Media: September 2009 Archives

Elan may well be the Lindsay Lohan of pharma. The long-troubled, press-worthy company courts controversy and our attention.

So now...It is reported that, on September 24, the US Securities and Exchange Commission subpoenaed the Dublin-based Elan for information regarding 2 announcements from 2008. The SEC subpoena was revealed in Elan's most recent filing with the Commission.

According to the filing, the SEC is investigating Elan's July 29, 2008, announcement of phase 2 data for bapineuzumab and the company's July 31, 2008, announcement of 2 Tysabri-related cases of progressive multifocal encephalopathy (PML). Elan currently comarkets the monoclonal antibody Tysabri (natalizumab) with Biogen Idec for the treatment of multiple sclerosis and is codeveloping the anti-amyloid monoclonal antibody bapineuzumab with Wyeth for the treatment of Alzheimer disease (AD).

The July 29 filing ("Elan and Wyeth Present Encouraging Results from Phase 2 Clinical Trial of Bapineuzumab at International Conference on Alzheimer's Disease"), which parrots an Elan press release of the same date, optimistically described the phase 2 results of bapineuzumab in patients with mild-moderate AD. The study results were used to promote the drug's ongoing clinical development, despite the fact that a statistically significant difference between the mAb and placebo for the primary endpoint was not observed. Dose-dependent vasogenic brain edema was also reported with bapineuzumab, especially in patients with the ApoE4 allele.

The phase 2 bapineuzumab data were first publicized by Elan in a July 17, 2008, press release (discussed here)—in which the missed primary endpoint was buried in the second paragraph and favorable post-hoc results were highlighted. Initial news of the study results was associated with substantial increases in Elan's and Wyeth's share prices (10.6% and 4.8% bumps, respectively) and generally favorable Wall Street buzz. However, after the same data were presented in the sober context of the International Conference, the companies' respective share prices dropped 19.6% and 11.2% (see "Bapineuzumab and Share Prices of Elan/Wyeth: What a Difference Some Undefined Thing Makes").

It seems reasonable to speculate that the SEC is investigating Elan's presentation of the bapineuzumab data in conjunction with a pump-and-dump-like scheme.

Reasons for the SEC's investigation of Elan's report of the PML cases are less obvious. The filing of July 31, 2008, described 2 European patients with multiple sclerosis who developed the potentially fatal, opportunistic infection after prolonged Tysabri monotherapy (14 and 17 months). To date, 11 cases of Tysabri-related PML have been reported since the drug's reintroduction into the marketplace in 2006. The risk of PML with the drug increases substantially with prolonged therapy (>12 months).

Two short weeks ago, JNJ closed its highly publicized buyout deal with Elan, in which JNJ acquires the rights to Elan's AD immunotherapy program. The program includes the development of bapineuzumab. The major sticking point of negotiations between the 2 companies became JNJ's potential access to Tysabri. Tysabri comarketer Biogen cried breach of contract with Elan over the initially proposed buyout, and a federal judge agreed. The newly cemented JNJ-Elan deal (for $100 million less than the original offer of $1.5 billion) omits the mAb.

A movement by editors to eradicate ghostwritten articles in medical journals is featured in today's NYT. The perhaps-too-cute term for the movement, "ghostbusting," was coined by the editors of Blood in January.

The most draconian of proposed steps to thwart ghostwriting—which typically involves an unacknowledged medical writer who is employed (either directly or indirectly) by pharma—include immediate article retraction, lifetime banning of the named author, and a report to the author's institution for investigation. Editors at PLoS Medicine recently described these punishments and their disdain for ghostwriting in firm, albeit clumsy, terms.

Medical journal editors need to decide whether they want to roll over and just join the marketing departments of pharmaceutical companies. Authors who put their names to such papers need to consider whether doing so is more important than having a medical literature that can be believed in.

Ideally the Age of Ghostbusting heralds an era of the medical writer as a contributing author and not the avoidance of the medical writer by the physician author—who generally can't write his way out of a paper bag.

While Elan has another 16 days to rework a buyout deal with JNJ—the new crux of which is the potential rights to the MS drug Tysabri (natalizumab)*—this week's NEJM offers 3 reports on the mAb-associated risk of PML.

Chen et al detected the subclinical reactivation of JC virus (the cause of PML) in 19 patients receiving natalizumab monotherapy. After 12 months of treatment, the prevalence of the virus increased significantly, from 19% to 63%, in urine. After 18 months of treatment, JC virus was detected in 20% (3/15) of plasma samples and in 9 of 15 samples of peripheral mononuclear cells. The shedding of JC virus was associated with a significant drop in the virus-specific cellular response.

Wenning et al describe the rocky, but successful, treatment of natalizumab-associated PML in a 52-year-old woman with MS. After 12 mAb infusions, the patient underwent plasma exchange and immunoadsorption therapy to remove natalizumab. She briefly improved but then developed immune reconstitution syndrome (IRS)—a condition otherwise familiar to HIV docs. Pulsed corticosteroid therapy resulted in clinical stability, followed by improvement.

A similar clinical course is provided by Linda et al, who describe the emergence of PML-consistent symptoms after 14 months of natalizumab treatment. Initially JC virus DNA was not detected in the spinal fluid by means of PCR; however, the virus was detected by quantitative PCR after 16 months of therapy (in association with clinical deterioration). Plasma exchange was performed. Three weeks later, the patient developed IRS; JC virus was no longer detected. Ultimately the patient improved.

The risk of PML with natalizumab therapy appears to depend on the length of therapy—an issue addressed in yesterday's WSJ by Shirley Wang. According to Biogen, the comarketer of Tysabri (along with Elan), there have been 11 cases of PML among 56,500 treated patients since the drug's 2006 reentry into the US market, for a crude, absolute risk of 0.02%.**

But the risk of natalizumab-associated PML appears to increase with prolonged therapy (eg, >12 months)—a fact that necessitates the use of an actuarial calculation (although Biogen disagrees). Wang calculates the actuarial risk of natalizumab-associated PML at about 0.08%. Citing neurologist Robert Fox, she also reports a risk of greater than 0.1% when therapy extends beyond 30 months. 

A quantitative risk-benefit analysis of natalizumab treatment, published last year, indicated that the "actual" risk of PML with the mAb would have to increase more than 7 times to reduce the relative benefit of therapy below that of interferon beta. The authors used an annual PML risk that was based on the published risk estimate of 1 per 1000 patients treated for an average of 17.9 months.

* For the necessary biz background, check out the In Vivo blog and the WSJ blog.

** Biogen actually calculates the absolute risk at about 0.01%, according to the WSJ.

HIV = human immune deficiency virus; mAb = monoclonal antibody; MS = multiple sclerosis; PCR = polymerase chain reaction; PML = progressive multifocal leukoencephalopathy.

NYT science reporter Amy Harmon has neglected to provide important follow-up on Insmed's clinical development of Iplex. In May, Harmon covered the story of Joshua Thompson, a victim of ALS, who was trying to obtain compassionate access to the experimental drug—a synthetic insulin-like growth factor that is linked to a binding protein.

Harmon's unidimensional coverage stressed the cruel fallout of a corporate battle over drug ownership and FDA bureaucracy—both of which, she implied, impeded Thompson's access to Iplex (for important background, go here). And Harmon downplayed the total absence of clinical data (including safety data) to support the use of Iplex in ALS; the promise of the drug lay solely in its theoretical ease of access to the central nervous system and in pumped-up anecdotes found on the World Wide Web. After publication of Harmon's story, Insmed experienced a substantial increase in its share price.

The epilogue of Iplex development, for those who care and remember, can be found by searching Google News and by reading Insmed's press releases. On June 25th, the company reported highly disappointing results from a phase 2 trial of the drug in myotonic dystrophy. Insmed's low-priced stock plunged overnight, from about $2.25 to a dollar.

Then one month later, Insmed announced it would no longer supply Iplex to new patients. The company lost its capability to manufacture the "extremely complicated" drug following the sale of its Boulder, Colorado, facility to Merck (a sale which was announced in March).* Insmed also reported that it would discontinue the drug's clinical development. Specifically a planned phase 2 study of Iplex in ALS would be postponed. (This, after a statement in May, in which Insmed reported that it was "working diligently" with the FDA to "make the necessary preparations" for a US clinical trial of Iplex in ALS.)

Insmed stated that the existing, limited supply of Iplex would be reserved for the 70 currently treated ALS patients (12 in the United States [including Thompson] and the rest in Italy through an expanded access program). The inventory would provide coverage for "no more than 24 months."

In response to the news, the ALS Association issued, in part, the following statement:

The Association encourages the FDA and INSMED to establish partnerships with the ALS community to ensure that the program yields meaningful results that will guide the next steps in determining whether IPLEX is effective and safe for people with ALS.

Based on existing clinical and scientific evidence, The ALS Association cannot encourage or recommend the off-label use of this medication without substantive evidence of its efficacy through a rigorous clinical trial. The ALS Association is continuing to monitor and assess information about IPLEX as it becomes available to provide the public with the most up-to-date reports about its potential for ALS.

Since early August, Insmed can only offer penny stock. The company's pipeline currently consists of 2 molecules, rhIGFBP-3 and INSM-18, which may have antitumor activity. The company hopes to find a corporate partner(s) for their clinical development.

ALS = amyotrophic lateral sclerosis.

* In mid-February, Insmed announced that it was selling its follow-on biologics platform to Merck for $130 million. The money would be used, in part, to finance the clinical development of Iplex. The sale was completed in early April.

Two days ago, I posted a somewhat snarky response (although this is a blog) to the NYT's expose of Forest's 2004 marketing plan for Lexapro (which was drafted in 2003). Contained within the company's leaked, abridged marketing plan was a proposal to use "reporters" from selected psychiatry journals, including "CNS News"—which was probably meant to be written as "CNS Spectrums"—to cover Lexapro data at major psychiatry meetings. (CNSNews is a conservative, mainstream, online news source.) The reports would be included as supplements in the journal and provide continuing medical education (CME) credit.

CNS Spectrums is a monthly neuropsychiatric journal published by MBL Communications, Inc, which offers some CME-certified articles in conjunction with its accredited partner, the Mount Sinai School of Medicine. The general reputation of the journal among clinicians is that of a "throwaway" publication. To wit, I used to receive unsolicited, free issues of CNS Spectrums by mail; I'd glance at them and then throw them away. Nevertheless the journal, despite its lackluster reputation, is included in the National Library of Medicine's PubMed database.

So as a follow-up exercise (and because I'm slightly nuts), I examined the articles that made it into the supplemental issues of CNS Spectrums during 2004. The objective was to determine to what extent Forest's Lexapro marketers realized their described plan, at least with respect to this particular tactic. My methods consisted of 1) a PubMed search within the confines of the year 2004 and the search term "CNS Spectr"[Journal]; 2) a directed search of the CNS Spectrums web site; and 3) a review of clinical supplements listed at the CNS Spectrums web site.

Here are the results:

At least by my search, there is no evidence that a Forest-sponsored article made it into a supplement of CNS Spectrums during the 2004 calendar year. In 5 cases, however, the supplements could not be accessed by using the search function provided at the publication's web site** or through the PubMed link (when provided). Nevertheless, in these cases, it is unlikely that Forest sponsored the supplements (ostensibly to promote the antidepressant Lexapro), given the designated topics—for instance, Alzheimer disease, antipsychotic use, or bipolar disorder.

There is also no evidence that any of these supplements were certified for CME, given the absence of designated learning objectives and other ACCME-required language. Although in 2 cases, the supplements were supported by an "unrestricted, educational grant" (both from GlaxoSmithKline). Whether any or all of these 2004 articles, all of which have clinician authors, were ghostwritten by "reporters" is just about anybody's guess. 

2004 Supplement	Topic	Sponsor	CME	Faculty Disclosures
February	Rapid-cycling bipolar disorder (panel discussion)	AstraZeneca	No evidence	No
April	Anxiety disorders (panel review)	UCB Pharma	No evidence	Yes
June	Mood and anxiety disorders (4 articles)	GSK	No evidence*	Yes
July	Alzheimer’s disease (5 articles)	No data**	—	—
August	Bipolar disorder in women (1 article)	GSK	No evidence*
August	Antipsychotic-associated hyperprolactinemia (1 article)	No data**	—	—
August	Anxiety disorders (1 article)	No data**	—	—
September	Antipsychotic use (4 articles)	No data**	—	—
October	Psychosis/schizophrenia (4 articles)	No data**	—	—
November	Bipolar disorder (3 articles based on data presented at the 2004 APA meeting)	None indicated	No evidence	No

* Although funded by an "unrestricted, educational grant."
** An "error" occurred when attempting to access the article at the CNS Spectrums web site. The error message advises contacting the web designer, which has the unfortunate name of spinindustry.com.

A review of listed clinical supplements at the CNS Spectrums web site reveals only 1 that was sponsored by Forest: "Bridging the Clinical Gap: Managing Patients with Co-occurring Mood, Anxiety, and Alcohol Use Disorders." Published in April 2008, the supplement consists of 5 articles (including an introduction), none of which appear to offer CME credit. Faculty disclosures are provided with each article, and "editorial assistance" is acknowledged by name (Eileen McGee, Marsha Kellar, and Joyce Waskelo) and company (Hudson Medical Communications, which is described as a promotional firm at the web site of its parent company). The acknowledgement appears to be an attempt at editorial transparency and to undermine accusations of ghostwriting. But given the suspicion that McGee, Kellar, and Waskelo actually drafted the articles, they should have been defined as coauthors.

In the 5 articles, "escitalopram" (ie, Lexapro) is mentioned exactly 4 times in the text bodies and in conjunction with other antidepressants (eg, citalopram [Celexa], fluoxetine [Prozac], and paroxetine [Paxil]).

ACCME = Accreditation Council for CME; APA = American Psychiatric Association.

Just to be different.

Dr. Thomas Frieden of the Centers for Disease Control and Prevention (CDC) conducted this week's broadcasted press conference on the status of the novel H1N1 epidemic in the United States.

Points made.

• The bad news: Novel H1N1 virus is here and spreading, and notably, infection didn't abate during the summer ("very usual"). Expect to see more cases in the coming months.
• The good news: The virus has not mutated, as yet, to become more deadly; and so far, antiviral-resistant strains of H1N1 have not been observed. (See Addendum.)
• The caution: But influenza is unpredictable, and readiness for the worst is imperative.
• The verified data:
  a) There have been 36 pediatric deaths in the United States, details of which are in the latest issue of the MMWR; children with special needs appear to be particularly vulnerable to infectious complications, including death.
  b) Recent experience in the Southern Hemisphere (5 countries) is similar to that in the United States (during the Spring); there have been hospitalization challenges but no increase in the H1N1-related death rate.
  c) The Institute of Medicine (IOM) issued a report today recommending fitted N95 respirators, instead of the typical face mask, for healthcare workers who interact with H1N1-infected patients.*
• The unverified data: A 1-dose vaccine, which was recently approved in China.
• The 2-dose vaccine:
  a) Still expected in mid-October.
  b) To induce effective immunity, 2 doses are anticipated to be necessary.
  c) Recommended groups for vaccination remain the same.
  d) The vaccine itself is free, although administration may not be; the government is in the process of releasing $1.5 billion to enable/facilitate vaccine administration.
  e) Vaccination programs will be run on the local level (eg, state). 
• The upcoming surveillance: For possible adverse events (eg, Guillain-Barre syndrome, miscarriages) associated with vaccination.
• The challenge to safeguard healthcare resources:
  a) Most cases of novel H1N1 infection are mild and don't necessitate laboratory testing or antiviral treatment.
  b) Stay home if you're sick.
  c) Cover your face when coughing or sneezing.
  d) Wash your hands.
  e) Don't go to the doctor unless you're severely ill or have an underlying condition (although it's important to be seen promptly in these cases, so that antiviral therapy can be instituted in a timely fashion [ie, within 48 hours of symptom onset]).
  f) To employers: Don't require a permission note from an employee's doctor before the employee can return to work; in general, telecommuting may be a good idea.

* The IOM was not charged with considering cost, when making its recommendation.

Depiction of H1N1 virus from Wikipedia.

09/05/09 addendum: In its August 12th report, WHO indicated knowledge of 12 cases of disease that is resistant to oseltamivir (Tamiflu; Roche). The mutated virus, however, remains sensitive to zanamivir (Relenza; GSK). Oseltamivir-resistant cases occurred sporadically throughout the world and were apparently not connected.