May 2009 Archives

State of Play (2003): Not the recent Russell Crowe movie, but the BBC mini-series (on which the movie was based). There's no rule of privacy that British journalists won't violate when investigating the death of an MP's mistress. The series, comprising 6 twisty episodes, is notable for its prescient casting of up-and-comers Kelly Macdonald (No County for Old Men) and James McAvoy (Atonement). Lesser-known UK actors* John Simm, Bill Nighy (Shaun of the Dead), Polly Walker ("Rome"), Marc Warren, and David Morrissey round out the excellent cast. Morrissey, in particular, is spot-on as the distressed, self-interested MP.

MP = Member of Parliament.

* At least lesser known in America.

A newly discovered arenavirus, which caused fatal hemorrhagic fever in 1 Zambian and 3 South Africans* last year, has been named Lujo virus. The name is derived from the first 2 letters of the cities where victims manifested their illnesses: Lusaka, Zambia, and Johannesburg, South Africa. Lujo virus is the first Old World arenavirus discovered in 3 decades that is known to cause hemorrhagic fever, according to a new report in PLoS Pathogens.

A case of nonfatal hemorrhagic fever due to Lujo virus also occurred in a South African nurse, who cared for one of last year's deceased victims. The nurse evidently responded to ribavirin treatment and has completely recovered. Human-to-human transmission of Lujo virus is believed to be through contact with infected body fluids. How the index case acquired infection is unknown, but disease-causing arenaviruses are typically transmitted from rodent vectors.

* A Zambian safari employee (index case), a South African paramedic, a South African nurse, and a South African hospital employee.

Photo of house mouse (Mus musculus), which is the rodent vector for the Old World arenavirus, lymphocytic choriomeningitis virus, from Wikipedia.

Parents who refuse pertussis (whooping cough) vaccination for their child increase the child's risk of infection by about 20-fold. This conclusion is derived from a first-of-its-kind study of medical records within the huge Kaiser Permanente Colorado health plan (N > 430,000 members). Results of the study were published in the latest issue of Pediatrics.

Investigators extracted individual-level data from the medical charts of children (age 2 months-18 years) about documented vaccine refusal and pertussis infection during a 12-year-period (1996-2007). A total of 156 laboratory-confirmed cases of pertussis were discovered; 9 (6%) required hospitalization.* Among these 156 cases, the parents of 18 children (~12%) had refused all or nearly all of the recommended pertussis vaccinations.** Among a randomly selected, matched control population (n = 595), the vaccine refusal rate was 0.5%.

Two case-control analyses (primary and secondary) were used to determine the odds of pertussis infection as a function of vaccine refusal. (In the secondary analysis, subjects were continuously enrolled in the health plan between the ages of 2 and 20 months.)

Case-Control Analysis	Odds Ratio (95% CI)
Primary (all ages)	22.8 (6.7, 77.5)
Secondary (2-20 months of age)	19.3 (3.5, 104.5)

Assessments of attributable risk suggested that all 18 cases of pertussis in unvaccinated children were due to vaccine refusal.

The investigators acknowledged that a potential bias in the study was the fact that physicians were 3 times more likely to test for pertussis in unvaccinated children who presented with a respiratory infection. But this bias was probably offset by the fact that unvaccinated children with a respiratory infection were less likely to present for evaluation than vaccinated children. 

* Notably the annual incidence of confirmed pertussis cases increased over time; more than three quarters occurred after 2001.

** The parents of 14 children had refused all routine immunizations. Most of these parents were white, older than 30 years of age, and of higher socioeconomic status.

Photo of symptomatic child with pertussis from pertussis.com.

[Beat.] How old is it?

Human remains in Rajasthan, India (24°43'N 73°59'E) provide the oldest known evidence of infection with leprosy. Anthropologists from North Carolina and India describe tell-tale signs of bone pathology, consistent with the infection, in a 4000-year-old male skeleton uncovered about 40 km northeast of Udaipur. Findings unearthed at the site of the large Copper Age settlement are described in the latest issue of PLoS One.

The investigators describe widespread evidence for leprosy throughout the bones, including changes in the remarkably intact skull. Findings there are consistent with the characteristic rhinomaxillary syndrome (or leonine facies) of lepromatous leprosy (for an example, see Fig. 1 at link). Other possible infectious causes, like syphilis, leishmaniasis, and TB, were ruled out by the investigators, but additional data to support the conclusion of leprosy will be obtained from any recovered Mycobacterium DNA in the skeleton and geographically related bone collections. The oldest archeological evidence of leprosy, previous to this discovery, dated to the 1st millennium BC in Uzbekistan.

The authors claim that their skeletal remains support contemporaneous Sanskrit text in the Atharva Veda,* which described a plant treatment for leprosy.

Born by night art thou, O plant, dark, black, sable. Do thou, that art rich in colour, stain this leprosy, and the grey spots!...The leprosy which has originated in the bones, and that which has originated in the body and upon the skin, the white mark begotten of corruption, I have destroyed with my charm.

*Dating to the end of the 2nd millennium BC, according to Wikipedia.

Photograph of 4000-year-old skull shows various findings of bony erosion, remodeling, resorption, and necrosis, consistent with lepromatous leprosy.

And not to flattering effect.

The Chicago Tribune, a high-profile newspaper with a generally less-than-stellar reputation, nevertheless gets it right with its recent coverage of the father-and-son duo Mark and David Geier and their horrifying Lupron treatment for autism.

'Miracle drug' called junk science by Trine Tsouderos

Physician team's crusade shows cracks by Steve Mills and Tom Jones

In a noteworthy side bar (A flawed rationale for treatment), data from one published study by the Geiers (which they use repeatedly to support Lupron treatment in autistic children) are found to be specious by 3 nationally recognized pediatric endrocrinologists: Paul Kaplowitz, Alan Rogol, and Peter Lee.* Specifically Dr. Rogol labels the Geiers' FSH levels "irrelevant," and states that any conclusions based on the testosterone reference range of 0-10 ng/dL are "worse than meaningless." He also concludes that some of the Geiers' pediatric subjects were too old to be diagnosed with precocious puberty.

Mark and David Geier respond that these pediatric endocrinologists are "not qualified to discuss hormone disorders in autistic children." This forehead-slapping rebuttal is made despite the fact that 1) Mark Geier has no specialized training in pediatric endocrinology and 2) David Geier possesses no more than a BA degree.

* The Geiers' 2006 Hormone Research article was scrutinized at this blog in October of 2008.

Fail-Safe

(1964): With its self-important tone and preposterous ending, it's more miss than hit for director Sidney Lumet and his original* cold-war drama. But as a time capsule of doomsday angst, the film has its merits, including a surprisingly touching performance by Larry Hagman (pre-"I Dream of Jeannie") as the President's Russian translator.

* In 2000, Fail-Safe was remade as a live TV broadcast, starring Richard Dreyfuss and George Clooney.

To provide potentially constructive direction to those interested in the clinical investigation of ALS, here are some novel (and not so novel) treatments that are currently being (or will be) assessed in US-based trials, according to the NIH database.

• Arimoclomol: A small molecule that upregulates cellular "molecular chaperones," which are believed to enhance responses to cellular stress. Positive preclinical data in ALS rodent models have been reported.
• E0302 (mecobalamin): A form of vitamin B12.
• GSK1223249: A humanized monoclonal antibody against Nogo-A, a neurite-outgrowth inhibitor.
• SB509: A zinc finger DNA-binding protein transcription factor that is designed to upregulate the expression of VEGF.

Actively recruiting (or not-yet-recruiting) US-based trials in ALS:

Trial Phase	Treatments	Company Sponsor
2/3	E0302 IM (mecobalamin) vs placebo	Eisai
2/3*	Arimoclomol PO vs placebo	None
2/3	Lithium + riluzole vs placebo + riluzole	None
2	SB509 IM (open label)	Sangamo Biosciences
Not yet recruiting
2	Arimoclomol PO vs placebo	CytRx
1	GSK1223249 IV vs placebo	GSK

N.B. Contact information for trial enrollment is available through the links.

ALS = amyotrophic lateral sclerosis; SOD1 = superoxide dismutase 1; VEGF = vascular endothelial cell growth factor.

* Patients with SOD1-positive, familial ALS.

(For important background on this story, please see Tuesday's initial post).

According to Insmed's website, Tercica (comarketer of Increlex) and Insmed (sole manufacturer of Iplex) "plan to enter into negotiations concerning the development of IPLEX™ for the treatment of ALS." Insmed writes that clinical development is contingent on data from Italian ALS patients who received (or are receiving) Iplex on a compassionate basis, as well as FDA requirements. At present, there are no clinical trials of Iplex in patients with ALS at the NIH database website.

Insmed also provides a summary of the first 2 years of the "Italian experience" with Iplex. According to the pdf, more than 500 patients, with various disorders, have been exposed to Iplex, most often at dosages ranging from 0.5-2 mg/kg/day. Insmed reports, "Positive effects on statural growth, insulin sensitivity, glycemic control, dyslipidemia, muscle strength, endurance, and functional abilities have been demonstrated [emphasis added]."*

In the Italian Expanded Access Program, subcutaneous Iplex (typically 1 vial or 36 mg) is being taken daily. Of 110 ALS patients (most of whom have advanced disease), 53 remain on treatment (at least at the time of the pdf draft—the date of which is not provided).

A total of 57 discontinued Iplex treatment (52% dropout rate): 34 died; 10 withdrew consent (1 due to an adverse effect, described as "muscle twitching")**; for 6, the court order was annulled or expired or there was "logistic difficulty" with the program; 5 experienced an "unsatisfactory" therapeutic effect; and 2 were lost to follow-up.

Disease progression is being measured by the ALS Functional Rating Scale. Because there is no control population, the deterioration of the functional score can only be assessed and possibly compared to historical/natural-history data (although such a comparison is incredibly problematic, probably to the point of being useless). For what they're worth, mean longitudinal scores are provided for 24 patients who completed 12 months of expanded-access nonblinded treatment (possible score range, 0-48).

Pretreatment	6 Months	12 Months
30.2 ± 7.9	27.8 ± 8.2	25.2 ± 7.8

Five patients discontinued Iplex as a result of possible treatment-related adverse effects: 1 case of nonserious "muscle twitching"; 1 case of fatal cholelithiasis and infection (patient had a history of gallbladder disease); and 3 cases of fatal cardiopulmonary arrest (1 patient had a history of hypertension and silent MI). The fatalities that were believed to be due to ALS (33) occurred at a time frame consistent with the known progression of the disease.

Insmed indicates that it is "working diligently" with the FDA to "make the necessary preparations" for the US clinical trial of Iplex. The company's share price has risen sharply since the FDA provided expanded access to Iplex in March and okayed a clinical trial of the drug in ALS.

* Presumably Insmed means "or" instead of "and" in its description, unless all of the effects were demonstrated in each condition studied--which is highly doubtful.

** Which may well be a manifestation of ALS.

Last weekend's NYT featured a lengthy story on ALS victim Joshua Thompson ("Fighting for a Last Chance at Life") and his struggle to obtain access to the investigational drug Iplex (from Insmed) on a compassionate basis. Like most patient-centered articles in the mainstream press, the feature is heart breaking...and arguably irresponsible.

In what turns out to be really a very cloying piece, writer Amy Harmon takes the usual easy, uninformed (or perhaps just uninformative) road in pharma journalism by 1) stressing the ostensibly cruel indifference of corporate America and FDA bureaucracy; 2) downplaying the total absence of clinical data to support the use of Iplex in ALS; and 3) completely sidestepping the issue of poor medical policy as bullied into existence by an Internet-fueled public.

So here's the...

Necessary Background

Iplex, a synthetic insulin-like growth factor (IGF-1) that is linked to a binding protein (IGFBP-3), was FDA approved in December 2005 for the treatment of growth failure in children with severe, primary IGF-1 deficiency. The drug received a priority review and was designated an orphan drug, because of the rarity of its indication. But Iplex was removed from the market in early 2007 after Insmed settled a patent dispute with Tercica and Genentech. These companies held the patent on a similar rival drug, Increlex, a synthetic IGF-1 without the binding protein. Increlex was FDA approved in August 2005 for the same rare condition.

In its defense, Insmed pleaded that Iplex should be made available and its development continued, given the drug's other potential indications, including ALS and multiple sclerosis. Proponents also argued that the drug's distinctive binding protein (in contradistinction to Increlex) facilitates entry of IGF-1 into the central nervous system—a purely theoretical proposition. Bolstering Insmed's argument was the fact that the Italian Ministry of Health had asked Insmed to make Iplex available to the country's ALS patients, despite the fact that no clinical (or even published preclinical) data existed to support the drug's efficacy or safety in the condition. Through several court rulings, Insmed then worked out a deal with Cephalon, the European patent owner of IGF-1, to provide Iplex to about 100 Italian citizens in an expanded access program (which the government paid for, to the tune of $100,000 USD per patient per year).

In the United States, some ALS patients had acquired Iplex off label before the drug was pulled. In online testimonials, these patients crowed about the drug's benefits—thereby prompting individuals like Joshua Thompson and their families to invest tremendous hope, time, and effort in acquiring Iplex by whatever means necessary. Thompson even contemplated moving to Italy, until he discovered that Iplex was only available to Italian citizens.

Harmon chronicles the crusade of Joshua's mother, Kathy, to get compassionate access to the unproven drug for her son. Perhaps most disturbing is Harmon's unwitting example of the insidiousness of the online testimonial: Because of a single forum post maligning the effect of Increlex, when compared with Iplex, Kathy Thompson believed that only Iplex would help her son. 

IGF-1 Clinical Data Disappoint

Up until recently, results of well-controlled clinical studies of subcutaneous IGF-1 (Increlex) were mixed. In a double-blind, placebo-controlled, randomized trial of 266 North American ALS patients, IGF-1 significantly slowed the progression of functional impairment in an apparent dose-dependent fashion. However, a similarly designed European study (N = 183) showed no benefits with IGF-1 treatment in ALS. Then last year, results of a definitive, phase 3 trial (N = 330) revealed no difference in the primary or secondary outcomes between IGF-1- and placebo-treated ALS patients at 2 years.*

The negative clinical-trial results with IGF-1 in ALS apparently eased the way for compassionate access to Iplex in the United States, since Tercica and Genentech could not hold a competitive position in this therapeutic area. More important, safety data provided to the FDA by the Italian Ministry informed the agency's decision to grant restricted access to Iplex. So in March of this year, the FDA—bowing to the grass-roots demand for Iplex from Kathy Thompson and others—decided to allow access to the drug under an IND application. This decision was made to the consternation of several ALS experts (for excellent and more detailed coverage of this story angle, see the May 4th issue of Neurology Today). The 2 methods by which American ALS patients could (or can) obtain Iplex: 1) a single-patient IND application to the FDA that had to be received by March 6, 2009,** and 2) a randomized clinical trial.

Through his single-patient IND, Joshua Thompson received his first dose of Iplex on March 25th. An NYT epilogue reveals that Joshua reported subjective improvement in his swallowing with treatment; however, on April 12th, he was hospitalized with pneumonia and placed on mechanical ventilation, where he evidently remains.

ALS = amyotrophic lateral sclerosis; IND = investigation new drug.

* A small, double-blind trial of 2 doses of intrathecal IGF-1 in Japan (N = 9) provided mixed, but largely disappointing, results.

** Harmon writes that it's unclear who's paying for the drug.

Werner Herzog and Klaus Kinski: two crazy men who are crazier together. And it all started with Aguirre, the Wrath of God (1972), the story of a power-hungry conquistador (Kinski) on his psychotic quest for the mythical El Dorado along the Amazon River. Although the story is only very loosely based on fact, Herzog's allegiance to 16th-century detail—costuming, customs, hair*—conveys a powerful authenticity and, moreover, keeps the movie from becoming dated.

Warning: Some animals were possibly harmed in the making of this film.

* Nothing worse than anachronistic hair.

A "highly accurate" index to predict the risk of dementia during late life has been developed by investigators in Northern California and Pittsburgh. The scale, which is available in the latest online issue of Neurology, is based on data from more than 3000 community-dwelling adults* (≥65 years of age) in the Cardiovascular Health Cognition Study and identifies 11 potential risk factors for late-life dementia. 

Points are allotted for the following risk factors, and the tallied score (range, 0-15) can be used to stratify dementia risk among subjects. The accuracy of the index (defined by the c statistic, which is similar to the correlation coefficient) was calculated at 0.81 (95% CI: 0.79, 0.83) and is close to that of a previously published dementia-risk index for middle-aged individuals.

Dementia Risk Factor	Points
Age 75-79 y	1
Age 80-100 y	2
Low Modified MMSE score	2
Low Digit Symbol Substitution Test** Score	2
Body mass index <18.5	2
≥1 APOE ε4 allele	1
MRI: white matter disease (grade ≥3)	1
MRI: enlarged ventricles (grade ≥4)	1
Internal carotid artery thickness ≥2.2 mm	1
History of coronary artery bypass	1
Time to put on and button shirt >45 s	1
Lack of alcohol consumption	1

Among subjects with low scores (0-3), about 4% developed dementia during the next 6 years. Moderate scores (4-7) were associated with a 6-year dementia risk of 23%, and 56% of subjects with high scores (≥8) developed dementia. Among those subjects who acquired dementia (n = 480 or 14%), 245 had Alzheimer disease, 62 had vascular dementia, 151 had mixed dementia, and 22 had other forms of dementia.

Because some of the identified dementia risk factors may be difficult to determine in routine clinical practice (eg, grading of MRI parameters, APOE ε4 status), the authors are performing additional analyses to determine if a simpler, but equally accurate, index can be generated.

In the meantime, drink up—in moderation, of course. Of course. 

* Mean age at baseline = 75 years; ~60% women, 15% African American.

** A measure of attention and mental-processing speed.

A brand of water-based face paint caused a cluster of skin reactions, including rashes, itchiness, burning, and swelling, in children at an "organized event," reports the FDA. The paint contained "significant microbial contamination" according to the agency, and the US seller, Fun Express, is issuing a voluntary recall.* The product was manufactured by Shanghai Color Art Stationery Company Limited in Shanghai, China.

The date and place of the organized event and the number of children affected were not revealed by the FDA. Also the nature of the paint contamination was not specified in the FDA's online press release. However, the AP reports that the agency found elevated counts of yeast and mold in the paint.

The advertised chemical composition of the paint, according to the product label, consists of water, paraffin wax, petroleum, glycerine, calcium carbonate, stearyl alcohol, sodium benzoate (an antimicrobial preservative), acacia senegal, dextrin, and "perfume for body." The label also states that the "paint is made from FDA approved, high quality ingredients, however, as with most cosmetics, a few people may experience an allergic reaction." Fun Express claims that the face paint was sold to 130 customers, and that 95% of these sales were before January of this year—suggesting that the reported cluster of skin reactions was an isolated event.

In 2007, millions of toys were recalled by Mattel after its Chinese-made products were found to be coated with lead-containing paint. The same year, tens of thousands of Chinese-made crayon and paint sets were recalled by Toys "R" Us because of lead contamination.

In 2006, Chinese-imported glycerine (aka glycerol, aka glycerin) that was contaminated with diethylene glycol caused more than 100 deaths of Panamanians who consumed tainted cough syrup. The historical use of diethylene glycol as a deadly, ersatz glycerin substitute has been heavily covered at this blog. Skin contact with diethylene-glycol-containing resins has been reported to cause allergic reactions. 

* Although there is no recall notice at the company's web site or at the web site of its Omaha-based parent company, Oriental Trading Company. The Fun Express web site currently describes its face-paint products as being out of stock.

05/14/09 update: The Columbus Dispatch reports that 43 children in Delaware County, Ohio, who had their faces painted at a Girl Scouts event on Saturday, February 28, developed facial rashes. The local health district revealed today that the purple and red paints caused the most rashes, which typically appeared where the paint was applied. Rashes returned on some children days later, after being exposed to the sun. Three children received medical care for their rashes. In its investigation, the health district received one report that "the paint seemed old, had separated, and was hard to squeeze out of the tube." In the meantime, the Fun Express web site still provides no indication that the products have been recalled.

A major conflict looms between Eisai and Pfizer over the marketing of Aricept (ie, donepezil), the number-one prescription medication for Alzheimer disease. Last week, the Japanese-based company informed Pfizer that it had a legal right to terminate their comarketing agreement, after Pfizer's anticipated aquisition of Wyeth, reported the WSJ. Not surprisingly, Pfizer bristled at the warning, especially given that Aricept generated $482 million in sales for the US company last year.

The comarketing agreement, which has been in place since 1994, currently allows Pfizer to copromote Aricept (which was discovered and developed by Eisai) in the United States and several other countries, according to news reports. Pfizer also claims that is has an exclusive license to sell Aricept in certain other countries.

Pfizer's $68-billion acquisition of Wyeth is expected to be completed by the end of this year. Eisai's justification for getting out of its comarketing agreement may have something to do with Wyeth's development of a competitive product. Wyeth (with Elan) is currently investigating bapineuzumab, an anti-amyloid monoclonal antibody. However, results from phase 2 and 3 clinical trials in AD have been less than exhilarating—something that Pfizer probably didn't bet on.

Aricept, a cholinesterase inhibitor, was approved by the FDA for the treatment of AD in 1996. The basic patent on Aricept will expire in November of 2010.

Cutter's Way (1981): Romantic idealism struggles with complacency in the characters of Alex Cutter (John Heard), a conspiracy-minded disabled vet, and his best friend Richard Bone (Jeff Bridges), a kind of ne'er-do-well gigolo. The issue: Whether to go after a local mogul suspected of murder. Directed by Ivan Passer, a Milos Forman compatriot.

The 50-game suspension handed down yesterday to the LA Dodgers' power hitter Manny Ramirez brings another performance-enhancing drug to public attention: human chorionic gonadotropin, or hCG. Best known as the hormone assayed in urine or serum to confirm early pregnancy, hCG is used to treat infertility in women by stimulating ovulation (eg, Pregnyl; Organon). In men, the substance is also injected to treat infertility or to reverse hypogonadism; the hormone stimulates the testicular Leydig cells to produce testosterone.

But because hCG is less efficient than anabolic steroids for increasing muscle mass,* it is most likely injected by power athletes to treat androgen-induced hypogonadism, either during or after a course of anabolic steroids. The substance, consequently, is an indirect indicator of steroid abuse.

In healthy males, hCG normally occurs at low, but measurable, levels in serum or urine, and serum assays are sensitive. However, most doping surveillance tests are performed on urine, and the suitability of the assay in this context has not been defined, according to a recent report. No matter for Manny. His penalty for hCG doping was reportedly based on evidence in his medical files, not on a positive drug test, according to the NYT.

* hCG is also more expensive than anabolic steroids, but what does that matter to an MLB player.

Image of chorionic gonadotropin preparation from APP Pharmaceuticals.

At least 4 placebo-controlled trials of cholinesterase inhibitors* (ChEIs) have been conducted in patients with mild cognitive impairment (MCI), a likely precursor of Alzheimer's disease. And none has demonstrated a significant effect on primary outcome measures, either progression to AD or standardized, cognitive tests.

Now add another largely negative trial, the results of which are available in this week's issue of Neurology. In a multicenter, double-blind, randomized study of 778 patients with MCI, donepezil (at a maximum dosage of 10 mg/d) was no better than placebo for altering cognitive scores at 1 year. However, a small, but statistically significant difference was noted between the modified ADAS-Cog scores of donepezil- and placebo-treated patients. Other secondary measures also favored donepezil, but treated subjects were much more likely to discontinue the drug because of adverse events (18.4% vs 8.3% with placebo).

The authors speculate that standard measures of cognition, function, and global impairment may be insensitive to the more subtle, progressive changes observed in patients with MCI. In a related editorial, David Knopman of the Mayo Clinic suggests that biomarkers—like hippocampal atrophy, low CSF amyloid-beta/tau protein ratios, and APOE ε4 genotypes—may provide better endpoints in MCI trials. All have been associated with higher rates of progressive cognitive dysfunction in these patients.

N.B. The study was supported by Eisai and Pfizer. Two of the 8 authors are employees of Eisai; 2 are employees of Pfizer.

ADAS-Cog: Alzheimer's Disease Assessment Scale-cognitive subscale.

* Donepezil (Aricept; Eisai/Pfizer), rivastigmine (Exelon; Novartis), and galantamine (Razadyne; Ortho-McNeil).

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

Fingolimod, a novel oral agent from Novartis, outperformed the standard treatment of IM interferon beta-1a (Avonex; Biogen Idec) in patients with moderately severe, but stable, relapsing-remitting multiple sclerosis (RRMS), according to phase 3 data (N = 1292) presented last week at the annual meeting of the American Academy of Neurology in Seattle. Specifically the annualized relapse rate (the primary endpoint) and the percentage of relapse-free patients at 1 year were significantly better with fingolimod at a dosage of 0.5 mg per day.

Endpoint	Fingolimod 0.5 mg po q d	Avonex 30 µg IM q week	P Value
Annualized relapse rate (primary endpoint)	0.16	0.33	.001
Relapse-free patients at 1 year, %	83	69	.0001
Confirmed disability progression at 1 year, %	5.8	7.7	NS
Change in mean EDSS score	-0.08	+0.01	.06
New or enlarged T2 lesions during 1 year	1.5	2.1	.06
Mean no. new gadolinium-enhancing T1 lesions	0.23	0.51	.001

The mean number of new, gadolinium-enhancing lesions on T1-weighted MR images was also significantly lower with fingolimod. A higher dosage of the novel agent was no more efficacious than the lower dosage and was associated with an increased frequency of adverse effects.

Adverse events seen more frequently with fingolimod at either dosage included malignancies (12 vs 2 with interferon), fatal herpes infections (2 vs none with interferon), and bradycardia or AV block (20 vs none with interferon). Nevertheless, fingolimod was reported to be well tolerated; 87% of fingolimod-treated patients completed the study.

Fingolimod, a sphingosine-1-phospate receptor modulator, reduces circulating lymphocyte counts by trapping them within lymph nodes. The agent may also have direct deactivating effects on CNS cells.

Other novel, oral agents in development for MS include fumerate (Fumaderm or BG-12; Biogen Idec), laquinimod (Teva), and teriflunomide (sanofi-aventis). Merck KGaA and its Merck Serono division plan to submit phase 3 data to the FDA sometime this year for the fast-track approval of oral cladribine in patients with RRMS. Favorable, 2-year, placebo-controlled, phase 3 data for oral cladribine in RRMS were also presented last week at the AAN annual meeting.

AV = atrioventricular; EDSS = Extended Disability Status Scale; NS = not significant.

Primary sources: AAN, MedNewsToday.

Odd Man Out (1947): A young James Mason rocks an Irish accent as a fugitive leader, Johnny McQueen, of a guerilla warfare group in Belfast. Things go horribly wrong during the cell's attempted robbery of a local mill, and an injured, delirious McQueen is left to endure an Odyssey-like journey among the city's ambivalent citizens. Nighttime chase scenes foreshadow director Carol Reed's treatment of similar events in The Third Man (1949).