BioMS: Hype or Hope?

Large price swings frequently occur when botech companies release data from a phase III study. If primary endpoints do not reach significance, NDA submission to the FDA is unlikely. Strong results with good safety data bring the drug one step closer to approval. Narrow hits and misses or safety concerns result in continued uncertainty until longer term data or a second phase III becomes available.

These can be binary events for smaller companies that have only one lead candidate, often resulting in price drops greater than 50% or increases greater than 200%. Larger companies, not dependent on one or two candidates, are unlikely to see price changes greater than 10-20 % after release. A lag period of 1 to 3 months is common between study completion and topline data release. More complete data is typically presented at conferences 3 to 6 months later.

Before phase III data is released, bets on a company’s future are placed based on the more limited results from earlier phase II studies.

BioMS

BioMS (MS on Toronto Exchange and BOMSF.PK on OTC) completed their study of MBP8298 (also known as dirucotide) in late May 2009 and topline data from the MAESTRO-01 study will be released shortly. This study compared dirucotide to placebo in 553 patients with secondary progressive multiple sclerosis.

The primary endpoint compared the time to sustained worsening of disability using a standard scale. From phase II studies, dirucotide appears to be a very safe medicine and needs to be infused only twice a year. Secondary progressive multiple sclerosis (without relapses) has no current treatment and FDA approval for this indication could lead to sales over 1 billion/year.

BioMS and Lilly (LLY) entered into a global licensing and development agreement on December 17, 2007 regarding dirucotide. BioMS received upfront payments of $87 million and will have potential development and sales milestones of $410 million and possible further escalating royalties.

Multiple Sclerosis

With about 400,000 patients, MS affects more than 1 out of every 1000 Americans. About 85% present with relapsing remitting MS (RRMS) and half of these eventually develop secondary progressive MS (SPMS). The other 10-15% present with primary progressive or progressive relapsing multiple sclerosis.

Thus, there are about 160,000 patients in the US and Canada with SPMS. There are currently 6 FDA approved medicines for MS: Betaseron (Bayer, BAYRY.PK), Avonex (Biogen Idec, BIIB), Copaxone (Teva, TEVA), Rebif (Merck KGaA, MKGAY.PK), Novantrone (Merck KGaA and generic) and Tysabri (Elan and Biogen, ELN, BIIB). These treatments have efficacy for RRMS and some also for the relapses of early SPMS.

However, there are no current medications that are FDA approved for non-relapsing SPMS. Thus, dirucotide will not effect use of other MS drugs much.

Clinical Studies

We have data from two phase II studies, one small study involving 32 patients with progressive MS and another involving 218 patients with relapsing remitting MS. In the first, smaller, study, there was no significant difference in disability progression between placebo-treated and dirucotide-treated patients.

However, when the 20 patients who had at least one copy of either MHC HLA DR2 or DR4 were evaluated separately, there was a significant difference in disability progression between treated and untreated patients.

The MINDSET-01 phase II study in RRMS enrolled 70% patients with either HLA DR2 or DR4 and the study planned to examine all enrolled patients and this subset of patients separately. They were followed for 15 months.

The primary endpoints of relapse rate reduction and MRI changes were not met in either the whole population or the HLA DR2/DR4 subgroup. However, the secondary endpoint of reduced disability progression was met in the treated HLA DR2/DR4 subgroup. Patients with one or both of these genes comprise 50-70% of MS patients.

Thus, there are about 100,000 potential secondary progressive MS patients in the US and Canada and about 200,000 worldwide.

MAESTRO-01 and MAESTRO-03 are similar studies in the EU and US, respectively, with > 500 patients each. Secondary progressive MS patients, who have at least one copy of either DR2 or DR4, were enrolled and treated with either 500 mg IV dirucotide every 6 months or placebo. MAESTRO-01 ended in late May and MAESTRO-03 will end in late 2010.

As BioMS is currently trading at $2.35 and has a market cap of about 215 million dollars (252 million CAD), the topline data release shortly will lead to a huge swing ---- but in which direction?

Hints from prior studies

The purported mechanism of action for dirucotide is immune tolerance induction. This implies that repeated infusions of this molecule should induce a potent anti-inflammatory response by down-regulating the immune system’s attack on myelin.

However, inflammatory MRI changes were not reduced in the MINDSET study. Also, relapses, that should have been reduced by tolerance induction, were unaffected by dirucotide. Could there be another non-inflammatory mechanism of action that is more specific to the secondary progressive degenerative process?

That is possible, but neuroprotection is hard to prove and difficult to establish in a one or two year study. It is just as likely, or more likely, that the effect on disability noted in the first phase II study was random chance in a small subgroup of only 20 patients.

Thus, I believe there is a high likelihood that dirucotide will miss its primary endpoint in the MAESTRO-01 study and that its stock price will drop by half or more. Absence of a trend would doom the product and BioMS. Lilly would just take a small hit, write off the program and move on.

Hopefully, I’ll be proven wrong as SPMS patients who no longer have relapses need a safe medication that can retard disability progression. If MAESTRO-01 hits with great numbers, then the similar MAESTRO-03 study should also meet endpoints and submission to the FDA could occur in early 2011.

If that occurs and the drug is approved, dirucotide could be used by up to 50,000 SPMS patients in the US and Canada within two to three years of approval and a similar number in the ROW. That would lead to sales well over 1 billion a year. Even after LLY takes the lion’s share, milestone and royalty payments would drive BioMS share prices to impressive gains.

If one believes that the trial has a better chance of succeeding than I do, then the ‘pot odds’ would support an investment decision. I’ll sit this one out.

Disclosure: No position in BioMS or Lilly. Long Elan. I have served as a speaker and/or on advisory board for Biogen and EMD Serono (Division of Merck KGaA).

Comments

[Cary Polevoy:]

Please allow me to correct one thing you mentioned. Novantrone (mitoxantrone), produced by EMD Serono, IS approved by the FDA for the treatment of secondary progressive multiple sclerosis (MS). In addition to closely following the pharma industry as a former securities analyst, I happen to have secondary progressive MS. Cary J. Polevoy

Jul 13 09:54 AM

[Richard Sater:]

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.

Jul 13 12:32 PM

[Ivor O'Shea:]

I think your article – while trying to be genuinely fair & clearly written by an expert in the field – ended up underplaying Dirucotide’s Phase III trial prospects and subsequent commercial potential.

Phase III Trial Prospects
* In August 2008, an interim efficacy review of the 1st 200 completers of the MAESTRO-01 trial was passed by the trial’s DSMB. No details were published but Eli paid BioMS a $10m milestone – as per their licence agreement. Given this covered 1/3rd of the trial participants, it’s difficult to see how it could have been a complete efficacy bust and yet continuation of the trial to completion was recommended. This indicates some form of efficacy trend/signal was observed.

* BioMS’s Q1 2009 results, noted that 95% of MAESTRO-01 completers were enrolling into the open-label MAESTRO-02 trial. In addition, less than 2% of MAESTRO-02 participants were withdrawing early (and none were due to adverse events). Again, there’s no definitive proof here but this is consistent with a successful Phase III programme.

* MINDSET-01 for RRMS was indeed a bust. However, 2 secondary endpoints – EDSS & MSFC – were met (p<15% - and management later stated 1 of these 2 had p<5%). Critically, these are the primary and secondary endpoints of the pivotal MAESTRO-01 & MAESTRO-02 trials. I think this is a very important observation. In addition, differences in EDSS progression need time to emerge – the MAESTROs’ durations are 9 months longer. Statistical powering is also much better for the MAESTRO’s as they both have nearly 3 times as many patients.

* Finally, the Eli deal contained zero milestones for the RRMS indication. This indicates Eli & BioMS weren’t taking the RRMS indication very seriously. It seems MINDSET-01 was more about gathering safety data for later stage RRMS patients who could get prescribed Dirucotide. However, I accept this indicates poor judgement by BioMS management who should have downplayed MINDSET-01 expectations in company presentations/reports.


Commercial Potential
* The 5 approved RRMS drugs have $9.04bn in sales (based on annualising Q1 09 sales). BioMS assert there is roughly the same number of SPMS patients as RRMS patients worldwide (although your figures look different). If this is right, then the market for Dirucotide is $4.5bn-$6.3bn – based on 50%-70% having the correct genetic subgroup and assuming pricing & patient take-up should be similar to RRMS

* Critically, no other commercial SPMS drug candidate is in Phase III trials. That indicates Dirucotide has a 3-4 year lead over the market. In addition, the only Phase II candidate I’m aware of is Merck Serono’s Cladribine – a drug not yet even submitted to the FDA for the RRMS indication and which has safety concerns. Ironically, Dirucotide’s main competitor could be off-label Tysabri (Elan/Biogen) – which is in a Phase I/II trial for SPMS (presumably based on the emerging data over long-term improvements in EDSS scores). However, Tysabri still has to live down the hysterical (in my mind, anyways) concerns over PML.

Finally, the European Journal of Neurology 2006 article - covering the small Dirucotide Phase II trial – noted the 20 genetic subgroup patients actually included both SPMS and primary progressive MS (PPMS) patients. A grand total of 6 were PPMS! This is clearly trivial data but gives real hope if efficacy is proven in SPMS. In particular, the lack of treatments for PPMS could lead to significant off-label use – and the PPMS market could be worth $2bn-$3bn.

Disclosure : I’m long on both BioMS & Elan. No positions in Eli Lilly, Merck Serono and Biogen Idec.

Jul 13 07:28 PM

[Kyle Kimme:]

Richard -

If I'm reading correctly, it sounds as though you believe MAESTRO-01 will fail to meet its primary end point based on the fact that the Phase II results for MINDSET-01 did not meet its primary end points. As you know, the primary end points for MINDSET-01 was three fold: 1) Reduce the rate of relapses, 2) Reduce MRI activity, and 3) Slow disease progression. Per the Phase II results, Dirucotide did not succeed in meeting these goals.

However, what you are not discussing is the fact that certain secondary end points for MINDSET-01 were met, including positive changes in the Expanded Disability Status Scale ("EDSS") and the Multiple Sclerosis Functional Composite ("MSFC") score.

MAESTRO-01 is primarily for non-relapsing SPMS. As such, the primary end goal for MAESTRO-01 is NOT to slow relapses or reduce MRI measures, but to improve/stabilize the EDSS for patients with SPMS. The secondary end goal for MAESTRO-01 is to improve the MSFC score for patients with SPMS.

Given Dirucotide proved successful in regards to both the EDSS and MSFC score for patients with RRMS in the MINDSET-01 trials, I believe that is a very encouraging sign that MAESTRO-01 will in fact reach its primary AND secondary endpoints (which is focused on EDSS and MSFC; not relapses, MRI activity, or growth progression).

Could you please provide me your thoughts on this? I would appreciate any thoughts you may have on this matter.

Thank you,

Kyle

Jul 13 07:29 PM

[Richard Sater:]

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.

Jul 13 10:39 PM

[rrtzmd:]

...that's easy -- HYPE!...or, more approriately -- SCAM!!!...Toronto Stock Exchange???...HELLLOOOOO -- stock SCAM capital of the world!!!...

Jul 14 09:32 AM

[Kyle Kimme:]

Richard,

Thanks for the quick response. Maybe I don't fully comprehend the science, but I am having difficulty with the logic. I understand where your coming from regarding Dirucotide not having an affect on relapses and MRI activity for RRMS patients (MINDSET-01), so it seems reasonable to assume it will not have an affect on SPMS either (unless there is another non-inflammatory mechanism that is more specific to SPMS as you mentioned).

However, using the same logic, isn't it reasonable to assume that since Dirucotide had a positive affect on the EDSS and MSFC scores for RRMS patients, that it will also have a positive affect on SPMS patients?

If so, wouldn't it be reasonable to assume that the Phase III test for MAESTRO-01 will be successful in that it's primary and secondary end points relate to the EDSS and MSFC scores?

Also, I'm not sure how the process works, but when a patient completes the trial period, are they told if they were on the placebo or the drug? What I'm trying to get at is, of the 95% patients that enrolled in MAESTRO-02 trials, would they have known if they were on the placebo or Dirucotide during MAESTRO-01 or would they have not known and just elected to enroll since there wasn't any negative side effects?

Any insight would be much appreciated.

Thanks again,

Kyle

Jul 16 11:09 AM

[steve1035:]

Richard,
appreciate your valuable analysis. Do you have any opinion on how differences in EDSS scores between placebo and treatment groups might have affected the data in the phase II trial?
When you look at the average time a patient spends at each EDSS score you will find that a patient with a EDSS score from 3-5 will progress to the next level on average in 12-18 months. For an EDSS score from 6-8 the average time to progressing is about 32-48 months. In the very small phase II trial the placebo group had 3 patients with scores between 3-5, the rest were 6-8. In the treatment group there was only 1 patient with an EDSS score from 3-5, the rest were 6-8. So based on averages you would predict that in a 24 month study 3 out of 10 placebo group patients will probably show disease progression. (actual result was 6/10) where as only 1 out of the 10 in the treatment group would progress. (actual result 0/10)
So based on just the EDSS scores of the patients going into the study would you not have expected more patients in the placebo group to progress than patients in the treatment group? Thanks,

Steve

Jul 21 01:19 AM

[Richard Sater:]

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

Jul 21 07:35 PM

[steve1035:]

Thanks again Richard for the info. For the phase II trial this is what they used:
"Clinical progression was defined as a sustained (6 months) increase in EDSS scores of 1 unit if the baseline score was <5.5 or of 0.5 units if the baseline was 5.5 or higher"

Jul 21 11:15 PM

[Kyle Kimme:]

Thank you very much for your insight Richard. It is much appreciated.

Jul 22 12:19 PM

[DennisA:]

Richard: I assume that Eli Lilly did extensive due dilligence with multiple scientists on this drug before they invested in such a major way. What might they have discovered in that effort that would overcome similar doubts as yours? Or why would they make such an investment if there analysis was similar to yours?

Thanks again for sharing your extensive experience.

Regards.

Jul 24 11:24 AM

[DennisA:]

Richard: Sorry, I'm "User 460167". I goofed up the entry. Have a great day.

Jul 24 11:29 AM

[sleepdoc:]

Looks like the answer is Hype....very nice call.

www.biomsmedical.com/d...

Dirucotide Does Not Meet Primary Endpoint in Phase III MAESTRO-01 Trial In Secondary Progressive Multiple Sclerosis

Jul 27 05:41 PM