Primary and Secondary Endpoints
A trial endpoint of a clinical trial should fulfill three
criteria: (1) be measurable and interpretable, (2) sensitive to
the objective of the trial, and (3) clinically relevant. The endpoint
can be either clinical or surrogate in nature.
If you are
developing a drug to lower cholesterol or to increase survivability after a
traumatic brain injury, it is pretty easy to define your endpoints.
When it
comes to autism, one of the major hurdles is to define objective measurable
endpoints. As it stands today, none of
the assessment tools are really fit for purpose, when Big Pharma is supposed to
come along and invest hundreds of millions of dollars in some bright spark’s
idea.
Arbaclofen, Seaside Pharma & Roche
The Swiss
giant, Roche, recently had just such a problem.
They had partnered with a spinout company from MIT called Seaside
Therapeutics. One of the projects was to
complete the trials of a fragile X targeted drug, called Arbaclofen (STX209). During the 4+ years of trials Seaside had
changed the primary endpoint. Arbaclofen
started out as drug to treat one aspect of behaviour, but by the time they got
to phase 3 clinical trials this had been changed to lethargy and social
withdrawal scores from the Autism Behavior Checklist (ABC).
Quite
logically, Roche assessed the result of the stage 3 trial against its primary
endpoint. Based on the total cohort in
the trial, Roche determined the drug to be a failure and pulled the plug on
financing the drug further.
The owner
and developer of the drug, Seaside, even though they have recently raised $90
million, said they could no longer continue to fund the trial and all those
kids in the trial would have to be weaned of Arbaclofen ASAP.
It turns out
that among the families involved in the trial there were many reports of
wonderful improvements on Arbaclofen.
They even formed a group to lobby for a continuation of the trial. There website is interesting.
It now
appears that Seaside has had a rethink and will try again with a new trial with
a new primary endpoint (mark 3).
Background on Arbaclofen
Some of the
first studies of Arbaclofen were conducted in patients with Fragile X syndrome,
a genetic condition caused by a change in a gene called FMR1, which normally is
needed to make the brain grow properly. Fragile X is the most common form of
inherited intellectual disability in boys and can be a cause of autism or
related disorders. In those Phase 2 trials, Arbaclofen was shown to decrease
social withdrawal and improve adaptive social function.
A Phase 2a study conducted at 8 sites and
involving 32 children showed significant positive behavioral outcomes,
including improved scores on the Aberrant Behavior Checklist-Irritability Score
(ABC-I) and on the ABC-Social Withdrawal Scale. The most common adverse events
were agitation, irritability, fatigue, psychomotor hyperactivity, insomnia and
diarrhea. Most resolved without dose changes, but one serious adverse effect
did occur during down-titration of the medication.
In July 2011,
Seaside Therapeutics, announced that 25 sites across the nation will be
involved in a new clinical trial to involve approximately 150 ASD patients
between the ages of 5 and 21.
STX209 is an
orally-administered GABA-B agonist; the drug acts by stimulating the release of
GABA, a neurotransmitter in the central nervous system. GABA inhibits the
release of glutamate, an excitatory neurotransmitter, for which an overabundance
negatively affects the ability of neurons to communicate with each other.
The GABA
"A" receptor, is a chloride channel, while STX209 targets the GABA
"B" receptor, which is a G-protein coupled receptor and regulates a
different set of molecules from GABA "A".
The original basis for
starting this blog was my success with bumetanide, which is affecting the GABA “A”
receptor. In the brain, bumetanide blocks the NKCC1 cation-chloride
co-transporter and thus decreases internal chloride concentration in neurons.
Medicine as an art and a science
Mark Bear is
a neuroscientist at MIT and he was the co-founder of Seaside Therapeutics. He is clearly a very brainy guy.
There is a
derivative of his Arbaclofen called Arbaclofen Placarbil. I found it interesting that this substance
was also being trialed as a therapy for Multiple Sclerosis and GERD. GERD is the medical term for heartburn/indigestion.
Incidentally,
Arbaclofen Placarbil failed both trials.
Now to the Clever Chiropractor and
her Pancreatic Enzymes
People
outside the US will find it very strange that in the US chiropractors and osteopaths
have the same right to prescribe drugs as conventional medical doctors.
Outside of
the US, if you want to be a doctor you have to apply to medical school and in
most countries the competition is very tough. There is no plan B if your exam
grades slip. In the US it is different,
if your grades and resources are not taking you to the Harvard, you can opt to become
an osteopathic physician or a chiropractic physician.
Rather than Harvard or MIT, Joan Fallon trained as a chiropractor
at Palmer University. Not surprisingly the scientific community is skeptical of her autism treatment, which is linked to pancreatic enzymes. After all, how can a chiropractor know more than Ivy League neuroscientists?
Peter, on the other hand, thinks that Fallon is actually
far more savvy than the very brainy people over at Seaside. Her therapy may, or may not be effective, but
her method of developing it is highly effective.
First she raised $6 million to start her company
Curemark, then as trials progressed she very recently she raised another $18
million.
The reason I like what Fallon is doing is that she has
figured out which sub-type of autism is helped by her therapy and she has
identified a bio-marker for that subgroup.
Hallelujah, a street-smart autism researcher !
If you want to enroll in a
clinical trial for Curemark’s CM-AT,
first they will screen out the 50% that do not have the biomarker. Fallon is making sure that her clinical trial
results look as good as possible, by only including those subjects most likely
to benefit. This may sound like common
sense, but in autism research this is a revolution.
CM-AT therapy and the biomarker
The reason the autism world are
skeptical of Fallon, is that she is going on about Secretin and pancreatic enzymes.
Many years ago parents thought
that Secretin was going to be the wonder cure for autism; it turned out not to
be. By reading her patents, it is clear
that Fallon has some faith in the role of secretin, in addition to enzymes
produced in the pancreas.
What impressed me was how she
has screened the kids allowed into her clinical trials.
Eligibility
·
Inclusion criteria:
o Child is 3-8 years
old
o Child has a
diagnosis of autistic disorder
o
Child must have a
low fecal chymotrypsin level (we will measure)
·
Exclusion criteria:
o Child must have no
dietary restrictions (other than for a nut allergy)
o
Child may not have
an allergy to pork products
o Child may not have
a history of severe head trauma or stroke
o Child may not have
had a seizure within the past year
o Child may not be
diagnosed with: HIV, cerebral palsy, endocrine disorder or pancreatic disease
o Child may not be
taking any enzyme product, amino acids, secretin product or stimulant
medication currently
“Low fecal chymotrypsin level” is a standard lab test
available all around the world. Over the
years Fallon has found that it is a biomarker of the kids who benefit from her patented
mix of enzymes sprinkled on their meals.
You actually can buy a very similar product called Creon,
or Kreon, depending on which country you live in.
The reason why you cannot be in the trial if you have a pork allergy, is
that they use the pancreas of dead pigs to make the enzymes. This is bad news if you are Jewish, Muslim, a
Seventh Day Adventist, or indeed the pig.
The active ingredient in Creon is Pancreatin. Pancreatin contains the pancreatic
enzymes lipase, amylase and protease. These assist the digestion of fat,
carbohydrates and proteins.
Update on trials of CM-AT
Here is a link to the always-helpful Simons Foundation,
with the expected skeptical comments from experts:-
Now Curemark have finished there phase 3 trial, and guess
what? It met both primary and secondary endpoints and has been “fast-tracked”
by the FDA.
Congratulations Joan !!!
One of the secrets of her success was to have the good
sense to enroll herself in a course on clinical investigation run by Harvard/Massachusetts
general hospital.
Curemark Begins NDA Submission for CM-AT Autism
Treatment
CM-AT had
previously been granted
Fast Track status by the FDA, a designation given to drug candidates
that treat serious or life-threatening conditions and demonstrate the potential
to address unmet medical needs. The rolling submission process allows companies
with a Fast Track designation to submit the NDA in sections to the FDA as they
are completed.
“Initiating our
‘rolling NDA’ submission is a major step in the registration process for
CM-AT,” said Dr. Joan Fallon, Curemark founder and CEO. “We have an
extraordinary opportunity to help many children with autism improve the quality
of their lives and we will continue to work closely with the FDA to make that
happen.”
Curemark previously announced the successful completion of its Phase III
multicenter clinical trial of CM-AT for autism. CM-AT met both primary and secondary endpoints in its
double-blind, randomized, placebo-controlled study of children with autism at 3
to 8 years of age.
Conclusion I would suggest those researchers who believe that diet can be an effective therapy in sub-types of ASD take good note of Joan Fallon's methods. You might indeed be right, but unless you can prove it, the skeptics will always hold sway.