Personalised and Precision Medicine

The Future of Rare

Disease Therapies
Dr Matthew Klein at PTC Therapeutics discusses gene therapies, the impact
of COVID-19, and regulatory processes with ICT

ICT: How do you see the landscape of forth. Researchers and drug developers it’s a pretty big bucket. Within blood
gene therapy trials for rare diseases have long wanted to be able to cancers, for example, there are several
looking in the future? leverage information about the sub-categories of disease with distinct
unique genetic makeup, or, perhaps, characteristics. It’s certainly been
Dr Matthew Klein: Ever since the other specific individual factors, to the case in cancer treatments that
human genome was cloned, there tailor treatments. The evolution of the better we can understand, and
has been the potential for using gene understanding diseases starts with what precisely we
therapy to target diseases, particularly a broad category description, can identify, for
rare diseases, many of which result and then a development of sub- example, in the
from missing or inactive genes. Over categories. If you look at cancer,
the past few years, we have finally
caught up in terms of having
the necessary understanding,
technology, and experience to
not only discover potential gene
therapies, but develop them.
What we’re seeing right now,
not surprisingly, is an explosive
growth in the development
of gene therapies targeting
rare diseases because
there’s always been a lot
of understanding that
rare diseases typically
result from biological
defects related to missing
or inactive genes. The
landscape now is chock
full of efforts looking at gene
therapies for rare diseases,
and I think that’s going to
be increasingly the case. It's
really an exciting time for gene
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therapy, and gene therapy for rare

diseases.

How has precision medicine

developed since it was first discovered?

Over the years, the term personalised

and precision have gone back and

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genetic subtype, the better we are at
developing a treatment that will be
effective for that specific individual. I
think cancer really gives us a very good
framework for this because if I told you
today that I have a therapy for cancer,
you’d say that seems awfully broad.
How can you expect that one therapy
would work for someone who has
breast cancer, pancreatic cancer, bone
cancer, blood cancer, lung cancer?
Even if I told you I had the treatment
for lung cancer, you would say, well,
it’s not going to work for everyone
with lung cancer, because there are
different types of lung cancers. That
really brings to light the importance
of understanding these individual
characteristics so we can drill down.
Cancer has really led the way in
thinking about this and we are now
trying to implement these learnings into
other disease areas.
Globally, scientists have always wanted
to do this, and now we’re trying to do
it in other areas. We have developed
really great genotyping abilities, such
as biochemical typing individuals, and
increasingly powerful laboratory tools
that allow us to identify differences
among individuals and then think
about tailoring therapies for those
specific individuals.
It’s one thing to be able to say,
"wouldn’t it be great if", it’s another
to be able to say "we actually can".
One of the things we know about
rare diseases is that 'rare' does not
equal homogeneous. That is often a
misunderstanding. As we think about
rare diseases and understanding
within different diseases, there
are individual buckets. Duchenne
muscular dystrophy is a great example
of a rare disease, but there are
different types of mutations; there
are nonsense mutations, there are
specific point mutations, and what
you’re starting to see is therapies
being developed to target, for example,
specific point mutations. What you
start to have within rare diseases is
the ability to utilise precision medicine
and gene technologies to develop
bespoke therapies for patients with
International Clinical Trials | February 2021
different genetic mutations. That
is the realisation of the promise of
personalised medicine.
Are you seeing any particular pathways
of research in rare disease trials?
One of the promises of gene therapy
is to be able to treat a condition at its
source. If it’s a disease that results
from a genetic problem, a missing or
inactive gene, or a defective gene, then
being able to treat that disease at its
source (e.g., with genetic therapy) is
incredibly powerful. You’re not worrying
about whether that treatment is going
to be strong enough or potent enough
to overcome a genetic basis of disease.
In rare diseases, what we always keep
front of mind that rare doesn’t equal
homogeneous. Therefore, we need
to think about how we can group
patients in ways that make them likely
to respond to a particular therapy.
How can we find some similarities in
patients that will allow us to study a
therapy? The way we go about doing
that is going to depend on the therapy
itself. If we have a gene therapy
targeting a specific genetic defect, we
would approach a rare disease and
group, or select, those patients that
correspond to having that genetic
defect. That’s the precision part – you
would basically match your therapy
to those who are most likely to benefit
from that therapy.
How has COVID-19 affected gene
therapy trials?
The pandemic has had an impact on
everything, in many ways. Obviously,
if you have medical centres that are
clinical trial sites for gene therapy
development, and are focused on
taking care of patients with COVID-19,
they just don’t have the capacity to
take care of non-COVID-19 patients.
Many centres have closed for research
because of the risk to patients travelling
there. If you have patients who are ill
and can’t really travel, because they
would be particularly susceptible to
COVID-19, that’s obviously going to
have an impact. Then you start to
think about other things; many of the
external commercial manufacturing
organisations that we would work with
are actually working on COVID-19.
Different therapies that are being
developed for COVID-19 use a lot of
the same external companies that
work on gene therapies. They may be
limited in their ability to have a lot of
staff because of COVID-19, they'll be
socially distanced, but those limited
staff members may now be 100%
focused on developing therapies for
COVID-19. That has had an impact on
development.
The patients themselves are scared.
We deal with very, very sick patients.
Though it has been challenging to
conduct trials in the pandemic,
and many were delayed for a while,
we've actually just started a trial in
mitochondrial disease. Mitochondrial
disease patients themselves are very
susceptible to seasonal illnesses. A
seasonal flu for mitochondrial disease
patients could be fatal. Even getting
immunisations can be such a stress
to these patients, and have serious
consequences. People are really,
necessarily scared. As physicians, we
are taught to ‘first, do no harm’; we
want to make sure that while getting
therapy in clinical trials, everyone is as
safe and secure as possible.
Precision medicine and gene therapy, in
general, are expensive options for many
patients, what do you think is needed
for these therapies to become viable
treatment options?
I think it is already a viable treatment
option, and I think the question
becomes: for what populations is it
a more viable treatment option, and
how can it become a more viable
treatment option for all populations?
The work involved in discovering and
developing the gene therapies is many
years, and costs many millions of
dollars. It becomes easier to think about
developing a therapy that will be usable
and helpful to hundreds and thousands
of people, and harder to think about
how you would develop a therapy for a
very small number of people. However,
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 when you are only treating that small
patient group, the budget impact of a
gene therapy is also very small, and, of
course, it is a one-time treatment with a
lifetime benefit.
The pharmaceutical industry is a highly
regulated industry. Many years, and a
lot of effort, goes into developing drugs.
This is not unique to gene therapy.
This is a true challenge for many rare
disease communities. I speak with
many parents who have children with
very rare diseases, and I can think of
a couple specifically where there may
be only three or four known patients
with that disease in the US, or even the
world. They deserve to have therapies
too. As physicians, as drug developers,
and as human beings, we would want
to have paths to get therapies for
everyone. Gene therapy shouldn’t be
a privilege, or an opportunity for only
certain diseases, they should be able
to be developed for anyone who could
possibly benefit. But that’s an ideal,
and something we should think about
working towards. The point really is that
there’s a great number of rare diseases
that result from missing or inactive
genes that could certainly benefit from
gene therapy.
Do you think that gene therapy could
become a cornerstone in all disease
treatment?
The way we think about gene therapy
now is being particularly well suited
for diseases that have a clear genetic
basis, such as aromatic L-amino acid
decarboxylase (AADC) deficiency.
That’s one paradigm. What about more
common diseases, or diseases that may
not have the same genetic aetiology, or
may not even have a genetic aetiology
at all, but have a common pathway?
Think about cardiovascular disease,
cardiomyopathy, or diabetes. Could
gene therapies provide alternative or
new treatment options? Genes make
proteins; the gene comes in and
produces a protein that’s necessary for
normal biology, biochemistry, cellular
and organ function. You can also
imagine administering genes that could
produce proteins not to replace missing
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or inactive genes, but to actually counter
some other aspect of the disease – for
example, a biological patch that has
cells that make, and continue to make,
insulin. This could sense when glucose
levels are high, then drive insulin
production from the cell.
I remember being in medical school
when the human genome was cloned,
and my genetics professor stood in
the front of the classroom and said,
“We can now cure all diseases!” Well,
no, maybe that’s not the case, but the
obvious place to start was with gene
therapies for genetic diseases. We
can think about gene therapy as the
provision of essential proteins that are
important in disease processes. If you
look at that as the definition, the disease
process could start with a genetic basis,
it could start with an environmental
basis, it could result from a number
of different processes, then you can
think about intervening anywhere along
that pathway with a protein that can be
beneficial in altering the course of that
disease.
What’s your opinion on the stringent
regulatory processes for precision
medicine?
The regulatory process is consistent
across all therapeutic approaches. If
you think of precision medicines as
being gene therapies or cell therapies,
they’re just more complex, which
makes the regulatory process more
complex. The fact that we’re still
relatively new in this experience, as
are the regulatory authorities, means
that everyone is learning as we move
forward together. The processes are
stringent, but necessarily so. The
regulatory authorities have to ensure
that before they even go into humans,
therapies are safe and have a promise
of being effective. Then, as you advance
the therapy towards approval, there’s
got to be a clear demonstration of this,
that a therapy is safe, and that the
benefit-to-risk ratio is favourable when
weighed against the disease itself.
That’s the same for all drugs that are
developed. The intricacies of some of
the cell and gene therapies are a little
more complicated. In gene therapy,
for example, it’s not like you can turn it
off. If you take a pill, and you have an
allergic reaction, you stop taking the pill.
If your doctor puts you on a medication
and tells you to take 25mg a day, and
you find out that you actually need a
higher dose, they can have you take
50mg. Gene therapy is administered
and you can’t necessarily turn that off.
That’s actually a big deal, we want to
be really sure that what we're giving is
safe, and that the dose is effective. The
other part of it is that gene therapies
are typically administered with what’s
called a viral vector. The viral vector
is the bus that drives the gene to
where it needs to go; it puts it in the
cell. That has considerations as well;
because we inactivate the virus, so
the virus itself can’t replicate, it can
sometimes cause immune reactions if
your body has seen that virus before.
I bring all this up to mention that
there are a number of complexities
that are unique to gene therapies that
make the process a bit more rigorous.
Dr Matthew B Klein, MD, MS, FACS is Chief
Development Officer at PTC Therapeutics.
Prior to joining PTC, Matthew was CEO
and Chief Medical Officer of BioElectron
Technology Corporation, a biotechnology
company focused on developing redox
active small molecules for mitochondrial
disease and related disorders of oxidative
stress. Prior to joining BioElectron, he was
the Auth-Washington Research Foundation
Chair of Restorative Burn Surgery at the
University of Washington. Dr Klein completed
his undergraduate degree at the University
of Pennsylvania, US, where he graduated
summa cum laude and Phi Beta Kappa, and
received his MD degree with honours from
Yale University, US.
International Clinical Trials | February 2021