Why I Doubt the FDA Will Approve Acorda's Fampridine

Yesterday there was an announcement that Acorda (NASDAQ: ACOR) has amended their NDA application for fampridine. After after taking a closer look at their Phase III study (MS-F203), here is a reason why come February 23, 2010 the FDA will provide a verdict of NOT APPROVED or at best APPROVABLE. Either case, it will have a detrimental effect on the stock's price.

Here is my analysis of the pivotal study (MS-F203):

The primary endpoint of this study was to measure the percent of patients who improve their walking ability from baseline. Again, the primary endpoint does not quantify the significance of improvement from baseline and how that relates to clinical benefit. So, to use an analogy, say I have a miracle drug that will lower ALL patients' blood pressure, but I don't say by how many mmHg. Is this clinically meaningful? Suppose I say that it was by 1mmHg, but that ALL patients' blood pressure will be lowered. Would you approve this drug? The same goes for this endpoint. Furthermore, the the results from this study showed that only 35% of patients taking fampridine demonstrated a response compared to 8% placebo. And what exactly is this response? A.51ft/sec (6 inches/sec) improvement in walking speed.

So what about the 65% of patients who didn't respond? A 16ft/sec (2 in/sec) improvement in walking speed, no better than a sugar pill (placebo) .10ft/sec improvement.

The FDA will not approve a drug that only helps 35% of the patients walk 4 inches/sec faster than the placebo while having a side effect profile causing seizures, anxieties, and loss of balance. The benefits are just not there over the risks the drug pose.

Interestingly, also look at the patient characteristics in the study. It is skewed in favor of the Fampiridine group.

Look at the male/female ratio:

• Placebo 40%/60%
• Fampridine 29%/71%
• Non-responders 31%/69%
• Responders 24%/76%

As you can clearly see, it looks like males have poorer outcome with this endpoint than females, as demonstrated by more males not responding to the drug vs. responders. Furthermore, there is a skew towards more males in the placebo group who are more less likely to have positive outcome.

In conclusion, I question the validity of the primary endpoint. Simply stating that a higher percent were able to walk faster is not a valid endpoint.

Finally a telltale sign is the insiders' transactions.

Disclosure: None

Comments

[Furd Turgeson:]

I concur completely. This is a great short. Nice analysis, well done.

Apr 24 08:37 AM

[hoopdreamer...:]

Are you really a Doctor?

Apr 24 08:59 AM

[Dr. Anthony:]

Even Better Doctor of Pharmacy


On Apr 24 08:59 AM [e-mail] wrote:

> Are you really a Doctor?

Apr 24 09:12 AM

[User 401371:]

I guess you are ignoring the fact that Acorda negotiated this end point with the FDA as part of an SPA before trial...

Apr 24 10:14 AM

[Reg Expert:]

In several instances, the SPA terms that were negotiated with the FDA are interpreted differently by the company and the FDA. Also on several occasions, the company usually misleads the public and the investors. You will only find out the real SPA terms after we see the FDA review analysis posted during the advisory committee meeting. Examples, GPC's Satraplatin, Dendreon's Provenge etc etc


On Apr 24 10:14 AM User 401371 wrote:

> I guess you are ignoring the fact that Acorda negotiated this end
> point with the FDA as part of an SPA before trial...

Apr 24 11:16 AM

[Dr. Anthony:]

meeting SPA cleared endpoint does not constitute automatic approval. Again referring to Spectrum and GPC's Satraplatin. Their phase III study satisfied SPA cleared endpoint. However the way the data was analyzed did not impress the FDA, resulting in NOT APPROVED


On Apr 24 10:14 AM User 401371 wrote:

> I guess you are ignoring the fact that Acorda negotiated this end
> point with the FDA as part of an SPA before trial...

Apr 24 11:21 AM

[080105:]

I hope you are wrong. I respect your pharmacology background but MS is a complicated immunological disease that affects every patient differently. There are no known biomarkers to show which MS patients will respond to which drugs - primary therapy or ancillary therapies. Look at the primary MS disease modifying therapies, only 33% of patients really respond to any of the therapies which is why heavy R&D continues. The majority of MS patients are women thus the skewed male/female ratio. And for an MS patient who experiences difficulty walking -- anything that could help with speed or distance is important. This population (MS specialists, patients, etc) is well versed in risk benefit decisions as evidenced by drugs like Tyusabri and Novantrone.

Apr 24 12:38 PM

[dgmontana:]

My knowledge of fampridine is anecdotal only, but persuasive. I work with a man who has a progressive form of MS. Ten years ago he was in a wheelchair full time. Now he walks, sometimes with the aid of small arm braces, but often unaided. As he puts it, not metaphorically but literally, "I can hike ten miles." This is not a small shift, or a manipulation of statistics--this is a man who has been given his life back by fampridine. Whether it works so successfully with others, I don't know--but for my colleague, it has been a miracle.

Apr 25 10:30 AM

[Richard Sater:]

I enjoyed reading your article but disagree with your conclusion. I've traded ACOR a few times in the past but currently have no position.

A few points:
1. An improvement of 0.5 feet per second sounds minimal to a healthy person who walks 25 feet in 5 seconds (5 feet per second to 5.5 fps). But a person who is only able to walk 25 feet in 16 seconds will have a perceptible improvement (1.5 fps to 2 fps) and will have a correspondingly greater range. A responder who goes from a walker to a cane has a re-discovered freedom that leads to a greater quality of life and becomes less dependent on others.

2. A responder rate of 35% is acceptable. Some drugs work for an individual and some don't. What's nice with 4-AP is that you will know within a week or two. With a background in pharmacy, how often have you seen people switch from one medicine to another to treat the same problem. Would they be switching if they were responding? Most meds I use have a response rate of 25-75%.

3. This is the first drug that will be FDA approved that can actually help some MS patients with primary progressive or more advanced secondary progressive MS who are unlikely to respond to immunomodulatory agents. This is a niche that needs to be filled and moderate response rates and side effects are more acceptable when no other option exists.

4. Side effects are acceptable. A 1% risk of seizures is high enough that anyone with a seizure history will need to be excluded, but others will need to understand the risk and determine if they are willing to take that 1% risk for a 35% chance of benefit. The other side effects (anxiety, agitation and loss of balance) are mild problems that may last for hours and are not much different from somnolence or dry mouth that may accompany other drugs.

5. I've used immediate release 4-AP in some of my MS patients and have had variable success. A couple noted improved strength and/or gait. Some had agitation (more likely to occur on immediate release than time release) and quit and others had no benefit and quit.

Apr 25 01:10 PM

[Dr. Anthony:]

You made some compelling counterpoints and I enjoyed reading your point of view.

With regards to your rebuttal abou the endpoint, it was only a .4fps improvement not 1.5-2 fps improvement. And this improvement was only seen in 35% of the responders. I believe that a better endpoint would have been walking improvement in all patients in the fampridine group.

I also understand that there is a definite medical need for a drug that can help patients cope with the disability caused by this devastating disease, especially patients with secondary progressive MS. Again, if the study was designed to specifically target SPMS then I believe it will have a better shot at approval. However, this study was not designed as such, coupled with what I mentioned above will have a difficult time conving the FDA.

I understand that you and many others have personal experiences where you have seen these drugs help individual patients. No matter how much this may sway your views about the product, it needs to taken with a grain of salt as individual experiences will vary greatly with every patient. After all, 8% of patients saw improvement with a sugar pill.


On Apr 25 01:10 PM Richard Sater wrote:

> I enjoyed reading your article but disagree with your conclusion.
> I've traded ACOR a few times in the past but currently have no position.
>
>
> A few points:
> 1. An improvement of 0.5 feet per second sounds minimal to a healthy
> person who walks 25 feet in 5 seconds (5 feet per second to 5.5 fps).
> But a person who is only able to walk 25 feet in 16 seconds will
> have a perceptible improvement (1.5 fps to 2 fps) and will have a
> correspondingly greater range. A responder who goes from a walker
> to a cane has a re-discovered freedom that leads to a greater quality
> of life and becomes less dependent on others.
>
> 2. A responder rate of 35% is acceptable. Some drugs work for an
> individual and some don't. What's nice with 4-AP is that you will
> know within a week or two. With a background in pharmacy, how often
> have you seen people switch from one medicine to another to treat
> the same problem. Would they be switching if they were responding?
> Most meds I use have a response rate of 25-75%.
>
> 3. This is the first drug that will be FDA approved that can actually
> help some MS patients with primary progressive or more advanced secondary
> progressive MS who are unlikely to respond to immunomodulatory agents.
> This is a niche that needs to be filled and moderate response rates
> and side effects are more acceptable when no other option exists.
>
>
> 4. Side effects are acceptable. A 1% risk of seizures is high enough
> that anyone with a seizure history will need to be excluded, but
> others will need to understand the risk and determine if they are
> willing to take that 1% risk for a 35% chance of benefit. The other
> side effects (anxiety, agitation and loss of balance) are mild problems
> that may last for hours and are not much different from somnolence
> or dry mouth that may accompany other drugs.
>
> 5. I've used immediate release 4-AP in some of my MS patients and
> have had variable success. A couple noted improved strength and/or
> gait. Some had agitation (more likely to occur on immediate release
> than time release) and quit and others had no benefit and quit.
>
>

Apr 26 07:13 PM

[Notaplacebo:]

You should limp a mile in my shoes brother before dumping on the promise of this drug.

From my understanding of it, the drug improves the conductivity of myelin stripped nerves. Improvement of walking speed should therefore be but one example of its potential benefit. So I'm unclear as to why they focused just on that in their study. Perhaps it was something they could objectively measure? Or they want it as a prescribing criteria?

Even so, 6 inches per second translates into 600 yards in an hour. A small step for you, perhaps, but it's a giant leap for me.

If you also think about the fact that impairment of walking is a very common effect of MS, and that the drug doesn't cure this condition (only makes living with it easier) the market potetial of this drug is pretty huge.

Hopefully the FDA has a deeper knowledge of MS than you, as I've waited a long time for a drug like this.

Apr 30 11:59 AM

[WillRunAgain:]

OK. Is anyone here actually taking the drug? Well I am and let me tell you that for the first time in 5 years my feet do not feel like they weigh 200 pounds each. And it is the feeling of "heavy feet" that contribute to my instability.

I have MS and I have said that I will run again. I know running is tied to balance issues controlled by my vestibular system, but I have to tell you that since I have been on Fampridine my claim that I will run again actually feels like a possibility.

May 07 12:57 PM