News | Pharma Strategy Blog

What's in Placebos: Who knows? Analysis of randomized, controlled trials

By MaverickNY on October 19, 2010

Background: No regulations govern placebo composition. The composition of placebos can influence trial outcomes and merits reporting.

Purpose: To assess how often investigators specify the composition of placebos in randomized, placebo-controlled trials.

Data Sources: 4 English-language general and internal medicine journals with high impact factors.

Study Selection: 3 reviewers screened titles and abstracts of the journals to identify randomized, placebo-controlled trials published from January 2008 to December 2009.

Data Extraction: Reviewers independently abstracted data from the introduction and methods sections of identified articles, recording treatment type (pill, injection, or other) and whether placebo composition was stated. Discrepancies were resolved by consensus.

Data Synthesis: Most studies did not disclose the composition of the study placebo. Disclosure was less common for pills than for injections and other treatments (8.2% vs. 26.7%; P = 0.002).

Limitation: Journals with high impact factors may not be representative.

Conclusion: Placebos were seldom described in randomized, controlled trials of pills or capsules. Because the nature of the placebo can influence trial outcomes, placebo formulation should be disclosed in reports of placebo-controlled trials.

via www.annals.org

Thanks to Bruce Lehr of the Big Red Biotech Blog for bringing this topic to my attention.

In many trials of new drugs in development such as cardiovascular, dermatology, neuroscience etc, the test agent is typically compared to a placebo with a similar formulation such as a pill, topical cream etc, but as the journal points out, rarely is the composition defined in detail.

This is not surprising, as the authors of the paper reported that they found that only a paltry 8.2% of the 86 studies they looked at actually stated clearly what the contents of the placebo were.

Does it matter?

Well, you might think it's just a 'sugar pill', but as this article in the LA Times noted, some placebos in cardiovascular trials might consist of olive oil or other polyunsaturated oils, thereby potentially reducing cholesterol and heart disease. Certainly something to think about, as they may have unexpected effects.

Although most cancer clinical trials are typically comparing a new treatment to the standard of care, often placebo is used in the comparator combination. A recent example is the abiraterone trial reported last week at ESMO in men with advanced, castration resistant prostate cancer after prior docetaxel therapy. The study compared abiraterone (a pill) with prednisone (a steroid) to placebo (pill) plus prednisone. Based on the information provided in clinicaltrials.gov, it isn't clear what the placebo actually was.

I liked the quote from the authors in the LA Times article above:

"Perfect placebo is not the aim, rather, we seek to ensure that its composition is disclosed."

Given the placebo could have unexpected effects or at least have an impact, perhaps we should start disclosing what's actually in them.

Biotech is booming in Boston

By MaverickNY on September 14, 2010

Yesterday I was on my way back from Marblehead and the Tufts Cycle for Life event and stopped by Boston for meetings.

While standing on the pavement contemplating my schedule, I checked out my industry news feeds to see what was happening.

Beantown was hopping around me yesterday!

Ariad

Announced the phase II trial of it's multi-kinase inhibitor, AP24534, which targets the T315I mutation in CML and is now named ponatinib. The drug also inhibits FLT3-ITD and the FGFR pathway.

According to Ariad:

"The PACE (Ponatinib Ph+ ALL and CML Evaluation) trial is designed to provide definitive clinical data for regulatory approval of ponatinib in this setting."

The goal will be to focus on the refractory setting after failure of Sprycel or Tasigna:

"The PACE trial is a global, single-arm clinical study of oral ponatinib in 320 patients with chronic phase, accelerated phase, or blast phase CML, as well as Ph+ ALL. Patients resistant or intolerant to dasatinib (Sprycel) or nilotinib (Tasigna), or with T315I mutation of BCR-ABL, will be enrolled in the trial."

Originally, this would have meant ponatinib would be used in 3rd line after imatinib, the dominant front-line therapy, and then either dasatinib or nilotinib in 2nd line. However, as the 2nd generation therapies move up to first-line, with nilotinib already approved in this indication and dasatinib due to be reviewed by the FDA soon, this could well mean that ponatinib could be used in 2nd line in the future should it garner good data and approval from the FDA.

This is a particularly promising agent because it is the leading compound being evaluated for the T315I mutation in CML, which none of the existing drugs target.

Genzyme

While all attention is on the seemingly never ending dance between Sanofi-Aventis and Genzyme over the possible buyout deal and price, an interesting press release from the biotech firm quietly announced the divesting of the genetic testing business to Lab Corp:

"LabCorp will purchase the business in its entirety, including all testing services, technology, intellectual property rights, and its nine testing laboratories. LabCorp is committed to offer employment to the unit’s approximately 1900 employees upon closing, including senior management. The agreement is subject to customary closing conditions, including the Hart-Scott-Rodino Antitrust Improvements Act of 1976, with the goal of closing before the end of the year."

This comes after the announcement late last week that 1,000 jobs will be lost over the next 2 years, which was rolling over the local news channels over the weekend. The mood in MA was less the buoyant as a result. The fallout from the manufacturing problems and subsequent fines are clearly having a major impact on the troubled biotech. I wonder what will be next to go?

Ironwood

Last but not least, a more uplifting development yesterday was the announcement by Ironwood and Forest Labs regarding positive top-line results from the first of two Phase 3 clinical trials assessing the efficacy and safety of their investigational drug, linaclotide, in patients with irritable bowel syndrome with constipation (IBS-C).

According to the press release:

"The two co‐primary endpoints required by the European Medicines Agency (EMA) were met in this study, showing statistical significance and clinically relevant improvement for linaclotide treated patients both for abdominal pain/abdominal discomfort responder and IBS degree of relief responder over the three‐month period. Significant improvement was also achieved for all pre‐specified main secondary endpoints (stool frequency, stool consistency, straining, and bloating).

The safety results were consistent with those observed in previous linaclotide clinical trials, with diarrhea being the most common adverse event in linaclotide‐treated patients."

This is very good news indeed for people suffering with the condition, especially as two huge global drug makers (GSK and Novartis) both tried, but failed, to bring a drug to market and keep it there.

Bear in mind that IBS is a debilitating and inconvenient condition that affects a lot lot of people, perhaps as many as 30 million suffer from the effects. It might sound a little dramatic, but IBS has unfortunately become a sort of sword-in-the-stone challenge to big Pharma. Ironwood may well be the young 'Arthur' for millions of people suffering with IBS.

If the safety and efficacy data hold up with the regulatory authorities, an approval for linaclotide would be very good news indeed for people suffering from this condition.

Photo Credit: Werner Kunz

Diabetes drug may protect against cancer

By MaverickNY on September 2, 2010

Yesterday, I covered some of the key pathways and kinases associated with cell energy metabolism, LKB1 and AMPK. These, together with Insulin-like Growth Factor-I (IGF-I) and the insulin receptor (IR), appear to play important roles in the broader regulation of energy and homeostasis. Experimental evidence suggests that an overexpression of IGF-I is implicated in pancreatic tumours, for example. Increased IGF-II and decreased IGF binding protein (IGFBP)-3 serum concentrations have also been linked to a number of other cancers (see journal link below).

If we look at the IGF-IR pathway, we can see more clearly how they all interlink and how mTOR, LKB1 and AMPK may all be a critical part of the process:

Source: Tao et al., (2007)

Research conducted over the past two decades has shown the importance of the type 1 insulin-like growth factor receptor (IGF-1R) in tumorigenesis, metastasis, and resistance to existing forms of cancer therapy. We also now know that feedback and cross-talk between IGF1R and IR can exist, driving hyperglycemia and free insulin production, as shown in a previous post regarding IGF-1R inhibition with figitumumab.

Clearly, there are drugs commercially available that reduce hyperglycemia in diabetes, so the next logical step would be to see what happens if they were to be used in cancer patients or people with a very high risk for developing cancer.

Background:

The journal Cancer Prevention Research has just published an interesting series of research papers around metformin, a generically available oral biguanide for the treatment of Type II diabetes, in cancer prevention. An excellent overview to the topic was covered in a comprehensive review of metformin for oncology applications by Michael Pollak, which is well worth reading.

In short, metformin was originally derived from a plant extract from the French lilac and activates AMPK in the liver. This means that it plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose. In diabetes, metformin therefore improves hyperglycemia primarily through its suppression of hepatic glucose production, ie gluconeogenesis.

If we accept the research that shows high levels of free IGFI (from the higher IGF-I/IGFBP-3 molar ratio) are important in cancer growth, then it makes logical sense to see what effects taking metformin might have on cancer prevention and risk reduction in animal models and humans.

Effect of metformin on lung cancer

Memmot et al., published a paper entitled, "Metformin Prevents Tobacco Carcinogen– Induced Lung Tumorigenesis" in Cancer Prevention and Research. The idea was that activation of the mammalian target of rapamycin (mTOR) pathway is an important and early event in tobacco carcinogen–induced lung tumorigenesis, thus therapies that target mTOR might be effective in the prevention or treatment of lung cancer. Since metformin activates AMPK, which in turn inhibits mTOR, they decided to investigate the possibilities in a mouse model. The mice were given a known cancer causing carcinogen, nitrosame ketone (NNK) and a group were treated with metformin and compared to controls (no treatment).

What they found was startling:

"Oral administration of 1 or 5 mg/mL metformin decreased lung tumor burden in mice by 38% and 53%, respectively."

What happened to the control mice who did not receive metformin? 100% of them developed tumorigenesis. To put these findings into perspective:

"The steady-state levels of metformin in mice given 5 mg/mL are similar to those in diabetic patients using metformin, suggesting the possibility that clinical prevention of lung cancer could be achieved with standard oral dosing."

Unsurprisingly even greater results were observed with direct intravenous metformin:

"intraperitoneal administration of metformin was more effective than oral administration and decreased tumor burden by 72%."

Overall, the researchers found that inhibition of the mTOR pathway in tumours was associated with decreases in levels of circulating IGF-I and insulin, which may well explain the dramatic results they saw with metformin.

Effect of metformin on colorectal cancer

Animal models are all very well, but what about human data? Japanese researchers have now reported the first study of metformin in people without diabetes, albeit on a small scale. Hosono et al., published an article, "Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial" after their earlier work in rodents. Rectal aberrant crypt foci (ACF) are an endoscopic surrogate marker of colorectal cancer, essentially an early precursor to malignant disease.

This work looked at prospectively randomized people without diabetes (n=26) with ACF to either treatment with metformin (250 mg/d, n=12) or no treatment (control, n=14). The initial results are promising:

"At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 ± 6.45 before treatment versus 5.11 ± 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 ± 6.65 versus 7.56 ± 6.75, P = 0.609)."

In other words, this is the first reported trial showing that metformin can inhibit colorectal carcinogenesis in man. It also provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation and may be a potentially useful agent for early cancer chemoprevention.

Conclusions

In an accompanying editorial, Engelman and Cantley provided some useful commentary on the underlying pathways and highlighted the promise of metformin for cancer prevention and therapy in the lung and other sites.

Of course, no pharma company is going to sponsor large scale epidemiology trials as metformin is now available generically, but given the prominence given to chemoprevention by Harold Varmus in his NCI acceptance speech earlier this year, perhaps we will see some progress from both the NCI and the NIH in this field. It's really a public health issue that needs a broader perspective than individual companies can offer alone.

We all intuitively know that preventing or catching cancer as early as possible will likely yield better long term outcomes for patients than treating end-stage metastatic disease with highly expensive therapies.

Additional References:

Douglas JB, Silverman DT, Pollak MN, Tao Y, Soliman AS, & Stolzenberg-Solomon RZ (2010). Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 Molar Ratio and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699371

Tao Y, Pinzi V, Bourhis J, & Deutsch E (2007). Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway–therapeutic perspectives in cancer. Nature clinical practice. Oncology, 4 (10), 591-602 PMID: 17898809

Chitnis MM, Yuen JS, Protheroe AS, Pollak M, & Macaulay VM (2008). The type 1 insulin-like growth factor receptor pathway. Clinical cancer research : an official journal of the American Association for Cancer Research, 14 (20), 6364-70 PMID: 18927274

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Michael Douglas has throat cancer?

By MaverickNY on August 16, 2010

This afternoon I was chatting with a Pharma friend via IM when she sent me a surprise link:

Michael Douglas to Undergo Chemo for Tumor in Throat Cancer

Oof, he was one of my favourite actors growing up as a child – I just loved the Streets of San Francisco! He also made Gordon Gekko famous in Wall Street.

There's a lot of throat cancer in the news lately. The most recent was Alex Higgins, the incredible Irish snooker player who was a truly sensational player from my childhood.

I wrote about him recently here. Be warned – the before and after pictures are a little shocking.

A recent photo of Michael Douglas on ABC News was also a shock, as he looks much more haggard than I remember 🙁

Lately, I've been watching re-runs in the evenings of the classic gritty but violent English detective drama from the 1970's, The Sweeney, starring John Thaw and Dennis Waterman. Idly clicking through to IMDB, I wondered what had become of Thaw, who also starred in Inspector Morse, only to discover that he, too, had passed away in 2002 – from throat cancer.

What is common with these three men? Well, alcohol and cigarette smoking contributed no doubt, as the American Cancer Society lists both of these as two of the potential risk factors for laryngeal and hypopharyngeal cancer, the medical term for throat cancer, which is often referred to as oesophageal cancer in the UK. The median age of diagnosis is round 65, so Douglas, Thaw and Higgins were all around the peak of the age range bell curve (60-65).

Hopefully, Michael Douglas's cancer has been picked up early and he will make a full recovery from chemotherapy. I really hope so, it's very sad to see one's favourite childhood heroes dropping 🙁

Photo Credits:

Manny the Movie Guy

The Sweeney Info

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Chemoprevention in Prostate Cancer – do 5alpha-reductase inhibitors make things worse?

By MaverickNY on August 12, 2010

There's a lot of media coverage today surrounding use of 5alpha-reductase inhibitors such as finasteride (Merck) and dutasteride (GSK) and their generic equivalents for chemoprevention of prostate cancer following publication of a study on finasteride by the American Association of Cancer Research (AACR) and one earlier this year on dutasteride in the New England Journal of Medicine (see references below for sources and the journal articles).

So what do these drugs do?

The drugs in the 5alpha-reductase class were developed for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to:

Improve symptoms
Reduce the risk of acute urinary retention
Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and prostatectomy.

Fair enough, but how does this relate to prostate cancer?

Well, testosterone is the major circulating androgen in men and is converted to the major intracellular androgen, dihydrotestosterone, by steroid 5alpha-reductase isoenzymes, designated as type 1 and type 2. Finasteride inhibits the type 2 isoenzyme, whereas dutasteride inhibits both.

Many of you will be aware that in early stage prostate cancer, most men are hormone sensitive and respond to androgen deprivation therapy (ADT), which effectively acts as chemical castration to suppress the growth of the tumour of the prostate. Later, when castration resistance sets in (CRPC), the disease is more advanced. These days, if they are asymptomatic or mildly symptomatic, then a vaccine called sipuleucel-T (Provenge) can be considered or if metastatic and symptomatic, then chemotherapy with docetaxel (Taxotere) can be considered as a first-line option or cabazitaxel (Jevtana) after docetaxel has failed.

The goal of using the 5alpha-reductase inhibitors early was therefore to prevent or at the very least delay the development of malignant prostate cancer, essentially reducing the risk of developing the disease later. Several studies have been published over the last decade to answer this question.

The big question is does this approach actually work?

My thinking was if it was that obvious, then surely urologists and primary care physicians would be rushing to prescribe either therapy? Trouble is, they're not, as this succinct AACR press release shows.

One of the problems is that the original Prostate Cancer Prevention Trial (PCPT) study back in 2003, a large randomized controlled trial consisting of 18,000 men, appeared to have conflicting results, since it showed:

a 25 percent reduced risk of prostate cancer.
a 27% increased risk in high-grade tumours, which was highlighted in the accompanying editorial.

This fact seems to have created doubt and concern amongst urologists and PCP's.

Subsequently, there have been other reported studies with finasteride in 2008 (reanalysis of the 2003 data) and with dutasteride in the NEJM earlier this year, suggesting in both cases that the risk did not exist. The doubt, however, still lingers as the AACR press release highlighted:

"64 percent of urologists and 80 percent of primary care physicians never prescribe finasteride for chemoprevention.

When asked for reasons for their decision, 55 percent said they were concerned about the risk of high-grade tumors and 52 percent said they did not know it could be used for chemoprevention."

Another issue is the conflicting consequence of PSA suppression, which is still used by many urologists as the main biomarker for diagnosis and ADT treatment. The NEJM editorial earlier this year noted the challenge:

"Among men without cancer, both finasteride and dutasteride treat lower urinary tract symptoms, produce dramatic prostate shrinkage, and reduce serum levels of PSA by 50% or more.

However, for the patient who believes that he is taking a drug to prevent prostate cancer, this decline in PSA level can lead to a false sense of security."

Why is this? The editorial went on to explain:

"Data from the PCPT indicate that finasteride produces a progressive suppression of PSA for the duration of treatment. To estimate what the “true” PSA level would be if finasteride were not taken, it is necessary to multiply the PSA level by 2.0 for the first 2 years, by 2.3 for years 2 through 7, and thereafter by 2.5.

However, if the PSA level ever begins to rise at all, a biopsy should be performed, because with an increase in PSA level, the risk of cancer is increased by a factor of 3 and the risk of high-grade disease is increased by a factor of 6.

In the Finnish study, men who received finasteride for more than 4 years had a risk of high-grade disease that was increased by a factor of 2.6."

After reading all of the evidence in the various studies (cited below), I can see why physicians might be:

Confused
Concerned

It's hard to make solid sense of the real impact of all the research, even as an unbiased scientist given the data that has emerged. My overall takeaway from all the articles was as follows:

Dutasteride and finasteride do not prevent prostate cancer.
They do shrink tumours that have a low potential for being lethal.
They do not reduce the risk of a positive biopsy in patients who have an elevated PSA level or an abnormal digital rectal examination.
Use of these drugs for prevention may be controversial because PSA levels are suppressed, giving a false sense of security.
If prostate cancer develops, the diagnosis may be thus delayed (by artificially low PSA levels) until they have high-grade aggressive disease that may be more difficult to cure.

My final observation is that perhaps we should be monitoring other markers of disease such as circulating tumour cells (CTCs) in the blood rather than PSA. Whether this would be a better measure of disease or not remains to be elucidated, but would certainly be worth looking at in future studies to see if it is a more accurate biomarker in early prostate cancer.

Hamilton RJ, Kahwati LC, & Kinsinger LS (2010). Knowledge and Use of Finasteride for the Prevention of Prostate Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology PMID: 20699373

Andriole, G., Bostwick, D., Brawley, O., Gomella, L., Marberger, M., Montorsi, F., Pettaway, C., Tammela, T., Teloken, C., Tindall, D., Somerville, M., Wilson, T., Fowler, I., & Rittmaster, R. (2010). Effect of Dutasteride on the Risk of Prostate Cancer New England Journal of Medicine, 362 (13), 1192-1202 DOI: 10.1056/NEJMoa0908127

Walsh, P. (2010). Chemoprevention of Prostate Cancer New England Journal of Medicine, 362 (13), 1237-1238 DOI: 10.1056/NEJMe1001045

Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, & Coltman CA Jr (2003). The influence of finasteride on the development of prostate cancer. The New England journal of medicine, 349 (3), 215-24 PMID: 12824459

Lucia, M., Darke, A., Goodman, P., La Rosa, F., Parnes, H., Ford, L., Coltman, C., & Thompson, I. (2008). Pathologic Characteristics of Cancers Detected in the Prostate Cancer Prevention Trial: Implications for Prostate Cancer Detection and Chemoprevention Cancer Prevention Research, 1 (3), 167-173 DOI: 10.1158/1940-6207.CAPR-08-0078

Murtola, T., Tammela, T., Määttänen, L., Ala-opas, M., Stenman, U., & Auvinen, A. (2009). Prostate cancer incidence among finasteride and alpha-blocker users in the Finnish Prostate Cancer Screening Trial British Journal of Cancer, 101 (5), 843-848 DOI: 10.1038/sj.bjc.6605188

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Menopausal hormone therapy and subsequent risk of invasive breast cancer subtypes

By MaverickNY on August 10, 2010

There has been much conflicting evidence out there on risk factors associated with various cancer types that it is sometimes hard to remember what’s important.

A press release from the American Association of Cancer Research (AACR) on menopausal hormone therapy and the risk of developing breast cancer therefore caught my attention with these highlights:

Risk varied according to BMI, with greater risks for thinner women.
Longer duration of hormone therapy increased breast cancer risk.

The latter was no surprise at all, but seriously, I thought I had read before that a higher not lower BMI was associated with an increased breast cancer risk, but on reflection, that may have been in pre-menopausal not menopausal women.

The authors of this particular research noted that:

“There is substantial epidemiologic, experimental, and clinical evidence that the risk of breast cancer is elevated with the use of menopausal hormone therapy (HT), with formulations containing estrogen and progestin (EPT) resulting in a substantially higher risk than formulations containing estrogen only (ET).”

Despite this evidence, many physicians (PCP’s and gynaecologists) still prescribe different formulations of hormone therapy for treatment of menopausal symptoms:

“It remains unclear whether the number of days per month of progestin use affects risk, specifically whether the continuous-combined EPT regimens (e.g. Prempro) differ from sequential regimens. Continuous combined HT was associated with the highest risk of hormone-sensitive breast cancer in some, but not all studies.”

Breast cancer is clearly getting increasingly more complex these days with many subsets to consider based on numerous biomarkers and risk factors:

“Some evidence supports a selective increase in risk of particular breast cancer subtypes associated with EPT use, i.e., the estrogen receptor–positive and progesterone receptor–positive subtypes (ER+/PR+).”

This additive effect with EPT can be explained by an increased mitogenic effect of progesterone in the breast tissue. There is also a need to understand what happens in poor prognosis subsets such as women with triple negative breast cancer (i.e. ER-/PR-/HER2-).

The authors thus reported on the California Teachers Study, a longitudinal epidemiologic trial, which looked at hormone replacement therapy use among 2,857 women for almost 10 years.

Overall, the AACR press release I received summarised the findings nicely:

Breast cancer risk seemed dependent on body mass index (BMI).
Those with a BMI less than 30 appeared to have an increased risk of breast cancer with combined hormone therapy; the risk was strongest among women with BMI less than 25.
In contrast, obese women (i.e. BMI of 30 or more) had no further increase in risk associated with using combined hormone therapy.
The risk of breast cancer was confined to tumors that were positive for both estrogen and progestin receptors. The risk was somewhat weaker for HER2 negative tumors.

Overall, as we have seen with other studies, the research demonstrates that there is a consistent increased risk of breast cancer from hormone therapy use, but it also underscores the need for individual risk-benefit discussions before women begin such therapy, because some subgroups may have different risk profiles.

{UPDATE: the DOI link is not yet working in research blogging so here is the direct link to the abstract and article for now. Will edit the link later once it has been processed.}

Saxena, T, Lee, E, Henderson, KD, Clarke CA,, West, D, Marshall, SF, Deapen, D, Bernstein, L, & Ursin, G (2010). Menopausal Hormone Therapy and Subsequent Risk of Specific Invasive Breast Cancer Subtypes in the California Teachers Study Cancer Epidemiology, Biomarkers & Prevention, 19 (9) :10.1158/1055-9965.EPI-10-0162

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Celgene buy Abraxis Bioscience for $2.9B

By MaverickNY on June 30, 2010

I did a double take at my inbox alerts this morning as things have been rather quiet of late in the Pharma and Biotech world. You can read the financial aspects of the deal in Celgene's press release.

While the timing might be a little bit of a surprise, the strategic acquisition is not and makes a lot of commercial sense for Celgene. There are a number of reasons for my thinking here:

It continues to build out of hematology with the beginnings of a solid tumour franchise since Abraxane is approved for breast cancer and has trials ongoing in pancreatic, lung, melanoma and bladder cancers.
The patent life for Abraxane is something like 2023, much longer than lenalidomide (Revlimid) and with few near term opportunities in the oncology pipeline, this adds extra protection.
Abraxane, while more expensive than generic paclitaxel, has probably been underfunded in clinical development and marketing efforts to date, so Celgene's thorough and aggressive approach may well kick start things, especially as they have cash to do so.
Buying Abraxis gives them access to nanotechnology, which I think will become more important in the future as an improved drug delivery system.

Late last year, while at the AACR Molecular Targets meeting in Boston, I wrote about nanoparticle technology and how it appears to offer a chance of improved outcomes in pancreatic cancer using Abraxane. The concept described by the researchers at Mass General was solid and promising, as was the early phase I data. Sometimes, it's not just about drug A being better or more potent than drug B, but the science and thinking behind solving a problem is elegant and well thought out. This was one of those cases. A couple of Phase II trials have so far yielded early but promising results in a devastating disease. The latest results, reported by the Abraxis in May this year, look encouraging so far.

Of course, most oncology specialists will know that melanoma, pancreatic and lung cancers as probably three of the four toughest cancers to get positive results in from phase III trials (the fourth is glioblastoma), but if any of them actually pan out with a significant difference in overall survival and FDA approval, then Celgene will have another winner on it's hands. I say 'if' because the road to approval and cancer drug development is littered with promising phase II studies that flopped or were sadly cancelled for futility in phase III.

Time will tell if this was a good acquisition or not, but for now, it's early but promising. That's ultimately both the lure and the heartache that is oncology.

You have to make the big plays to win.

New imaging technique shows promise in detection of Alzheimer's Disease

By MaverickNY on June 25, 2010

"Dr. Skovronsky thought he had a way to make scans work. He and his team had developed a dye that could get into the brain and stick to plaque. They labeled the dye with a commonly used radioactive tracer and used a PET scanner to directly see plaque in a living person’s brain. But the technology and the dye itself were so new they had to be rigorously tested.

And that is what brought Dr. Skovronsky, a thin and eager-looking 37-year-old, to his e-mail that recent day.

Five years ago, Dr. Skovronsky, who named his company Avid in part because that is what he is, had taken a big personal and professional gamble. He left academia and formed Avid Radiopharmaceuticals, based in Philadelphia, to develop his radioactive dye and designed a study with hospice patients to prove it worked.

Hospice patients were going to die soon and so, he reasoned, why not ask them to have scans and then brain autopsies afterward to see if the scans showed just what a pathologist would see. Some patients would be demented, others not.

Some predicted his study would be impossible, if not unethical. But the F.D.A. said it wanted proof that the plaque on PET scans was the same as plaque in a brain autopsy."

Source: NY Times

If you haven't already read the article in the NY Times, click on the link above and check it out. It's well worth reading. How many of us have elderly parents who have Alzheimer's, who sadly died from the devastating condition or know friends going through the trials and tribulations as caregivers?

I love this story – a scientist gets germ of an idea, is convinced it will work, leaves his employment and sets up a company (Avid Radiopharmaceuticals) to research the possibilities. That's the very entrepreneurial spirit that made America great.

Basically, the concept is that using a special dye to highlight the plaques would show up on brain scans in Alzheimer's patients. At moment, the only known way of showing proof of the disease is when a pathologist looks for the black specks of plaques in the brain during a post mortem. Finding a way to be sure that the disease exists earlier has proven elusive so far. In the NY Times article, they showed what Dr Skovronsky has found so far. You can see the plaque buildup (red) in Alzheimers on the bottom compared to someone who did not have the disease:

Source: Dr Skovronsky in the NY Times

If the results prove conclusive and the dye gets FDA approval, researchers will have the first reliable method of detecting the disease early and also a potential marker of determining whether any future therapies are having an impact in reducing the plaques.

The data is being presented next month at the Alzheimer's Association so there is bound to be a lot of excitement and anticipation surrounding the data. This is the sort of thing we scientists get excited about, even if it's not in our field. My first thoughts on reading the NY Times were, "A dye? Wow, I wish I had thought of that!" I got goosebumps just reading it.

Of course there is a long way to go, but let's hope for the future of new drugs in the pipeline that the dye will turn out to be a great marker and the tide turns on future development of better and earlier pharmaceutical intervention for a devastating disease.

Should use of CT scans be reduced?

By MaverickNY on June 24, 2010

Last night I was reading about the latest Iressa (gefinitib) data in lung cancer published in the NEJM, but unfortunately the DOI code isn't yet available for easy tagging and linking of the article in Research Blogging, so it will have to wait until it's out.

There was, however, a pair of interesting articles on computerised tomography (CT) scans (see references and links below). While the use of such scans has clearly improved diagnosis, it has come at a cost – both in terms of expenditure and also with respect to increased risk of radiation exposure:

"We found that the risk of cancer from a single CT scan could be as high as 1 in 80 — unacceptably high, given the capacity to reduce these doses."

Source: Smith-Bindham, NEJM

"Changing the culture of medical practice to encourage more thoughtful use of imaging today will help to ensure that future patients will benefit from continued imaging innovation."

Source: Hillman and Goldsmith, NEJM

Good points both, but little is likely to change unless the payers and insurers force them economically. Physicians are typically cautious and conservative by nature and would rather check to see if any cancer might be present than risk missing it or be hit with a law suit for negligence. Given that radiation has not been shown conclusively to be cancer-causing, most would probably rather be safe than sorry.

Smith-Bindman, R. (2010). Is Computed Tomography Safe? New England Journal of Medicine DOI: 10.1056/NEJMp1002530

Hillman, B., & Goldsmith, J. (2010). The Uncritical Use of High-Tech Medical Imaging New England Journal of Medicine DOI: 10.1056/NEJMp1003173

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Two new cancer drugs approved – cabazitaxel and nilotinib

By MaverickNY on June 18, 2010

Yesterday brought two new approvals in a day from the FDA in completely different cancer types.

In the morning, sanofi-aventis' cabazitaxel (Jevtana) was approved in castrate-resistant prostate cancer after failure of docetaxel (Taxotere) several months ahead of schedule. This approval comes hot on the heels of Dendreon's sipuleucel-T (Provenge) in asymtomatic metastatic prostate cancer last month.

What this means is that once androgen ablation therapies stop working, there are three new treatment options for men with prostate cancer, none of which compete with each other, with the possible exception of the chemotherapies, since docetaxel is often given in second-line in men who previously responded well and have had a treatment break. It will be interesting to see if this approach continues or if oncologists will prefer cabazitaxel in those with a good performance status.

The real impact of cabazitaxel though, is on other agents in development. Currently, abiraterone (Cougar Biotech/J&J) and MDV3100 (Medivation/Astellas) were being tested in docetaxel refractory prostate cancer, but now there is a new standard of care, whereas previously there was none. Clearly, common sense suggests that their role might be more impactful earlier in the disease, either after hormonal therapies fail, instead of or in combination with them, especially given that they are oral therapies, making them attractive to urologists.

Classic drug development usually means starting in the relapsed or refractory metastatic setting. The next few years will be thus be interesting to watch, especially if the agents in clinical trials prove successful. For now, Dendreon have a couple of years breathing space until the market potentially starts to get more crowded.

The other Priority approval yesterday was for Novartis' nilotinib (Tasigna) in newly diagnosed chronic myeloid leukemia (CML) on the basis of higher and earlier response rates versus the current standard of care, imatinib (Gleeevc). Full approval follows later once the survival data is more mature, but the early 12 month data looks interesting with a significant advantage to nilotinib over imatinib. It's still early though, survival curves can do strange things over time and can cross over.

Still, it's a promising start and a good result, especially since the bar was raised very high by imatinib. Prior to imatinib, ten year survival in CML was 10 to 20% at best with high dose interferon, but imatinib raised that dramatically to 90%. The second generation TKIs such as nilotinib and dasatinib (BMS) will thus potentially represent incremental survival improvements to 93 or 94%, to put them in context.

Of course, nilotinib's approval will possibly impact dasatinib (Sprycel) since they have just filed for the same indication, making Priority review more unlikely. The last time that happened to two drugs in the same cancer type was for Erbitux (ImClone) and Avastin (Genentech), who filed a few weeks apart, but in two different indications (newly diagnosed and 3rd line).

If dasatinib does get a Priority review after nilotinib it will set a new precedent, but if it doesn't get Priority review, I wonder if an ODAC will occur given that's usually what happens with standard 12 month review?

What's fascinating about the dasatinib data is that it also demonstrated earlier and deeper responses than imatinib, but the front-line data presented by Drs Kantarjian and Baccarani at ASCO and EHA respectively, did not appear to show any earlier survival benefit at 12 months for dasatinib vs imatinib, unlike nilotinib. I say 'appear' because the curves were very close together and no P value was given, so my assumption is that they weren't significantly different at this stage. That may change over time, but for now, the DASISION data presented by Dr Kantarjian showed a 12 month OS of 97.2% to dasatinib and 98.8% to imatinib, presumably not a significant difference. Deaths in the two arms were 10 and 6 respectively, again favouring imatinib, but not significantly.

Obviously, comparing these curves at 5 years would be a much fairer comparison for overall survival, but for now, the 12 month data is all we have to go on and there are early differences between nilotinib and dasatinib.

It was also interesting to watch the often hyped and inelegant reporting of the data by the media at the Congresses proclaiming superiority. We know that in solid tumours, shrinkage or tumour response does not always lead to an improved survival benefit for the patient. Similarly, in leukemia, we also measure response rates – in this case – complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR), as initial surrogate markers for initial approval, but survival is also critically important for full approval in the US. Interestingly, the early log 4 reduction (CMR) rates seemed to slightly favour nilotinib over imatinib (but not significantly), however none were presented at ASCO or EHA for dasatinib over nilotinib (unless I missed the slides).

Ultimately, ASH will herald the 2-year and 18-month data for nilotinib and dasatinib respectively, which will hopefully be an important milestone on the way to seeing how the mature five year surviv
al data will evolve.< /p>

Disclosure: I'm a former Novartis employee and marketing director for Gleevec, so naturally I'm slightly biased towards imatinib :). Many thanks to @erohealth for proofreading suggestions.

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Two new cancer drugs approved – cabazitaxel and nilotinib