Pharma: July 2011 Archives

Forbes dishes big dirt about former CEO and micro-manager Jeff Kindler's last frazzled days at Pfizer before his abrupt ouster last December. And former HR president Mary McLeod, who used to helicopter from her home in Delaware to Pfizer HQ in Manhatten (!), comes off looking like some kind of ridiculously entitled Iago in this Shakespearean drama. Snakes, indeed. Yeesh, makes you glad to be a low-level schlemiel.*

* Excepting those huge severance packages.

Teva's launch-generic-at-risk business model is well-known. The strategy is intended to produce huge profits by making early (premature) generic drugs in the possible wake of losing, or more likely settling, patent-infringement suits. The company's most recent legal tangle on this front is with Pfizer, the paragon of big bad pharma companies, which would like to retain its patent monopoly on the blockbuster Lipitor.* Three weeks ago, Teva launched its own version of the statin in the United Kingdom, and Pfizer responded predictably (and Teva counter-responded).

But Teva also makes its own branded medicines, most notably a disease-modifying drug for multiple sclerosis, Copaxone, which provides the company with a substantial amount of revenue. According to today's WSJ, this MS drug (with a current monthly cost of more than $3500) produced $3 billion in sales last year for Teva or nearly 20% of total company's sales. And now, generic drug makers Mylan and Momenta want to produce their own versions of Copaxone, ahead of the drug's key expiration dates in 2014 and 2015. And so in response, Teva finds itself in the position of its nemesis Pfizer, by using expected legal counter-strategies to defend its still-patented cash cow.

* Which expires next year.

A new cost-effectiveness study in Neurology, the possibly legitimate methods of which elude me and an editorialist, suggests that disease-modifying drugs* (DMTs) for multiple sclerosis are not cost-effective over the long haul. This conclusion is largely informed by the very high cost of the drugs over a 10-year period, which was balanced against the benefits of the drugs for averting work loss and use of the healthcare system during the same time period. The calculated cost-effectiveness of all DMTs, expressed per the standard quality-adjusted life-year (QALY), was a staggering $800,000. For the purposes of comparison, a range of less than or within $50,000-$100,000/QALY has been generally chosen as the arbitrary benchmark for the cost-effectiveness of a medical intervention.*

While I'm not in a position to justify or criticize the methods of this study, I am able to examine the cost of DMTs in the study (Table 2) and perform simple math to conclude that the monthly price of these drugs has increased substantially—no, ridiculously—since 2008 (the year of the cited Red Book reference in the study). The following is my table comparing the average monthly costs of available DMTs for the time of the study and those supplied currently by destinationrx.com. And while jacked-up costs for these drugs over the last year are nothing new (see here, for instance), the price increases during the last 3 years are really astonishing—especially in the case of Teva's Copaxone, which has nearly doubled in price for no apparent good reason.

DMT	Average Monthly Cost 2008 Red Book	Monthly Cost July 21, 2011	Increase
Interferon beta
1b, 0.3 mg, 15 doses (Betaseron; Bayer Healthcare)	$2260.00	$3568.57	58%
1a, prefilled kit 30 μg, 4 doses (Avonex; Biogen Idec)	$2061.43	$3306.96	60%
1a, 44 μg, 6 doses (Rebif; EMD Serono/Pfizer)	$2124.27	$3048.84	44%
Glatiramer acetate, 30 prefilled syringes (Copaxone; Teva)	$1952.15	$3753.83	92%

Authors of the cost-effectiveness study wrote that reducing the cost of DMTs would have "by far the greatest impact on the cost-effectiveness of these treatments." For instance, reducing the cost of Biogen Idec's Avonex by two-thirds (to approximate the UK-based cost) would bring the cost-effectiveness value for this drug to a somewhat more rational $164,000/QALY.

* And I don't know who decided that.
** Interferons beta and glatiramer acetate (Copaxone).

Just because you can detect brain amyloid, doesn't necessarily mean that you should—at least not in clinical practice.

But that word of caution isn't stopping 3 companies from pushing forward with their late-phase development of radiolabeled* tracers for the protein—which is a pathologic signature for Alzheimer disease but is also seen, importantly, in a substantial chunk of cognitively normal elderly.

Who are we kidding? Reflection is not the bailiwick of industry.

The furthest along is Avid/Lilly's florbetapir (Amyvid), which has been the subject of many a critical post at this blog. Last word is that the company is working with the FDA to establish a reader-training program, an agency requirement for approval.

GE's flutemetamol is in phase 3 development, according to entries at clinicaltrials.gov, and the company is promoting at the current ICAD meeting 1) the tracer's comparability to the reference standard of amyloid-imaging agents, Pittsburgh compound B, and 2) the success of its own reader-training program.

Bayer's tracer, florbetaben, is just entering phase 3 study, but the compound may be the easiest to use in practice (notwithstanding the issue of knowing what to do with the results), because PET imaging may be performed up to 130 minutes after the tracer is injected.

For a recent review of the 3 amyloid-detecting compounds, see a comprehensive write-up in July's Lancet Neurology.

ICAD = International Conference on Alzheimer's Disease.

* All use 18F, which has a substantially longer half-life than the 11C-labeled Pittsburgh compound B, the reference standard for amyloid imaging. The longer, 18F-labeled amyloid tracers were developed because the short-lived Pittsburgh compound requires an on-site cyclotron. The longer-acting tracers mean that the compound can be administered and then the patient transported (if necessary) to a PET-imaging center.

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

A number of notable presentations from the ongoing International Conference on Alzheimer's Disease (ICAD) in Paris, most of it ouch-inducing for Lilly.

Dismal news about Lilly's now-defunct semagacestat: Patients with AD who took the company's experimental anti-amyloid gamma secretase inhibitor in a placebo-controlled phase 3 study remain clinically worse 7 months after stopping the drug. The take-home warning from medical pundits is that researchers should stay away from targeting gamma secretase in their zeal to clear beta amyloid, the protein that accumulates in the brains of AD patients. Lilly pulled the plug on semagacestat development in August of last year.

A protein complex, gamma secretase processes amyloid precursor protein, which produces beta amyloid. The tentative conclusion: target beta amyloid (if at all) directly. Bloomberg notes that BMS is also developing a gamma secretase inhibitor, avagacestat (BMS-708163), for the treatment of AD. The compound, in phase 2 development, may or may not be associated with a similar class-effect outcome. But...

Brain edema continues to plague clinical development of anti-amyloid compounds: Regardless of the structure or mechanism of anti-amyloid compounds, one thing appears to be consistent. They all seem to be capable of causing brain edema—probably because they all clear (or facilitate clearing of) amyloid that surrounds cerebral blood vessels. Reuters reports that 3 patients who received the experimental BMS drug developed vasogenic edema. And in January, Lilly's CEO announced that 1 patient in a solanezumab trial had developed brain edema, the adverse effect that has plagued Pfizer/JNJ's anti-amyloid mAb, bapineuzumab. Phase 3 results of Lilly's solanezumab, an anti-amyloid monoclonal antibody, are expected in the 3rd quarter of next year, but The Street isn't sanguine. Les Funtleyder, a NY-based portfolio manager and healthcare strategist, told Bloomberg that he doesn't think the drug will be approved. [A clarification to the parenthetical statement: Lilly would officially argue, if its tracer is approved to rule out amyloid-related dementia, that florbetapir is most useful for distinguishing between clinical AD that is associated with brain amyloid and non-amyloid dementias—like frontotemporal dementia. Presumably the clinical AD patients with very low levels of amyloid in this study do not have pathologically defined AD but some other kind of dementia.]

Lilly continues to put a positive spin on its neuroscience program for AD: While attempting to reassure investors that it hasn't bet everything on the idea that amyloid is the target in AD, Eric Siemers, MD, the senior medical director for the Alzheimer's Disease Team, told Bloomberg, "We haven't put all our eggs in the amyloid basket," and he talked up the company's preclinical efforts to go after tau protein, the component of AD's neurofibrillary tangles.

Nevertheless Lilly is still heavily promoting its not-yet-approved PET amyloid tracer, florbetapir (trade name, Amyvid), through the medical literature generally and the ICAD meeting specifically. The latest from ICAD is that positive scans may predict further cognitive decline in patients with mild cognitive impairment (MCI) on the basis of the existing amyloid burden in the brain. (Although, without a disease-modifying intervention, file this outcome under "What am I supposed to do with this information in practice?")

Lilly bought florbetapir, along with its manufacturer, Avid Pharmaceuticals, in November of last year for $300 million, and will fork over another $500 million if the tracer is FDA approved. In March, the agency said that it would require Lilly to establish a reader-training program to ensure the reliability of scan interpretations. The requirement was made after an FDA advisory committee recommended conditional approval of the tracer (with the indication of ruling out, not ruling in, "pathologically significant levels" of brain amyloid) in January. One month later, Lilly's neuroscience chief, David S. Brendt, MD, PhD, abruptly left the company.*

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

* Update: JNJ "poached" Bredt, said the WSJ Health Blog in March. So it appears that Bredt wasn't ousted from Lilly but was wooed by JNJ (which is developing the troubled bapineuzumab along with Pfizer).

Avid*/Lilly continues to flood the medical literature with data to ostensibly promote its PET amyloid tracer florbetapir (Amyvid). And while the company wants to give the world the impression that its tracer has diagnostic use, a repeated heaping helping of caveat emptor is appropriate.

The latest case of industry-funded promotion as peer-reviewed research: Another brain-amyloid imaging study—while showing significant differences among subjects with probable Alzheimer disease (AD), mild cognitive impairment (MCI), and other healthy controls—nevertheless also demonstrated considerable overlap in the burden of brain amyloid among these clinical subgroups. The PET data, pooled from four of the company's phase 1 or 2 clinical studies, showed that the mean value for brain amyloid (described as the cortical-to-whole-cerebellar SUVR) was significantly different among the subjects, but that also about 20% of older healthy controls demonstrate an amyloid load consistent with pathologically defined AD. And about 30% of these healthy elderly (>55 years) exhibit any level of brain amyloid, as detected with florbetapir. Conversely a substantial number of patients with clinical AD did not demonstrate pathologic levels of amyloid. (Lilly would argue that this is where its PET tracer is most useful—in ruling out AD on the basis of a low amyloid burden in suspect patients.) The amyloid burden was also significantly more likely among carriers of the APOE4 gene, for which the AD subgroup was enriched, and with each decade of life in older healthy controls.

The amyloid-overlap data are consistent with those from autopsy and other PET studies, which show, on a cumulative basis, that about 30% of cognitively normal elderly will demonstrate some level of AD-consistent brain pathology, and that many of these subjects meet the neuropathologic criteria for AD despite the absence of cognitive impairment (during life in the case of the autopsy studies).**

The $64 question for Avid/Lilly is how PET imaging for brain amyloid can be practically integrated into clinical practice, if at all. Currently the tracer appears to have its greatest use in assessing the clearing of protein in trials of investigational anti-amyloid compounds (which have their own safety problems). In the context of practice and beyond the issues of cost, PET access, and inter-reader reliability (see here, for example), the most important question is what to do when PET images demonstrate brain amyloid—given the substantial percentage of older healthy adults who demonstrate the AD-linked substance. By my read of this study, unless the florbetapir-enriched PET scan shows an amyloid burden that is undeniably above that of healthy controls or really, really low, the results are functionally useless.

* Avid is a wholly owned subsidiary of Lilly, which bought the company for $300 million and will fork over another $500 million if florbetapir ever becomes FDA approved.
** The issue of what to do with these data becomes a bit zen-like. Are these positive amyloid scans an indicator of impending AD, if the patient lives long enough? And if so, so what (especially if clinical AD is unlikely to emerge until 10 years later and/or there are no useful interventions)?
PET = positron emission tomography; SUVR = standard uptake value ratios.

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

A new meta-analysis of 14 Chantix (varencicline) trials raises safety concerns, perhaps rashly, about the short-term (≤1 year) cardiovascular risks of the drug. And while the absolute effect size with Pfizer's smoking-cessation drug, versus placebo, was tiny (1.06% - 0.82% = 0.24%), the potential cardiovascular effects of Chantix at least make more physiologic sense than some other studies proposing a short-term risk of cancer with certain antidiabetic drugs (like Actos and Avandia).

In a company press release, issued July 4th,* Pfizer said it "stands behind the benefit/risk profile of Chantix" and "expressed concerns about the reliability of the meta-analysis." Specific concerns related to the "appropriateness of the authors' measure of cardiovascular risk...which combines events that do not share a common biological cause." The probable main objection here is the inclusion of arrhythmias in the composite endpoint, which may not have anything to do with the process of vascular disease. Pfizer also stressed the small absolute difference between Chantix- and placebo-treated patients. The company reported that it plans to conduct its own meta-analysis to assess the potential cardiovascular risks of Chantix.

In June, the FDA posted a warning about the potential, albeit small, cardiovascular risks of Chantix. The warning was based on data from a 1-year, randomized, placebo-controlled trial of 700 smokers. Both the efficacy and safety results are tabulated here. Clearly Chantix improves the chances of quitting (which should lower tobacco-related cardiovascular and cancer risks—!), but short-term cardiovascular risks may also exist with use of the drug.

Outcome	Chantix (n = 350)	Placebo (n = 350)	P Value
Continuous quit rate, % (4 weeks)	47	14	<.0001
Continuous abstinence rate, % (weeks 9-52)	19	7	<.0001
Nonfatal MI, %	2.0	0.9	Not calculated
Need for coronary revascularization, %	2.3	0.9	Not calculated
Angina requiring hospitalization, %	2.3	2.3	Not calculated
New diagnosis of PVD or PVD procedure, %	1.4	0.9	Not calculated

N.B.--For the safety analysis, the n value in the Chantix arm was 353.

Notably this trial was not powered to detect statistically significant differences in the safety analysis portion of the study. The FDA affirmed that, on the basis of these data, it was "requiring the manufacturer to conduct a large, combined analysis (meta-analysis) of randomized, placebo-controlled trials" to further define the potential, short-term cardiovascular risks of Chantix.

* No holiday for public relations.