Richard Sater

Novartis: Powering into the Multiple Sclerosis Market

Thank you for pointing out the error about Opexa and Novartis. The deal does not cover Tovaxin, the MS agent.

BioMS: Hype or Hope?

Kyle:
The 1/30/09 press release said “Dirucotide did meet certain secondary endpoints related to the progression of the disease, including mean change from baseline in the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) score.” On the surface that looks promising.

However, mean change from baseline is not a measure the FDA finds acceptable when looking at disability progression. Instead, they use Kaplan-Meier analysis of time to confirmed worsening of disability to measure progression. Though MSFC may one day overtake EDSS as the official measure of disability, the FDA only recognizes EDSS as a primary endpoint.

Indeed, in the NIH database of clinical trials (clinicaltrials.gov/ct2...), the official secondary endpoints of MINDSET were: (1)Time to confirmed worsening of disability by Expanded Disability Status Scale (EDSS) and (2) Time to confirmed worsening of disability by Multiple Sclerosis Functional Composite (MSFC). MAESTRO 1 and 3 both use time to confirmed worsening of disability by EDSS, only, as their primary endpoint. The press release implies that they met two additional secondary endpoints, not the official secondary endpoint --- we usually call these tertiary endpoints. And, as I discussed above, we don't know whether the two groups are matched --- a frequent problem in Phase II that is usually less of a problem in larger phase III.

So, does significance in a non-validated measure of disability in a medium sized phase II trial of RRMS lead one to assume that there will be significance in the more validated measures of disability progression in a larger phase III of SPMS? That's the billion dollar question. If Phase III hits convincingly, there could be a HGSI sized move.

I hope I'm wrong about MBP8298, as SPMS patients without relapses could benefit from an effective medicine. And if MBP8298 works through non-inflammatory mechanisms to help SPMS patients (the RRMS data implies it does not work through inflammatory mechanisms), then PPMS patients might benefit as well.

In studies I've participated in, when patients roll over into OLE at the end of the blinded study, they are informed about which drug or placebo they were on. As SPMS has few options (esp. if non-relapsing) and the drug is safe and well-tolerated, high rollover would be expected, regardless of how a patient did during the first 2 years.

Steve:
You are correct that progression of disability is generally faster from 3 - 6 than from 6 - 8. This factor is not ignored in the 'official' way that disability progression is evaluated and is also important in understanding why the FDA considers time to confirmed disability progression more valuable than mean change in EDSS. All Phase III studies (and likely Phase II) do not consider one point worsening on the EDSS to be equivalant to another point. Indeed, most studies will use a definition of "disability progression" to mean 1.5 points worsening if entering study at 0, 1.0 point worsening if entering at 1.0 to 5.0 (though CLARITY used 4.5) and a one half point worsening if entering at 5.5 or higher. "Confirmed" usually mean that the worsening was sustained for 3 months (rarely 6 months is used). So a patient who goes from 3 to 4 to 3.5 at 3-month intervals does not count.

You bring up an important analysis of the 20 patient SUBSET of the tiny phase II study. I am not sure whether this small Phase II with progressive MS (SP and PP) used the above definition for progression. If they used 1 point and the distribution at entry was so skewed, then there is less significance to their finding as it is much easier to go from 3 to 4 than from 6 to 7.

Richard

BioMS: Hype or Hope?

Ivor and Kyle:
Thank you for your comments. I'll try to address them all:

Ivor:
Phase III Prospects:

1. DSMB: The DSMB (Data and safety monitoring board) meets regularly to review the study and their recommendations have consistently been that the study should proceed. The purpose of the DSMB is not to establish efficacy. Rather it is an independent review board that does interim analysis to evaluate (1) the integrity of data (protocol deviations, enrollment too slow, enrollment appropriate, are dropouts so high as to affect integrity of study...) and safety (mostly serious AEs). It is not set up to evaluate efficacy --- though, depending on the type of study, some efficacy measures may be evaluated to ensure that the treated group is not doing much worse than the placebo group and that the effect is not so large that continuing with a placebo group becomes unethical. Therefore, the fact that the study passes the interim DSMB study offers no clue to the strength of the data. The milestone is contractual. I have no concern that there would be any significant safety concern for dirucotide.
2. Rollover rate: SPMS without relapses has no other treatments and tolerability and safety are excellent --- so it is reasonable that patients would stay in the study and that placebo patients would like to switch to active treatment.
3. MINDSET showed success in EDSS and MSFC: I’ve seen the press release but not the actual data. What was the average EDSS at entry and for each group? What was average duration of disease? Were there differences in males vs females or in age between the two groups? All these matter in interpreting the data. In RRMS, MRI changes occur fairly frequently, relapses less frequently and disability progression infrequently – even in control patients. If you look at Kaplan Meier curves from other RRMS studies, usually 80% of placebo patients and about 85% of treated patients will be progression of disability free at 12-15 months. Recall 70% were HLA DR2/4 positive and thus only about 75 patients would be in each treated or placebo groups…of which 80% would not have been expected to progress in disability, even if treated. So we are talking about comparing numbers like 10 vs 15. Obviously the study is not powered to give meaning to a significant p value. Especially if differences in the two groups were present at entry.
4. RRMS never taken seriously: I would think any indication would be taken seriously. I can’t easily explain the purpose of a large Phase II if failure was expected.

Commercial Potential:
I agree with you 100% that the market for their drug will be huge if efficacy is proven in both MAESTRO studies. The real value is likely closer to 1-2 billion a year instead of the 5 billion you propose for many reasons. First, I believe that a closer estimate of the prevalence of SPMS is 50-65% of RRMS, not equivalence – I couldn’t find a source but I’ve heard many times that about 50% of MS patients go on to develop SPMS over 15 years. Though not proven, the current medications are likely altering the course of MS and maybe now only 1/3 of MS patients go on to develop SPMS over a similar time frame. Second, it took many years for the treatment rate of RRMS to pass 50% of patients. The RRMS dollar values are more likely to reflect a steadier state. Third, many SPMS patients are more advanced (in nursing homes, bed-bound, i.e. EDSS>7) and these patients are not hooked into neurologic care and they were excluded in the study. Few RRMS patients are that advanced. Fourth, SPMS with relapse patients may continue on current therapies and are included in the 9.04B value you proposed.

PPMS could be up to a quarter of the use, though insurance companies would likely only pay for on-label use, complicating calculations. In reality, when patients are transferred to my care, it is sometimes difficult to differentiate between PPMS and non-relapsing SPMS. If 6 of 20 patients had PPMS in the small study then the decision to proceed to two expensive Phase III studies was made on only 14 SPMS patients, 7 on treatment and 7 on placebo!

Kyle:
Some of your comments are answered above. Part of my concern is the mechanism of action. Little is published with MBP8298, though more is published with other MBP polypeptides covering the same region of the molecule. Studies with related MBP8596 showed some patients had variable suppression of CSF anti-MBP antibodies. This is the basis of the tolerance induction mechanism that is proposed. However, if tolerance was induced, why weren’t the MRI parameters and relapse rate affected by dirucotide? To me, this implies the purported mechanism is wrong. So, how does MBP lead to less disability? One would need to propose a neuroprotective mechanism (such as BDNF production, effect on oligodendrocyte death or other non-inflammatory actions) that would up-regulate fast enough to affect EDSS and MSFC. My opinion would be different if I saw some data exploring other mechanisms.

BioMS: Hype or Hope?

Cary:
You are correct. Novantrone is FDA approved for secondary progressive, progressive relapsing and 'worsening' relapsing remitting MS. I've used Novantrone for over 20 patients for all of these indications. There is no official separation between relapsing and non-relapsing SPMS, but the distinction beteween these two phases guides therapy. The transition from relapsing remitting MS (RRMS) to SPMS is gradual and the diagnosis of SPMS is made retrospectively after a period of time when disability worsens and relapses are stopping. So, a typical patient will spend many years as RRMS, then half of these patients eventually develop relapsing SPMS and then after several years or more develops non-relapsing SPMS.

Many neurologists feel that Novantrone is much more effective for relapsing SPMS than for non-relapsing SPMS. Though Novantrone is approved for non-relapsing SPMS, it gets used mostly for relapsing SPMS and aggressive RRMS. As you probably know, the interferons and Tysabri are also FDA approved for relapsing forms of secondary progressive MS (but not for non-relapsing). So the FDA recognizes both phases of SPMS. The Novantrone studies were actually fairly small with the major Phase III study being only 188 patients split between placebo and two doses of Novantrone. Patients with aggressive RRMS and any form of SPMS were included. As the non-relapsing SPMS patients were not evaluated separately and numbers were small, its efficacy for this phase of SPMS is not certain. The second study with 42 patients was in relapsing SPMS only. A poster at the AAN in April also showed that the risk of secondary leukemia with Novantrone is much higher than initially felt and is closer to 1:125. Thus, a safer and more effective medication for non-relapsing SPMS is clearly needed.

I hope you are do well with your MS.

Disclaimer: The above information is for educational purposes only. These opinions are not to be taken as medical advice or recommendation. Any treatment decisions must be made between a patient and their own treating physician.