Recently in Pharma Category

In a 3-part criminal and civil agreement with the Department of Justice, Allergan, the maker of Botox, has dropped its free-speech suit against the FDA—which had the potential to be a pivotal case on the rights of commercial free speech. In addition, the company has pleaded guilty to a single misdemeanor "misbranding" charge, stemming from the off-label promotion of Botox during 2000-2005, and will pay $375 million. Last Allergan will fork over another $225 million to resolve civil claims made by the DOJ under the False Claims Act (concerning qui tam or whistleblower complaints). The plea agreement was announced yesterday in a company press release and also by the DOJ.

According to the government, Allergan, during the described time period, "exploited" an approved indication for cervical dystonia (obtained in 2000) to expand the off-label use of Botox for headache. Company reps were also instructed to call on doctors who typically treat off-label conditions (like pediatric spasticity), and Allergan held workshops to inform healthcare providers on how to be reimbused for injecting Botox off label.

The civil settlement resolved 3 qui tam lawsuits, with whistleblowers Dr. Amy Lang (a former Allergan consultant), Charles Rushin (a former Botox sales rep), Cher Beilfuss (a former Regional Healthcare Policy Manager for Allergan), Kathleen O'Conner-Masse (a former Payor Reimbursement Account Manager for Allergan), and Edward Hallivis (a former I-don't-know-what). They will split $37.8 million.

The current, FDA-approved indications for Botox (not Botox Cosmetic) in adults are the following:

• Cervical dystonia
• Primary axillary hyperhidrosis
• Blepharospasm and strabismus
• Upper limb spasticity (approval obtained March 2010)

The FDA advises that a combination drug for Parkinson disease may increase the risk of cardiovascular events—like MI, stroke, or CV death. The drug, containing carbidopa, levodopa, and entacapone and marketed by Novartis as Stalevo, is the focus of a 15-trial meta-analysis conducted by the agency to further determine the associated CV risks of the drug, when compared with the foundational treatment of carbidopa/levodopa (aka Sinemet) alone.

Entacapone, a peripheral inhibitor of the enzyme COMT, is also sold separately by Novartis as Comtan.* The drug is intended to smooth out the fluctuating clinical responses or dyskinesias associated with Sinemet treatment. (For a comprehensive 2009 review of entacapone, go here). Entacapone's sole competitor is tolcapone (Tasmar; Valeant), the use of which is limited by significant hepatotoxicity.

The FDA's retrospective review is prompted by data from the STRIDE-PD trial (published in July), which showed an increased number of heart attacks with Stalevo. During the 134-week study, there were 7 MIs and 1 CV death in 373 Stalevo-treated patients and none in 372 Sinemet-treated patients. The FDA's meta-analysis revealed 27 CV events with Stalevo and 10 with Sinemet, for a relative risk of 2.46. But removal of the STRIDE-PD data reduced the relative risk to 1.67. Most of the trials (11) included in the meta-analysis were briefer than 6 months, which makes a solid assessment of CV risk difficult. Other confounding factors include the fact that the baseline CV risk in PD patients is relatively increased, primarily owing to age.

An elevated risk of CV events with entacapone is counterintuitive, at least from a biochemical perspective. Inhibition of COMT reduces, at least in theory, homocysteine synthesis. High homocysteine levels have been suggested to raise the risk of atherosclerosis, although the American Heart Association has not yet labeled homocysteinemia as an official risk factor for heart disease.

The STRIDE-PD data also prompted the FDA to evaluate the risk of prostate cancer in men given entacapone (rates, 3.7% vs 0.9% with Sinemet). (Why COMT inhibition would increase the risk of prostate cancer is also a mystery.) 

The FDA estimates that 154,000 patients have received Stalevo since its approval in June 2003 (through October 2009).

COMT = catechol-O-methyl transferase, which degrades catecholamine neurotransmitters like dopamine; CV = cardiovascular; STRIDE-PD = Stalevo Reduction in Dyskinesia Evaluation-Parkinson's Disease.

* The drug, by itself, has no antiparkinsonian effect. It is intended to prolong the half-life of levodopa by inhibiting the peripheral action of the dopamine-degrading enzyme COMT.

Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers from Wikimedia Commons.

One part of a much-publicized 3-part Innogenetics assay appears to predict dementia in Parkinson disease. According to an early-release, prospective, cohort study (N = 45) from U Penn, low and declining levels of beta amyloid 1-42 in spinal fluid are associated with cognitive impairment in the disorder. There is no association, however, between dementia and CSF levels of total tau, phosphorylated tau, or any tau-to-beta-amyloid ratios. In fact, adding any tau measurement to the mix actually diminishes the predictive value of the beta-amyloid measure in PD patients.

During the 1-3-year PD study, baseline beta amyloid 1-42 levels of less than 192 pg/mL, which are considered diagnostic for Alzheimer disease, significantly increased the risk of dementia. On the basis of their data, the authors concluded that a PD patient with a low CSF beta-amyloid level would "progress from essentially normal cognition to a level consistent with [PD-associated dementia] within a 2-year period of follow-up." CSF beta-amyloid levels also correlated with apolipoprotein E ε4 carrier status among the small number of PD patients (15) who carried the AD risk factor.

Last week, the full 3-part Innogenetics assay (which measures CSF levels of beta amyloid 1-24, total tau, and phosphorylated tau) was promoted to predict AD in people with mild cognitive impairment (see Alzheimer Assay Deserves Qualified Embrace). In this study, there was a distinctive pattern change as MCI progressed to mild AD and then to advanced disease: CSF beta amyloid levels fell while tau levels rose. The former event appears to be true in PD patients who develop dementia. Lower levels of CSF beta amyloid reflect the underlying amyloid pathology of the dementing aspect of the disease and may be due to the sequestration of beta amyloid into developing amyloid plaques. At least that's the speculation.

The Penn authors concluded that the CSF level of beta amyloid 1-42 "may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD." Dementia may occur in the disorder in up to 80% of patients.

A Belgian company, Innogenetics was acquired by Solvay Pharmaceuticals in 2008 and is listed on Euronext Brussels (ticker, INNX)

Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers from Wikimedia Commons.

Eli Lilly announced today that it is pulling the plug on semagacestat, a gamma secretase inhibitor in phase 3 development for Alzheimer disease. Preliminary results from 2 large, ongoing, multinational phase 3 trials* showed that AD patients taking semagacestat actually performed worse on measures on cognition and activities of daily living than placebo-treated patients. Semagacestat treatment was also associated with a relatively increased risk of skin cancer (although the company's press release did not indicate what kind of skin cancer).

Lilly says it is still moving forward with its phase 3 clinical trials of another anti-beta-amyloid compound in AD: solanezumab, a monoclonal antibody. The drug works differently than semagacestat, an inhibitor of the enzyme (gamma secretase) that produces beta amyloid. The company also assures everyone that it will publish the results of its semagacestat trials.

By my estimation, Lilly is/was the frontrunner in clinical AD trials. Late-phase study of another anti-amyloid mAb, Pfizer/JNJ's bapineuzumab, has been complicated by underwhelming efficacy results and vasogenic brain edema.

* IDENTITY and IDENTITY-2.

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

A pattern of 3 markers in CSF—beta amyloid 1-42, phosphorylated tau, and total tau—appears to strongly predict Alzheimer disease in people with mild cognitive impairment (MCI), according to a newly published and highly publicized study from the US Alzheimer's Disease Neuroimaging Initiative. But the study findings, which can be found in the Archives of Neurology (subscription required), do not necessarily mean that the CSF assay should be incorporated immediately into clinical care—despite the fact that 1) the authors are lobbying hard for the test to be included in the diagnostic criteria for AD and 2) an accompany editorial urges clinical use of the CSF assay with the wince-inducing title, "Sharpen That Needle."

The "AD signature" of low beta amyloid 1-42 and elevated tau levels was found in 90% of AD patients (n = 102), 72% of MCI patients (n = 72), and 36% of cognitively normal subjects (n = 114). Consequently the sensitivity of the test is 90% (the rate of positivity in AD patients), and the specificity is 64% (the percentage of cognitively normal subjects who don't show the AD CSF pattern [ie, 100% - 36%]).

Among a subset of 68 people with autopsy-confirmed AD, 64 (94%) showed the AD CSF pattern, which correlates well with the 90% sensitivity measure in clinically diagnosed AD patients (via the MMSE). In another subset of 57 patients with MCI who developed AD during 5-year follow-up, all exhibited the AD CSF pattern for a sensitivity of 100%.

Rather than view a positive CSF assay in cognitively normal people as a failing of the test (ie, it has limited use in normal subjects), the authors conclude that these people are at risk of AD. This conclusion may well be true, but it seems that further study is warranted before such a bold statement can be made. The authors did find an "enrichment" of the apolipoprotein E ε4 allele, a recognized genetic risk factor for AD, in this population, but the finding was not uniform.

At least ABCNews, unlike many other news sources, found medical commentators who advise against the whole-hearted embrace of this assay. Cliff Saper, who is one of the most level-headed neurologists I've ever met, said there is no reason to perform the test until there is a successful treatment for AD. "This test shows up positive in presymptomatic individuals, and Alzheimer's disease is a common disorder," Saper was quoted. "The main value would be to detect [Alzheimer's disease] in atypical cases." For what it's worth, I agree.

The CSF assay currently appears to be most useful in the context of research—as an additional tool to reinforce the diagnosis of MCI or AD in clinical studies. Assay results may also inform the use of investigative therapies at different stages of cognitive decline. One of the most intriguing findings from the study is that there appears to be a distinctive pattern change as MCI progresses to mild AD and then to advanced disease: CSF beta amyloid levels fall while tau levels rise. Anti-beta-amyloid therapies like bapineuzumab, may provide relatively greater benefit in MCI or very early AD, while anti-tau therapies may have their place in more severe dementia. 

In the meantime, Innogenetics, which employs or employed several of the authors, provides the tripartite CSF assay (Inno-Bio AlzBio 3) for "research use only." Information on the cost of the assay, after several Google searches, remains elusive. 

CSF = cerebrospinal fluid.

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

But try explaining that concept to a jury.

The clinical data, and they are imperfect to say the least, suggest that there may be an idiosyncratic link between Accutane use and depression or suicide. But studies (not case reports) do not collectively support a bona fide association between the drug and affective disorders in users.*

It turns out that the same may be true for any posited association between Accutane and inflammatory bowel disease (IBD)—despite the hundreds of personal-injury cases brought against Accutane's former maker, Roche, in mass-tort litigation.**

There are at least 3 compelling case reports (here, here, and here) suggesting that Accutane causes or exacerbates enteritis or colitis and that these flares remit and recur with withdrawal and reuse, respectively, of the drug. And the drug's PI warns against the occurrence of IBD with Accutane use. (The mechanism by which Accutane, a vitamin A analogue, might cause IBD is unknown.) But a recent, population-based study in Canada found no association between Accutane use and the development of IBD. The study, which was not funded by Roche, is evidently the first of its kind to examine any such association, outside of case reports.

By using the Manitoba Health databases, the Canadian authors identified a similar percentage of patients (age cutoff, <40 years) who used Accutane before or after their first diagnosis of IBD (see adapted Table). These data suggest no association, much less a causal link, between Accutane use and the development of IBD. Moreover, Accutane use among matched controls (for age, sex, and residence) without IBD was similar (1.1% and 0.9% for the before and after populations, respectively). And the mean time between the diagnosis of IBD and the last Accutane prescription was lengthy (1048 days or ~2.8 years), suggesting that any cause-effect relationship in the 25 "before" IBD cases is unlikely.

Accutane Use	Cases (%)	Matched Controls (%)	Odds Ratio (95% CI)
IBD
Before dx	25 (1.2)	213 (1.1)	1.16 (0.73, 1.77)
After dx	23 (1.2)	182 (0.9)	1.25 (0.77, 1.94)
None	1960 (97.6)	19,419 (98.0)
Crohn’s
Before dx	14 (1.3)	120 (1.1)	1.15 (0.61, 2.02)
After dx	14 (1.3)	115 (1.0)	1.21 (0.64, 2.12)
None	1090 (97.5)	10,801 (97.9)
Ulcerative colitis (UC)
Before dx	11 (1.2)	93 (1.1)	1.16 (0.56, 2.20)
After dx	9 (1.0)	67 (0.8)	1.33 (0.58, 2.69)
None	870 (97.8)	8618 (98.2)

A more recently published, case-control study from UNC largely confirmed the Canadian findings, but the US authors concluded a "strong" association between Accutane use and UC among 24 total cases of IBD (OR for ulcerative colitis = 4.36 [95% CI: 1.97, 9.66]). The risk of UC appeared to increase with Accutane dosage and duration of treatment among the small number of cases (only 0.3% of subjects in the total IBD population had been exposed to Accutane). The US authors concluded, "Although the absolute risk of developing UC after taking [Accutane] is likely quite small, clinicians prescribing [Accutane] as well as prospective patients should be aware of this possible association." 

* Whatever Emory psychiatrist Doug Bremner may say on YouTube in his not-particularly-sophisticated interpretation of his and others' data.

** One of these cases was brought by actor James Marshall of "Twin Peaks" and A Few Good Men fame. Marshall, who is reportedly corralling celebrity witnesses to argue his case, claims that Accutane caused his IBD, which in turn put the kibosh on what would have been a James Dean-like film career (without the violent, early death, presumably). See last week's Bloomberg story.

Photo of Roaccutane, aka Accutane, from Wikipedia.

08/06/10 addendum: Yesterday the New Jersey Superior Court Appellate Division repealed the $10.5 million verdict for the plaintiff in Kendall v Hoffman-La Roche. The appellate court ruled that the Roche was hobbled during trial by restrictions on the presentation of background data for the incidence of IBD. Kendall, who was treated several times with Accutane for nodular acne during adolescence and young adulthood, developed UC at the age of 15 years, which coincided with Accutane retreatment. However, her bowel condition was not uniformly exacerbated by further treatments with Accutane.

Kendall's case hinges on the argument that Roche failed to warn of the risk of IBD, and Roche's warnings are based on risk data known at the time of Kendall's Accutane treatments. Bloomberg covered the story; the appellate decision can be found here.

A similar appellate reversal was made in McCarrell v Hoffman LaRoche, and the retrial resulted in an even bigger verdict for the plaintiff. An appeal on this verdict is reportedly in the works.

Nearly 8 months after the FDA refused to file Merck Serono's application for oral cladribine as an MS treatment, the company says the drug has now received priority review.* Merck Serono resubmitted its application to the agency in June. Related coverage from the WSJ indicates that the company expects an FDA decision in the fourth quarter, although the goal for a priority review is a bit longer, at 6 months.

With cladribine, Merck Serono has been in a nose-to-nose horse race with Novartis, which is developing fingolimod (Gilenia). One of these companies is very likely to be the first to offer an FDA-approved, orally administered disease-modifying drug for the relapsing-remitting form of the disease. (Current, approved, disease-modifying medications for RRMS, like interferon beta, are injected subcutaneously or intramuscularly.)

According to the WSJ and Reuters, oral cladribine for RRMS was approved in Russia earlier this month and is awaiting a nod in Europe. In June, an FDA panel voted overwhelmingly in favor of fingolimod's approval—at least with respect to its efficacy. Safety issues with Novartis's agent include opportunistic infections, and analysts have speculated that the FDA will institute some kind of access-limiting REMS program for the drug, if/once it is approved.

A new survey analysis indicates that US neurologists are considerably more aware of cladribine than fingolimod—probably because the former has been available as an injectable anticancer drug since the Stone Age (ie, the early 1990s), and fingolimod is a new molecular entity (NME).

MS = multiple sclerosis; REMS = Risk Evaluation and Mitigation Strategies.

* According to the FDA, a "Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. A Priority Review means that the time it takes FDA to review a new drug application is reduced. The goal for completing a Priority Review is six months."

The original source of Baxter's contaminated heparin, which killed scores of Americans in 2007 and 2008, has still not been identified, according to letters sent between the FDA and Congressmen Joe Barton (R-TX), who is investigating the matter. The heparin, which was intentionally spiked with oversulfated chondroitin sulfate (OCSC), was traced early to Baxter's Chinese supplier of crude heparin, Changzhou SPL, but the FDA has apparently not been able to get beyond the company to implicate any of Changzhou's suppliers. (A colorful expose by the WSJ in 2008 about the unregulated production of raw heparin in China showed just how hard it might be to identify the perpetrator.)

According to the agency's response letter of June 16, officials of China's State Food and Drug Administration (SFDA) have stifled the FDA's investigation beyond Changzhou SPL, and "repeated" follow-up requests to the SFDA have yielded only "general information." The latest from Chinese officials to the agency: There have been no breakthroughs in the case. However, Congressman Barton, in his latest volley with the FDA, suggests that the US agency has been lax in its follow-up and specifically in its investigation of several suspect Chinese firms, including transparently bogus "front companies." (For more on these suspect firms, read the letter.)

In its efforts to protect the American public, the FDA posted testing methods for OSCS and initiated a "sampling program" to examine products on entry to the country. In addition, specific Chinese firms, like Changzhou, have been given an "import alert" status, in which products can be confiscated without inspection.

Leading the search for a synthetic version of heparin, which would entirely circumvent any reliance on the crude harvesting process (in China or elsewhere), are investigators at Rensselaer.

SPL = Scientific Protein Labs.

Dr. George Lundberg, MedPage's Editor at Large, is really excited about an article that was published in March in the Journal of Clinical Investigation. And he predicts big things for the article's authors, like a Nobel Prize.

The article, by California academicians and an employee at AntiCancer, Inc., describes how vasculogenesis* of irradiated tumors can be inhibited by an already approved drug, AMD3100, in a mouse model of glioblastoma multiforme—the deadliest of brain cancers.

AMD3100 is also known as plerixafor or Mozobil, which is owned by Genzyme. The injectable drug is currently indicated, in combination with G-CSF, to mobilize hematopoietic stem cells for autologous transplantation in patients with non-Hodgkin lymphoma or multiple myeloma. So human trials of the drug and uncontrolled case studies can begin, Lundberg argues, more or less immediately.

G-CSF = granulocyte-colony stimulating factor (eg, filgrastim [Neupogen; Amgen]).

* Which is distinguished from angiogenesis or "the sprouting and proliferation of endothelial cell from local vessels. The authors posit that tumor recurrence after radiation is largely mediated by vasculogenesis, the "colonization of circulating endothelial or other cells primarily from the bone marrow."

Photo of Ted Kennedy, who died last year of glioblastoma: Biographical Directory of the United States Congress.

If you're looking for a break from the FDA's much-covered review of Avandia,* try the refreshing In Vivo Blog. The latest from the armchair bloggers (talk about redundant phrasing, and heh, takes one to know one) is their follow-up of biomarker data from JNJ and Pfizer on bapineuzumab, the anti-amyloid mAb in phase 3 development for Alzheimer disease.

Presented at the Alzheimer's Association International Conference on Alzheimer's Disease 2010 in Honolulu (Altoona wasn't available?), the biomarker data don't concern a reduction of amyloid with bapineuzumab treatment. Instead the data (and they're phase 2 clinical data) show a drop in CSF levels of P-tau, at least when they're pooled.

The examination of P-tau, as a "downstream" biomarker, may be scientifically valid in studies of anti-amyloid therapies. P-tau is certainly an important marker of AD pathology generally, and investigators seem to be more enthusiastic about direct, anti-tau therapies than anti-amyloid therapies. But the tau angle is also commercially savvy. It's a way of bolstering interest in the continued investigation of the leading anti-amyloid drug, which has provided underwhelming clinical results to date.

* heartwire.org provides the most detailed description of yesterday's contentious agency meeting, IMO--just short of live blogging it.

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

CSF = cerebrospinal fluid; mAb = monoclonal antibody.