bush Government was a well known opponent of stem cell research, while the incoming Obama Administration was publicly supportive of such research.  It therefore came as no surprise last week when the FDA suddenly allowed clearance of the first human clinical trial using embryonic stem cell therapy in patients with acute spinal cord injury.

On Friday, the CEO of Geron Corp, Dr Tom Okarma, was interviewed live on CNBC and had this to say:

"There's no question that the Bush administration was very instrumental in slowing down the progress in a number of ways. But we have really no direct evidence that that actually influenced the FDA's review. So, we really have no view that there was a political overhang at the FDA."

You can find out more from the company press release and the online recording of the webcast.

Geron's website explains their approach with stem cells quite succinctly:

"Geron is developing first-in-class biopharmaceuticals for the treatment of cancer and chronic degenerative diseases, including spinal cord injury, heart failure and diabetes. The company is advancing an anti-cancer drug and a cancer vaccine that target the enzyme telomerase through multiple clinical trials. Geron is also the world leader in the development of human embryonic stem (hESC) cell-based therapeutics. The company has received FDA clearance to begin the world's first human clinical trial of a hESC-based therapy: GRNOPC1 for acute spinal cord injury."

The whole stem cell field is based on a entirely different approach from patients popping a pill or being given an injection or infusion of a drug therapeutic.  Instead, the restoration of organ function achieved by the injection of healthy, functional replacement cells manufactured from human embryonic stem cells.  Embryonic stem cells are pluripotent, which means they can turn into any type of cell in the body and can self renew indefinitely in the undifferentiated state due to high levels of telomerase.

So how does the treatment work?  In the WSJ Health Blog, they summarised it as thus:

"The therapy is designed to generate new myelin, the protective sheath that covers nerve cells and is often severely damaged in spinal cord injuries. A previous study found that paralyzed rats who received the treatment within days of injury generated new myellin (sic) and improved their ability to walk more than rats treated with a placebo."

It should be noted that the clinical trial is a very early phase I study and there are no guarantees that the concept with translate from animals to humans.  In this trial, researchers will inject a stem cell-based therapy directly into the spinal cords of patients who have recently suffered severe spinal injuries. 

Overall, it's an interesting concept and thus we wait with baited breath for a while to see how the results will pan out.

Related articles by Zemanta

• FDA OKs human stem cell therapy testing
• Human embryonic stem cell study gets green light
• F.D.A. Approves a Stem Cell Trial

Market meltdown offers opportunities for big Pharma with cash

The recent financial crisis and market meltdown that led to a credit crunch will have impacted many start-ups and baby biotechs, many of whom will have a year or less of cash to survive.

This creates new opportunities for buyouts from larger pharma companies with cash in their pockets looking for good deals - Pfizer, Novartis, Roche and GSK are all known to have reserves as do medium sized biotechnology companies such as Celgene.  Baby biotechs with good products and data will not have a problem finding a suitor but it in the current depressed market they may be forced to consider this option earlier than anticipated and for a lesser price.  Such is life.

The first example of this trend is GSK, who announced the successful completion by its wholly-owned subsidiary Gemstone Acquisition Corporation for shares of common stock of Genelabs Technologies, Inc. (Nasdaq: GNLB). The tender offer expired at 12:00 midnight, New York City time, on Tuesday, January 6, 2009.  Genelabs is a biotechnology company focusing on infectious diseases such as hepatitis C and antiviral treatments, therapy areas which fit in well with GSK's portfolio.  In November, Genelabs reported revenues of $0.3 million and a net loss of $4.9 million, or $0.11 per share, for the third quarter of 2008. This compares to revenues of $4.6 million and a net loss of $0.1 million, or $0.00 per share, for the third quarter of 2007.

Overall, judging by the requests we are getting to analyse portfolios and evaluate oncology opportunities, I can see more of these kind of deals emerging in 2009 as small biotech fight for survival.  Given the challenges big pharma is facing with major patent expiries over the next 2 years and dwindling pipelines, this could well be a marriage in heaven for some, but there will be some pain with increased layoffs and 'cutting the fat' as pharma tries to get lean and mean will preserving profit margins.  Savvy people in business development and licensing should still, howver, be able to get excellent value for their companies in the current market.