Neurology: October 2008 Archives

Another case of progressive multifocal leukoencephalopathy (PML) was reported in a US patient with multiple sclerosis who was treated with Tysabri (natalizumab; Biogen Idec/Elan). According to an SEC report filed yesterday by the drug makers, the diagnosis was made by detecting JC virus DNA in spinal fluid, given disease-consistent clinical signs and MRI findings.

The patient had previously received beta interferons and glatiramer acetate (Copaxone; Teva) for MS, along with methotrexate for a "rheumatological condition." Fourteen infusions of Tysabri, as monotherapy, had been administered.

This newest case can be added to 2 cases of Tysabri-related PML reported in August. These patients had also received extended monotherapy (>1 year) with the monoclonal antibody for MS. PML cases before the market withdrawal of Tysabri in 2005 included 2 cases in MS patients and 1 case in an individual with Crohn's disease.

According to a recent risk-benefit assessment, the risk of PML with Tysabri would have to increase more than 7 times to reduce the drug's net benefit below that of interferon beta. Stockholders apparently don't care.

According to WHO.

CHD = coronary heart disease; COPD = chronic obstructive pulmonary disease; CV = cerebrovascular; TB = tuberculosis.

The holy grail in multiple sclerosis—other than cure—is oral disease-modifying therapy. All of the currently available, immunomodulating drugs must be injected, either SQ or IM by the patient herself or IV in the doctor's office. So anyone who cares about MS is watching the clinical development of Biogen Idec's oral drug fumarate (or Fumaderm* or BG00012 or BG-12) with a fair amount of interest.

And to that end, placebo-controlled phase 2b data were just published in the latest issue of The Lancet. These data show that fumarate, 240 mg tid, significantly reduced the number of new MS brain lesions at 3-6 months, including new active lesions (ie, gadolinium enhancing) by nearly 70%, in patients with relapsing MS. What's not so impressive is that fumarate reduced the annualized relapse rate by only about 30%, when compared with placebo, a relative reduction that did not reach statistical significance.** (Although a press release indicates that the study was not adequately powered to evaluate relapse endpoints.)

Nevertheless, these clinical data support the ongoing phase 3 investigation of fumarate (here and here), which is believed to work by activating a transcription factor (NRF2) that has cellular antioxidant properties. One phase 3 trial is using glatiramer acetate (Copaxone; Teva) as a comparator drug; the other is placebo controlled. The primary endpoint of both trials is clinical relapses.

Other novel, oral agents in phase 3 development for relapsing MS include fingolimod (Novartis), laquinimod (Teva), and teriflunomide (sanofi-aventis). Laquinimod is being compared with interferon beta-1a IM (Avonex; Biogen Idec), and the fingolimod and terifunomide studies are placebo controlled.

If fumarate prevails in phase 3 studies and becomes FDA approved, Biogen Idec will have a nice trifecta (triumvirate?) of immunomodulatory agents for MS: oral Fumaderm, IM Avonex, and IV Tysabri (natalizumab).

* FumaDERM?

** But this placebo-controlled rate reduction is comparable to that with the interferon betas.

After making the rounds at every general neurology or multiple sclerosis meeting within recent memory, the phase 2 Campath study in MS (CAMMS223) is finally sanctified in the NEJM. And the results are, not surprisingly, not surprising.

If I've written it once, I'll write it again...In more than 300 patients with previously untreated relapsing MS, the anti-CD52 mAb (alemtuzumab; Genzyme/Bayer Schering Pharma) significantly reduced the rate of sustained accumulation of disability and the annual relapse rate by more than 70% each, when compared with interferon beta-1a (Rebif; EMD Serono), during a 3-year period. (This efficacy is roughly equivalent to that of natalizumab [Tysabri; Elan/Biogen Idec] in relapsing MS.) Moreover, the mean disability score actually improved minorly with alemtuzumab treatment. MRI parameters were also significantly better with the mAb than with interferon beta.

Adverse effects with alemtuzumab, which are also no mystery, included autoimmune thyroid disorder (more than 20% of patients) and the very worrisome ITP (3%). During the trial, one patient died of ITP, and the disorder was diagnosed in 2 more subjects. As a result, alemtuzumab treatment was suspended from September 2005 to May 2007, when proactive measures were implemented to identify at-risk patients. Infections were also very frequent with either treatment, which is to be expected when you mess around with the immune system.

The particular formulation of interferon beta-1a used in the study is given at a dosage of 44 µg subcutaneously 3 times per week. Alemtuzumab, 12 or 24 mg IV, was given for 5 consecutive days the first month and then on 3 consecutive days at months 12 and 24. (The final dosage was at the discretion of the treating physician, depending on the CD4 cell count.) The authors found no difference in outcomes between the high and low dosages of alemtuzumab.

The same 2 dosages of alemtuzumab are also being compared with the same interferon beta-1a therapy in the actively recruiting, company-sponsored phase 3 trials, CARE-MS I and CARE-MS II.

For what it's worth, Genzyme stock is doing better than the DJI, which may have something to do with the publication of the CAMMS223 study. How's that for going out on a limb?

ITP = idiopathic thrombocytopenic purpura; mAb = monoclonal antibody.

For some completely unknown reason, today's WSJ gives free publicity to Pamlab, LLC, a Louisiana company that sells an oral, "high-dose" vitamin B supplement for peripheral neuropathy. 

Treatment of neuropathy with various forms of vitamin B has been around for at least decades, and the promotion of B supplementation rears up periodically in the lay press (as in the case of today's WSJ) and mostly bottom-feeding medical journals. The popularity of vitamin B6 (pyridoxine), specifically, as a neuropathy treatment probably has its genesis in the use of the vitamin to reduce the risk of isoniazid-induced neuropathy when treating tuberculosis. We're talking Eisenhower era.

The problem is that clinicians forget (or never knew) that high-dose B6, itself, can cause a toxic sensory neuropathy, which was documented in 1983 in the NEJM. Reversible B6 neuropathies were also described in 172 women in 1987 who used lower vitamin dosages (mean, 117 mg/d ± 92). These clinical neuropathies were more likely to occur with longer durations of treatment.

Pamlab's supplement contains 25 mg of the active form of pyridoxine, with a recommended dosage of 1-2 tablets per day. This dosage is within the standard deviation of the B6 range reported in the 1987 case series. Pamlab says that its supplement (which is only available by prescription and costs a stunningly high $40-$70 per month) has been shown in unpublished clinical trials to improve foot sensation and pain, writes the WSJ. (The supplement also contains 2.8 mg of L-methylfolate [the active form of folate, or B9] and 2 mg of methylcobalamin [a form of B12].)

The WSJ also cites a Cochrane review from July, which concluded that there is currently insufficient evidence to use vitamin B supplementation for neuropathy. The Cochrane authors found only 13 randomized or "quasi"-randomized studies (N = 741) from the mid-1960s to 2005, which compared vitamin B supplementation with placebo in general peripheral neuropathy. A considerably fewer number of trials compared vitamin B complex with an active control. Placebo-controlled trials provided mixed efficacy results, and active-comparator trials suggested that vitamin B supplementation is less efficacious in the short term than other agents. (Specific forms of vitamin B, with the exception of thiamine, are not highlighted in the Cochrane abstract.)

Pamlab informed the WSJ of an unblinded study of its vitamin B supplement, which was presented last month by a podiatrist at an unidentified scientific conference. The NIH Clinical Trials database includes a randomized, double-blind, placebo-controlled phase 4 study of the proprietary product in patients with type 2 diabetic neuropathy. The study is currently recruiting patients at selected US locations.

Why the WSJ chose to showcase Pamlab's vitamin B product, without 1) having more definitive scientific information to support its use in neuropathy and 2) citing the risk of neuropathy with B6 supplementation, is a minor mystery. 

The federal court ruling that requires PTC Therapeutics to give its experimental drug to a teenager with muscular dystrophy "could easily destroy" the drug's clinical-trial program. This argument is found in one of 2 amici curiae (friends-of-the-court) briefs, which were recently filed in the appeal of the really bad decision in Gunvalson v. PTC Therapeutics. (Background here.)

One amicus brief is on behalf of a 13-year-old boy with Duchenne muscular dystrophy, and the other is from the disease-advocacy groups Parent Projects for Muscular Dystrophy Research, Inc, and United Parent Projects Muscular Dystrophy. Both are in support of the defendant-appellant, PTC Therapeutics, and are now available at the Drug and Device Law blog, which is operated by 2 lawyers involved in the appeal proceedings.

Among the briefs' arguments:

The court's ruling, which allows one person to access to PTC124 (currently in the middle of phase 2 development), is unfair to others with DMD who must wait for FDA approval of the drug.

The ruling creates a precedent for more drug-access litigation, which will unfairly tax the resources of PTC Therapeutics specifically and those of drug-development companies generally. According to the PPMDR/UPPMD brief, 3 parents contacted the PPMDR founder and president to ask whether litigation is an effective means to obtain PTC124. The close relationship between the Gunvalsons and PTC Therapeutics, cited by the ruling judge as a "unique" factor that should mitigate the risk of similar lawsuits, is actually common in the DMD community.

The ruling impedes the clinical-trial process by 1) undermining communication between companies and families that eases or enables clinical-trial enrollment and 2) creating a disincentive for subjects to enroll in trials in which they may receive placebo. (It should be noted that the subpopulation of DMD patients with a nonsense mutation—the pool of potential enrollees for PTC124 trials—is small, approximately 1700.

The ruling undermines the public interest and informed decisions by Congress and the FDA, which state that publicly available drugs must be proven safe and effective (by means of well-controlled clinical trials). The FDA has declared that expanded access to drugs before approval must not compromise enrollment in clinical trials. One brief goes so far as to indicate that the ruling "could easily destroy the PTC124 clinical trial program and render impossible FDA approval that would permit access to the drug for all patients."

And in a curious side note...

The ruling prompted a recent educational program, "Compassionate Use: Changes You Should Make Following Gunvalson et al v. PTC Therapeutics," which indicates that companies should make changes to their compassionate-use policies on the basis of the decision. (The CD, featuring lawyer Clint Hermes, is available for the bargain [cough] price of $199.00.)

Hepatitis B vaccination generally does not increase the risk of pediatric CNS demyelinating diseases—like multiple sclerosis—in the short or long term; however, the Engerix B vaccine (GlaxoSmithKline) brand may, in the long term. These conclusions are based on a population-based, case-control study conducted in France, which was published online this week in Neurology. The investigators stress that their results require confirmation.

By matching 349 pediatric cases of clinical CNS demyelination—either single episodes* without relapse or MS—to 2941 controls (median control no. per case, 9), investigators calculated an adjusted odds ratio of 0.74 (95% CI: 0.54, 1.02) for an index episode of demyelination within a 3-year period of vaccination. Similar results were obtained when assessing more detailed time periods, number of hepatitis B vaccines received, and vaccine brand last received.

General rates of hepatitis B vaccination were similar in the case and control groups (24.4% and 27.3%, respectively). Notably a family history of MS was significantly higher in the case cohort (2.3% vs 1.1% in controls; P < .05); but calculated odds ratios were not significantly different when cases with a family history were excluded from analysis.

When considering cases and controls that were compliant with vaccine guidelines, exposure to Engerix B vaccine more than 3 years before the index episode was associated with an increased risk of CNS demyelination (adjusted OR, 1.74; 95% CI: 0.93, 2.43), and particularly MS (adjusted OR, 2.77; 95% CI: 1.23, 6.24). A trend toward an increased risk of CNS demyelination 3 years from the time of exposure to the GenHevac B vaccine (sanofi-aventis) was also observed in vaccine-compliant cases (adjusted OR, 1.50; 95% CI: 0.71, 3.17).

Other vaccines assessed in the study, which was supported by the Société Française de Neuropédiatrie and the French Ministry of Health, included HBVax (Vabiotech), Twinrix (GSK), and Recombivax (Merck). The authors propose that risk differences among vaccine brands may be due to the particular section of the hepatitis B surface antigen (HBsAg) used or variable reactions to yeast proteins (HBsAg is produced in yeast cells).

The prevalence of pediatric CNS demyelinating disorders is not well defined, but it is estimated that 12,000-22,000 people (2.7%-5.0%) living with MS in the United States or Canada received a diagnosis before the age of 16 years. 

CNS = central nervous system.

* Single episodes of demyelination (n = 198) included acute disseminated encephalomyelitis (ADEM), optic neuritis, transverse myelitis, and brainstem dysfunction. Cases were matched to controls for age, sex, and area of residence.

The mAb alemtuzumab (Campath; Genzyme/Bayer Healthcare) appears to provide the same kind of robust efficacy in multiple sclerosis as natalizumab (Tysabri; Elan/Biogen Idec). But like natalizumab, alemtuzumab is not without its risks.

Extension data from the ongoing phase 2 trial of alemtuzumab (CAMMS223) in patients with early, relapsing MS were presented last week at the World Congress on Treatment and Research in MS. Impressive efficacy outcomes with the drug in previous reports appear to be sustained at 36 months.

Specifically alemtuzumab significantly reduced the cumulative number of relapses and the time to sustained disability by more than 70%, when compared with interferon beta-1a (Rebif; EMD Serono/Pfizer). The percentage of relapse-free patients was also significantly higher with alemtuzumab (80% vs 50%), and the EDSS score actually dropped by 0.39 points with alemtuzumab treatment. (The EDSS score with interferon beta increased by 0.38 points.)

Adverse events of note are shown.

36-Month Outcome	Alemtuzumab	Interferon Beta-1a
No. patients with grade 3 infections	13	1
No. patients with grade 4/5 infections	0	0
Autoimmune thyroid dysfunction, %	23	3
ITP, %	2.8	0.5

Of acute concern is the rate of ITP with alemtuzumab treatment, an event which may be anticipated by platelet monitoring. Two, industry-supported, phase 3 studies (here and here) of alemtuzumab and interferon beta-1a in relapsing MS are currently recruiting patients. Primary outcome measures are the relapse rate and the time to sustained disability at 2 years. Blood monitoring will be performed monthly.

Alemtuzumab, a humanized anti-CD52 mAb, is FDA approved for the treatment of B-cell CLL. Interferon beta-1a is approved for the treatment of relapsing MS and has been shown (like other available interferon betas) to reduce the relapse rate in MS by approximately one third, when compared with placebo.

CLL = chronic lymphocytic leukemia; EDSS = Expanded Disability Status Scale; ITP = idiopathic thrombocytopenic purpura; mAb = monoclonal antibody. 

Fab fragment of alemtuzumab linked to antigen (yellow) from Wikipedia.

HT: Medscape Medical News