After announcing December 11 that Ionis Pharmaceuticals’ gene-silencing drug for Huntington’s disease safely reduced the production of the toxic HD protein, company officials analyzed the firm’s successful Phase 1/2a clinical trial and discussed the next step: larger trials that are designed to test IONIS-HTTRx’s efficacy in alleviating symptoms by modifying the course of the disease.
I met with two
lead scientists from Ionis’ HD team at company headquarters in Carlsbad, CA:
Frank Bennett, Ph.D., Ionis senior vice president of research and the franchise
leader for the company’s neurology programs, and Anne Smith, Ph.D., the Ionis
director of clinical development and the individual responsible for the
day-to-day management of the trial.
Drs. Bennett and
Smith stressed that, because the two-year trial ended just last month, they
could provide only an initial assessment of the results. The company plans to present detailed clinical trial findings at
medical conferences in early 2018 and then publish the results in scientific
journals.
Ionis will
transfer administration of the next clinical trial phases to Roche, a
key partner in the project since 2013. Roche now holds the license to IONIS-HTTRx,
will lead further development, and handle all potential sales. Phase 1/2a took
place in Canada, England, and Germany, but the next phase will have sites in
the U.S. and other countries, to be determined next year by Roche. Ionis will
continue to play an advisory role in the project.
“We are very
appreciative of the community, and the patience that the community has
exhibited,” Dr. Bennett said. “We understand how important this is for the HD
community. We’re very pleased it’s going forward. The community has been very
respectful towards the company and has allowed us to conduct this study in a
way that was very robust.”
Drs. Bennett and
Smith focused on how the trial revealed a reduction in the mutant huntingtin
protein that “substantially exceeded our expectations,” according to the
December 11 press release. The key, initial piece of trial data came from the
measurement of the protein in the HD patients’ cerebrospinal fluid (CSF). Other
trial data such as brain scans and blood samples will become available later.
IONIS-HTTRx
and other Ionis drugs are antisense oligonucleotides (ASOs, artificial strands
of DNA), which alter the expression of genes. In August 2016, Ionis and its
partner Biogen actually halted a Phase 3 trial of an Ionis ASO in infants with
spinal muscular atrophy (a motor neuron disease) because the drug was extending
their lives. The FDA (Food and Drug Administration) approved the drug, with the
commercial name SPINRAZA, in December 2016.
In October, Ionis
and Biogen won a biotechnology prize for SPINRAZA (click here to read more). Ionis is also collaborating with Biogen to develop a drug for
amyotrophic lateral sclerosis (Lou Gehrig’s disease).
Dr. Frank Bennett (left) with Gene Veritas (aka Kenneth P. Serbin) and Dr. Anne Smith (photo by Kristina Bowyer, Ionis)
Following are
key excerpts from the interview.
Compelling changes in mutant huntingtin
levels
GV: How did patients react to the
intrathecal administration of the drug, that is, via a spinal tap?
AS: We didn’t
hear from any of the physicians that there were any difficulties. There was
probably some nervousness, but there were few side effects, and that ones they
had were manageable. I think it’s telling that all 46 patients completed the
trial.
GV: What was observed in the HD patients
in this trial?
AS: We’re still
in the process of getting these next waves of data in. That will come out over
months. It’s important to recognize that the trial just ended in November. But
at this stage we did see a promising safety profile, meaning that we didn’t
have any clinical concerns with the drug.
We saw clear,
compelling changes in mutant huntingtin levels in the CSF. It was sort of gravy
in this study. It’s designed as a safety study. We didn’t know when we entered
the study whether we’d be able to even measure mutant huntingtin in CSF. But it
is the best evidence of target engagement that we have – meaning that it is
evidence that the drug is doing what it ought to do.
We were pleased
that the assay [lab test] was developed to the point that we could use it to
measure mutant huntingtin. The test is relatively new and fortunately came
online at about the right time that we needed it.
The label from the first vial of the Phase 1/2a clinical trial, administered in London, September 2015 (photo by Gene Veritas)
GV: The reductions of mutant huntingtin
“substantially exceeded” your expectations. To what extent?
FB: When we
began the program with Roche, we picked a target level of reduction of mutant
huntingtin in CSF, and, based upon that, we would decide to go forward with the
program [into the next phase].
We put the
mutant huntingtin data at the top of the list, because it was the data that was
going to drive a business decision from Roche, but also, importantly, it was
the data that would help them design the next study. So we prioritized that as
being the first thing we would look at. It’s the basis for telling us what are the
doses that we should be using for the next study.
GV: So can you specify the amount of
mutant huntingtin reduction?
FB: We’re going
to save that for a medical meeting.
Phase 1/2a too early for improving
symptoms
GV: You project from your pre-clinical animal
studies that the level of reduction in the brain itself should be greater than
what is seen in the CSF, correct?
FB: Yes. An important
nuance for the community is that the level of reduction that we’re seeing in
CSF is not a one-to-one correlation with the level in [brain] tissue, which is
where you want the drug to be working. We haven’t proven it in patients, but
we’re very confident that it will translate [into higher levels of reduction in
the brain].
AS: We’ve tested
this drug in several species and are able to understand that relationship
between what you see in CSF versus what you see in [brain] tissue, which is why
it was really important this assay [CSF measurement] was online. It really is a
window into the brain.
To understand
that relationship in animals, the animals have to be sacrificed, to measure the
level in the [brain] tissue. So we won’t ever ‘prove’ it in humans, so to
speak, but we have a good understanding of it through the animals. And that
it’s consistent from species to species is comforting. We can draw a conclusion
about what’s likely happening in the human.
GV: Many in the HD community want to
know: in this trial, did you see any signs of disease modification? Were there
any hints at all from the doctors or from the data?
AS: We get
anecdotal reports from physicians, but this is a population with a high placebo
effect. These are motivated and excited physicians and patients as well. So I
wouldn’t read anything into that. It’ll be several months before we have an
understanding, though I would really caution any expectations along those
fronts, because this is a short-term study.
We’re not
expecting to see any sort of disease modification, just because of the way the
study was designed. We dosed for three months, but it wasn’t even full drug
effect for three months, because you build up the effect. This is the precursor
to what would be long-term dosing.
GV: Have you observed whether there was
also a reduction in the wild type (normal) huntingtin protein that all HD
patients also have?
FB: There isn’t
a good assay [lab test] for measuring wild type at this point. We have the
samples, and once the assay is robust enough, we’ll look at it. The team is
working on it, as well as others.
GV: Were there any surprises in the data
that you’ve seen so far?
FB: It’s only
surprising that it’s worked as we predicted it would [laughter]. Oftentimes
when you go from pre-clinical to clinical, things don’t quite work out as well.
But the drug is doing what it should be doing, which is lowering mutant
huntingtin in cerebrospinal fluid. I think it’s all very positive from that
perspective.
Phase 2 versus Phase 3
GV: What have you learned that will be
helpful in planning phase 2?
FB: We asked a
lot of the sites and the patients – because we collected a tremendous amount of
data from them – for data that will be useful in designing a Phase 3 trial. We
wanted to figure out which of the clinical outcome measures, which of the
imaging measures, is actually reproducible, robust, and sensitive, to make sure
it’s not “noisy” data.
AS: Another
important learning will be whether there are differences from site to site. In
a multi-site, multi-country trial, if a particular test just doesn’t translate
well to German, for example, then we’ll have learned that. We can spare Roche
from collecting data that are difficult to interpret, because they’re difficult
to operationalize across sites and countries.
GV: You said “Phase 3” and not Phase 2.
Why?
FB: Yes. At this
point, Roche has not made a final decision on the next step. One of the options
being considered is going right to a Phase 3 study. There’s a trade-off. You can
do a smaller Phase 2 study – get more data that make it more probable that
you’ll be successful for the Phase 3 – or you can go directly to a Phase 3
study. Those are the decisions that Roche is looking at right now very
carefully.
The plus side
is: if they go right to Phase 3, it would accelerate getting the drug to
market. When we’ve reviewed with them the size of the study and the time of the
study, there’s not a big difference between doing a Phase 3 and doing a more
traditional Phase 2 first. It’s more expensive to go right to Phase 3, but it
would save a lot of time.
GV: For an entity such as the FDA, is it
okay to go from a Phase 1/2a to a Phase 3?
FB: The FDA will
pay a lot of attention to the safety of the drug which – so far, knock on wood
– looks very good. And then they leave it to the sponsor whether they want to
risk the program. They may advise – because they ultimately want the drug to be
successful, too – that this isn’t the best thing to do, but ultimately that’s
the drug company’s decision. Roche will engage with the FDA.
GV: What is leading Roche to think it
could maybe go directly to a Phase 3?
FB: It’s safety
and tolerability [shown in Phase 1/2a], and the fact that we now know what dose
of the drug produces this level of huntingtin lowering. Without that, they
wouldn’t be able to go to Phase 3, but with that data, you could say that “this
dose” should then produce “this level” of huntingtin lowering.
GV: Going straight to Phase 3, how much
shorter would the whole program be?
AS: It’s
definitely in the years.
FB: Yes, because
if they were to do a Phase 2 study first, it would probably take three years to
enroll and run. Roche wants to get this drug to patients as quickly as
possible, assuming it works. They understand the disease. They understand the
need for the patients.
GV: Whether Phase 2 or 3, when would the
next study begin?
FB: I would
anticipate towards the end of next year.
An important milestone
GV: What is the historical significance
of the Ionis breakthrough?
FB: It’s an
important milestone for the Huntington’s community. The mutation in the
huntingtin gene was described in 1993. This is the first drug to go into
clinical trials that is directly on target. It addresses the cause of the
disease. We’re extremely excited that we’re actually seeing this basic science
and all the work that NIH and other agencies have funded over the last 25 years
now being translated into something that could actually have an impact for
Huntington’s patients.
This bodes well
for other neurological diseases. It has potential to markedly change how we
treat those diseases. Perhaps this technology platform [the Ionis
gene-silencing approach] would be beneficial for them as well. For patients out
there overall, this is extremely important.
(For additional information about next
steps in the IONIS-HTTRx program, click here for a Q & A with Dr. Ed Wild, an advisor and investigator of the program. You
can also read a FAQS from the Huntington's Disease Society of America by clicking here.)
(Disclosure: I hold a symbolic amount of
Ionis shares.)
(In the video below, watch my report on
the December 11 Ionis announcement.)
