MPL Review for the FDA - Cervarix, April 18, 2008

STONY BROOK UNIVERSITY MEDICAL CENTER
 School of Medicine
 Department of Neurology


To: 

Nancy Miller


From:

P.K. Coyle, MD


RE:

MPL Review for the FDA


Date:

April 18, 2008

The following is my response to the four questions asked, based on my review of the provided material.
1.Do you agree with the neuroinflammatory diagnoses assigned? A.HPV Study, MPL 1.Subject 704: I agree with the diagnosis of optic neuritis, 9 days after the first vaccine dose
2. Subject 1264: I disagree with the formal diagnosis of multiple sclerosis(MS). I would consider the patient to have a diagnosis of multifocal first attack/clinically isolated syndrome (CIS), and to be at high risk for MS. A definite MS diagnosis would require documentation of further disease activity (either clinical or MRI). This event occurred 25 days after a second vaccine dose.
3. Subject 2030: I disagree with the myelitis diagnosis. Involvement of Face/hearing puts the lesion higher, above the spinal cord. Although the diagnosis could be a multifocal first attack CIS, the normal MRI and cerebrospinal fluid (CSF), along with purely subjective abnormalities (sensory, hearing) not objectively verified, would raise a remote possibility of anxiety/hyperventilation/functional complaints. Of course, this is a rule out diagnosis, and there is not enough information to verify this diagnosis. This episode occurred 47 days after the second vaccination.
4. Subject 0037: I would classify the patient as first attack high risk CIS (both brain MRI and CSF are abnormal). This occurred 129 days after the second vaccination.
5. Subject 1020: I agree with the optic neuritis diagnosis, 15 months after the third vaccination.
6. Subject 2475: I would consider this as optic neuritis high risk CIS, occurring 17 months after the third vaccination. The patient cannot have a definite MS diagnosis until further clinical or MRI activity is documented. B.HPV Study, non MPL (in essence, this serves as a control group).

7. Subject 1658: I would consider the diagnosis as brainstem first attack CIS, not MS. A MS diagnosis requires further clinical or MRI events. 

This event occurred the day of the third dosing.

8. Subject 11937: I agree with the optic neuritis diagnosis, developing more than 4 months after the third dose.
9.Subject 14111: I agree with the optic neuritis diagnosis, 23 months after the third dose. C.C. Allergenic Study

10.Subject (b)(6) I agree with a diagnosis of acute transverse myelitis,one month after the fourth and final dose. D.D. HSV Study

11.Subject 1605: I would consider the diagnosis brainstem first attack CIS. There is no evidence for myasthenia gravis, and it is very focal for encephalitis. This occurred 10 days after the second dose.
12.Subject 1435: I agree with the diagnosis of second MS relapse, since there was a first attack high risk CIS episode 3 years earlier. This occurred 8 months after the third dose.
13.Subject 3869: The diagnosis is acute transverse myelitis first attack high risk CIS; MS must be established by further clinical or MRI activity. This occurred 6.5 months after the third dose.


2.Is there anything unique/different/extraordinary about the cases?
 I would say no; I am not struck by anything during my case reviews.
3.Association and biologic mechanism?
 If one considers in the HPV study that the non MPL group is a control, then (if entry numbers are equal) there were 3 more cases in the MPL group. Is this an association? I believe that time from event must be a consideration. I would see 3 months (12 weeks, 84 days) as a generous temporal association requirement. In the postpartum period for MS, 30% of women relapse in the 12 weeks/3months postpartum, presumably due to abrupt termination of the immunosuppressive pregnancy state. If that time frame is used, then only HPV cases 1,2, 3, and 7; the allergenic case; andthe HSV 11 case show a true temporal relationship to the purported triggering exposure agent. 

I do not feel this data is sufficient to establish a link, although I think it is sufficient to raise concern, and there should be further monitoring.

From a biologic viewpoint, MPL binds to toll-like receptor 4 (TLR 4).TLR 4 as well as CD14 receptors are expressed on central nervous system(CNS) components: the circumventricular organs, choroid plexus, and leptomeninges (Brain Behavior Immuno12003;17: 13). This could influence CNS permeability, as well as cerebrospinal fluid parameters. One could postulate this leads to greater CNS permeability and therefore higher risk for CNS events. Clearly the TLRs have a number of critical immunomodulatory effects that are not fully understood, so imune system changes could also play a role. 

4.The figures most commonly quoted for frequency of optic neuritis are up to 6.4 cases per 100,000 population in the United States, and for transverse myelitis 1 to 8 cases per million population. If you look at the causes of a monocular optic neuritis and an incomplete transverse myelitis, about 70% turn out to have relapsing MS. These are people in the prime age risks, 15 to 45/50 years of age (not too young and not too old). The other 30% of cases will include parainfectious single events (the next most common cause of an optic neuritis or transverse myelitis), as well as a host of other disorders. 

For post marketing surveillance, I would make sure the other countries where MPV is now being used are aware of the concerns raised, so that these disorders are tracked. Most would prompt a referral to Neurology and/or Ophthalmology, and would be treated acutely with high dose steroids. Perhaps such features would provide additional tracking parameters.

