- Primary endpoint met with confirmation of drug’s safety and
tolerability
- Strong effects on secondary endpoints on activity markers
and disease progression
- Improvement or stabilisation across different measures of
motor function & strength
- Activity on the targeted CD49d immune cells consistent with
drug’s proposed mechanism of action
- New MRI data suggests stabilisation of percentage of fat in
muscles and preservation of functional muscle mass
- International KOLs are supportive of Phase IIb
plans
- Submission made to European Medicines Agency for Scientific
Advice on Phase IIb design
Antisense Therapeutics (“ANP” or the “Company” ASX:ANP | US
OTC:ATHJY) is pleased to advise that the Phase II clinical trial of
ANP’s immunomodulatory therapy, ATL1102 for Duchenne Muscular
Dystrophy (DMD) has met its primary endpoint confirming the safety
and tolerability of ATL1102 for advancement into a potentially
pivotal Phase IIb clinical trial.
Importantly, the final trial results have also confirmed the
drug’s positive effects on the secondary trial endpoints that
assessed the drug’s activity and efficacy including measuring the
effects on immune cell numbers in the blood and measuring the
participants’ functional capacity as evaluated via Performance of
Upper Limb Test (PUL2.0), grip and pinch strength and distal
mobility (using the MyoSet, MyoGrip, MyoPinch and MoviPlate tools,
respectively).
Additionally, the Company is very pleased to report that MRI
assessment of the upper limb muscles of the patients with DMD has
also shown the drug’s apparent beneficial effects in stabilising
the fat fraction percentage within the muscles of the forearm
(increase in fat levels is another key marker of disease
progression in non-ambulant DMD boys). The data shows a
stabilisation in the percentage of fat in the forearm muscles and
an increase/maintenance of functional muscle mass, which is both
outstanding and unexpected for a drug treating the inflammation
(and not the muscle dystrophin loss).
Results overview
The primary objective of the ATL1102 trial was to assess the
safety and tolerability of 25 mg of ATL1102 administered once
weekly (subcutaneous injection) for 24 weeks in nine non-ambulatory
DMD participants. ATL1102 was assessed to be generally safe and
well tolerated. No Serious Adverse Events were reported with no
safety concerns expressed by the Data Safety Monitoring Board.
There were no participant withdrawals from the study. The most
commonly reported adverse events have related to the subcutaneous
administration of the drug, mainly injection site erythema and skin
discoloration which were generally regarded as mild and either
resolved or were close to resolution at the end of the monitoring
period. Overall, ATL1102 demonstrated an excellent safety profile
in this trial.
Dr Ian Woodcock, Paediatric Neurologist and Honorary Fellow at
The Murdoch Children’s Research Institute, Melbourne and the
Principal Investigator of the ATL1102 Phase II DMD trial said, “the
study met its primary endpoint showing ATL1102 to be safe and well
tolerated with no serious adverse events being reported and no
participant withdrawing from the study. With very few treatment
options for boys with Duchennes who are no longer ambulant, it has
been great to enable the boys to participate in this clinical trial
and I am most encouraged by the outcomes of the study”.
ATL1102 is an inhibitor of CD49d expression on certain immune
cells (e.g. T lymphocytes). It has been reported in research
literature that patients with DMD who have a greater number of CD4+
and CD8+T lymphocytes with high levels of CD49d have more severe
and rapid disease progression. ATL1102 is the only drug in clinical
development for DMD targeting CD49d and one of a very limited
number of treatments being tested in non-ambulant boys with
DMD.
In assessing the effects of ATL1102 on immune cell numbers in
the blood of participants, the immune cell data has shown a
consistency in the mean reductions in the number of lymphocytes
including T-lymphocytes (i.e. CD3+, CD3+CD4+, CD3+CD8+ and
importantly, those expressing CD49d) measured from baseline to week
8, 12 and 24 (end of dosing) with a rebound of these markers to
around starting levels post dosing at week 28. As previously
reported, the mean number of CD3+CD49d+ T cells (i.e. mostly
CD3+CD4+CD49d+ and CD3+CD8+CD49d+cells) at week 24 is statistically
significantly lower vs week 28 (p=0.030 paired T test) suggesting
the drug is working through its targeted mechanism of action. We
further report that the mean number of NK lymphocytes
(CD3-CD16+CD56+) and NK lymphocytes expressing CD49d+ at week 8,12
and 24 is statistically significantly lower vs baseline using a
mixed model for repeated measurements (p=0.018), with comparable NK
lymphocyte numbers at week 28. This data demonstrates the drug’s
positive effects on modulating CD49d+ lymphocytes in the blood
during treatment.
As reported in December 2019, the PUL2.0 data showed that 7 of
the 9 participants demonstrated either increases or no change in
their PUL2.0 scores from baseline over 6 months, with a positive
mean change of 0.9 (95% CI: -1.33, 3.11) in this key parameter
indicative of disease stabilization. This contrasts to the losses
in PUL2.0 reported in the published literature in longer term (1
year plus) studies (Pane et al 2018). Similarly, MyoGrip and
MyoPinch assessments using the Myoset system showed a significant
improvement in muscle strength compared to the loss of muscle
strength reported in the Ricotti et. al. 2016 publication in a
similar non-ambulant patient population on corticosteroids assessed
over 6 months. MoviPlate data (an assessment of muscle function),
has also demonstrated improvements in a majority of the
participants with a mean increase from baseline to 6 months of 1.9
points (95% CI: -6.08, 9.85).
Dr Jean-Yves Hogrel, PhD, Director of the Neuromuscular
Physiology and Evaluation Laboratory, Institute of Myology, France,
a developer of the MyoSet assessment tools stated that “First, I
would like to highlight the quality of the data that proves the
expertise and dedication of evaluators in following standardised
operating procedures. The intra-individual variability is very
moderate and reflects this measurement quality. My observations
based on the MyoSet data from the study suggest that the patients
were generally stable.”
Overall, the study has shown that ATL1102 treatment results in
consistent improvements or stabilisation across the different
measures of motor function and strength.
In a post hoc analysis of the data, there appears to be a
correlation between the individual patient PUL2.0 scores at the end
of dosing (week 24) and their week 24 vs week 28 CD4+CD49d+ T cell
changes. Of the eight participants with normal starting levels of
lymphocytes, six demonstrated either an improvement or maintenance
in their PUL2.0 scores and had a ‘rebound’ in the CD4+CD49d+ T
cells at week 28, while two of the eight participants who had a
loss of PUL2.0 at week 24 did not see a rebound in these cells at
week 28 vs week 24. This data suggests that the drug is working
through a targeted CD49d mechanism of action with down-modulation
of CD4+CD49d+ T cells during treatment providing clinical benefit,
with the two patients not responding at 24 weeks, potentially
requiring longer and/or higher dosing to see similar effects. While
this correlation was only observed with the PUL2.0 disease
progression parameter (the expected primary efficacy endpoint for
future trials), it is the Company’s view that as PUL2.0 assesses
the performance of a large group of muscles of the upper body
(unlike Myoset which specifically assesses grip and pinch strength
and distal mobility) it is appropriate to draw out this correlation
as it may be a helpful future prognosticator of response to
therapy.
Importantly the MRI data assessing the fat fraction percentage
of the muscles of the dominant forearm of the participants has
delivered a further most positive finding with the data showing a
slight mean reduction in these levels compared to the significant
increases in fat fraction reported in the Ricotti 2016 publication
with the comparison showing to be statistically different on some
of the MRI parameters. The change in percentage fat fraction from
baseline to 24 weeks was (mean (SD); Median) -0.5 (6.6); 1.4 for
the central reading and corroborated by the proximal and distal
readings (-2.1 (7.1); -0.4 and -5.1 (14.6); 2.0, respectively).
Furthermore, the lean muscle area (i.e. non-fat) showed a change
from baseline to 24 weeks (Mean (SD); Median) of 13.9 mm2 (SD:
112.5); 5.8 mm2, indicating a maintenance of and possible increase
in functional muscle mass. This is a somewhat unexpected but highly
encouraging observation for a drug treating the inflammation and
not the muscle dystrophin loss (the exon skipping drug’s
target).
Dr Valeria Ricotti MD, Researcher and Honorary Clinical
Lecturer, Great Ormond Street Institute of Child Health University
College London, UK, stated that “Based on the MRI data from the
study, the observed stabilisation in the percentage fat fraction
with ATL1102 treatment would not be expected in the natural course
of disease in DMD even under corticosteroid treatment. Furthermore,
the stabilisation of fat fraction percentage combined with the
observed maintenance/increase of remaining muscle area is
suggestive that ATL1102’s effect could preserve the contractile
muscle mass.”
Further data analyses performed by Dr Jean-Yves Hogrel looking
at the correlation between MRI results for remaining muscle area
(removing the fat fraction) with the results of the MyoGrip
assessments for the individual participants has shown a highly
significant positive correlation between these measures.
Dr Hogrel stated that “this positive correlation of remaining
muscle area (the lean muscle), with grip strength suggests a
consistency of the results across the different parameters of
muscle structure and muscle force.”
Quality of Life (PedsQL) questionnaires were completed by
parents of the younger boys in the study and by two of the teenage
boys. Both the teens that completed the questionnaire showed a mean
improvement in all the domains; problems of daily activities,
treatment management, problems with communication and worry. The
results for the younger patients where the parents completed the
questionnaire also showed improvements in daily activities and
treatment domains but increased problems with communication and
worry domains.
Respiratory parameters (FVC and PEF) were also measured. As
noted in the December 2019 announcement in our experts' view the
variability in this data makes it difficult to draw any meaningful
conclusions on this parameter, which is best assessed in larger
studies of 12 months and longer. Nevertheless, with the PEF
assessment a slight mean increase in percentage predicted PEF was
observed which is consistent with the data observed for the other
parameters.
Professor Thomas Voit MD, Director, NIHR GOSH Biomedical
Research Centre, UK had this to say about the trial results and the
efficacy being observed in this Phase II trial of ATL1102: “The
data certainly suggests an overall ‘stabilisation’ in disease
progression at the very least which of itself is a very positive
clinical outcome. MRI data confirms the positive changes at a
muscular/cellular level and supports the observed physical
stabilisation/improvements in muscle strength and function. The
consistency of positive clinically relevant effects of ATL1102
treatment across muscle measures of structure, strength and
function are very pleasing and provide great encouragement for the
treatment of non-ambulant patients with DMD”.
The results are highly supportive of the Company’s plans for a
Phase IIb clinical trial of ATL1102 in DMD. Scientific Advice
meetings held with three European regulatory authorities affirmed
the agencies’ general acceptance of the proposed trial efficacy
endpoints (PUL2.0, MyoSet), safety monitoring plan, dosing duration
(12 months) and the use of higher doses. The Company has made a
submission to the European Medicines Agency for Scientific Advice
with the results of their evaluation due mid-year, which will then
direct the Company on its preparation and submission of its
clinical trial application.
Our international Key Opinion Leaders and advisors are
encouraged by the results of functional endpoints (physical
parameters) that demonstrate strong initial efficacy. Measurements
of a number of functional parameters indicate that a majority of
the boys experienced either improvement or no deterioration in
several upper body measurements. These results compare favourably
with data reported in a variety of historical studies of
progressive and continuous deterioration in physical function in
non-ambulant patients with DMD over time.
Dr Gil Price M.D., ANP’s Consultant Medical Director, said: “In
a small study with nine boys of only six months duration at a
single low dose we not only achieved our primary endpoint of safety
we also i) achieved significance in demonstrating an effect on our
secondary endpoint relating to modulation of CD49d; ii) achieved
positive outcomes in the important upper body function parameter of
the PUL 2.0 test, and finally iii) achieved fat fraction percentage
reduction in important upper body muscles. That each of these three
effects were observed in an initial study in DMD boys at the lowest
dose where we might have anticipated a biological effect is truly
surprising and highly encouraging”.
Next steps
The Company is extremely delighted by the trial results and our
international experts’ support which provides encouragement to move
ATL1102 into a Phase IIb trial.
European Medicines Agency Scientific Advice due mid-year is the
next milestone in preparation for submission of clinical trial
application for a Phase IIb trial in Europe and UK. The Company is
also in the process of preparing submissions for Orphan Drug
Designation for ATL1102’s use in DMD in the US and the EU.
As ANP continues to prepare for a Phase IIb, the Company will
look to gain a deeper understanding of the drug's effects. This
activity is likely to include further laboratory analysis of
retained serum to attempt to tease out more insight on broader
inflammatory processes and a deeper analysis of our data against
the natural history of the disease with key experts.
In parallel, encouraged by observations of the anti-inflammatory
actions of ATL1102, ANP is now also investigating other potential
diseases including those that are inadequately controlled with
corticosteroids such as other muscular dystrophies and neurological
conditions. As previously advised, the Company is working on
selecting and prioritising new indications where it is best
positioned to leverage its expertise, intellectual property and
relationships with clinical experts involved in treatment of those
diseases.
Mark Diamond, CEO of Antisense Therapeutics said: “Our focus is
to continue planning and to methodically and efficiently move our
DMD program through Phase IIb in Europe. There is great interest in
the DMD space. As we gain further certainty from the regulatory
process on the parameters of the next trial, which may lead to
early market approval, we will assess funding and trial management
options and also engage in discussions with interested potential
partners ahead of commencement of Phase IIb. This will allow the
Company to consider the most advantageous way to proceed with the
pivotal trial on its own or with a partner. Potential partners’
input into the trial program may also be beneficial for future
commercialisation plans. The Company is now in the process of
confirming the manufacture of additional clinical supplies of
ATL1102 and will provide further updates in due course”.
This announcement has been authorised for release by the
Board.
ATL1102 Phase II DMD results presentation webinar
For the results presentation webinar to be held at 9:00AM (AEST)
on Friday 22 May | UK 12AM | US PDT 4:00PM: EDT 7.00PM (Thursday 21
May) and details of how to register online please follow this
link:
https://us02web.zoom.us/webinar/register/WN_DCVk0mvJQr28qqHviPLG-Q
About Antisense Therapeutics Limited (ASX:ANP | US
OTC:ATHJY) is an Australian publicly listed bio-pharmaceutical
company, developing and commercialising antisense pharmaceuticals
for large unmet markets. The products are in-licensed from Ionis
Pharmaceuticals Inc. (NASDAQ:IONS), world leaders in antisense drug
development and commercialisation. ATL1102 (injection) has
successfully completed a Phase II efficacy and safety trial,
significantly reducing the number of brain lesions in patients with
relapsing-remitting multiple sclerosis (RRMS). ATL1103 drug
designed to block GHr production successfully reduced blood IGF-I
levels in Phase II clinical trials in patients with the growth
disorder acromegaly. The Company is conducting a Phase II clinical
trial of ATL1102 in patients with DMD at the Royal Childrens
Hospital, Melbourne.
About ATL1102 ATL1102 is an antisense inhibitor of CD49d,
a subunit of VLA-4 (Very Late Antigen-4). Antisense inhibition of
VLA-4 expression has demonstrated activity in a number of animal
models of inflammatory disease including asthma and MS with the MS
animal data having been published in a peer reviewed scientific
journal. ATL1102 was shown to be highly effective in reducing MS
lesions in a Phase IIa clinical trial in patients with RR-MS. The
ATL1102 Phase IIa clinical data has been published in the medical
Journal Neurology (Limmroth, V. et al Neurology, 2014;
83(20): 1780-1788).
About ATL1102 DMD Trial The Phase II clinical trial of
ATL1102 in patients with Duchenne Muscular Dystrophy was an open
label six-month dosing trial of ATL1102 administered SC at 25mg per
week in nine non-ambulant patients with DMD aged between 10 and 18
years. The trial was conducted at the neuromuscular centre of the
Royal Children's Hospital (RCH) in Melbourne, Australia. The
primary endpoints of the trial related to the safety and
tolerability of ATL1102. The efficacy of ATL1102 was also assessed
in terms of its effects on disease processes and progression (e.g.
the upper limb strength and function of the boys). Given the
exploratory nature of this first trial in boys with DMD, it was not
powered to see a statistical difference on these disease
progression endpoints, which would be expected in future
longer-term clinical studies in a larger number of patients.
However, highly encouraging positive trends across multiple
parameters have been reported in this Phase II clinical trial.
Further details on the trial are available here on the Australia
and New Zealand Clinical Trials Registry.
About DMD Duchenne Muscular Dystrophy (DMD) is an
X-linked disease that affects 1 in 3600 to 6000 live male births
(Bushby et al, 2010). DMD occurs as a result of mutations in the
dystrophin gene which causes a substantial reduction in or absence
of the dystrophin protein. Children with DMD have dystrophin
deficient muscles and are susceptible to contraction induced injury
to muscle that triggers the immune system which exacerbates muscle
damage as summarized in a publication co-authored by the Director
of the FDA CDER (Rosenberg et al, 2015). Ongoing deterioration in
muscle strength affects lower limbs leading to impaired mobility,
and also affects upper limbs, leading to further loss of function
and self-care ability. The need for wheelchair use can occur in
early teenage years for patients on corticosteroids with a mean age
of 13, with respiratory, cardiac, cognitive dysfunction also
emerging. Patients with a greater number of immune T cells
expressing high levels of CD49d have more severe and progressive
disease and are non-ambulant by the age of 10 despite being on
corticosteroid treatment (Pinto Mariz et al, 2015). With no
intervention, the mean age of life is approximately 19 years. The
management of the inflammation associated with DMD is currently
addressed via the use of corticosteroids, however they are
acknowledged as providing insufficient efficacy and are associated
with significant side effects. As a consequence, there is an
acknowledged high need for new therapeutic approaches for the
treatment of inflammation associated with DMD.
Rosenberg AS, Puig M, Nagaraju K, et al. Immune-mediated
pathology in Duchenne muscular dystrophy. Sci Transl Med 2015, 7:
299rv4.
Bushby et al for the DMD Care Consideration Working Group/
Diagnosis and management of Duchenne muscular dystrophy, part 1
Lancet Neurol. 2010 Jan;9(1):77-93 and part 2 Lancet Neurol.
2010 Feb;9(2):177-89 .
Pinto-Mariz F, Carvalho LR, Araújo AQC, et al. CD49d is a
disease progression biomarker and a potential target for
immunotherapy in Duchenne muscular dystrophy. Skeletal Muscle 2015,
5: 45-55.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20200521005411/en/
Antisense Therapeutics Mark Diamond Managing Director +61
(0)3 9827 8999 www.antisense.com.au Investment Enquiries
Gennadi Koutchin XEC Partners gkoutchin@xecpartners.com.au +61 423
500 233 US Enquiries Erin Cox erin.cox@antisense.com.au +1
206 579 3457
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