Recently in Pharma Category

A remarkable, unprecedented development. Roche's anti-amyloid MAb, crenezumab (for which there are no entries at PubMed—!), will be given in an attempt to stave off familial Alzheimer disease. According to Reuters and the NYT, the experimental drug will be studied in members of an extended Colombian family who harbor mutations in a deterministic gene (presenilin 1*) for AD. The US DHHS and Banner Health are providing $16 million and $15 million, respectively, to fund the study. The US government's support is part of the new National Alzheimer's Project (announced yesterday), which has an advertised goal of finding an effective treatment for AD by 2025.

Also according to news coverage, crenezumab was chosen as a potential preemptive treatment for AD among "25 rivals," primarily because it does not cause vasogenic edema—for instance, like Pfizer/Janssen's bapineuzumab. This information is sourced in news write-ups to a Colombian neurologist. Although I have to say Roche's MAb has really come out of left field. As someone who has followed the investigational development of anti-amyloid drugs fairly closely, this molecule has flown way under my radar—partly because it has been registered heretofore under the unfriendly research name of MABT5102A. (Nevertheless, the oversight says something about my limitations.)

According to the NIH database, crenezumab/MABT5102A is currently being investigated in two phase 2 studies in the United States, Canada, and/or the United Kingdom (see here and here). Respective study completion dates are currently designated as June and August of 2014. Presumably the data regarding vasogenic edema (or lack thereof) were determined during phase 1 study and/or confirmed during the ongoing phase 2 trials.

Roche also has the investigational anti-amyloid MAb gantenerumab, which is also in phase 2 development.

As previously written, phase 3 data for the anti-amyloid MAbs bapineuzumab and solanezumab (in existing AD) are expected sometime this summer—which is drawing nigh.

DHHS = Department of Health and Human Services; MAb = monoclonal antibody.
* Presenilin 1 is a component of a metabolic enzyme that cleaves amyloid precursor protein to ultimately create beta amyloid--the stuff the aggregates and forms plaques in the brains of patients with AD.

Update: AC Immune, from which crenezumab was licensed by Roche/Genentech, reported last year that the "drug showed no signs of cerebral vasogenic edema in any of the [phase 1 trial] patients at any dose."

Another update: You have to wonder, though. If crenezumab doesn't cause (or isn't associated with) vascular edema, how effective is it at removing amyloid? If the cause of vasogenic edema with these anti-amyloid compounds is due to the immune-mediated vascular removal of amyloid and/or a direct attack on vascular amyloid (see, for instance, Figure 5 in Sperling et al. Lancet Neurol. 2012:11:241-249), then you would expect some kind of class effect given the putative mechanism of action. Consequently I wonder at the efficacy of an anti-amyloid MAb that doesn't cause some vasogenic edema in a percentage of patients. Certainly amyloid PET imaging in this Colombian study will allow researchers to visualize the removal or prevention of amyloid buildup with crenezumab. So...wait to see. Of course, the bigger question is whether the targeting of amyloid is associated with clinical improvement or, as in this study, the prevention of AD dementia.

For the Internet's edification, the phase 3 trials of MAbs in AD are tabulated by drug (bapineuzumab, solanezumab) and expected completion date.

Although the phase 3 trial of bapineuzumab in APOE ε4 carriers (NCT00575055 or ELN115727-302) reached its estimated completion date last month, the online buzz indicates that Pfizer/Janssen won't publicly release these data until the phase 3 study in noncarriers is completed in August of this year. As readers may recall, the phase 2 data of bapineuzumab suggested that APOE ε4 noncarriers with AD (meaning generally those patients with a lower beta-amyloid burden) fared somewhat clinically better than APOE ε4 carriers and were specifically less likely to develop vasogenic brain edema.

The public release of phase 3 solanezumab data is also expected imminently or at least (I would think) this summer.

Bapineuzumab (Pfizer/Janssen) Phase 3 Trials*

Subjects	Clinical Trials Identifier	Approximate Duration	Estimated Completion Date
1121 APOE ε4 carriers	NCT00575055 (aka ELN115727-302)	1.5 years	April 2012
1300 APOE ε4 noncarriers	NCT00574132 (aka ELN115727-301)	1.5 years	August 2012
Subjects who participated in above studies	NCT00937352	2.5 years or marketing application	June 2012
1100 APOE ε4 carriers	NCT00676143 (aka 3133K1-3001)	1.5 years	June 2013
Subjects who participated in above study	NCT00998764	4 years (extension)	June 2017
1000 APOE ε4 noncarriers	NCT00667810 (aka 3133K1-3000)	1.5 years	June 2014
Subjects who participated in above study	NCT00996918	4 years (extension)	June 2018

Solanezumab (Eli Lilly) Phase 3 Trials**

Subjects	Clinical Trials Identifier	Approximate Duration	Estimated Completion Date
1000 AD patients	NCT00905372	~1.5 years	April 2012
1000 AD patients	NCT00904683	~1.5 years	June 2012
1250 AD patients	NCT01127633 (extension)	2 years	July 2014

In addition, there are several phase 3 studies evaluating IV Ig (eg, Baxter's Gammagard) in patients with AD. Clinical data from these trials aren't expected until 2013 and later.

MAb = monoclonal antibody.

* Owing to a dose-dependent effect on the risk of amyloid-related imaging abnormalities (aka vasogenic edema and microhemorrhages), particularly in APOE ε4 carriers, the dosage of bapineuzumab received by APOE ε4 carriers is now the lowest, tested dosage: 0.5 mg/kg. APOE ε4 noncarriers are receiving 2 dosages of bapineuzumab (0.5 or 1.0 mg/kg) in phase 3 clinical trials.

** Treated patients are receiving one, standard dosage of the MAb.

Much to my disquiet, the FDA approved Amyvid (florbetapir), an amyloid imaging agent, late last Friday. The radiolabeled tag for amyloid-beta, which is intended to be used with PET scanning, latches onto the stuff of neuritic plaques in the brains of people with Alzheimer disease (AD) and shows up as bright red on color-coded images. Amyvid is the product of a Lilly subsidiary, Avid Radiopharmaceuticals. (In November 2010, Lilly bought Avid for $300 million, and will now fork over another $500 million to Avid with approval of the amyloid tracer.)

Last March (meaning 13 months ago), the agency all but rejected Amyvid, after an advisory panel gave its unanimous recommendation for conditional approval in January of 2011. The FDA said that it wanted Avid/Lilly to establish a reader training program, because of potential problems with inconsistent interpretations among readers of Amyvid-enhanced PET images. The lack of inter-reader reliability with the tracer-enhanced PET images has been a major concern of the pharma watchdog group Public Citizen. Presumably the FDA was satisfied with Avid/Lilly's response to this issue.

Amyvid's package insert (found here) stipulates that use of the amyloid-imaging agent is intended to...

...estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s Disease (AD) and other causes of cognitive decline. A negative Amyvid scan indicates sparse to no neuritic plaques, and is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition; a negative scan result reduces the likelihood that a patient’s cognitive impairment is due to AD. A positive Amyvid scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination has shown this amount of amyloid neuritic plaque is present in patients with AD, but may also be present in patients with other types of neurologic conditions as well as older people with normal cognition. Amyvid is an adjunct to other diagnostic evaluations.

In other words, clinical context is mandatory when using Amyvid-enhanced PET, particularly because of the high rate of brain amyloid in cognitively normal elderly (~30%). In some cases, the PET scans of elderly individuals with ostensibly normal cognition* are indistinguishable from those of patients with clinical AD. This fact and the associated caveat are stressed in a 2009 article by Rabinovici et al in the context of using a different, purely investigative amyloid tracer, 11C-Pittsburgh compound B (PIB).**

The high rate of PIB-positivity in normal controls underscores that a positive PIB scan cannot be interpreted without a careful clinical evaluation, and emphasizes that amyloid imaging alone must not serve as a surrogate for a clinical diagnosis of AD or dementia.

Clinical utility aside, physicians and their patients will have to decide if the staggering cost of PET imaging is worth the marginally useful information that may be provided. The possible clinical scenarios—dementia with brain amyloid, dementia without brain amyloid—may help establish the presumptive clinical diagnosis: Alzheimer dementia or some other dementia type (eg, Pick's disease), respectively. But if treatment is not substantively altered, what's the point of 1) exposing a patient to a radiolabeled tracer, 2) requiring that a cognitively impaired patient be transported to the nearest PET imaging center, and 3) leaving a patient to deal with the enormous cost of the study?

According to the WSJ, Amyvid will cost $1600 per dose, and various online sources indicate that the price of brain PET imaging ranges from $3000 to $6000. Moreover, there's no indication that Medicare will pay for or supplement the cost of new imaging agents for PET; although Lilly is reportedly hoping to change the relevant Medicare policy.

PET = positron emission tomography.
* Although more sophisticated neuropsychiatric tests may indicate small, but distinct, cognitive impairments in these people, according to a recent study.
** PIB has a substantially shorter half-life than Amyvid, and its use therefore requires an on-site PET-imaging facility. Amyvid, on the other hand, has a substantially longer half-life (~110 minutes), and can be administered at a site fairly remote from a PET scanner (to which the Amyvid-injected patient must be transported).

N.B.--Two other amyloid tracers are in late-phase clinical development: GE's flutemetamol and Bayer's florbetaben.

And at least one questionable wholesaler, Thomas Houghton through his UK-based River East Supplies, appears to be involved in both the February and most recent transactions.

The WSJ traces the route of fake Avastin that cropped up in the United States in February:

1. Swiss drug wholesaler Hadicon AG ordered Avastin from an Egyptian company, Sawa—the legitimacy of which is questionable.
2. An intermediary working for Sawa contacted a Syrian businessman, who located (the fake) Avastin in Istanbul, Turkey, from which the drug was shipped (through yet-another murky intermediary) to Hadicon.
3. Hadicon then shipped the drug to a Danish wholesaler, CareMed Aps in Copenhagen, which passed it onto River East Supplies in Nottingham, England.
4. River East Supplies then exported the drug to the United States through Montana Healthcare Solutions in Belgrade, Montana (which Houghton may have also owned). The fake Avastin was distributed to several oncologic practices (most of which are located in California or Texas) through Volunteer Distribution in Gainesboro, Tennessee.

In the latest case of fake Avastin (or really fake Altuzan) in the United States, the drug was imported again from Turkey (but this time from an unnamed or unknown source) to UK-based Richard's Pharma,* a licensed wholesaler. Richard's Pharma bought 120 packs of the counterfeit drug and exported 28 of these directly into America. The remaining 82 packs were sold to River East Supplies, which also exported the fake drug into the United States.

Not surprisingly wholesalers involved in both cases claim that they didn't know the peddled Avastin/Altuzan was fake. No matter: The FDA says that the importation of non-approved drugs into the United States is illegal.

* AKA Richards Pharma, Richards Services, Warwick Healthcare Solutions, or Ban Dune Marketing, Inc, according to the FDA.

With an emphasis on "may." Newly published post-hoc data from bapineuzumab's phase 2 studies indicate that the anti-amyloid MAb reduces CSF levels of tau—a traditional downstream marker of neurodegeneration in AD (as well as in similar diseases). These data appear to have been originally presented at the AAIC in 2010, and the focus on tau, instead of amyloid, may be a way of maintaining investor interest in the ongoing investigation of bapineuzumab. The MAb provided underwhelming clinical benefit in the same phase 2 studies and, consequently, some have cooled toward the idea that attacking amyloid is the way to go when searching for a disease-modifying treatment in AD. Hence, the emphasis on tau.

According to the pooled data from a post-hoc analysis of the two placebo-controlled phase 2 studies of bapineuzumab (n = 46), the CSF level of tau (and particularly phosphorylated tau) declined with treatment* (from baseline to week 54), while the CSF levels of beta amyloid (Aβ) did not (see mocked-up table).

CSF Biomarker	Change From Baseline		P Value (Bapineuzumab vs Placebo)
	Bapineuzumab (n = 27)	Placebo (n = 19)
Total tau	–72.3 (P = .03)	–5.6 (P = .80)	.09
Phosphorylated tau	–9.9 (P = .001)	–2.6 (P = NS)	.03
Aβ1-42	–10.5 (P = .44)	–6.1 (P = .75)	.79
AβX-42	32.2 (P = .02)	13.8 (P = .06)	.89
Aβ1-40	–188.5 (P = .78)	–700.4 (P = .84)	.72

The table shows a treatment-related statistical difference only in the CSF levels of phosphorylated tau, but importantly (and curiously) not in any Aβ level. In addition, a figure in the article (Figure 2) demonstrates a substantial amount of overlap between all CSF measures for bapineuzumab- and placebo-treated patients. So, take these data (particularly with such a small sample size) cum grano salis. The lack of change in any CSF Aβ level by the anti-Aβ MAb is "attributed to clearance of cortical Aβ through other pathways than CSF or, alternatively, oligomerization of Aβ or binding of Aβ to chaperones or to the therapeutic antibody that masks a change in CSF Aβ with treatment. For these reasons, the Aβ results have to be interpreted with caution." Maybe. But one might otherwise expect a rise in CSF Aβ, if the MAb were truly disease modifying.

Of course, any changes in AD biomarkers are arguably irrelevant if there's no favorable clinical correlate. And here's where the authors (some of whom are employees of Janssen or Pfizer, the current codevelopers of bapineuzumab) make a considerable effort to defend a long-term clinical endpoint for a potentially disease-modifying drug in AD, particularly in contradistinction to comparatively shorter endpoints (eg, 6 months) for symptomatic treatments, like cholinesterase inhibitors.

They write upfront, "[T]herapies aiming to slow the progression of the disease may require clinical trials with longer duration to observe clinical improvement owing to downstream therapeutic effects on the underlying pathophysiological process." This statement is intended to justify the use of biomarkers as early endpoints (which it does), but it also seems to be a couched defense of anticipated phase 3 results, which may be disappointing at the studies' currently defined endpoint (18 months, I believe). Perhaps they're laying expectations for a longer period of clinical observation. Who knows? And clearly, I speculate.

The authors also imply that cholinesterase inhibitors, by distinction, are merely symptomatic therapies—which may be true; but there are published arguments to the contrary (see an article from an Eisai** employee here, for example).

AD = Alzheimer disease; CSF = cerebrospinal fluid; MAb = monoclonal antibody.
* Most patients received all 6 intended doses of bapineuzumab over the 52-week treatment period. Ten patients received 0.15 mg/kg; 5, 0.5 mg/kg; 6, 1.0 mg/kg, and 4, 2.0 mg/kg.
** Which comarkets the cholinesterase inhibitor Aricept (donepezil) with Pfizer.

Presumably powered on expectations about bapineuzumab and its phase 3 results—which are expected to be released later this year (possibly at the AAIC in mid-July). But see Adam Fuerstein's article of March 19th for an appropriate, cautionary reminder.

Bapineuzumab, an anti-amyloid MAb, has been codeveloped by Pfizer and JNJ (or really, Janssen), along with original co-owner Elan,* and the drug performed marginally (if at all) in earlier phase 2 studies of patients with AD. The bottom line: the MAb targets amyloid and removes it (or targets it for immune-mediated removal), but this mechanism doesn't appear to be associated with clinical improvement. Specifically enrollees who were APOE ε4 carriers (meaning those enrollees at greater risk of AD and who probably have a greater amyloid burden) didn't benefit as much (if at all) as APOE ε4 non-carriers—a finding that patently contradicts the rationale for targeting amyloid in the first place.

Last bapineuzumab has been associated with brain edema in about 17% of patients (a phenomenon that has been dubbed ARIA-E), and this edema was more likely in APOE ε4 carriers (again, those patients who probably have a greater amyloid burden) and when using the highest bapineuzumab dosage (which was discontinued for phase 3). The mechanism by which bapineuzumab—and other anti-amyloid compounds, for that matter—cause edema is unclear; however, one compelling explanation is through the removal of vascular amyloid, which results in leaky vessels.

And yet the seemingly mindless runup on Elan stock continues, just like it did (albeit less robustly) in 2008 before the disappointing phase 2 results were presented. The share price is now, in fact, at a 3-year high.

* The original co-developers of bapineuzumab were Elan and Wyeth, which were respectively bought up by Janssen and Pfizer. Janssen and Pfizer then formed the Alzheimer's Immunotherapy Program (AIP), the putative darling of which is bapineuzumab.

AAIC = Alzheimer's Association International Conference; AD = Alzheimer's disease; APOE = gene encoding apolipoprotein E; MAb = monoclonal antibody.

There may be no good guys in the questionable chain of international drug wholesalers that recently peddled fake Avastin. Yesterday the WSJ reported that the 2 managing directors of the Danish wholesaler ran afoul of local law in 2007 by illegally importing medicines into Denmark. Although the paper, citing the Danish National Board of Health, was not able to convey the particulars—eg, what medicine from what country.

Previous news reports imply that it was either the Danish wholesaler or the Swedish outfit that notified US authorities of the counterfeit Avastin, which then passed through a British wholesaler, River East Supplies, Ltd., before reaching the United States. Canadian Thomas Haughton reportedly manages a network of drug distributors, including River East Supplies, Ltd, as well as the US supplier of the fake drug, Montana Healthcare Solutions, which Haughton acquired in 2010 through a Barbados holding company. The Avastin-that-was-not-Avastin was then distributed by a Tennessee-based distributor to 19 medical practices, most of which are in California or Texas. It is unclear whether any cancer patient actually received the fake IV drug, which contained salt and starch (among other inactive ingredients).

The origin of the fake Avastin is also unclear. Named suspects include China, Egypt, and Turkey.

The most recent lots of counterfeit Avastin (Roche), which found their way to various oncology clinics in the United States (most of which are in California), originated in Egypt and were essentially a slurry of inactive ingredients, reports Fox News. The fake vials of the purported anticancer drug contained a hodgepodge of salt, starch, citrate, isopropyl alcohol, "propandiol" (probably propylene glycol), t-butanol, benzoic acid, difluroinated benzene, acetone, and phthalate—but no bevacizumab, the monoclonal antibody and active ingredient in Avastin that is intended to suppress angiogenesis and tumor growth.

The counterfeit vials were reportedly processed through legitimate distributors in Switzerland, Denmark, and Britain before entering the United States, where the fake drug was sold to 19 oncology clinics or physicians by Quality Specialty Products (aka Montana Health Care Solutions). A company with the terribly generic name of Volunteer Distribution,* located in Gainesboro, Tennessee distributed QSP's products, according to the FDA.

A web search reveals an address for Volunteer Distribution in Gainesboro: 101 W. Gore Ave. Google Maps provides this lovely screenshot for the Tennessee address, although the location is identified on the annotated street view as "Anderson & Haile Drug Co Phrm." A web search also reveals the listed phone number for Volunteer Distribution as 931-268-4506; that for Anderson & Haile is 931-268-0233.** Important update: Further searching of Google Maps and its street-view feature shows that Anderson & Haile is actually located in a commercial property at the corner of W. Gore Ave. and S. Union St. in Gainesboro, Tennessee.

Fake Avastin (or Lucentis) on the market is evidently an ongoing problem for Roche (and susceptible patients). Shanghai was the source for a bogus version in 2010, and Syria in 2009, says Fierce Pharma.

What vials of Avastin should contain are bevacizumab (the active ingredient), along with trehalose dihydrate, sodium phosphate (both monobasic monohydrate and dibasic), polysorbate 20, and water.

* I suppose that "Volunteer" must refer to Tennessee.

** And another web search provides these listed contacts for Anderson & Haile at 101 W. Gore Ave: Teneal Jenkins and Christie Banker. Yet another web search shows that Teneal Jenkins is "doing business as" Anderson and Haile Drug Company, a pharmacy and supplier of medical equipment and supplies. And yet another web search shows that Teneal Jenkins has a PharmD. A license lookup at the Tennessee Department of Health shows that Teneal Chaffin Jenkins of 101 W. Gore Ave in Gainesboro, Tennessee (Anderson and Haile Drug Co.) graduated with a PharmD in 2004 from the University of Tennessee (Memphis) and has sustained no disciplinary or significant liability claims.

And a clarification: I have no idea if Anderson & Haile Drug Company, located at 101 W. Gore Ave., in Gainesboro, TN, or pharmacist Teneal Jenkins and Volunteer Distribution, located at the same commercial building, have (or had) any connection whatsoever. Although it would be an unfortunate coincidence for Anderson & Haile and pharmacist Jenkins if they did not. FWIW, street images of the area, courtesy of Google Maps, show unreadable hanging shingles and ascending stairs to an entrance at the back of the building.

Forbes's Matthew Herper recalculates the cost of drug development and comes up with an average of $4 billion per approved drug—which is $3 billion more than the oft-cited number of $1 billion (from the oft-cited DiMasi study). Moreover, some companies (Amgen, Novartis) have been a whole lot better—or a whole lot luckier—at parlaying their R&D investment into marketable products. AstraZeneca, with a nearly $12-billion-per-approved-pill cost: Eh, not so much.

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.