MaverickNY | Pharma Strategy Blog

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

By MaverickNY on December 18, 2009

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

You can see the review here.

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

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

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

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

W2W4 (what to watch for) in 2010?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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There's no such thing as a free coffee in Pharma

By MaverickNY on December 17, 2009

Is a free cup of coffee in a conference exhibitor’s booth an inducement to prescribe?

Image by Omar_MK via Flickr

It was interesting to see exhibitors at the recent American Society of Hematology meeting place conspicuous signs in booths that had a café, alerting health care professionals that they should not ask for a free cup of coffee, tea or water if their licensing State, Government or Institution prohibited them from doing so.

Massachusetts and Vermont are two states that have recently banned health care professionals with prescribing authority from accepting anything of value directly from a pharmaceutical or medical device manufacturer including food & drink where the gift is linked to promotional activities. Other states such as New Jersey may soon follow suit.

Manufacturers are businesses with products to promote. They try and attract health care professionals to stop by their exhibits by offering information, and in some cases comfortable seating or refreshments such as biscotti or small ice cream. Nobody raises any questions about the subsidy to the meeting costs that exhibitors effectively provide, yet the offer of a coffee, tea or water at a booth that a doctor, nurse or physician’s assistant voluntarily chooses to visit is now regarded as a “gift” that several states have banned.

To me, the pendulum has swung too far in the regulation of pharmaceutical promotional activity if people really think a health care professional is induced to prescribe based on a free coffee at a conference exhibit booth. It is rather insulting if regulators think a doctor can be so easily bought.

If fewer health care professionals visit the booths due to lack of chotckhes or refreshments, the day may well soon come when exhibitors begin downsizing their booths and paying less for the privilege. The end result in the long run may well be higher registration fees for all, including physicians.

Perhaps there should be a minimum value of “gift” that is regarded as ‘de minimis’ and exempt from oppressive regulation. Long live free coffee at conference exhibit booths!

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Tarceva maintenance therapy in non-small cell lung cancer

By MaverickNY on December 16, 2009

Chomping at the bit, like many others today, to hear how the FDA ODAC meeting goes on regarding Tarceva maintenance therapy in lung cancer.

The initial OSI company presentation appeared to go well, but Q&A session did not; the committee clearly had concerns about the statistics. The SATURN data in adenocarcinoma was not as impressive as hoped, with the overall survival benefit being one extra month as opposed to taking the drug second line after initial chemotherapy failing and then getting 3 months of extra benefit with either Tarceva or docetaxel. Sometimes waiting and recovering will get you better results.

We posted about the original trial designs earlier this year in February and the initial results from the May ASCO meeting.

More at around 3pm ET today.

{UPDATE: ODAC VOTING 1 YES, 12 NO}

ASH09 meeting report: chronic lymphocytic leukemia (CLL)

By MaverickNY on December 16, 2009

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!

#ASH09 Report: Acute Myeloid Leukemia

By MaverickNY on December 15, 2009

Acute myeloid leukemia (AML) is a truly nasty disease and one I hope never to have the misfortune to be diagnosed with.

Last month, at the Chemotherapy Foundation in New York, Dr Norman Wolmark gave an entertaining lecture on what he called the "Decade of Discontent" in colorectal cancer, a bleak period where no new therapies or stunning ideas emerged and the researchers bogged themselves in answering minutiae rather than focusing on the bigger picture.

He could well have been describing AML.

Why?

Take a look at this slide that was shown at the AML Super Friday educational symposium (the reference is from Dohner et al., (2009), published in Blood and how complex the disease has become with a myriad of phenotypes being described:

But this approach begs a most important question:

Which of these mutations or phenotypes are actually relevant and what is driving the cancer's survival and ability to outwit treatment?

No one really knows and thus it illustrates the frustration inherent in making a nasty disease ever more complex. Just because a mutation exists or a pathway is overexpressed does not mean that it is critical to the survival of the leukemia cells! Sometimes the mutations occur as artifacts, a function of a generally increasing leukemic burden over time as the disease gets more established.

Image via Wikipedia

Undoubtedly, the 14% of AML patients who have no additional mutation beyond the t(9,11) translocation that defines the disease, probably do best and at least attain a complete response (CR). The issue of how to keep them there, thus preventing relapse from occurring is an entirely different matter. We need more smart young researchers like Dr Gail Roboz in New York who asked the Chemotherapy Foundation audience what can be done to keep more AML patients in remission?

In ALL, which is more common in children than adults, there are well accepted maintenance therapy strategies for maintaining remission. In AML, post transplant or chemotherapy, there are none. Why it is not clear, but certainly something that can be easily tested with the plethora of targeted agents we have available on the market or in the clinic.

At the American Society of Hematology meeting in New Orleans this week, we attended a number of education and oral sessions discussing AML and read many posters on the topic too. What was startling was how little real progress has been made over the last five years… there were numerous versions of induction and conditioning regimens associated with stem cell transplantation, a general agreement that using the current targeted agents in late stage relapsed or refractory disease is doomed to failure because the leukemic burden is too high…

Dr Wolmark's 'decade of discontent' comment rang loudly in my ears while walking around a huge cold hangar on Monday reading poster after poster with little positive news to inspire or encourage. Skipping to the CML, CLL or NHL poster sections brought cheer and hope by comparison.

Part of the problem with AML is that many of the patients are diagnosed in the elderly, thereby limiting options either because the regimens are highly toxic and less well tolerated, transplant is not an option (survival decreases in the over 55 yo) or they have co-morbidities and multiple mutations, reducing the effectiveness of therapy.

There is, therefore, a clear need for alternative approaches in this population as well as better therapies for the very young who at least have a chance of cure by preventing relapse.

At ASH, some abstracts did catch my eye. Genzyme's clofarabine (Clolar) is one such interesting drug, currently approved for acute lymphocytic leukemia (ALL) and being tested in elderly AML patients. FDA's ODAC recently declined to approve clofarabine in elderly AML patients in the relapsed/refractory setting because the trial was compared to placebo. The same thing happened with Vion's laromustine (Onrigin) in the elderly AML setting. We will probably have to wait until the comparative trial data is available for clofarabine in 2010 before any major decision can be made as to the drug's safety and efficacy in the elderly population. There were no new abstracts on laromustine at this ASH meeting.

Meanwhile, some other interesting companies with early phase I/II data in AML included Sunesis and Cyclacel, both of which have seen their stock price rise since ASH on publication of the data.

Sunesis are developing voreloxin, a chemotherapy given as an infusion and used either alone or in conbination with cytarabine (araC) in heavily pre-treated AML. In the combination study (#645), the researchers found that:

"Among evaluable first relapse (n=36) and primary refractory patients (n=28), preliminary median overall survival is 7.8 months and the remission rate is 31% (complete remission [CR] 27%, complete remission without full platelet recovery [CRp] 2% and complete remission with incomplete recovery [CRi] 2%).

Historical median overall survival data in primary refractory and first relapse patients on currently available chemotherapies range from Voreloxin in combination with either bolus or continuous infusion cytarabine was generally well-tolerated. Infection-related toxicities were the most common Grade 3 or higher non-hematologic adverse events. In addition, Grade 3 or higher oral mucositis was observed."

A poster (#1037) was also presented on voreloxin in elderly AML, and while the data looks interesting initially, I would have major concerns about the registerability of the data given that it is a single arm study of the sort that the FDA and ODAC has repeatedly baulked at:

"Median survival was 8.7 months in Schedule A; 5.8 months in Schedule B; and 7.3 months (preliminary) in Schedule C (72 mg/m2 on days one and four).

Median duration of remission was 10.7 months and one year survival was 38% for Schedule A. For the other schedules, median duration of remission has not been reached and one year survival is too early to evaluate.

Patients age 75 or older (N=49) with at least 1 additional risk factor at diagnosis, a population identified by the National Comprehensive Cancer Network (2010) AML Guidelines as having poor outcome to standard treatment,experienced a CR rate of 30% and a 30-day all-cause mortality of 5%.
Survival in these patients was too early to evaluate.

Based on trial results, Schedule C has been determined to be the recommended pivotal dose regimen. For Schedule C, response rates (CR and CRp) are 38%; 30- and 60-day all-cause mortality are 7% and 17% with improved tolerability over Schedule A."

Cyclacel is a NJ biotech developing an oral prodrug for AML, MDS and CTCL called sapacitabine, a nucleoside agent that targets DNA synthesis and cell cycle arrest. Several phase II studies were presented at ASH, including interesting data on long term follow up in elderly AML patients from an MD Anderson study (#1061) and another in MDS (#1758).

It should be noted that while the one-year follow up data looks promising in AML, the study design suffers from the same issue as tipifarnib, clofarabine, laromustine, and voreloxin in that there is no comparator arm from which to compare and determine if the investigational agent is actually significantly prolonging life in AML.

Overall, it was a disappointing meeting in AML and I sincerely hope that some mre enlightening data emerges in 2010 rather than face the dreaded precipice that Wolmark so pithily described.

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In Memorium…

By MaverickNY on December 13, 2009

I'm getting to the age where the death of family and friends is starting to happen more frequently. Just before the recent American Society of Hematology meeting, the news hit the Pharma grapevine that two old Novartis colleagues had both sadly died in their 40's.

That was a bit of shock. The fragility of life, of light and darkness, really hits you at moments like these.

RIP Ian and Kyle. We will remember you both.

Understatement of the decade?

By MaverickNY on December 11, 2009

At the American Society of Hematology meeting last weekend, I had the pleasure of listening to an enlightening education session on CML from Drs Brian Druker, John Goldman, Moshe Talpaz and Tim Hughes, all leading lights in the field.

Prof Goldman's talk was particularly riveting because he always uses examples from history to illustrate the challenges of today, then offers a fair and thoughtful strategic road map for the future. One such example was to remind us that way back in 1996 before the clinical trials with tyrosine kinases even began, a paper appeared in Cancer Research describing the synthesis of a new compound:

These sort of articles appear in science and cancer journals every day as a new compound is born and the big question is whether is will end up a drug star or wither and be terminated in the Pharma pipeline scrapheap. However, what was touching about the article was the rather European statement in the abstract noting the following:

May have?

Wow, I love a droll understatement… CGP 57148 went on to become renamed imatinib (Gleevec) and became a cancer blockbuster, changing the lives of many patients with CML, GIST and some rare myeloproliferative diseases driven by PDGF or KIT.

Later today I will post an update on what's hot in chronic myeloid leukemia from ASH and how the new second generation TKI's nilotinib and dasatinib may offer yet more hope for patients with CML in the near future, as well as other agents in development for the rare T315i mutation that none of the approved TKI's currrently inhibit.

For now, it is sometimes good to reflect on history and feel a sense of awe and wonder that a small molecule chemical compound could eventually lead to 60-70% of CML patients attaining a complete cytogenetic response. I'll guarantee those results turned out to be far more stunning than the authors of the paper ever imagined.

{Disclosure: I'm a former Novartis marketing director who was involved in the new product development and subsequent launch of imatinib in CML and GIST, so my bias and enthusiasm for both the drug and the many wonderful and brave CML and GIST patients who participated in the clinical trials is apparent.}

Buchdunger E, Zimmermann J, Mett H, Meyer T, Müller M, Druker BJ, & Lydon NB (1996). Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer research, 56 (1), 100-4 PMID: 8548747

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#ASH09 Update: Multiple Myeloma

By MaverickNY on December 10, 2009

In the past, single agent and double agent regimens have been a mainstay in the treatment of multiple myeloma, yet the five year survival rate has remained steadfastly low around 3-4 years, on average. Typically, younger and fitter patients do better than elderly patients with a poorer performance status, yet the majority of new diagnoses are found in the elderly. Finding new treatment approaches is therefore a key imperative.

2009 has seen the advent of new triple, and even quadruple, combinations in an effort to improve efficacy and survival, hopefully not at the expense of increased side effects. Two of the most commonly used drugs, bortezomib and
lenalidomide, for example, differ in their side effect profile with an increased
tendency to peripheral neuropathy and deep venous thrombosis,
respectively. New dosing regimens have begun to look at new strategies in the form of modified dosing regimens, which are potentially more patient friendly, without compromising efficacy.

Important trial results from two European groups at this American Society of Hematology (ASH) meeting, for example, demonstrated that a four
drug combination improved durable responses and progression-free survival in
elderly patients. Both studies showed that a
weekly schedule of bortezomib (Velcade) maintained efficacy with fewer toxic side effects (i.e. significantly decreased the incidence of grade 3-4 peripheral neuropathy) compared to the standard
twice weekly schedule.

In
newly diagnosed myeloma patients the combination of bortezomib with
melphalan-prednisone (VMP) has been previously shown to be superior to MP, while in relapsed-refractory patients the four drug combination bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high
proportion of complete responses (CR).

An Italian phase III study therefore looked at the four drug combination in the upfront setting and showed that induction therapy with a four drug combination of bortezomib,
melphalan, prednisone, and thalidomide (VMPT) followed by maintenance
therapy with bortezomib and thalidomide (VT) achieved superior response rates and PFS compared to VMP.

A Spanish study noted that previously in elderly patients with newly diagnosed myeloma, the VISTA trial demonstrated that the combination of bortezomib plus
melphalan – prednisone (VMP) is significantly superior to MP alone.
However, it is unclear which agent is the optimal partner
for bortezomib: an alkylating agent or an immunomodulatory drug, so they set out to answer this critical question by comparing VMP to VTP, where T is thalidomide.

The results indicated that:

"1. Both modified induction schedules (VMP and VTP) are highly effective with similar ORR and CR rates, but a
clear different toxicity profile (more neutropenia, but less cardiac
toxicity and peripheral neuropathy with VMP)

2. Maintenance therapy with either VT and
VP markedly improve the quality of responses with a good safety
profile

3. The combination of these induction and
maintenance schedules seems to overcome the poor prognosis of high-risk cytogenetic abnormalities in elderly MM patients"

It should be noted that while melphalan causes more neutropenia, the cardiac toxicity seen with thalidomide is more difficult to manage, so the VMP combination is likely to be more suitable going forward in newly diagnosed elderly patients with myeloma.

One triple combination that garnered a lot of interest earlier this year at ASCO, was a trial looking at combining lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone (RVD) in relapsed or refractory myeloma patients, with overall response rates (ORR) of 69%, including 26% complete/near complete responses (CR/nCR) and manageable toxicities Anderson et al. ASCO 2009). The phase I portion of the study (Richardson et al. IMW 2009) found the maximum tolerated dose (MTD) of this combination in newly diagnosed myeloma patients to be lenalidomide (25 mg/day), bortezomib (1.3 mg/m²), and dexamethasone (20 mg). In all phase I patients, the ORR was 100%, including 31% CR, 9% nCR, and 75% very good PR (VGPR).

At this ASH meeting, we heard results reported for patients treated in the phase II portion of the study as conditioning prior to autologous stem cell transplantation (ASCT) by Dr Richardson, who concluded that:

"These phase II results suggest that RVD is a highly
effective combination, with a pre-ASCT ORR of 100% and high rates of CR/nCR, and encouraging time-to-event analyses to date. RVD
was well tolerated, with limited rates of grade 3 peripheral neuropathy and DVT/PE despite
prolonged use of bortezomib and lenalidomide."

The data are summarised in the table below, based on all patients (n=35):

Patients	ORR, %	CR/nCR, %	≥VGPR, %

Response at cycle 4 (n=31)	78	12	12
Response at cycle 8(n=24)	100	33	67
Best response	100	54	69

Some of the most exciting new developments in myeloma could be found in both the oral and poster sessions.

A new generation proteasome inhibitor, carfilzomib (PX-171), has been generating consistent results in the bortezomib refractory setting. An ongoing phase II study presented at ASH looked at carfilzomib monotherapy in myeloma patients with relapsed or refractory disease following 1–3 prior therapies, ie a heavily pre-treated population. Updated data for the bortezomib-treated cohort were reported at ASH and the authors concluded that:

"18% ORR (CBR 30%) is notable for this steroid- and
anthracycline-sparing regimen. Single-agent carfilzomib is well tolerated, even
in patients with renal insufficiency, and both myelosuppression and peripheral neuropathy
are uncommon."

Carfilzomib was originally developed by Proteolix, who have just been acquired by Onyx. This should ensure more solid funding for the development of the phase III program, which looks promising in the relapsed, refractory setting.

Perifosine (Keryx) modulates Akt, and a number of other signal transduction pathways,
including the JNK and MAPK, all of which are associated with programmed cell death, cell growth, cell
differentiation and cell survival. Updated data from a phase I/II study in 84 patients who were heavily pre-treated with a median of 5 prior lines of therapy (range 1-13), showed that the overall response rate (ORR) was 41%, for the bortezomib relapsed group, 65%, and for the bortezomib refractory group, 43%.

Approximately 60% of patients
demonstrated progression (or stable disease (SD) for 4 cycles) at some point in their
treatment and received 20 mg dexamethasone, four times per week, in
addition to perifosine plus bortezomib. Responses occurred both with
patients taking perifosine in combination with bortezomib and with
patients receiving the combination plus dexamethasone. The ORR for the perifosine plus bortezomib arm was 25%, with an increase to 38% when dexamethasone was added. Survival data in the 73 evaluable patients was 6.4 months for PFS and 25 moths for overall survival (OS).

Another exciting new compound in development is MLN4924 from Millennium, the novel mechanism of which was recently described in detail (see article below) and was the also subject of a Nature article. The compound works very differently from proteasome inhibitors, which target the proteasome substrate. MLN4924 is involved with neddylation rather than direct ubiquination.

Neddylation activating enzyme (NAE) is the E1-activating enzyme for the ubiquitin-like protein Nedd8.
NAE catalyzes the first step in the neddylation cascade leading to
modification of cullin-based ubiquitin ligase activity. This results in
specific protein substrates, with important roles in cancer cell
survival, being targeted for degradation as shown the diagram below:

Source: Soucy et al., 2009

The end result is that MLN4924 inhibits neddylation by disrupting the cullin-RING ligase-mediated protein turnover, leading
to apoptotic death in human tumour cells by a new mechanism of action,
the deregulation of S-phase DNA synthesis.

A phase I dose escalation study in myeloma and NHL patients with MLN4924 was reported at ASH. The primary objectives were to determine the maximum
tolerated dose (MTD) and safety profile of MLN4924, as well as describe the
pharmacokinetics (PK) and pharmacodynamics (PD) in blood. Among the 22 patients enrolled to date, the median age was 65 years, 14 had myeloma and 8 had NHL.

The results showed that NEDD8-Cullin levels in peripheral blood myeloma cells (PBMCs) were inhibited and Nrf-2 target gene
transcripts in whole blood were higher vs. baseline after MLN4924
administration, which is indicative of NAE inhibition. Cdt-1 and Nrf-2 levels in skin increased above baseline following the
second dose of MLN4924, which is indicative of NAE inhibition in peripheral
tissue. These results are promising and provide early proof of concept for the role of neddylation in myeloma.

Overall, this was a good meeting on the myeloma front with lots of promise for triple and quadruple combinations, as well as new agents being developed in both the newly diagnosed and refractory settings that augers well for the future, both in terms of improved survival and also more tolerable regimens.

Soucy, T., Smith, P., & Rolfe, M. (2009). Targeting NEDD8-Activated Cullin-RING Ligases for the Treatment of Cancer Clinical Cancer Research, 15 (12), 3912-3916 DOI: 10.1158/1078-0432.CCR-09-0343

Soucy, T., Smith, P., Milhollen, M., Berger, A., Gavin, J., Adhikari, S., Brownell, J., Burke, K., Cardin, D., Critchley, S., Cullis, C., Doucette, A., Garnsey, J., Gaulin, J., Gershman, R., Lublinsky, A., McDonald, A., Mizutani, H., Narayanan, U., Olhava, E., Peluso, S., Rezaei, M., Sintchak, M., Talreja, T., Thomas, M., Traore, T., Vyskocil, S., Weatherhead, G., Yu, J., Zhang, J., Dick, L., Claiborne, C., Rolfe, M., Bolen, J., & Langston, S. (2009). An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer Nature, 458 (7239), 732-736 DOI: 10.1038/nature07884

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Impact of the OIG guidelines on Pharma and Biotech

By MaverickNY on December 9, 2009

One of the most noticeable changes at the American Society of Hematology meeting this weekend was the impact of banning chotchkes and giveaways for health care professionals in the US:

Traffic in the exhibition hall was noticeably slow, except for a couple of booths
The booths were much smaller
Pharma companies provided more medical information staff and fewer sales reps
With the lack of credit and high cost of the booths, several small biotechs were also noticeably absent

Of course, when you needed a pen to jot something urgent down, none was to be found. I tried switching to the notepad on the iPhone to record a name and phone number and managed to drop the call twice. Oops.

Talking to several oncologist and hematologists in the exhibit hall about the topic was interesting. Getting pounced on by desperate or bored reps trying to promote something is never pleasant. They don't want to collect tonnes of paper based clinical trial and medical information when a flash key is smaller and easier to manage/access later. Of course, several Pharma companies defensive response was that legal had taken a draconian position of ultra conservatism and declared flash keys chotchkes and therefore not allowed under any circumstances.

Several of the booths had interesting interactive tools for browsing clinical trials or their pipeline for useful information. The problem was, you could only see it on the screen, no printouts or downloadable files of any kind, rendering the fancy program pretty but totally useless and impractical.

Here's some ideas they could have considered:

Mini CD's or flash keys with relevant medical or clinical trials information on them for later use.
Interactive tools for case based management enquiries, which allow the doctors to sign up and ask an expert peer for advice on patients via email, video or phone later.
Ditto, but have materials available in label that the sales reps can deliver offline post meeting.
Ditto, but information based on ongoing company clinical trials with a visit from the MLSO. This would encourage more trial participation in US or EU co-operative studies.
Incorporating social media programs that foster engagement and dialogue between peers to improve patient outcomes.
Sign up to have specific medical information enquiries about data presented at the meeting answered via SMS or email with a protected link to relevant clinical information from the medical affairs department.
Create useful and interesting medical iPhone and Droid apps such the excellent BlackBag news one that J&J did (but wasn't in evidence at the ASH meeting) so doctors can play with a demo at the booth and request an email with a link to the app for later downloading and use.

The ideas are endless, if applied creatively.

What was marketing thinking just creating loads of glossy paper based brochures no one wanted to carry home or destroy the forests? Or all those ads on light boxes pushing the name of your product?

Instead, Pharma seems slow to change from old media (print) and push marketing (DTC, ads) to more useful interactive PDA apps or digital tools, yet the vast majority of doctors were walking around with PDA's and using them constantly. A wasted opportunity to interact and build deeper relationships with your most important customers in many ways.

Maybe it's time for the industry to run syndicated surveys at a neutral booth to learn what health care professionals attending their annual meeting actually want or need? They can then tailor future programs to what the customers want.

For me, I'm mourning the loss of flash keys, the single most useful giveaway I can get hold of yet can never get enough of.

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How the costs of cancer care negatively impact patients

By MaverickNY on December 7, 2009

Pharma Strategy Blog has reached an exciting double milestone today – 500 posts and 100,000 views! Although the blog was started in 2006, most of the posts have been written over the last 18 months on a wide variety of topics from AIDS/HIV to cancer to rare stromal tumours, as well as notes from numerous conferences and observations on diseases, the Pharma industry, mergers & acquisition, industry leaders and even political reform of health care. We hope you have all enjoyed the ride and will continue to do so in 2010. Do keep your suggestions for interesting topics to cover coming in, we're only as good as the readers who share in the experience.

Right now, I'm in New Orleans covering the American Society of hematology meeting, which is one of my favourite annual meetings, and one I've regularly attended for the last 14 years. Just before I headed south I interviewed Dr Mary Ann Burg about the recent survey undertaken by the Association of Social Work (ASOW). The organisation released an important report late last week, describing the financial and emotional impact of the cost of cancer care on patients, caregivers and how social workers can help facilitate and ease the process as part of a multi-factorial team.

What particularly struck me forcefully in the brief discussion with Dr Burg is summarised in this chart below:

The excellent AOSW report also focused on multiple myeloma as an example of what happens to cancer patients going through treatment and how the costs of prescription drugs can have an impact. For example:

This data reminded me very clearly how much more expensive Celgene's Revlimid is compared to Millennium's Velcade (around a third to twice the cost). Myeloma is a big focus at this ASH, as you will see in other posts this week around the new exciting data coming out in lymphomas, leukemias and myeloma.

The report was also poignant given that the WSJ reported this morning that Allos Therapeutics were launching pralatrexate (Folotyn) in PTCL, a rare form of NHL, at a cost of $30,000 per month. To me, that's unconscionable, especially as the drug has only be seen to shrink tumours and not impact overall survival. We'll see how they fare, but I think I would rather die with my dignity intact than face the sort of extreme stress and financial worries described in the excellent ASOW report than even the co-pay would require. It does beg the question of:

What price a life?
What were they thinking?

Part of being a sensible corporate citizen in the pharma industry is recognising that we all have a duty to be fair minded, responsible and caring; greed in it's extreme form at the expense of patients well being is just nauseous and reprehensible.

Here's a rare call for action.

Please read the AOSW information here and digest the full impact of their findings for yourself. This affects all of us, as industry professionals, friends, caregivers, maybe even as a patient. Share it with others, if you blog or Tweet, write something about the report yourself or share this post or the ASOW link.

More on the ASH meeting and more about the AOSW will continue in other posts later this week.

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Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

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

There's no such thing as a free coffee in Pharma

Tarceva maintenance therapy in non-small cell lung cancer

ASH09 meeting report: chronic lymphocytic leukemia (CLL)

#ASH09 Report: Acute Myeloid Leukemia

In Memorium…

Understatement of the decade?

#ASH09 Update: Multiple Myeloma

How the costs of cancer care negatively impact patients