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Two articles in this week's Neurology consider the significance of biomarkers for Alzheimer disease in the cognitively normal elderly.

Essentially confirming a recently published Mayo Clinic study, investigators from Texas reported the high prevalence of beta amyloid deposits (detected with Avid Pharmaceutical's PET tracer florbetapir) in the brains of a substantial portion (~20%) of healthy elderly subjects (aged 60 years or older). A high burden* of beta amyloid was associated with 1) the presence of the e4 allele of APOE, a genetic risk factor for AD and 2) poorer cognitive performance on more sophisticated** cognitive tests. The authors, two of whom receive financial support or have a financial interest in Avid Pharmaceuticals, suggest that "subtle cognitive changes accrue as amyloid progresses." The implication being that brain amyloid in the so-called healthy elderly may be more predictive than not about the risk of AD (an essential point or spin, if you will, which argues for the clinical utility of Avid's amyloid tracer). However, the authors also concede that "the relative contribution of amyloid vs other well-demonstrated predictors of cognitive aging (eg, regional atrophy, leukoaraiosis) is unclear." Among recommended follow-up studies is the assessment of the long-term consequences of amyloid deposition—ie, Are cognitively normal elderly with high amyloid burdens more like to development AD...that is, if they live long enough?. The question can only be answered with longitudinal follow-up study, which is planned.

Another multi-multi-authored international study assessed the effect of aging on the diagnostic value of CSF biomarkers for AD—specifically the triad of decreased amyloid and increased total and phosphorylated tau—in cognitively normal elderly. This study was distinctive in that, in addition to assessing individuals with AD and healthy elderly controls, a short (2-year) longitudinal assessment was made of subjects with mild cognitive impairment (MCI). The related conclusions (if I'm reading this article correctly and can recall anything useful about specificity, sensitivity, and positive and negative predictive values***) are 1) that there is substantial overlap in the biomarker distributions among these subgroups with advancing age and 2) that (therefore) the specificity of the biomarkers for ruling out AD decreases with age. Nevertheless, the sensitivity (85% cutoff) for the triad in MCI and AD, perhaps not too surprisingly, remained stable. In other words, the biomarker triad lost its strength to identify people with truly negative results as they aged (a decreased negative predictive value), but its ability to recognize truly AD-consistent findings (positive predictive value) remained stable—at least according to the authors and/or how I'm reading the study.

The overall conclusion, therefore, is that positive biomarkers for AD become less and less meaningful (as an indicator of AD) in the general elderly population—which is, ironically, the group in which these tests are most likely to be needed and used.

Addendum: Some would view these study results to mean that amyloid deposits and the triad of CSF changes are suggestive (or even indicative) of age-dependent cognitive dysfunction, albeit very subtle cognitive dysfunction. But the capacity of these tests to support or even confirm a diagnosis of clinical AD—depending on how we're defining the condition (there's the rub, isn't it?)—appears to be eroded in the older, general population (because they're more likely to demonstrate these findings, regardless of whether they demonstrate clinical meaningful cognitive dysfunction).

APOE = apolipoprotein E; SUVR = standardized uptake value ratio.

* At a mean SUVR cutoff of 1.22 or greater.
** Meaning more sophisticated than the Mini-Mental State Examination (MMSE).
*** Damn you, rudimentary biostatistics, when will you leave me alone!

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

At last, something positive (albeit very preliminary) to report about the use of human embryonic stem cells (hESCs)...in disease, no less.

Yesterday The Lancet published (and made freely available—!) early safety results from Advanced Cell Technology's 2 prospective phase 1/2 clinical studies of hESC-derived retinal pigment epithelium in 2 blind patients, one with dry age-related macular degeneration and the other with a much rarer, genetic equivalent, Stargardt's disease. Both diseases result from the degeneration of the RPE, which leads to photoreceptor loss, and the former condition is the leading cause of blindness in the developed world.*

During the 4 months after subretinal transplantation of RPE cells, the investigators confirmed structural attachment and no evidence of hyperproliferation, other signs of abnormal growth, or rejection in either patient. In addition, the patients reported very modest improvements in vision from baseline; although a placebo effect in these cases is probably very strong. Most important, however, is that neither patient described a deterioration in vision.

The authors conclude that the "future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue." The estimated enrollment for each of the ongoing studies is 12.


* For leading causes of blindness in the world, go here.

Graphic of retina with evidence of AMD from an NIH web page.

01/25/12 addendum: According to an astute ophthalmologist, it should be noted that patients in these hESC transplantation studies require immunosuppression to reduce the risk of graft rejection, namely in the form of tacrolimus (eg, Prograf) and mycophenylate mofetil (eg, CellCept). Although it's been previously reported that hESC transplantation may be more feasible in the eye, because the environment is relatively immune privileged, this is only really true for the cornea and natural lens of the eye, which lack blood vessels. The retina and the underlying choroid are highly vascular; consequently immunosuppression is a must with the subretinal grafting of hESC RPE cells. Autologous retinal grafts (which appear to be in an even earlier stage of development) would preclude the need for immunosuppressants. This recent review describes the current status of using stem cells for the treatment of retinal diseases.

Medivation and partner Pfizer will cease development of Dimebon (latrepirdine), a now thoroughly defunct antihistamine, "for all indications and will terminate the ongoing open label extension study in Alzheimer's disease." The small biopharm company announced the official end of Dimebon development yesterday in a press release, and the story was picked up by the WSJ. Dimebon's demise is based on flat results in the companies' CONCERT trial, a phase 3 study in which Dimebon was assessed as add-on treatment to symptomatic treatment donepezil (Aricept) in patients with mild-moderate AD.

Previous news on Dimebon (March 2010) was that it failed to improve cognition or global functioning in a placebo-controlled phase 3 study of patients with AD, and Medivation's share price plummeted 30 points on the dated news. In 2008, Pfizer agreed to pay Medivation $225 million upfront and another $500 million when Dimebon was FDA approved. The agreement—which split development costs and potential profits on a 60-40 basis (Pfizer assumed the larger share)—also conferred licensing rights to Pfizer for use of the drug in Huntington's disease. But Dimebon also disappointed in this devastating condition.

Pfizer was evidently betting on the chance that Dimebon would sail through US clinical development, given very favorable phase 2 results published in The Lancet in July of 2008.  In a randomized, double-blind, placebo-controlled, multicenter study (N = 183) that was conducted entirely within Russia and funded by Medivation, patients with mild-moderate AD who received Dimebon demonstrated significantly less cognitive decline at 6 months, as measured by the ADAS-cog (mean score difference, 4.0; P < .0001). Although some were scratching their heads as to why an antihistamine would have a disease-delaying or merely symptomatic effect in AD. The ultimate, tired lesson: promising phase 2 results are not a harbinger of anything, except chancy phase 3 study.

Medivation reminds us that it's also developing an investigational drug (MDV3100) with Astellas for the treatment of advanced prostate cancer. The compound is in the phase 3 stage, and Medivation got a huge bump in its stock price in late October just before news of very favorable survival data was publicly released.

About one-third of cognitively normal elderly demonstrate an elevated load of beta-amyloid,* a pathologic hallmark of Alzheimer disease, in the brain, according to a newly published study from the Mayo Clinic. These data support previous observations, in which the PET-imaged brains of about a third of elderly, nondemented subjects will exhibit an abnormal accumulation of the AD-associated protein.

However, the Mayo investigators went a bit further by examining the potential association between the load of beta-amyloid, as measured with an established radiolabeled tracer (Pittsburgh compound B, or PiB) on PET images, and cognitive performance on various memory, language, attention, and visuospatial tests. As well, a relationship among brain amyloid, cognitive performance, and APOEe4 status (a well-known genetic marker for AD) was examined. What the researchers found was that poorer cognitive performance was associated with greater amyloid deposition, and that this relationship was more robust in APOEe4 carriers. Conversely the association between amyloid load and relative cognitive impairment was much weaker (ie, only "modest") in subjects who did not carry an APOEe4 allele, suggesting (the authors concluded) "that APOE isoforms modulate the harmful effects of [beta-amyloid] on cognitive function."

What any of this information means practically is very murky, however. Will some of these cognitively normal subjects with heavier amyloid burdens (and who perform less well on cognitive tests) develop AD—that is, if they live long enough? Is AD more likely in these subjects if they're APOE e4 carriers? We don't know, and obviously further longitudinal work is necessary. The Mayo authors do imply that follow-up is ongoing.

In an accompanying editorial, Buchman and Bennett commended the Mayo investigators for the size of the study (a highly respectable 408 subjects [with a median age of about 80 years]) and their "important contribution to our understanding of AD, illustrating that even among persons without dementia or [mild cognitive impairment], amyloid deposition is associated with very mild symptoms, especially among carriers of the APOE e4 allele." But "[w]hether...amyloid imaging agents will have clinical utility remains to be determined," the editorialists appropriately caution. They advise about the lack of data concerning the prognostic value of amyloid retention (presumably in any subjects, whether demented or not) and how amyloid retention may change over time. And they add that the utility of amyloid-imaging agents "will remain low in the absence of an effective amyloid modulating agent." In other words, what's the point of knowing the amyloid burden if you can't do anything to lighten the load?

A related issue, however, not explored by the editorial authors, is whether even removing amyloid in the context of cognitive impairment, is beneficial or, in fact, does more harm. Existing AD trials suggest that amyloid-modulating agents (eg, bapineuzumab) can cause brain edema—presumably due to the removal of vascular amyloid—and that they do so without improving cognition to any substantial degree overall.

Intervening earlier with anti-amyloid drugs in less cognitively impaired subjects, as proposed by some industry investigators, is a tricky move: obviously primum non nocere in persons with only mild cognitive impairment and certainly in individuals with no practical cognitive problems (regardless of their amyloid burden).

PET = positron emission tomography.

* Defined by a "global cortical PiB retention ratio" of greater than 1.50.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

First Jeffrey Kindler, then Lipitor, and now this: Pfizer announced today that it's* its dependency on the FDA's approval is over.

* Bloody hell.

Yesterday the FDA announced that it will evaluate postmarketing reports of "serious" bleeding in patients taking the anticoagulant Pradaxa (dabigatran); although the agency doesn't say how many reports of serious bleeding have been received since the drug was approved a little more than a year ago.* The FDA is basing its analysis on data from its own pilot program, the Mini-Sentinel system, as well as submitted information to its standard reporting system, AERS.

Currently Pradaxa is only available in the United States in the form of 150- and 75-mg pills, the latter approved for renally compromised patients (CrCL 15-30 mL/min) and solely on the basis of pharmacokinetic studies. The FDA has been criticized for failing to approve the 110-mg pill, which was shown to be comparable (ie, nonsuperior) to warfarin in the large RE-LY trial (for background, start here). According to SDI's proprietary national tracking services, cited by the FDA, about 1.1 million prescriptions for Pradaxa were dispensed in the United States between October 2010 and August 2011, and 371,000 patients received Pradaxa from outpatient retail pharmacies. Not a huge population, but not insignificant either.

The FDA also advises, wisely, that comparing postmarketing reports of bleeding with Pradaxa and those with warfarin is probably not helpful, because "warfarin has been marketed for over 50 years and is well known to cause bleeding, [consequently] patients and healthcare professionals are not likely to report bleeding in association with warfarin." The agency concludes, "Thus, a simple comparison between Pradaxa and warfarin...is of limited value." The FDA also says that it's working with Pradaxa's manufacturer, Boehringer Ingelheim, to assess a range of potentially adverse postmarketing events.

AERS = Adverse Events Reporting System.

* For the prevention of stroke and other cases of systemic embolism in patients with nonvalvular a-fib.

Today marks the generic availability of Pfizer's Lipitor, the blockbuster drug to beat all blockbuster drugs.

Duff Wilson of the NYT lays out how Pfizer is leveraging its short-term losses (for instance, it will get 70% of generic maker Watson's profits).

And Forbes's Matthew Herper gets nostalgic for the era of the widely prescribed money maker ("Why There Will Never Be Another Drug Like Lipitor"). Specifically he provides a concise history of Lipitor's rise and plateau; but he unfortunately omits one of the most interesting and important points of the early Lipitor campaign.

When first approved by the FDA in 1996, Lipitor was only indicated to reduce LDL cholesterol; it had not been shown to prevent clinical vascular events like its 4 existing statin competitors at the time. Nevertheless, trial data showed that Lipitor reduced LDL cholesterol by a relatively greater percentage than the other statins. And because clinicians believed (and still do) that LDL cholesterol is directly linked to the risk of vascular events, Pfizer was able to leverage this belief into ever-escalating sales during the next several years without having data to show that Lipitor actually reduced the risk of vascular events.* Clinicians made the a-to-b-to-c connection with prescription-writing alacrity.

Oh BTW, the generic name of Lipitor: atorvastatin.

* Lipitor wasn't approved by the FDA for this indication until 2004.

Delayed update (12/10/11): In an intriguing NEJM Perspective piece, Jackevicius et al expect that atorvastatin will "dominate" the statin market as a result of switching from generic simvastatin and branded Crestor. Specifically, in 3 years, they expect the market share of atorvastatin to reach 44%. They also estimate, on the basis of experience with simvastatin (which went generic in 2006), that the price of generic atorvastatin will be about 50% of the price of branded Lipitor, after the 6-month exclusivity period ends for the first generic manufacturer.

The projected overall cost savings by 2014, owing to the generic availability of atorvastatin: $4.5 billion annually; when factoring in the aging of the population, add another $30 million. These projections assume the "rapid availability and timely uptake of generic atorvastatin," which may be delayed thanks to industry maneuvers between Pfizer and generic drug makers (which are designed to limit competition). Pfizer is also reportedly planning to ask the FDA to approve an OTC version of Lipitor at some unspecified date.

Geron is dumping (or seeking a partnership for) its stem-cell development program, according to a company press release from November 14. The stated reason: Geron wants to focus on its "first-class" oncology programs, which are not beyond the phase 2 stage of development, in "the current environment of capital scarcity and uncertain economic condition."

So Geron is closing its "GRNOPC1 trial for spinal cord injury to further enrollment, although it will continue to follow all enrolled patients, accruing data and updating [the] FDA and the medical community on their progress." As of July, only 4 patients had been enrolled in the landmark and highly publicized trial, in which "GRNOPC1 has been well tolerated with no serious adverse events," according to Geron.

Geron's exit from clinical hESC investigation leaves Advanced Cell Technology as the only company, to my knowledge, that is actively engaged in clinical trials of human embryonic stem cells (specifically in cases of Stardgardt's disease and dry age-related macular degeneration [AMD]).

Besides oligodendrocyte hESCs (GRNOPC1), Geron is/was developing cardiomyocyte, pancreatic islet cell, dendritic cell, and chrondrocyte hESCs.

Transverse section of the thoracic spinal cord from Gray's Anatomy (1918).

Forbes's Matthew Herper on Bill Gates on vaccines and pharma: There's sufficient ink for undeniably venerable ideas and acts, but an "unimpressed" Gates disparages Novartis's Gleevac, a molecule that has completely revolutionized the treatment of CML.

“There’s always this divergence between what’s financially attractive and what has dramatic profit and the number of life years that you really save...Do the math on [Gleevac] versus, says, preventing Parkinson’s or preventing Alzheimer’s. It’s in a different universe."

On Friday, the FDA approved Xarelto (generic name, rivaroxaban) for the prevention of stroke in patients with nonvalvular a-fib.* Approval of the direct factor Xa inhibitor, a product of Janssen Ortho (essentially JNJ) and Bayer Healthcare AG, was based on the mammoth-sized (N > 14,000) ROCKET-AF trial, in which Xarelto was found to be noninferior (ie, comparable) to warfarin for the prevention of stroke and other systemic embolic events in patients with nonvalvular a-fib and other stroke risks (mean CHADS2 score = 3.5).

Xarelto is the second anticoagulant to seriously compete with the old-as-dirt warfarin for the prevention of stroke in patients with a-fib. In October of last year, the FDA approved Boehringer Ingelheim's Pradaxa (dabigatran), a direct thrombin inhibitor. Neither medication requires the usually cumbersome protime monitoring, but Pradaxa, unlike Xarelto, was shown to be superior (at the 150-mg BID dosage) to warfarin for the prevention of stroke in a similar patient population.

Other important differences between Xarelto and Pradaxa are 1) the package insert for the former contains a so-called black-box warning (against the risks of thrombosis after drug discontinuation and spinal/epidural hematoma); and 2) Xarelto is taken once a day, unlike the twice-daily Pradaxa.

Beyond superior-versus-noninferiority claims, potential drug-related risks, and any convenience of dosing, a distinction between Xarelto and Pradaxa may emerge with respect to pricing. According to destinationrx, a month's supply of Xarelto costs $218.70 (~$7.30 per pill or day).** A month's supply of Pradaxa (60, 150-mg pills) will set you back $236.20 (~$7.87 per day). Much of the cost distinction between these 2 drugs, however, will probably depend on how formularies classify the drugs and exact prescription co-pays on health-plan members. Branded warfarin (ie, Coumadin) is, of course, a fraction of these costs, and the price of generic warfarin (which some cardiologists are loathe to prescribe owing to the unpredictability of protimes) is even lower still.

* As well as for the prevention of deep vein thrombosis (DVT).
** 10 mg daily is the dosage for DVT prophylaxis; for the prevention of stroke in patients without renal dysfunction, the recommended dosage is 20 mg per day.