Results tagged “multiple sclerosis” from Pathophilia

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

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

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

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

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

For today: A report from the NY Times, which revisits the dubious idea of stenting jugular veins in patients with multiple sclerosis. According to the paper, interest in the unproven procedure remains fueled by unknown numbers of desperate, logged-on MS patients and a few rogue physicians—some of whom market, in cringe-inducing fashion, a "liberation package."

Oh my ugh.

But neurologist Stephen Hauser of UCSF correctly tells the NYT that evidence for the procedure "is quite scanty" and that its "biological plausibility is low."

Previous posts at this blog highlight 1) a conclusion from US neurologist John Corboy that the small drop in pressure provided by these jugular-vein procedures is unlikely to be pathologically significant; and 2) the correct decision by Stanford to shut down the jugular-stent program of a vascular surgeon until well-controlled data are available to support the treatment.

1. Early infection with Epstein-Barr virus.
2. Cigarette smoking.
3. Vitamin D deficiency (a factor that may explain the observed relationship between MS risk and residence in sunlight-deficient Northern latitudes).

Whether vitamin D supplementation favorably alters outcomes in MS was recently assessed in a randomized early-phase study of 49 patients.* Results of the open-label trial, which was conducted in Canada, were published last week in an advanced, online issue of Neurology.

Level-raising doses of vitamin D (up to 40,000 IU daily), along with supplemental calcium, appeared to reduce the number of relapses during the 52-week study and reduce the proliferation of proinflammatory T cells—both secondary outcomes. High-dose vitamin D did not cause hypercalcemia, persistent hypercalciuria, or nephrolithiasis and appeared to be well tolerated (the primary outcomes). "No significant" adverse events were observed, despite the fact that the mean level of 25(OH)D peaked at 413 nmol/L, which is well above recognized "toxic" levels (eg, 220 nmol/L).

Given the unblinded design of the trial, the favorable clinical outcomes can only be categorized as class level 4 evidence—in other words, data from an observational study that did not have an adequate control group.** The authors indicate that a multicenter, phase 2 proof-of-concept trial, incorporating clinical and MR outcomes, is currently underway.

The NIH database (clinicaltrials.gov) currently lists 3 trials that are assessing vitamin D supplementation in MS (the Canadian phase 2 study is evidently not registered yet).

A phase 4 Israeli trial of high- and low-dose vitamin D. The Merck Serono-supported study will assess the immunomodulatory effects of vitamin D supplementation on interferon-beta reactions.

A phase 4 Norwegian study of changes in bone-mineral density.

A phase 1 pilot study at Hopkins, which will assess the safety and immunomodulatory effects of low-dose vitamin D.

25(OH)D = 25-hydroxyvitamin D. (Measuring 25(OH)D is the standard for assessing the body's vitamin D status.)

* Forty-five patients had relapsing-remitting disease.

** Patients in the trial's control group were allowed to take vitamin D and calcium at their discretion.

The results of the placebo-controlled trial (N = 81), which were reported last week at the annual meeting of the American Academy of Neurology in Toronto, showed that atorvastatin 80 mg/d significantly reduced the odds of new T2 lesions on brain MR images at 12 months. However, the percentages of patients developing 3 or more new T2 lesions or 1 or more clinical relapses (the combined primary endpoint) were not significantly different between atorvastatin and placebo treatment (49% vs 56%; P = .65).** And while the odds of remaining free of active (ie, gadolinium-enhancing) MR lesions were higher with atorvastatin, this finding also did not reach statistical significance.

The study was originally designed to enroll 150 patients; however, because of slow recruitment, it was stopped after treatments were randomized to 81 patients. The study was sponsored by the NIAID and managed by the Immune Tolerance Network, which receives support from Pfizer and Biogen Idec.

The rationale for assessing atorvastatin in MS relates to its ability to modulate immune reactions and reverse disease in rodent models (ie, experimental autoimmune encephalomyelitis). Open-label studies also suggested clinical benefit with atorvastatin in relapsing-remitting MS.

At MedPage Today, the lead investigator, UCSF's Emmanuelle Waubant, indicated that the results are hypothesis generating—meaning that they warrant phase 3 study.

* AKA clinically isolated syndrome (CIS) manifesting, for example, as optic neuritis, spinal cord syndrome, or brainstem dysfunction.

** Those patients who experienced the primary endpoint were offered weekly IM interferon beta (Avonex; Biogen Idec).

T2-weighted supraventricular horizontal MR image from Harvard's Whole Brain Atlas. Multiple subcortical MS lesions are evident, including a very prominent lesion in the patient's right (left to the viewer) frontal area. The web site also offers a very cool time-lapsed movie of developing MS lesions.

Corboy assessed the clinical data of Italian vascular surgeon Paolo Zamboni, who first proposed that MS is caused by an insufficiency of the cerebral veins. Consequently Zamboni performed angioplasty in 65 patients with MS (including his wife) and claimed clinical and radiographic improvement in an uncontrolled trial.

Among Zamboni's rationales for addressing venous insuffiency in MS is to reduce perivenular iron deposits, a known pathologic feature of MS. (Although no causative link has been established between these deposits and MS, to my knowledge.) Pathologists consulted by Corboy implied that the small drop in pressure due to jugular-vein angioplasty or stenting is unlikely to purge these deposits—or anything else, for that matter.

A much larger follow-up blinded study at the University of Buffalo reaffirmed reduced blood flow in the extracranial veins of patients with MS and correlated these data with iron deposits on MR images. These data are scheduled to be presented tomorrow in a poster session at the AAN meeting (P03.126).

Last December, Stanford correctly shut down the jugular-vein stent program of surgeon Michael Dake, who had performed the procedure in 40 patients with MS. One died of cerebral hemorrhage, and the stent of another became dislodged and found its way to the patient's heart. Dake's interest in the procedure was indirectly sparked by chat-room enthusiasm for Zamboni's work.

Corboy concluded his review by advising that he would not recommend jugular-vein angioplasty or stenting in patients with MS "until we had a much better idea whether this approach has any merit whatsoever."

News source: MedPage Today.

Image of neck veins from Gray's Anatomy (1918).

The hypothesis is the "Big Idea" of Italian vascular surgeon, Paolo Zamboni—who has documented venous-outflow anomalies in patients with MS. These findings were the basis for Zamboni's uncontrolled study of venous angioplasty in 65 patients with MS, which was reported last year. Despite the fact that the study yielded mixed results, it apparently produced unbridled zeal in chat rooms, and the zeal found its way to Dake.

The WSJ reports that a "number" of Dake's patients experienced neurologic improvement after jugular angioplasty or stenting (thank you, placebo effect and the highly variable nature of MS), but 1 patient died of cerebral hemorrhage, and the stent of another became dislodged in his heart. The WSJ implies that Stanford and UCSF neurologists were instrumental in getting Dake's stent program shut down in December.

MS, which is currently treated with evidence-based disease-modifying therapies like interferon beta, is believed to be an autoimmune disorder. While cerebral venous insufficiency may be documentable in MS, it is unknown if this is a consequence of the disorder or merely an epiphenomenon. It is unlikely to be the cause.

* But not a neurologist.

Image of neck veins from Gray's Anatomy (1918).

Because profits from ocrelizumab would have been split 70-30, in Genentech's favor, the stalled development actually benefits Biogen Idec to some extent—because the company receives a greater share (40%) of the profits from Rituxan.* (Approval of ocrelizumab for RA, lupus, and any other condition would have eaten into Rituxan sales. A humanized mAb—meaning one that contains fewer mouse parts—is theoretically safer and provides greater long-term efficacy than a chimeric mAb, like Rituxan.)

Share prices of Roche, Genentech's owner,** are largely flat, while Biogen's stock price has climbed steadily since November for reasons that are unclear (to me). Biogen also sells the mAb natalizumab (Tysabri) and an IM version of interferon beta-1a (Avonex), both of which are FDA approved for the treatment of MS.

* An

** For those emerging from long-term unconsciousness: Last year, Roche bought Genentech for $46.8 billion USD.

Image of Son of Superman comic book cover from Wikipedia.

This under-the-radar news of the NDA submission comes as a surprise—not because the fingolimod NDA was submitted (that was actually expected back in December), but because the news was provided so sotto voce.* I merely stumbled across the information while I was looking for more dirt on the company's recent Trileptal plea agreement.

And just in case I missed news of the NDA submission back in December (despite blogging semi-feverishly about the race between Novartis and Merck Serono to market the first-ever disease-modifying pill for multiple sclerosis), I rechecked the Google news archives. Nope, nothing.**

So the question is: Why no big announcement of the Gilenia NDA submission, Novartis? In typical fashion, Merck Serono trumpeted the submission of its NDA for the fast-track approval of oral cladribine in September.

Perhaps the answer has something to do with the FDA's December announcement that it refused to file Merck Serono's cladribine NDA. But I have to admit: I'm kind of flummoxed.

* Not to mention, a month after it happened.

** Although, last week, both Dow Jones and Reuters reported Novartis's NDA submission of fingolimod. I am mentally flaggellating myself for missing these reports.

The overriding theme of these earlier trials was that the compound has a narrow therapeutic window—meaning that it improves mobility, but drug toxicity (ie, seizures, acute confusion) is associated with fickle serum-concentration spikes. This observation was the rationale for developing a sustained-release formulation, which is intended to produce adequate drug concentrations while averting the toxicity-inducing peak levels.

According to Ampyra's prescribing information, approval is based on 2, 14-week, multicenter, randomized placebo-controlled trials conducted in North America: a double-blind phase 3 study (N = 301) and a sequential single-/double-blind study (N = 239). Efficacy is supported by significantly improved speeds of a timed 25-foot walk in about one quarter to one third of treated patients (the percentage differences between dalfampridine- and placebo-treated patients). Positive effects on ambulation were seen in all forms of MS.

Although the Ampyra label does not carry a so-called black-box warning, the FDA advises of the risk of seizures, particularly in patients taking higher-than-recommended doses and in individuals with renal dysfunction. (Last time I checked, the baseline risk of seizure in MS patients was about 5%.) The maximum recommended dosage of the drug is 10 mg (1 tablet) every 12 hours. The label also states that a routine injection of interferon beta-1b (ie, Betaseron or Extavia) does not interfere with the pharmacokinetics of Ampyra.

Share prices of Acorda spiked at end-of-day trading on Friday, after momentarily plunging in mid-October when the FDA questioned the drug's safety and the meaningfulness of the trials' outcomes.

* Aka pyridine-4-amine, 4-aminopyridine, 4-pyridinamine, 4-pyridylamine, and fampridine.

** A directed PubMed search reveals that the first well-controlled trial of 4-aminopyridine was published in 1990 (Polman CH et al. 4-Aminopyridine in multiple sclerosis. Ann Neurol. 1990;28:589). 

And because I like to make comparative tables, here's another one providing the salient features of the 3 studies—all of which enrolled patients with relapsing-remitting MS.

* 2-4 "short" courses for the first 48 weeks, then 2 short courses starting at weeks 48 and 52 (total treatment, 8-20 days/year).
** Two in high-dose group: disseminated primary varicella zoster and herpes encephalitis.

What's the take-home?

Although trial-to-trial comparisons are problematic, both drugs appear to have comparable and significant efficacy. Novartis, developer of fingolimod, has an edge owing to its phase 2 study with the standard MS treatment of interferon beta.

But the uptake of these drugs, once they are approved (and I predict they will be...eventually), will likely depend on their safety profiles. Fingolimod, in particular, is associated with some wicked side effects.

AV = atrioventricular; CLARITY = Cladribine Tablets Treating Multiple Sclerosis Orally; FREEDOMS = FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; HTN = hypertension; TRANSFORMS = Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis.

No. 7: Pinning Down the Risk of PML With Tysabri

So do the benefits of Tysabri (natalizumab; Biogen Idec/Elan) in MS still outweigh the potentially deadly risk of progressive multifocal leukoencephalopathy (PML)?

Uh, probably. But as they say: Axe your doctor.

Head-to-head data with the standard treatment of interferon beta don't exist; but if we're using the common benchmark of placebo treatment,* the monoclonal antibody reduces the risk of clinical relapses by about 70% at 1 year. The interferon betas are about half as good.

At last count (October), there were 24 cases of PML linked to Tysabri since the drug's reintroduction into the marketplace in 2006, said the European Medicines Agency. But the risk of PML appears to depend on the length of therapy—an issue addressed in September by Shirley Wang of the WSJ.

According to Biogen Idec, the absolute risk of PML with Tysabri is 0.01%. However, the risk appears to increase with prolonged therapy (eg, >12 months)—which necessitates the use of an actuarial calculation, argued Wang and Cleveland Clinic neurologist Robert Fox in the WSJ. Wang calculated the actuarial risk of Tysabri-related PML at about 0.08%, and Fox reported a PML risk of more than 0.1%, when therapy extends beyond 30 months. The increased risk of PML with prolonged therapy has led some neurologists to advocate the use of so-called drug holidays; although data to support their use are lacking.

The risk of subclinical PML with Tysabri therapy appears to be substantially higher. In September, the NEJM published a study by Chen et al, who detected a significant rise in titers of JC virus, the cause of PML, among 19 MS patients after 1 year or longer of therapy. (The same NEJM issue also offered 2 case reports of attempted, and reasonably successful, therapy for PML.)

A quantitative risk-benefit analysis, published last year in Neurology, indicated that the "actual" risk of PML with Tysabri 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.)

The flagship organization for US neurologists, the American Academy of Neurology, provided its most recent recommendations for the use of Tysabri in MS last year. Because of the associated risk of PML, the AAN recommended that the drug be reserved for selected patients who are intolerant of other therapies (eg, interferon beta or glatiramer acetate [Copaxone; Teva]) or whose disease is unresponsive to other therapies. 

This month, the journal Multiple Sclerosis printed a company-sponsored supplement, defining "best practice recommendations" for the use of Tysabri. The 6-member panel, which was selected by Biogen Idec and led by neurologist Patricia Coyle, encouraged the "earlier and more rapid transition from first-line treatment to Tysabri." Editorial support for the supplement was provided by The Falk Group, LLC, a pharmaceutical marketing and advertising agency—a fact that doesn't necessarily negate the supplement's recommendations but makes their objectivity suspect.

In the meantime, the SEC is investigating Elan for its filing dated July 31, 2008, in which the company described 2 European patients with MS who developed PML after prolonged Tysabri monotherapy. The reason for the SEC's investigation of this particular filing remains unclear.

* Which is, admittedly, problematic.

No. 8: The Approval Race for an MS Pill

In 2009, Novartis and Merck Serono became the main contenders to market the first-ever pill for relapsing-remitting multiple sclerosis (RRMS).

Aaaaand they're off. Quickly way out, in the middle of the track, Merck Serono takes the early lead.

In January, Merck Serono described favorable 2-year data from an extension phase of its placebo-controlled phase 3 study (CLARITY) of an oral form of cladribine.*

He's challenged on the outside by Novartis, as they race into the turn.

Several months later, Novartis announced positive data from its phase 3 study, in which the novel oral agent, fingolimod, outperformed the standard treatment (not placebo) of IM interferon beta (Avonex; Biogen Idec).

Novartis moving up on Merck Serono as they round the turn.

In August, the FDA announced the approval of Novartis's copycat version of Betaseron (interferon beta-1b; Bayer Schering) for RRMS. Approval came by way of an intricate manufacturing deal with Bayer Schering that began 2 years ago and was apparently intended to prime Novartis's sales team in the MS market.

In the stretch. It's Merck Serono still in front. Merck Serono by a length and a half.

In October, Merck Serono announced its NDA submission for the fast-track approval of oral cladribine for RRMS.

But here comes Novartis on the outside. Novartis comin' after him.

The same day, Novartis announced positive data from its 2-year placebo-controlled phase 3 study of fingolimod in more than 4000 individuals with RRMS (FREEDOMS).

Also getting involved is Teva and Biogen Idec, and looking for a hole on the inside is sanofi-aventis. 

Other novel oral compounds in late-stage development for MS include Teva's laquinimod, Biogen Idec's dimethyl fumarate, and teriflunomide from sanofi-aventis.

Oh, going down now, going down, Merck Serono. Merck Serono takes a spill.

In December, the FDA announced that it refused to file Merck Serono's NDA for oral cladribine, probably on the basis of an incomplete application. The company said that it would request a meeting with the FDA to understand any deficiencies in its application.

Novartis had previously announced that it would file its NDA for fingolimod by the end of the year, but it doesn't look like that's going to happen.

The race isn't over.

CLARITY = Cladribine Tablets Treatment MS Orally; FREEDOMS = FTY740 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; NDA = new drug application.

* Cladribine, a purine analog, has been marketed as the injectable Leustatin [Ortho-Biotech] since 1993 for hairy cell leukemia.

Although the FDA has not publicly addressed its refusal to file Merck Serono's cladribine NDA, the agency's John Jenkins, director of the Office of New Drugs, provides a hint, according to the blog. Yesterday, during the FDA/CMS Summit, Jenkins addressed the agency's refuse-to-file notifications and a primary reason for drawing them up.

Jenkins implicitly chastised pharma for submitting incomplete NDAs and then providing additional information during the drug-review process—which may require an extension owing to the lack of necessary data.** Jenkins reportedly said that pharma execs who delay the submission of an NDA to ensure its completeness will ultimately save themselves time.

NDA = new drug application; PDUFA = Prescription Drug User Free Act.

* Hey, In Vivo Blog, you can quote the flattery.

** And thereby violates the 6-month "PDUFA clock."

Merck Serono submitted its NDA for the fast-track approval of oral cladribine at the end of September. According to yesterday's press release, the FDA acted within its allotted 60-day time frame to determine whether the company's NDA permits a "substantive review"; the agency evidently determined that the application was not "sufficiently complete."

Merck Serono states that it will request a meeting with FDA officials to understand and remedy any deficiencies of its NDA for oral cladribine. (The FDA's possible reasons for refusing to file an NDA can be found here.)

Data to support the review and approval of oral cladribine as a treatment for RRMS include the CLARITY and ORACLE MS studies, both of which are 2-year, placebo-controlled, phase 3 trials of monotherapy. A phase 2 study of oral cladribine as add-on therapy to interferon beta, the ONWARD study, was also used to support the NDA. Although publicly presented, none of these studies (to the best of my knowledge) has been printed in a peer-reviewed journal.

Another oral MS therapy, Novartis's fingolimod, is also in late-stage clinical development for RRMS. The company has indicated that it will submit an NDA for approval in the United States and Europe at the end of this calendar year...which is nigh approaching.

CLARITY = Cladribine Tablets Treatment MS Orally; ORACLE MS = Oral Cladribine in Early MS; ONWARD = Oral Cladribine Added on to Interferon Beta-1a in Patients With Active Relapsing Disease.

Last Friday, the reported number of Tysabri-related PML cases jumped to 23, according to European regulators.* The news led to an abrupt drop in share prices for Tysabri drugmakers Elan and Biogen Idec.

Identifying treated patients who are at particular risk for PML, an often fatal, opportunistic infection due to JC virus, becomes increasingly urgent as the Tysabri-related risk (albeit still small) appears to climb. It is generally believed that latent infection with JC virus occurs in up to 90% of all individuals. But Matthew Herper at Forbes reports that latent infection may exist in only 50% of us, according to Tysabri's inventor, Ted Yednock.

Yednock (whose recent work has evidently not been publicly presented or peer reviewed) argues that current antibody tests for JC virus also detect antibodies to the genetically related BK virus (which is only potentially clinically important in immunocompromised renal-transplant patients). Yednock and others are working on a more specific antibody test for JC virus that may be used to anticipate the risk of PML in Tysabri recipients or to identify Tysabri candidates.

A recently published case series by Chen et al identified the subclinical reactivation of JC virus in 19 patients who received Tysabri monotherapy. The prevalence of virus** in urine increased significantly, from 19% to 63%, after 12 months of treatment. After 18 months, JC virus was found in 20% of plasma samples and in most samples (9/15) of peripheral mononuclear cells. Measures of BK virus, used as a control, remained stable in urine and were not detected in blood samples. Increased shedding of JC virus was associated with a significant drop in the virus-specific cellular response. Whether the reactivation of JC virus in Tysabri-treated patients is associated with a limited antibody response (and I don't know if it is) may have repercussions for the utility of Yednock's antibody assay during therapy.

PML = progressive multifocal leukoencephalopathy; Tysabri = natalizumab.

* From 11 in September. 

** Detected by using quantitative polymerase chain-reaction assays.

10/30/09 update: Bloomberg reports the Tysabri-related PML case load at 24, with 4 deaths, according to the European Medicines Agency. 

Or, to put it another way: Merck Serono remains just ahead of Novartis in the race for approval of the first oral MS drug.

Yesterday the former company announced its NDA submission for the fast-track approval of oral cladribine, an anticancer drug, in the United States. Use of the agent in relapsing-remitting MS is supported by results from the publicly presented CLARITY study.

But Novartis isn't too far behind.

Also yesterday, Novartis announced that its investigational drug, fingolimod (or FTY720), significantly reduced the relapse rate and disability progression in a 2-year, double-blind, phase 3 study of patients with relapsing-remitting MS. Although the data have evidently not been presented at a public scientific forum, nor have they been peer reviewed.

In Novartis's so-called FREEDOMS study, 2 dosages of fingolimod, 0.5 and 1.25 mg po daily, were compared with placebo in more the 4000 individuals with RRMS. The primary endpoint was the annual relapse rate. The main secondary endpoint was the reduction of the progression of disability.*

MR data complemented the observed clinical efficacy of the drug, claimed Novartis. Fingolimod was "generally well tolerated," but fewer adverse effects were noted with the lower dosage. Given the comparable efficacies of the 2 dosages, continued clinical development will concentrate on the 0.5-mg treatment, wrote the company.

Novartis also states that it will submit data for the approval of fingolimod 0.5 mg in the United States and Europe at the end of this calendar year. The FREEDOMS data will be supported by results from another phase 3 study, TRANSFORMS, in which fingolimod outperformed IM interferon beta-1a (Avonex; Biogen Idec). Novartis is also conducting the follow-up FREEDOMS II study.

Fingolimod is a sphingosine-1-phospate receptor modulator, which is believed to reduce circulating lymphocyte counts by trapping them within lymph nodes. The agent may also have direct deactivating effects on CNS cells. Cladribine, a purine analog, has an extensive history as an anticancer agent—particularly in the treatment of certain leukemias and lymphomas. 

* Defined by the Expanded Disability Status Scale (EDSS).

CLARITY = Cladribine Tablets Treatment MS Orally; FREEDOMS = FTY740 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; NDA = new drug application; TRANSFORMS = Trial Assessing Injectable Interferon vs FTY720 Oral in RRMS.

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.

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.

Novartis's solution: Obtain approval to market a well-known drug in that therapeutic area before you launch your novel drug.

So...

Today the FDA announced the approval of Novartis's copycat version of Betaseron (Bayer Schering), or subcutaneous interferon beta-1b, for relapsing-remitting multiple sclerosis (RRMS). Novartis's right to market an identical interferon beta-1b product, trade named Extavia, comes by way of an intricate manufacturing deal with Bayer Schering that began 2 years ago.

And all of this maneuvering by Novartis is apparently in anticipation of its launch of fingolimod, a novel oral agent with positive phase 3 clinical data in RRMS. The new drug, also called FTY720, is in an approval horse race with oral cladribine (Merck Serono) for the same indication. Notably, in the United States, Merck Serono has been marketing its own version of interferon beta-1a (Rebif) for RRMS since 2002.

N.B. Novartis does have experience in the neurology market with existing products for Alzheimer disease, Parkinson disease, and epilepsy.

HT: WSJ Health Blog

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.

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.

Merck KGaA and its Merck Serono division will submit phase 3 data to the FDA in mid-2009 for the fast-track approval of oral cladribine in patients with relapsing-remitting multiple sclerosis (RRMS). The companies issued a press release on Friday, describing favorable 2-year data from an extension phase of a pivotal phase 3 trial, CLARITY.

In the 2-year, randomized, double-blind international study (N = 1326), the annualized relapse rate (the primary endpoint) with various cladribine regimens was approximately 60% lower than that with placebo (P < .001). Secondary endpoints of the study, including a reduction of MRI lesion activity, relapse-free rates, and disability progression were also significantly lower with cladribine.

Cladribine-specific adverse events included the expected lymphopenia. In addition, 4 cases of cancer—early-stage cervical, melanoma, ovarian, and pancreatic—occurred in RRMS patients who received cladribine, reports today's Bloomberg. Nevertheless, completion rates in the study were very high: 90% of cladribine-treated patients and 87% of placebo-treated patients.

Currently available, FDA-approved disease-modifying medications for RRMS must be administered by injection. These include a subcutaneous formulation of interferon beta for multiple sclerosis, Rebif, which is marketed by Merck Serono. Cladribine, a purine analog, has been marketed as the injectable Leustatin by Ortho-Biotech since 1993 for the treatment of hairy cell leukemia. Nonproprietary formulations are available from Bedford and Abraxis, according to the FDA web site.

Novel oral compounds in phase 3 development for MS include fumerate (Fumaderm or BG-12; Biogen Idec), fingolimod (Novartis), laquinimod (Teva), and teriflunomide (sanofi-aventis).

CLARITY = CLAdribine Tablets Treating MS OrallY.

Jayne M. Ness, MD, PhD, of the University of Alabama at Birmingham, and James F. Bale, Jr, MD, of the University of Utah, examined data from a recently published, population-based, case-control French study, which found a nonsignificantly increased risk of multiple sclerosis in children who received GSK's Engerix-B vaccine 3 years before their initial symptoms (OR = 1.68; CI: 0.92, 3.04). However, in 72 children with MS who were vaccine compliant, nearly one third had received Engerix-B vaccine more than 3 years before their index demyelinating episode (adjusted OR = 1.74; 95% CI: 1.03, 2.95).

Ness and Bale raise the possibility that this latter finding is a statistical fluke, fostered by the use of subanalyses. But, because a specific vaccine's makeup* and timing may influence the risk of immune-mediated conditions, they conclude that subanalyses in this case are justified. They stress that children with MS, in particular, "may provide invaluable insights regarding the pathogenesis of the disorder," because of the proximity of their disease onset to potential environmental triggers, like specific antigens.

It is important to note that at least 5 other retrospective or case-control studies (1999-2003) found no association between HepB vaccination and MS onset or relapse, and the US Institute of Medicine and other review panels have rejected a causal relationship between HepB vaccination and MS. While Ness and Bale acknowledge these data, they do not consider the issue of HepB vaccination and MS risk resolved. Nevertheless, they appropriately advise:

Before concluding that there may be a link between HB immunization and MS...other adult and pediatric MS populations must be studied in similar detail. If the association of MS with specific HB vaccines is substantiated, this finding may enable identification of triggers that may or may not have structural or antigenic similarities to the vaccine-associated HB antigens. In the meantime, current recommendations for widespread HB vaccination should be supported as the real risk of HB infection still outweighs the theoretical risk of developing MS.

* For instance, Engerix-B and Recombivax HB contain the recombinant 226-amino-acid S gene product of the hepatitis B major surface antigen, which is generated in cultures of Saccharomyces cerevisiae (baker's yeast). GenHevac B, which is not licensed for use in the United States or Canada, contains PreS2 and S recombinant proteins produced in a mammalian cell line.

Photo of infant undergoing vaccination from the CDC/Judy Schmidt.

The impression is that, without SEC filings, we wouldn't be able to keep tabs on the number of PML cases with Tysabri (natalizumab; Biogen Idec/Elan). Yesterday's report from Biogen Idec provides information on a fourth case of the opportunistic brain infection with use of the mAb in multiple sclerosis.

The unidentified German patient had received an approximately 26-month course of Tysabri monotherapy, although other disease-modifying therapies (including beta interferon) had been used in the past. According to the filing, the disease was caught early because of clinical vigilance. Diagnosis was established by the detection of JC virus DNA in spinal fluid and consistent MRI findings.

The third case of PML, since the reintroduction of Tysabri, was reported in October, and 2 cases of the condition were reported in August. Here's the obligatory and arguably useless* stock-price graph for the drug's manufacturer, Biogen Idec, and distributor, Elan:

As previously reported, the risk of PML with Tysabri would have to increase more than 7 times to reduce the drug's net benefit below that of beta interferon.

mAb = monoclonal antibody; PML = progressive multifocal leukoencephalopathy.

* At least outside of August.

HT: WSJ

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.

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.

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.

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.

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

Two new cases of Tysabri-related progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) were reported yesterday by comarketers Elan and Biogen. In both cases, the diagnosis was established by the detection of JC virus DNA in spinal fluid, along with clinical and MRI findings. The patients had received Tysabri monotherapy for more than a year. These new cases can be added to 2 cases of PML in MS patients who received Tysabri with Avonex (interferon beta-1a; Biogen) and 1 case in a patient with Crohn's disease given Tysabri monotherapy.

Reports of these new PML cases follow the publication in this week's Neurology of the long-term risk-versus-benefit of the agent in patients with relapsing-remitting MS. By assessing quality-adjusted life years (QALYs), investigators from the University of Rochester concluded that the PML risk with Tysabri would have to increase more than 7 times to reduce the drug's net benefit below that of interferon beta. This result is mostly due to the superior reduction of relapses with Tysabri.

The positive analysis notwithstanding, the news of the latest PML cases with Tysabri hit Elan and Biogen hard, with share prices dropping substantially.

Four courses of the monoclonal antibody Rituxan (rituximab) did not delay the time to confirmed disease progression in primary progressive multiple sclerosis, according to a 96-week, placebo-controlled phase 2/3 study. The results were announced yesterday by the drug's US marketers, Genentech and Biogen Idec. A senior scientist at Genetech, however, indicated that the drug exhibited "some evidence of biologic activity" in this uncommon and difficult-to-treat form of MS.

The results are not scheduled for presentation at the ongoing annual meeting of the American Academy of Neurology in Chicago, but safety and pharmacologic data from a 72-week phase 1 study (Bar-Or et al. S12.004) and pharmacologic data from a 48-week phase 2 study (Bar-Or et al. S22.002) of rituximab in relapsing-remitting MS will be presented today and tomorrow at the meeting. Phase 3 development of the drug in relapsing-remitting MS is stalled, because of a protracted dispute between Genentech and Biogen. The development dispute is currently in arbitration.