I have heard some of the criticisms of the bill, namely:

1. It exposes the patients to greater risk
2. It completely eliminates any burden to prove efficacy.

The standards for safety would not change.  Safety is established during the first phase of drug trials.  As far as I can tell, I don’t see any changes to requirements for establishing safety for new drugs.

Regarding efficacy, any accelerated approval requires post-market surveillance to prove effectiveness against clinical endpoints.  Initial approval is based on biomarkers.  This is nothing new.

The only thing new would be a change in the rules for getting a biomarker approved.  ULTRA would prevent the FDA from requiring previous clinical data to qualify a surrogate endpoint.  This data just doesn’t exist for many rare diseases.  For diseases where clinical data is not available, ULTRA would ask the FDA to use valid science and our understanding of biology to qualify biomarkers that are reasonably likely to predict that the drug works.

Is this the right choice?  You’re damn right it is.  I do not want to wait until there is rock-solid bulletproof evidence that a drug works before I can treat my kid.  I think that 99% of people who have terminally ill family members feel the same way.  Anyone that says that the system is working is crazy.  95% of rare diseases have NO TREATMENT.  By definition, that is broken.  We need game changing new laws.  New laws that will transform the landscape.

The world is changing.  Information technology enables people to make their own decisions.  Long gone are the days when people had to rely on a single group to “be their voice”.  This is a new world of ideas; A world where each of us can watch congressional hearings on Ustream and don’t have to travel to Washington.  This is a world where ideas spread fast and the grassroots can make their voice heard directly.  When it comes to ULTRA, the rare disease community has spoken.  We want treatment and we want it now.

We thank Congressmen Towns and Stearns for their leadership.  By introducing this bi-partisan bill they have shown that the giving hope to people with rare disease is not a Democratic or Republican issue.  Rather, it is a human issue. Drug development for this under-served population isn’t where it needs to be.  Everybody with a disease deserves treatment.

This upcoming year, a number of patient groups have pulled together to endorse ULTRA, the Unlocking Lifesaving Treatment Act.  It will remove key barriers to enabling accelerated approval for rare genetic diseases.  We believe it will unleash a huge amount of biotech investment and result in many new treatments for those suffering from the rarest of diseases.

If you can dream—and not make dreams your master;
If you can think—and not make thoughts your aim,
If you can meet with Triumph and Disaster
And treat those two impostors just the same:.
If you can bear to hear the truth you’ve spoken
Twisted by knaves to make a trap for fools,
Or watch the things you gave your life to, broken,
And stoop and build’em up with worn-out tools;

If you can make one heap of all your winnings
And risk it on one turn of pitch-and-toss,
And lose, and start again at your beginnings,
And never breathe a word about your loss:
If you can force your heart and nerve and sinew
To serve your turn long after they are gone,
And so hold on when there is nothing in you
Except the Will which says to them: “Hold on!”

If you can talk with crowds and keep your virtue,
Or walk with Kings—nor lose the common touch,
If neither foes nor loving friends can hurt you,
If all men count with you, but none too much:
If you can fill the unforgiving minute
With sixty seconds’ worth of distance run,
Yours is the Earth and everything that’s in it,
And—which is more—you’ll be a Man, my son!

I have tried my best to relay the information as I received it.  I am not a scientist nor am I a doctor.  So, with that said, I ask that you take my interpretation with a grain of salt.

Of course, I want everything to be positive.  I am a positive person!  However, I have tried to share the good news and the bad news as I received it without filtering.  In particular, I have already had parents reach out to me about Prof. Hopwood’s data showing a reduced efficacy of ERT in mice past a certain age. Regarding this data, I will share with you what I was told;  Humans are not mice.  There significant differences in anatomy in humans and mice; enough so that one cannot translate clinical outcomes of animal data to humans.  The primary hypothesis that was proven via the mice data was that, indeed IT ERT does work in animals. What this data may suggest is that there is A point where IT ERT doesn’t work anymore.  Understanding where the “point of no return” for humans is will require testing in humans, there is no way around that.

The temptation to extrapolate from mice data to humans is understood.  It doesn’t only happen to laypeople; researchers do it too.

What I liked:

1) Meeting the researchers

Professor John Hopwood - a true hero

2) Meeting the families:

Frederic and Charlotte Morel

3) Getting latest Info (Good and Bad), more details to follow

• Hopwood: Intrathecal ERT - In mice IT ERT doesn't seem to work if started after symptoms present clinically.  However, HUMANS ARE NOT MICE, and we hope to see data from Shire's Phase I/II in 6 months, at the end of the Phase I/II .  At that point they will have some efficacy data along with an idea of the correct dosing regimen.  Fingers crossed!
• Genistein: Professor Wergzyn and Brian Bigger presented data on genistein. There is growing consensus that it has an effect in mice at high doses.  There is interest in launching a double-blind placebo controlled trial for genistein within the next year.
• Important note: Dr. W showed that there was significant variability of genistin content in the "natural" version of these products.  Further, he showed that there were some negative synergies involved with some of the other compounds used in those products.  In other words, you may be better off using nothing than using the natural versions of this compound used in some supplements.
• As far as I know, the only way to obtain the pure synthetic version of genistein in the US is to either be part of Dr. Burton's study in Chicago or through Fallon Pharmacy.
• Natural History Study - Shire has identified several new biomarkers and learned much about the disease through the University of Minnesota study.  These biomarkers are so important, not only to understand what works from a treatment pespective but also to get drugs approved.  Accelerated approval relies on proper biomarkers as surrogate endpoints. Here are some of the key findings:
• Brain volume decreases along with time.  Also, it was shown to correlate well with the cognitive decline, as measured by the ratio of cognitive age to chronological age.
• Brain volume can be computationally measured by analyzing MRI data.
• Cerebro-spinal Fluid GAG levels are fairly constant with time.  In other words, the do not increase with disease progression
• Two new bio-chemical markers were found.  I don't recall both of their names but one was called Hepatocyte Growth Factor.

Me and Dr. Patrick Haslett from Shire

Dr. Haslett Presenting Shire's NHS Data.

• Inter cerebral Gene Therapy (France): At least one patient has been treated.  No safety issues so far.  Four French patients will be included.  The trial will expand to a phase III in a couple of years based on data from the Phase I/II.  A phase I/II study for Sanfilippo B patients will open by the end of next year.  They are looking to include eight European patients younger than 6 years of age.
• Dr Fu's Gene Therapy: Dr. Fu is using a new gene therapy vector than the folks in France.  Her vector can be administered intravenously - versus through direct injection to the brain.  They are completing the animal toxicology work and hope to open a Phase I/II trial in three or so years.
• Prof. Doug Mccarty, Dr. Fu's colleague, also described a program for gene therapy for MPS IIIA.  Like their type B program, it can be administered intravenously.  It is several years behind the Type B program and lagging further behind from a funding perspective.  On the positive side, they have learned much for their MPS IIIB gene therapy that has allowed them to produce a much more "efficient" vector for MPS IIIB.  That means that the viral vector used can work with fewer vectors.  This makes it more cost-effective and even safer.

I am very grateful for drug companies and the researchers who have taken up this fight along with families.  I am also grateful for the families that have participated in the Natural History Study of these diseases.  It is a tough choice for families to get involved.  The procedures are invasive and the time commitment is a burden.  However, the data is so valuable in the fight against these awful diseases.

Finally, we should all be very grateful for the contributions of Shire to our children.  They have shown an amazing commitment to Sanfilippo.  By their own financial statement one can assume that they have poured tens of millions into research.  Further, their openness in sharing their natural history findings and biomarkers is a contribution to the community as a whole.

Thanks for your support of ultra-orphan diseases. I am 100% behind this effort because its result would be tangible and measurable – namely how many rare diseases are granted accelerated approval based on a biomarker. For patients and their families the wait for treatment is agonizing – it simply cannot be described.

My son has Sanfilippo – a devastating and life limiting disease with no treatment. In the complete absence of hope, almost any parent I know would prefer get access to treatment based on some evidence of efficacy. Sanfilippo is based on a single genetic defect which results in the deficiency of a particular enzyme. The lack of this enzyme results in accumulation of a well-known substance that is implicated in the pathology of the disease. It stands to reason that reduction of this accumulated material should serve as a reasonable biomarker for efficacy of treatment. Parents of affected children who do not gain access to a clinical trial should not have to wait until trial patients are shown to not die to help their kids.

http://www.kakkis.org/blogs/post/2011/11/29/Ultra-orphan-Life-saving-TReatments-Act-of-2012.aspx

• More people, collectively, suffer from a rare disease than HIV + AIDs combined
• Accelerated Approval has only been used once for a rare disease treatment (since 1992)
• Accelerated Approval has been used dozens of times for HIV and AIDs

The typical drug approval process involves requires that companies prove a clinical benefit before it can be marketed.  This may take many, many years.

This is bad because:

1. It prevents many patients from gaining access to potentially beneficial treatments
2. It causes the development cost of new treatments to be high… so high that many extremely rare diseases just aren’t economically viable for treatment

Accelerated Approval involves granting tentative approval for a promising drug based on a biomarker versus clinical outcome.

Example:

To get initial approval to market the drug – in the case of Cancer, the drug would simply need to show that it shrinks a tumor rather than extending the life of the patient.  Post-market surveillance is used to determine clinical efficacy.

Of course, this approach has many applications outside of cancer.  In the case of many rare genetic diseases, the underlying mechanism can be isolated to a single genetic defect and biological pathway.  I am told that this makes the identification of biomarkers much easier.

In contrast to the classical approach, accelerated approval has the following advantages:

1. It gets drugs to as many patients as quickly as possible
2. It is grounded in science, assuming appropriate biomarkers are chosen
3. It reduces drug development cost by over 60%

The Ultra-Orphan Lifesaving Treatment Act of 2012 will help make accelerated approval available to rare disease.  Only a small percentage of rare diseases have treatment and this could be a game changer.

You can help.

Ask your patient group to sign on to the Congressional support letter

Talk to Julia Jenkins at patientadvocate@kakkis.org – Remember, you don’t have to be the a big foundation to sign on.  We need as many patient groups as possible to add their name to the letter.

Want to learn more? Watch the video PSAs:

In a way, online charity contests are a scientific measurement of how important issues are to people. These contests, by their very nature, are a test of how willing people are to get involved with pitching in to solve an issue.  They place some burden on participants and to some degree “measure” their willingness to overcome those burdens.

Contests force participants to:

• Release data to the company running the campaign
• Push promoters to campaign, engage traditional media and cajole people to vote
• Burden voters to vote each day for campaigns that run for weeks

Team Sanfilippo has already earned $350,000 this year alone through online contests. They won the Pepsi Challenge (earning $250K) and earned 2nd place in Vivint Gives Back (earning $100k).  They lost the Vivint event to FAST, who is raising money for Angelman’s Syndrome research.

Why do rare disease charities win?

Because, long before these contests arose, the patient population embraced social media!  They have mastered it.  Facebook is “home” to many parents dealing with these catastrophic diseases.  They use social media to follow each others stories.  They empathize as their friend’s children go to the hospital and even more with them after their children pass.

Traditional charities don’t compete well.  Many are stodgy, traditional groups that still rely on old school means to communicate and engage their patient population.  They can’t mobilize in the same way.

Here is the rub: basic research is great but I don’t believe that it will help my son or children like him.  He is four and already has a disease.  It is intellectually satisfying to believe that the reason our children aren’t being treated because the science just doesn’t exist.  Granted, for some diseases, this is true. But for many diseases it simply isn’t cost-effective to bring a drug to market.  We need to make the process of developing treatment more economically viable and that can’t be done by increasing drug costs ad infinitum.   We need to look at the cost side of the balance sheet.

Rare diseases need access to the accelerated approval pathway.  Yes, that will of course get drugs in the pipeline out faster, but perhaps even more importantly it what it does for drug development costs.  Kakkis et al. showed in their paper that accelerated approval reduces the cost of drug development by over 60%.  There are over 7000 official rare diseases.  Even with the Orphan Drug Act, many are still not economically viable for treatment (even though the science exists).  AA has been used 26 Cancer Drugs and 29 HIV drugs since 1992 but only once for rare genetic disease.

I understand that many patients have a fundamental distrust of pharma.  But it is important to understand that without them no treatments exist!  And without a sufficient ROI they can’t convince their shareholders to invest in developing treatment.

We need to harness all our resources to tackle the actual problem.   But to convince people to solve this problem, we have to package it in an easy to understand way.  It will happen, it’s bound to.

As a footnote, I love the following quote (attributed to Margaret Meade):

Never doubt that a small group of thoughtful, committed citizens can change the world. Indeed, it is the only thing that ever has.

I believe that it is our turn to make a dent in the universe.

As an example, the other day I was giving Reed a bath.  His sister walked in and was upset because I was using her new Loofah (not sure how you spell it – but you know what I mean) on him.  Aziza asked me not to use her Loofah on him because she was afraid she would get Sanfilippo.  Keep in mind she is eight years old.  I paused and then got angry and raised my voice at her.  I raised my voice because I thought she was being mean to him; that she really and truly understood and was just disrespecting him.  I said something to the affect of:

I don’t ever want to hear you disrespect your brother like that again.  You know that you can’t catch Sanfilippo.  Where did you get that from?  Are you friends saying stuff like this to you?

She walked into the room with the toilet, shut the door and cried… and I felt like crap.  There are days when I can’t do anything right.  As if I didn’t feel bad enough about Reed, now I was hurting his sister’s feelings too!  After I calmed down, I – of course – explained the situation.  I clarified that she can’t catch Sanfilippo and I think that she now understands; but I thought that she already understood, sigh.

Most days I can keep it together, but today I cried a bit.  Dear God, we need a bit of luck to come our way.  There are days when I can’t help but feel responsible – stupid as that sounds.

This video does cheer me up a bit.  It’s the kids getting ready for Halloween:

Quoting from Fran Hawthorne’s book “Inside the FDA”

The FDA has to focus on Type I mistakes, because the risks of allowing a dangerous drug on the market are simply so much higher than the risks of not allowing a good one.  The first type of risk is that the status quo will be disrupted and people will die much sooner than they otherwise would.  The second type is simply that people will not gain an improvement — that the status quo will remain.

For context, Hawthorne uses Type I vs. Type II errors to differentiate sins of commission vs sins of omission.  This statement is justifying the need to tilt toward being conservative because being too aggressive puts a large, reasonably healthy population at risk.  However, this argument breaks down with the risk of death without treatment is 100%.  That is true for Sanfilippo and for so many other rare diseases.

I have to be honest, this mistake is our own. The industry and patient groups have allowed this faulty reasoning to persist and we haven’t made our case: to regulators, lawmakers and apparently pundits and the media.  Applying a blanket set of rules based on reasoning that applies to the general population is killing people with rare disease – bottom line.

Parents of children with Sanfilippo are beating down the doors to get access to treatment (trust me, I know first hand).  Patient advocacy groups, Industry, parents and patients have to get together and get better at telling our story.  As Dr. William Gahl from NIH explains, “Patients with rare disease want to be protected but they don’t want to be protected to death”.

Until we do a good job of conveying this message, we only have ourselves to blame.