December 2007 Archives

The top story for 2007 begins, unfortunately, in 2006, when more than 100 Panamanians died of poisoning caused by diethylene glycol* contained in cough syrup made with tainted Chinese glycerin. Diethylene glycol is a well-known toxic solvent, with a long history of being used as a cheap, counterfeit glycerin. Covering this story for The New York Times, Walt Bogdonovich and company, in dogged praiseworthy pursuit, traced 46 barrels of the imported glycerin stock, labeled as 99.5% pure but containing approximately 24% of the toxin, from a Panamanian port through Spain to the Taixing Glycerine Factory in the Yangtze Delta.

 

Risks posed by over-the-counter products tainted with diethylene glycol bled into 2007 when the toxin (albeit at a much lower percentage) was discovered in Chinese-made toothpaste; tubes, some of which were marketed for children, were found throughout Latin America, as well as in Canada and the United States.

 

In March, a series of renal-failure deaths in dogs and cats led to the discovery in pet food of Chinese wheat gluten laced with melamine—a slow-release fertilizer and cheap, ersatz protein. Although the ability of melamine to cause the pet deaths was questioned, the discovery prompted concerns about the safety of animal feed generally and the possible toxicity posed to humans through indirect consumption. The FDA consequently banned the importation of Chinese wheat gluten—which made up 13% of the US import market—and opened a criminal investigation, according to the NYT.

 

In May, a second suspect molecule, cyanuric acid was discovered in the contaminated pet food, which led veterinary investigators at the University of California, Irvine to examine the toxicity of melamine, cyanuric acid, and the combination in cats. In animals fed either melamine or cyanuric acid separately, kidney function was unaffected. However, cats fed the combination developed acute renal failure, and histopathologic kidney findings were consistent with those published in September in pets previously affected by the contaminated products.

 

In August, the suicide of the owner of Lee Der Industrial—a longtime Chinese supplier for Mattel—was the culmination of a worldwide recall of Chinese-made toys coated with lead paint. According to the NYT, approximately 80% of the world’s toys are manufactured in China, mostly as a result of contract vending. Another Chinese toy manufacturer was also cited for supplying an Illinois toy company with lead-paint-coated wooden railway sets. Concerns among US consumer advocates resulted in wider testing, which revealed a concerning amount of lead in toys and bibs (no less) made of polyvinyl chloride.

 

The response from Chinese officials to the series of consumer-product debacles was a conflicting mixture of denial, defense, and affirmation to overhaul China’s food- and product-safety system. Perhaps in a show of general authority and assurance to the world at large, China executed its former head of the state food and drug administration in July, after he was convicted of bribery charges.

 

Last, from the disturbing to the just plain bizarre, toy beads manufactured in China by JSSY Ltd and marketed as Aqua Dots in North America were recalled after reports of illness, in some cases coma inducing, occurred in 14 children who ate the beads. Evidently the beads contained a cheap glue substitute, 1,4-butanediol, which is metabolized, once ingested, into gamma-hydroxybutyric acid (GHB)—otherwise known as the “date-rape drug.” The manufacturer issued a public apology in November, reporting “that it had not occurred to anyone to check whether [1,4-butanediol] would be dangerous for children to eat,” according to the company’s chairman in the NYT.

 

* Death caused by diethylene-glycol-contaminated products is direct from The Annals of History Repeating Itself. In 1937, more than 100 US citizens—many children—died after consuming Elixir Sulfanilamide, a raspberry-flavored antibiotic syrup manufactured by the S. E. Massengill Pharmaceutical Company of Bristol, TN. The difficult-to-dissolve antibiotic was ultimately mixed with the toxic solvent by the company’s head chemist, Harold Cole Watkins, who reportedly only tested the elixir for its appearance and palatability. The catastrophic event led to the passage of the 1938 Federal Food, Drug, and Cosmetic Act. In the 1990s, episodes of diethylene-glycol poisoning from syrup medications were reported in India and Haiti.

Vigilantism, in this case, is not necessarily meant in a negative way and certainly not in an unorganized way. The chief story underscoring the selection for the number-2 pick of 2007 is, of course, the string of independent safety assessments of Avandia (rosiglitazone; GlaxoSmithKline) published separately in the NEJM, JAMA, and Lancet in May and September. The strengths and weaknesses of these assessments and the overt or covert motivations behind them won’t be discussed here, but their power (along with the associated media attention) to instigate more than just passing reactions from GSK and the FDA cannot be denied (not to mention the arguably irrelevant input from congressional members).

 

The public-relations department at GSK clearly worked overtime responding not only to these 2- or 3-authored meta-analyses but also to the numerous editorials and letter responses and the multitude of lay-press reports that followed. A quick review of the Avandia Press Kit site (not to gloss over the fact that an Avandia Press Kit site even exists) reveals a string of PR responses, letters to the likes of the Baltimore Sun and the LA Times, and GSK testimony.

 

Fallout from the NEJM article prompted the FDA to appoint a 15-member advisory panel in June to review the safety data associated with Avandia and those of the thiazolidinedione class at large (which includes Actos [pioglitazone; Takeda]). Ultimate props should be given to the FDA for prevailing under the media-powered storm to pull Avandia, when it reported in August that the drug was sufficiently safe to remain on the market, but that a so-called black box warning would be added to the labels of all thiazolidinedione-containing drugs, emphasizing the risk of heart failure in certain patients. (This recommendation was in keeping with that of the advisory committee.) In November, the FDA announced that an additional warning would be added to the Avandia label, which references data from the NEJM meta-analysis.

 

The Avandia story also created a nice storm in the blogosphere, which introduces the complement of this regulatory-vigilantism post: the emergence and growth of medical/pharmaceutical blogs. These blogs—particularly those associated with established press organizations (eg, Pharmalot and the WSJ health blog) and even moreso those regularly written by active physicians or scientists (eg, Aggravated DocSurg, The Carlat Psychiatry Blog, and In the Pipeline)—are beginning to importantly inform the way we view the good and the ugly of the medical and pharmaceutical industries through their growing and active readership. The necessary irreverent nature of the blog format meshes nicely with any educated finger pointing, finger wagging, or all-caps screaming that may be considered necessary when distributing information or editorializing about these traditionally stodgy, cloaked industries to the big, bad world—this site not excepted.

For many clinicians and scientists who care about transmissible spongiform encephalopathies (TSEs), the idea that prions cause sheep scrapie, Creutzfeldt–Jakob disease (CJD), and bovine spongiform encephalopathy (aka mad cow disease) has largely been accepted by way of faith and capitulation. The notion is that the putative agent, normal host prion protein (PrP), causes disease by mutating into an abnormal, degradation-resistant form (PrP-res) that self-replicates without the aid of genetic material.

 

Now once you get beyond the utter heresy that protein replication can occur without nucleic acids, the prion theory will still require you to toss out Koch’s postulates, which have been used for more than a century to establish a causal link between microbe and infectious disease. You have to be okay with the fact that PrP-res is not invariably seen in highly infectious tissue samples, that its presence is not proportional to infectivity, and that it is not associated with reproducible infectivity—among other obstacles.

 

Consequently, the thought process required to embrace the prion theory (and a theory so fundamentally radical must be fully embraced, if it is to be acknowledged at all) necessitated a goodly amount of seeing a fabulous suit on a nude head of state. Nevertheless, witnessing the emperor fully clothed became a whole lot easier in 1997 when the committee for the Nobel Prize in Physiology or Medicine gave its big hug to Stanley Prusiner—professor of neurology, biochemistry, and biophysics at UCSF and chief proponent of the prion theory.

 

But now comes Laura Manuelidis, head of neuropathology at Yale, and her colleagues who published in the January online issue of PNAS their consistent identification of 25-nm virus-like particles in cell lines infected with a scrapie or CJD strain (EM photomicrograph). Notably, these viral particles were not observed in controls and bore no relation to the presence or production of abnormal prion protein. They were also similar to particles originally identified in 1968 in a mouse scrapie model by David-Ferreira et al, in 1971 in sheep scrapie, and in 2004 in primate and human CJD brain. Curiously enough, similar arrays of viral particles were identified by Baringer and Prusiner in 1978 in scrapie-infected brain samples, as the authors point out.

 

Manuelidis et al conclude that the causative agent of TSEs is most likely this 25-nm virion observed currently and historically in multiple varieties of disease but not in control cell populations (thereby fulfilling Koch’s first postulate) and that PrP-res is likely a late epiphenomenon of infection. Remaining are the large tasks of purifying the viral particles, demonstrating their infectivity, and recuperating them from inoculated host tissue.

In the May 10 issue of The New England Journal of Medicine, results from an international phase 3 trial showed that a quadrivalent human papilloma virus (HPV) vaccine (Gardasil; Merck) was 98% efficacious for reducing the composite risk of precancerous cervical lesions or HPV-related cervical cancer in young women who demonstrated no evidence of being infected with the most common causes of cervical cancer. A related study, reported in the same issue, indicated that the same vaccine was 100% efficacious for reducing the composite risk of genital warts and neoplastic cervical lesions in a similar group.

 

In the Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) II Study,* 12,167 women between the ages of 15 and 26 years received 3 doses of randomly assigned quadrivalent HPV vaccine (n = 5305) or placebo (n = 5260) in double-blind fashion at day 1, month 2, and month 6. The primary analysis was performed in the “per-protocol susceptible population,” which consisted of women who demonstrated no evidence of infection with HPV types 16 or 18 at 1 month after the third dose of vaccine. In this study population, the vaccine was 99% efficacious for reducing the composite endpoint of cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18 at a mean of 3 years. In the intent-to-treat population, the vaccine demonstrated 44% efficacy for the composite endpoint and 17% efficacy for the endpoint of high-grade cervical lesions.

 

In the companion study (FUTURE I), 5455 young women between the ages of 16 and 24 years received the same randomly assigned regimen of vaccine (n = 2723) or placebo (n = 2732). The vaccine demonstrated 100% efficacy in the per-protocol study population (as defined) for reducing the composite risk of genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer, as well as the composite risk of cervical intraepithelial neoplasia, adenocarcinoma in situ, or cancer associated with HPV type 6, 11, 16, or 18 at a mean of 3 years. The vaccine reduced the rate of any vulvar or vaginal perianal lesions by 34% and the rate of cervical lesions by 20%. Lesions were reduced regardless of the causative HPV type.

 

The Merck vaccine is a noninfectious, recombinant vaccine containing highly purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV types 6, 11, 16, and 18. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (amorphous aluminum hydroxyphosphate sulfate). HPV is known to cause essentially all cervical cancers, with types 16 and 18 accounting for approximately 70% of cervical cancers globally. Although HPV types 6 and 11 are rarely detected in high-grade cervical lesions, they are the causative agents of most anogenital warts.

 

On the basis of these phase 3 data and prior phase 2 data, Gardasil was approved by the FDA in June 2006 for administration to girls and women aged 9-26 years. The uptake of the vaccine has been robust, with 2007 sales reported at blockbuster status—$1.5 billion, and projected annual sales have been estimated at a whopping $3 billion. In addition, data presented November 7 at the 24th International Papillomavirus Conference in Beijing, China, indicated an approximate 90% efficacy of the vaccine in women aged 24-45 years, and Merck states that it plans to submit these data to the FDA for an expanded indication.

 

In related news, GlaxoSmithKline suffered a setback regarding US approval of its cervical cancer vaccine (Cervarix) on December 17 after the FDA requested additional information. The bivalent vaccine, which has been approved in the European Union, Mexico, and Australia, is designed to prevent cervical cancer related to HPV types 16 and 18 and is promoted as being formulated with a “novel proprietary adjuvant system” that is intended to prolong the duration of HPV immunity.

 

*Oy. Don't get me started on these study acronyms.

On September 24, interim results from a major, international, NIAID-cosponsored trial indicated that a Merck-developed vaccine does not prevent HIV infection. An independent data and safety monitoring board consequently recommended that the 3000 volunteers in the phase 2b “test-of concept” study no longer receive vaccine. It was also recommended that the vaccine not be administered to subjects in a companion South African study, which began February 2007.

 

In December 2004, the STEP study (also called HVTN* 502 or Merck V520-023) began enrolling uninfected volunteers to receive 3 doses of the Merck vaccine or placebo in randomized, double-blind fashion. The trivalent vaccine consisted of a replication-defective adenovirus 5 (Ad5) vector in which was inserted 1 of 3 synthetically produced HIV genes: gag, pol, or nef.^† The vaccine was intended to allow the re-establishment of nascent immunity against HIV-infected cells.

 

Among volunteers who received at least 1 dose of vaccine, the rate of HIV infection was 3.2% with the active vaccine and 2.8% with placebo vaccine, according to the interim results. In men who received at least 2 doses of vaccine, the infection rates were 2.8% and 1.6% with vaccine and placebo, respectively. Currently it is unclear if the vaccine fails to prevent HIV infection or actually increases the risk of infection.

 

Regardless, the reason for the failure of the vaccine is presently a mystery. However, investigators and observers speculate that the Ad5 vector may be responsible, by limiting the immune response in vaccinated men who have preexisting immunity to Ad5. According to a Merck press release, STEP was originally designed to include only those persons with low Ad5 antibody levels (≤200 units), with the expectation that those individuals would demonstrate the best vaccine response. However, persons with Ad5 antibody levels higher than 200 units were subsequently enrolled, because new data indicated that the vaccine was immunogenic in those subjects as well. Follow-up data from the interrupted STEP study, which may include subgroup analyses, are scheduled to be presented in February 2008 at the Conference on Retroviruses and Opportunistic Infections in Boston.

 

*HIV Vaccine Trials Network.

^†As a reminder, gag genes code for HIV structural components; pol codes for reverse transcriptase; and nef codes for a protein that promotes the survival of infected cells.

The flurry of 2007 lay-press reports that described isolated and clustered cases of methicillin-resistant Staphylococcus aureus (MRSA) produced more confusion than clarity by largely failing to discriminate between community- and healthcare-associated disease. The CDC defines community-associated (CA)-MRSA as a MRSA infection in an individual who has not been hospitalized or undergone a medical procedure (eg, catheter placement) within the last year. CA-MRSA infections are further distinguished from healthcare-associated (HA)-MRSA disease (which has been recognized for decades) when the diagnosis is established either in the outpatient setting or within 24 hours of hospital admission (by culture) and when there is no prior history of MRSA infection or colonization.

 

Although CA-MRSA appears to cause less severe infections generally than HA-MRSA, the former is more easily transmitted from person to person. In 2006, CA-MRSA was described as the most common cause of skin or soft-tissue infections necessitating emergency care in the United States. Certain biologic properties of CA-MRSA appear to be associated with its propensity to cause skin disease and its easy transmissibility. One proposed factor informing virulence was the bacteriophage-generated cytotoxin Panton-Valentine leukocidin (PVL). However, data reported in 2006 indicated that PVL-deficient strains of common CA-MRSA types were no less virulent or lethal in animal models than those expressing PVL.

 

In November, investigators from the NAIAD, Germany, and Washington state published online their study of a group of protein toxins in S. aureus that are related to the proinflammatory peptide toxins of S. epidermidis, labeled phenol-soluble modulin (PSM). Production of PSMs (α, β, and δ) in cultures of the most prevalent CA-MRSA strains was observed to be considerably higher than that in cultures of HA-MRSA strains. By using murine abscess and bacteremia models, they then examined the relative virulence of 2 common CA-MRSA strains, USA300* and USA400,^† from which various PSM genes were deleted. Notably, USA300 strains lacking PSMα genes—but not those lacking other PSM genes—were significantly less likely to cause severe skin lesions in mice, prompting the authors to conclude that PSMα peptides play an essential role in the generation of CA-MRSA skin infections. In the bacteremia model, mortality was significantly reduced when PSMα, and to a lesser extent δ-toxin, was deleted.

 

In their in vitro experiments, synthetic PSMα peptides, and particularly PSMα3, produced the greatest neutrophil-associated proinflammatory activity but also generated substantial neutrophil lysis. The latter finding was consistent with the considerably reduced ability of PSMα-deleted strains of CA-MRSA and of HA-MRSA to lyse human neutrophils.

 

The authors claim that the primary role of PSMs is to destroy leukocytes. But given the observed proinflammatory activity of PSMs, they also conjecture that, for CA-MRSA survival, PSM secretion should be confined to times when immune cells can be destroyed. Evidently all S. aureus PSMs are tightly controlled through the process of so-called quorum sensing via the accessory gene regulator (agr). Quorum sensing links gene expression to the local concentration of bacterial signaling molecules. They conclude that agr-mediated quorum sensing of CA-MRSA dictates the activation of PSM-producing genes when PSMs are needed for pathogenesis and the repression of PSM production when they endanger CA-MRSA survival.

 

*Aka LAC; most common cause of community-associated skin or soft-tissue infections in the United States.

†Aka MW2; typically causes sepsis in humans.

It was a confluence of infectious disease and the explosive celebrity of the hapless, clueless common man. Beyond inspiring another “Law and Order” episode, itinerant lawyer Andrew Speaker introduced the wider world to 2 ominous forms of tuberculosis—multidrug resistant (MDR) and extensively drug resistant (XDR). His story highlighted the difficulty of gauging the contagiousness of TB in the non-sick sick and negated the idea that educated, infected citizens will act responsibly.

 

Just a few days before Speaker knew that his bronchoscopy culture grew Mycobacterium tuberculosis, the CDC published a tally of known XDR-TB cases within the United States in its March 23 issue of MMWR. From 1993 to 2006, the US National TB Surveillance System identified 49 individuals with the extensively resistant pathogen—that is, TB resistant to first-line drugs isoniazid and rifampin, any fluoroquinolone, and at least 1 second-line injectable agent (amikacin, capreomycin, or kanamycin). Most were located in New York City (19) or California (11).

 To detect rough trends, investigators stratified the XDR-TB cases on the basis of their identification during 1993-1999 or 2000-2006 and observed that more recent cases were more likely to occur in Asians and in foreign-born individuals and less likely to affect persons with HIV coinfection (which correlates strongly with mortality). Among the 41 cases with known outcomes, approximately 30% died—leaving at least 29 persons alive with known XDR TB in the United States at the time of the MMWR report. Approximately 30% of XDR-TB deaths were associated with HIV coinfection. The microscopic detection of acid-fast bacilli (AFB) in sputum was more likely in the more recent cases (71% vs 47%). However, these data were not known for approximately 20% of identified persons—a disturbing statistic.

 

Transmission of TB, which is almost exclusively airborne, depends on 3 major factors (Marrie TJ, ed. Community-Acquired Pneumonia. New York, NY: Springer; 2001.): the contagiousness of the index case, the case’s proximity to others, and the susceptibility of others (eg, immunocompromise due to HIV coinfection). The contagiousness of a case depends on the following:

 

·         Site of disease (pulmonary infection obviously provides the greatest opportunity for airborne transmission);

·         Extent of disease (heightened risk of transmission is associated with laryngeal involvement);

·         Treatment (both its existence and effectiveness); and

·         Behavior of the individual (for example, risk is increased with frequent and forceful coughing).

 

When the sputum smear for AFB is negative but the culture is positive, contagiousness is considered negligible after 2 weeks of effective treatment (providing that the TB is drug susceptible). Risk of transmission also depends on the duration of exposure and the environment of contact: a cramped plane cabin on an overseas flight represents a bad scenario. In Speaker’s case, he hopped on no less than 7 flights in May—one of which was an Air France/Delta flight from Atlanta to Paris with 433 passengers and another of which was a Czech Airlines flight from Prague to Montreal with 191 passengers. Despite his risky behavior, passengers sitting in proximity to Speaker on either plane were reported to be uninfected as of late November.

 

An editor’s note accompanying the MMWR article advised that the identified XDR-TB cases are an underestimate, owing to incomplete data and the pitfalls of drug-sensitivity testing (DST). Approximately 20% of reported TB cases do not have positive cultures that enable DST, and only 22% of reported MDR cases were associated with complete DST results, thereby enabling the identification of XDR TB. Conversely, the consistency of DST results from laboratory to laboratory has been called into question: TB grown from Speaker and that of another publicized individual were downgraded from XDR to MDR.

 

The XDR variant likely resulted from the aggressive treatment of MDR-TB cases during the last part of the 20th century. But the relative contribution of person-to-person transmission of XDR TB and that of XDR TB emerging in an MDR-infected person are presently unknown.

As of December 18, the World Health Organization reported 77 cases of avian influenza worldwide, most of which occurred in Indonesia (40 cases). While the case number of infection this year is lower than that tallied in 2006 (115 cases), the mortality rate of human disease, at 60%-70%, remains high, and small outbreaks in wild and commercial poultry continue to be reported in Europe, raising imminent concerns about the eruption of bird-to-human illness beyond Southeast Asia. In the United Kingdom, H5N1 was detected at a turkey farm in January 2007—the first-ever report of the disease in commercial poultry in that country, and in November, the virus was identified in a flock of free-range* turkeys in England.

 

The reason we continue to care about avian influenza, beyond its documented and would-be effects on the commercial poultry industry (among other things), is the enduring potential of the virus to mutate, thereby enabling person-to-person transmission and blowing the human race to kingdom come. Veterinary investigators in Japan, Vietnam, and Wisconsin gave us an idea of the necessary steps of this transmutation process in a neat, attention-grabbing study, published in PloS Pathogens in October.

 

Hatta et al assessed the growth and replication of 2 highly virulent H5N1 isolates, VN1203 and VN1204, which were cultivated from the same 10-year-old Vietnamese boy who died of avian influenza in 2004 (Maines TR et al. J Virol. 2005; 79:11788–11800.). The 2 isolates differ in their coding for a total of 6 amino acids, but the authors elected to concentrate on the difference at position 627 of the cap-binding transcriptase (PB2) protein, because the host specificity of influenza A viruses (that is, human vs avian) appears to be determined, at least in part, at this site.^† VN1203 codes for lysine (Lys) at the 627 position, and VN1204 codes of glutamate (Glu). As a rough generalization, most human subtypes have Lys at 627 (PB2-627Lys), and avian subtypes typically have Glu (PB2-627Glu) at this same location.

 

The authors observed that Lys-encoded VN1203 and an engineered mutant of VN1204 with Lys at position 627 demonstrated greater replicative capacity in mice than wild-type VN1204 or an engineered version of VN1203 containing Glu at 627. Consequently, the Lys residue at position 627 of the PB2 viral protein appears to elevate viral-replication capabilities. This finding notably held true in mammalian cells at relatively lower temperatures—namely, temperatures simulating those of the upper-repiratory tract.^‡

 

It is therefore proposed that several H5N1 mutations, including the PB2 mutation, are necessary to confer efficient person-to-person transmission of avian influenza. Another cited mutation of importance consists of amino-acid substitutions in the viral-surface glycoprotein hemmaglutinin (HA), which detemines host-cell recognition. Mutated variants of HA bind to saccharide-containing cell receptors with either a terminating sialic acid α-2,3-galactose (SAα2,3Gal) on avian cells or sialic acid α-2,6-galactose (SAα2,6Gal) on human cells. The authors speculate that PB2-627Lys (which broadens susceptible cell types and enables low-temperature replication), SAα2,6Gal recognition (which enables human-cell binding), and other as-yet-unknown mutations are necessary for a human pandemic.

 

* I’m not sure why WHO makes a point of identifying these commercial birds as “free-range,” unless they were exceptionally free ranging.

† In addition, the PB2-627Lys variant may be associated with higher virulence and heartier replication capabilities. Specifically, the activity of its RNA polymerase is efficient at relatively low temperatures.

‡ A curious aside is that, in mice, titers of the engineered VN1204PB2-627Lys were appreciably higher than those of VN1203 (which also has PB2–627Lys), suggesting that coding differences beyond the 627 position determine growth efficiency of the virus.

On October 18, Pfizer publicly announced its decision to stop selling Exubera, the first inhalable human insulin approved by the FDA, because of poor market performance. The decision to terminate sales, 21 months after the drug’s approval, was a reported surprise to Exubera codeveloper Nektar Therapeutics, which learned of its breakup with Pfizer in Matt Damon-esque* fashion through Pfizer’s release of its 3rd-quarter results.

 

Sales of Exubera, which had been predicted to exceed the blockbuster threshhold of $1 billion per year, totaled just $12 million during the first 9 months of 2007 and consumed less than 1% of the insulin market, according to a New York Times report. To add insult to Nektar’s injury, the share price of Nektar stock fell more than 20% during the week after the announcement, while Pfizer stock dropped less than 5% during the same time period.

 

The seemingly abrupt decision to pull the Exubera plug by Pfizer’s CEO Jeffrey Kindler, a lawyer whose corporate experience included high-level positions at McDonald’s, was criticized for being misplaced in the steep-investment, slow-development world of the pharmaceutical industry. A prescription pharmaceutical’s not a McDLT (which may have actually been on the nationwide market longer than Exubera). But analysts were quoted as generally supporting the decision to pull the drug.

 

There were also blogging wags who couldn’t help but liken the crash-and-burn market performance of the highly anticipated Exubera to the Titanic and the Hindenberg; however, these analogies—more than most—miss their mark. Exubera was not withdrawn for safety reasons but for suboptimal market performance. It’s as if the White Star Line built its ship, but only a handful of people bought tickets.

 

Similarities can also be drawn between Kindler’s judgment and that of a hasty television executive, who prematurely cancels what is actually a reasonably good show because of poor Nielson ratings. There were diabetics who liked the versatility of insulin adminstration that Exubera provided, despite the tennis-ball-can size of the inhalation device, according to a Dallas News story.

 

Nektar specifically faulted Pfizer—the sales powerhouse of the pharmacetical industry—for its poor promotion of Exubera, and it is clear that certain marketing obstacles should have been anticipated and addressed by Pfizer from the get-go: physician and patient ignorance of the inhaler device, the required performance of baseline and periodic pulmonary function testing, and expense. The daily cost of Exubera is approximately $5 a day, about twice that of injectable insulin. Consequently, insurance coverage may have been limited, both for the drug and for pulmonary function testing, and a September report on behalf of the National Institute for Health and Clinical Excellence (NICE) indicated that, although the product is safe and effective, it is not cost-effective. But cost obstacles are nothing new to the US pharmaceutical marketplace.

 

Nektar executives were reportedly stunned at Pfizer’s feeble launch campaign for Exubera and the company’s inability to establish any marketing momentum with doctors or consumers. This frustration was apparently shared by at least one Pfizer insider, who posted at the free-wheeling cafépharma.com, “[T]he launch was an absolute joke,” and described Jeffrey Kindler as “the Jimmy Carter of corporate America” (clearly referring to Carter’s inefficacy as US President and not his post-Presidential humanitarianism).

 

Withdrawal Aftermath

 

On November 13, the burned Nektar and the possibly chagrined Pfizer announced the resolution of “all outstanding contractual issues in connection with Exubera,” which consisted of the transfer of all drug rights and, most importantly, a lump-sum payment of $135 million from Pfizer to Nektar. The joint comment from the respective CEOs is a head-spinning clinic in PR doublespeak, which describes the separation as an “agreement” that “strengthens our relationship.”^†

 

A tidy sum of money notwithstanding, Nektar reportedly has millions of doses of Exubera, without any imminent, practical way to unload them, and related fallout includes dramatic restructuring and job cutbacks at Exubera manufacturing partners Consort Medical and West Pharmaceuticals.

 

*With appropriate apologies to Mr. Damon, who famously announced his break up with Minnie Driver (allegedly unbeknowst to Ms. Driver) on The Oprah Winfrey Show. Mr. Damon has repeatedly denied that the actress did not know of the break up before he divulged the news on TV.

 

†I’ll say. As the quipsters at the Health Blog of the Wall Street Journal wrote, “Nothing says you’re sorry quite like $135 million.”

A gracious good morning, afternoon, evening, and welcome to the Inaugural Post of yet another health-related blog by another overly educated individual. To knock off 2007 and ring in 2008, the last 10 days of the year will be used to count down what have been decided solely and exclusively by me to be the top 10 medical/pharma stories of 2007. If you have absolutely nothing to do for the holidays and consequently stick around for all 10 stories, you’ll discover a really unsettling pattern.

 

For those who have stumbled across this site hoping to satisfy some unbelievably disturbing fetish and are compelled to leave feedback, just clean it up.

 

And here we go:

 

No. 10: Emerging Deadly Adenoviral Infection

 

From February to June, hospitalization was required for 53 of 140 US adults who were infected with a newly emerging pathogen, adenovirus serotype 14 (Ad14). Nine patients died of the infection; 7 were reportedly immunocompetent adults. Typically accounting for fewer than 2% of respiratory illnesses in civilian adults, adenovirus infection has been a historically benign illness outside of infancy and old age.

 

Persons hospitalized in 2007 for Ad14 pneumonia included 22 community-dwelling individuals in Oregon, 4 adults from a residential-care facility in Washington State, and 27 military trainees at Lackland Air Force Base, according to the MMWR. Twenty-four, or 45%, of these patients required ICU admission. The 2007 cases were preceded by the Ad14-associated death of a 12-day-old, otherwise healthy, full-term girl in New York in May 2006. The viral isolate from this case was genetically identical to isolates from the cases observed in 2007.*

 

Adenovirus outbreaks are certainly not unknown to US military bases, but infection in this setting infrequently necessitated hospitalization and rarely, ICU care. In addition to the cases described, the MMWR article retrospectively identifies 220 cases of Ad14-associated illness from March to September on three other Texas military bases, which received Lackland trainees. How these cases are related, if at all, has not been determined.

 

Adenovirus can be transmitted by more than one method: by inhalation, through the conjunctiva (think poorly chlorinated swimming pools), and probably by fecal-oral spread. Ad14 PCR testing at Lackland suggests that healthcare workers in contact with infected individuals are at risk for infection and for propagating transmission, but no staff or other residents at the Washington facility tested positively.

 

Why this Ad14 isolate appears more pathogenic than other serotypes is currently unknown. The 2007 serotype is distinct from the Ad14 isolate of 1955 (a serotype recovered from military recruits in The Netherlands), according to the MMWR, thereby indicating that the 2007 pathogen is new.

 

Surprisingly little is definitively known about how adenovirus enters host cells. In the case of serotype 2 or 5, the antenna-like fiber protein of the virus binds to the tight-junction protein coxsackie-adenovirus receptor (CAR), located near the basolateral surface of the respiratory epithelial layer (Walters RW et al. Cell. 2002;11:789-799.). Binding to CAR increases paracellular permeability, enabling the mobility of the virus throughout the airway. But how CAR-using adenovirus initially infects epithelial cells is up for debate (Goosney DL, Nemerow GR. Curr Biol. 2003;13:R99-R100.).

 

Tuve et al (J Virol. 2006;80:12109-12120.) confirm that some serotypes of group B adenovirus, to which Ad14 belongs, use the ubiquitous and often microbially exploited CD46 receptor for host entry. However, they allege that Ad14—or at least the 1955 serotype—uses an as-yet-unidentified, highly expressed glycoprotein “receptor X.” Knowledge of how adenovirus serotypes infect host cells not only has implications for understanding the pathogenesis of (and subsequent immunity to) adenovirus infection, but informs the success of gene therapies (eg, for cystic fibrosis) and vaccinations (eg, for HIV) that use modified adenovirus as a delivery vector.

 

Adenoviral infections are treated with supportive care, and prevention requires the typical infection-control measures. Adherence to infection control is important, because adenovirus can persist for weeks on fomites. The efficacy of the antiviral agents ribavirin, vidarabine, and cidofovir has not been definitively demonstrated.

 

Adenoviral Vaccination

 

Adenoviral vaccination has its own interesting history. Live, oral pill vaccines against serotypes 4 and 7—which were determined to be the most important disease-causing serotypes among military trainees during the mid-20th century—were developed and then implemented at US recruitment camps, beginning in 1971 (Russell KL et al. Vaccine. 2006;24:2835-2842.). According to the US Army Medical Materiel Development Activity (USAMMDA), the original vaccines were manufactured by Wyeth Laboratories, and clinical development was cosponsored by the US Army and the NIAID. The 2-pill vaccine was approved by the FDA in 1980 but was available earlier through an IND exemption. With the institution of the vaccine among military recruits, the rate of adenoviral infection dropped dramatically, by up to 96%.

 

In 1984, Wyeth asked the DoD to underwrite a $5-million renovation of its Pennsylvania vaccine manufacturing facility, to comply with FDA safety standards. According to an unclassified 2001 report by US Army Colonel Niranjan Balliram, Wyeth’s vaccine-production equipment was woefully outdated and in severe disrepair, with at least one machine worthy of donation to the Smithsonian Institute. Moreover, live adenovirus was being transported by gurney without appropriate infection precautions. The Defense Personnel Service Center in Philadelphia, which was responsible for the Wyeth contract, requested money from the Pentagon to fund the facility update, but the request was rejected. The search for other adenovirus vaccine manufacturers was fruitless.

 

The reasons for the Pentagon’s reluctance to support Wyeth’s facility upgrade are unclear; however, according to a DoD press release, the decision may have been based partly on data indicating that the vaccine was no longer necessary. In 1994, Wyeth declared that it would no longer produce the vaccine, and manufacture ceased in 1996. Viable stocks, with seasonal rationing, were exhausted by 1999 (Russell KL et al. Vaccine. 2006;24:2835-2842.).

 

After vaccination against adenovirus was terminated, a 5-year DoD surveillance identified a greater-than-3-fold increase in culture-positive adenoviral infections among recruits, with an average of 14,750 cases per year among 8 military training sites (Russell KL et al. Vaccine. 2006;24:2835-2842.). Adenoviral infection was the suspected cause of death of 2 naval trainees in July and September, respectively, during 2000 (MMWR. 2001:50;553-555.).

 

In 2001, William Winkenwerder, Jr., then Assistant Secretary of Defense for Health Affairs, urged the redevelopment and manufacture of the Ad4 and Ad7 vaccines, and a $35.4-million contract was awarded to Barr Laboratories for the effort. According to the USAMMDA, the Barr vaccine would be a redeveloped, updated version of the Wyeth products.

 

Barr’s 2006 annual report indicates that phase 1 study of its adenovirus vaccine (DR-5001) was completed at the end of 2006. A phase 3 study at the Great Lakes, IL, and Fort Jackson, SC, training centers is not yet recruiting subjects. According to the MMWR, “work is ongoing” to determine if the Barr vaccine will protect against infection caused by the Ad14 serotype.

 

* At the most recent meeting of the Infectious Diseases Society of America, Lewis et al retrospectively identified 31 cases of Ad14 infection in Oregon from November 2006 through April 2007; according to specimens logged at the state public health lab, PCR-confirmed Ad14 emerged in this state as early as 2005.