This extremely rare disease occurs in approximately 1 out of 300,000 people. The PML cases caused alarm and the drug temporarily disappeared from the market. (A 2006 FDA presentation estimated the incidence of Natalizumab-associated PML to be 1 out of 1000, source: Natalizumab Safety p. 24, marked as slide 60).
Natalizumab was re-released in 2006 with heavy restrictions from the FDA including the tracking all people involved with the taking the drug (prescribers, pharmacies, infusion centers, and patients). In addition, the FDA stipulated that the drug only be used for "relapsing forms of multiple sclerosis."
source: June 6, 2006 FDA letter to manufacturer [note: the last sentence was corrected from "In addition, the FDA stipulated that the drug only be used for multiple sclerosis when other treatment failed."]
Right now, despite showing no benefits compared to existing treatments and having a serious downside (PML), the drug is being pushed through the FDA as a Crohn's treatment.
Two weeks ago, because of its high risks and lack of added benefit in treating Crohn's disease, the drug was rejected by European health regulators (EMEA)--the FDA equivalent in Europe.
(see QUESTIONS AND ANSWERS ON RECOMMENDATION FOR THE REFUSAL OF THE MARKETING AUTHORISATION for NATALIZUMAB ELAN PHARMA 300 MG).
(Note, the drug is available in Europe for MS--a much more serious disease when weighing risks/benefits)
Today, the drug is pending US approval. Dr. Sacher, the chair of the FDA advisory panel and in favor of the drug, is voting based on his instincts, not statistics:
Dr. Judith Kramer, of Duke University voted against approval:
Data from that trial, she pointed out, were difficult to interpret because 30% of the patients were on concomitant immunosuppressive therapy.
The advisory committe, which voted 12-3 to approve the drug, used this briefing as the basis of its decision.
OK, Back to the timeline, here's how the drug has fared in the last 5 years. Remember Natalizumab, Tysabri, and Antegren are names for the same drug:
CCFA runs an "educational" webcast touting Antegren as the a "new hope for people with Crohn's disease." The webcast ignores side effects, and criticizes Remicade, a competitor already on the market.
". . . shares were rattled by the early morning announcement that a crucial test of the experimental drug Antegren had failed to meet certain guidelines in the treatment of Crohn's disease, a debilitating inflammatory gastrointestinal ailment that affects some 1 million people worldwide."
"[Elan] . . . surprised the market on Wednesday when it said it was filing for regulatory approval of Antegren as a treatment for multiple sclerosis (MS) a year ahead of schedule"
"In September of 2004, Elan Pharmaceuticals filed for approval of natalizumab with the European equivalent of the FDA for use in Crohn's disease, based on a completed Phase III study for induction and maintenance of remission. The large initial induction study known as ENACT-1, which enrolled 905 patients with Crohn's disease, did not show significant benefit over placebo . . ."
Use of Language in CCFA's article about this drug.
"[Elan]. . . surprised the market on Wednesday when it said it was filing for regulatory approval of Antegren as a treatment for multiple sclerosis (MS) a year ahead of schedule"
"FDA is issuing this public health advisory to inform patients and health care providers about the suspended marketing of Tysabri (natalizumab) due to two serious adverse events reported with its use. FDA has received a report from Biogen Idec, the manufacturer of Tysabri, of one confirmed, fatal case and one additional case of progressive multifocal leukoencephalopathy (PML) in patients receiving Tysabri for multiple sclerosis (MS). Both patients were enrolled in a long-term clinical trial and had been taking Tysabri for more than two years. There have been no previous cases of PML reported in patients taking Tysabri . . ."
Shares in Irish drugmaker Elan have plummeted once more after a third case of disease [PML] linked to Tysabri, its multiple sclerosis treatment.
. . . . But the case announced on Wednesday - involving a patient who died in December 2003 during a clinical trial for treating Crohn's Disease - is the first to affect someone using Tysabri alone.
"This is bad," said Alexander Hittle, analyst at AG Edwards.
"The best hope for the drug was that (the PML cases) was in some way the result of a combination of Tysabri with Avonex, and Tysabri could be brought back onto market as a stand alone therapy.
- It may only be used for "relapsing forms of multiple sclerosis"
- Distribution must be under a special program where prescribers, pharmacies, infusion centers, and patients are tracked
"The CHMP [Committee for Medicinal Products for Human Use] was concerned that there was insufficient evidence to show the effectiveness of Natalizumab Elan Pharma 300 mg . . . the CHMP was of the opinion that the benefits of Natalizumab Elan Pharma 300 mg in the treatment of Crohn's disease did not outweigh its risks."
Government reviewers also said Biogen did not conduct several safety analyses that FDA had requested. And many safety analyses the company did submit only tracked patients over a short time rather than over the long-term.
This month (August 2007), after receiving an endorsement from an FDA advisory committe, the drug will most likely be allowed for Crohn's disease. If you're thinking of taking Natalizumab-Tysabri-Antegren, please be aware of the following:
- The drug has shown no significant benefit for Crohn's patients
- It costs nearly $30,000 a year
- It requires enrollment in a special program to track for the risk of the aforementioned deadly viral disease (progressive multifocal leukoencephalopathy).
- It'll knock out your immune system.
- Due to patient deaths, it has already changed names once
Here are some "serious atypical lower respiratory tract infections" which developed in patients with Crohn's disease taking Natalizumab.
- Pneumonia with lung abscess
- Pulmonary aspergillosis
- Pneumocystis carinii pneumonia
- Varicella pneumonia
- Mycobacterium avium intracellulare complex pneumonia ["lesser-known cousin of tuberculosis"]
- Burkholderia cepacia infection
source: Review of Non-PML Safety Issues. March 2006. FDA Peripheral and Central Nervous System Drugs Advisory Committee.
Powerpoint slide: Infections other than PML: Long-term CD studies
The bottom line is that the doctors, the manufacturers, and the FDA do not know the full effects of this drug. In addition, its benefits for Crohn's patients are dubious to begin with.
For IBD patients, caveat emptor.