TOORAK, Australia, Sept. 2,
2014 /PRNewswire/ -- Antisense Therapeutics Limited ("ANP" or "the
Company") is pleased to report the primary efficacy results from
its Phase II clinical trial of ATL1103 in patients with the
potentially life threatening growth disorder, acromegaly. The Phase
II trial met its primary efficacy endpoint showing a statistically
significant average reduction in the serum insulin-like growth
factor-I (sIGF-I) levels of 26% from baseline (P<0.0001) at week
14 (one week past the last dose) at the 400mg per week dose
tested.
All patients treated with 400mg per week of ATL1103 had a
reduction in sIGF-I levels from baseline at week 14. Greater
reductions in sIGF-I were observed in patients who had lower body
weights and thereby received a relatively higher dose per kg
bodyweight (correlation of P=0.0001) with the patients who
received 5.5 mg/kg per week showing a 36% average reduction in
their sIGF-I levels.
The positive results achieved in this Phase II trial position
ATL1103 to move into Phase III stage of development. Consequently,
ANP will accelerate out-licencing activities to secure a
pharmaceutical development partner for the drug's further
development.
Chief Investigator for the study Dr Peter Trainer, Professor of Endocrinology, The
Christie NHS Foundation Trust, UK, said: "There are limited
therapeutic options for patients with acromegaly and there is an
acknowledged need for new therapies. The results achieved in this
Phase II trial suggest ATL1103 with appropriate dose adjustment
should be capable of achieving disease control in a significant
proportion of patients with acromegaly. ATL1103's profile as a
potentially efficacious and well tolerated conveniently dosed
therapy strongly supports its move into Phase III stage of
development."
Mark Diamond, Managing Director
and CEO of Antisense Therapeutics said: "We are very pleased to
have achieved this significant milestone in the late stage
development of ATL1103. These results greatly enhance our
partnering prospects for the drug and we expect a number of
interested pharmaceutical companies to enter formal due diligence
on ATL1103 in coming months."
Study Design and Detailed Results
The ATL1103 Phase II trial is a randomised, open-label, parallel
group study of the safety, tolerability, pharmacokinetics and
efficacy of two subcutaneous dosing regimens of ATL1103 in 26 adult
acromegaly patients dosed with ATL1103 for 13 weeks (3 months) with
two months of follow up. Two ATL1103 dosing regimens were tested
(a) 200 mg 3 times in the first week then once weekly thereafter
(200 mg/week) or (b) 200 mg 3 times in the first week then twice
weekly thereafter (400 mg/week).
The primary efficacy endpoint of the 26 patient trial was the
reduction of sIGF-I levels in acromegaly patients as they have
significantly higher levels than healthy individuals and sIGF-I
normalisation is accepted by clinical authorities as the
therapeutic goal for the treatment of acromegaly.
In this study, patients on the 400mg per week dose of ATL1103
achieved an average reduction in their sIGF-I levels of 26% from
baseline (P<0.0001) at week 14. In line with this a 30% average
reduction was achieved at week 13 (last week of dosing). All 13
patients treated with the 400mg per week dose had a reduction in
their sIGF-I levels from baseline at week 14. The best reduction
achieved by any patient at any time point was a 64% reduction at
week 13.
Greater reductions in sIGF-I were observed in patients who had
lower body weights and thereby received a relatively higher dose
per kg bodyweight (mg/kg). A statistically significant correlation
(P=0.0001) was observed between the mg/kg dose received and the
level of sIGF-I reduction thereby confirming a dose response
relationship on these parameters with the data showing an average
reduction in sIGF-I of 36% was achieved in the five out of 13
patients who received 5.5 mg/kg per week supporting the
expectation that higher dosing should result in higher sIGF-I
reductions.
The time-course data over the full 13 weeks of dosing at the 400
mg per week dose generally shows a progressive reduction in sIGF-I
over the dosing period and maintenance of the effect well past the
last dose. This suggests that continued dosing of ATL1103 for
longer than 13 weeks in a Phase III study could result in
additional reductions in sIGF-I.
At the 200 mg per week dose, no reduction in average sIGF-I
levels was observed at week 14, although there were sIGF-I
reductions noted in individual patients (four out of 13 patients
had sIGF-I reductions > 20%). Best achieved at the 200mg dose by
any patient at any time point was a 46% reduction at week 13. The
lower 200mg dose may nonetheless be therapeutically effective for
some patients, particularly with the view to a longer dosing
period.
Patients in this study had average baseline levels of IGF-I that
were 2.6 times the upper limit of normal (ULN) which appear
high compared to other acromegaly studies. sIGF-I levels were
normalised (brought below ULN) at any point in the study in two of
13 patients dosed at 400mg per week and in one out of 13 on the
200mg per week dose. Four patients at the 400mg per week dose had
reductions of their sIGF-I to below the minimum entry criterion of
1.3 times the ULN suggesting therapeutic benefit in these patients.
Reduction of sIGF-I to within the normal range in a significant
proportion of patients is the goal in longer term (6-12 month)
Phase III registration trials for acromegaly treatments.
The monitoring of patients post dosing in the trial continues
with the last patient visit scheduled for the end of September.
Data base lock is expected in October with final assessment of the
safety data to occur in November
2014. The safety review undertaken to date confirms that
there were no patient withdrawals or reports of any serious adverse
events related to dosing with ATL1103 and that ATL1103 has been
assessed as generally well tolerated. The most common adverse event
was injection site reactions which were predominantly mild and
typically resolved within days. There have been "no flu-like"
symptoms, no abnormalities in renal function, and no clinically
meaningful changes in other laboratory values reported as adverse
events. Liver enzyme elevations were noted as adverse events in two
patients but are not being regarded as clinically meaningful in
these instances. The positive safety profile demonstrated to date
suggests the drug may be tolerated at higher dose levels than 400
mg per week.
For a detailed summary of the ATL1103 Phase II clinical trial
results, please visit
antisense.com.au/investor-relations/asx-announcements
Preparation for Phase III Development
As previously reported, The Company plans to conduct a small
study at a higher dose than 400 mg per week for potential use in a
Phase III clinical trial.
Preparatory work for a Phase III clinical trial of 6 -12 months
of treatment includes manufacture and formulation of drug product
and further animal toxicology studies which ANP plans to undertake
with a future development partner.
The outcomes from the Phase II study are to be presented at the
7th International Congress of the GRS and IGF-I Society
in Singapore, 15 – 18 October 2014 by the Chief Investigator for the
study, Professor Trainer.
Contact Information:
Website: www.antisense.com.au
Managing Director: Mark Diamond +61
(0)3 9827 8999
USA Investor/Media: Joshua Drumm +(1) 212 375 2664;
jdrumm@tiberend.com
Australian Investor/Media: Annabel Murphy+61 (0)2 9237 2800;
amurphy@buchanwe.com.au
ATL1103 Phase II trial is a randomised, open-label,
parallel group study of the safety, tolerability, pharmacokinetics
and efficacy of two subcutaneous dosing regimens of ATL1103 in 26
adult patients with acromegaly dosed with ATL1103 for 13 weeks (3
months) with two months of follow up. Two ATL1103 dosing regimens
were tested (a) 200 mg 3 times in the first week then once weekly
thereafter (200 mg/week) or (b) 200 mg 3 times in the first week
then twice weekly thereafter (400 mg/week). The primary endpoints
or main purposes of the trial as listed on the trial protocol are
(i) to evaluate the safety and tolerability of ATL1103 in patients
with acromegaly, and (ii) to evaluate the single dose and multiple
dose pharmacokinetic profiles of ATL1103 via the subcutaneous route
in patients with acromegaly. Another important endpoint that is
also on the trial protocol is the evaluation of ATL1103's effect on
serum insulin like growth factor I (IGF-I) levels in patients. This
efficacy endpoint is the average percentage reduction in serum
IGF-I levels at one week past the end of treatment compared to
baseline levels for each of the two dosing regimens used in the
Phase II study.
ATL1103 is a second generation antisense drug designed to
block growth hormone receptor (GHr) expression thereby reducing
levels of the hormone insulin-like growth factor-I (IGF-I) in the
blood and is a potential treatment for diseases associated with
excessive growth hormone and IGF-I action. These diseases include
acromegaly, an abnormal growth disorder of organs, face, hands and
feet, diabetic retinopathy, a common disease of the eye and a major
cause of blindness, diabetic nephropathy, a common disease of the
kidney and major cause of kidney failure, and some forms of cancer.
Acromegalic patients are known to have significantly higher blood
IGF-I levels than healthy individuals. Reduction of these levels to
normal is accepted by clinical authorities as the primary marker of
an effective drug treatment for the disease. GHr is a clinically
validated target in the treatment of acromegaly. In the case of
diabetic retinopathy, published clinical studies have shown that
treatments producing a reduction in IGF-I levels retarded the
progression of the disease and improve vision in patients.
Scientific papers have been published on the suppression of blood
IGF-I levels in mice (Tachas et al., 2006, J Endocrinol 189,
147-54) and inhibition of retinopathy in a mouse retinopathy model
(Wilkinson-Berka et al., 2007, Molecular Vision 13, 1529- 38;)
using an antisense drug to the GHr. ANP have also reported that
ATL1103 suppressed circulating levels of IGF-I in primates. In a
Phase I study in normal volunteers, ATL1103 was assessed as being
safe and well tolerated, while also demonstrating a preliminary
indication of drug activity including suppression of IGF-I and the
target GHR (growth hormone binding protein) levels. ATL1103
commercialisation is covered by patents to at least 2024, with the
potential for extensions up to 2029 in some countries and 2030 in
the US.
Acromegaly is a serious chronic life threatening disease
triggered by excess secretion of growth hormone (GH) by benign
pituitary tumours. Oversupply of GH over stimulates liver, fat and
kidney cells, through their GH receptors, to produce excess levels
of (IGF-I) in the blood manifesting in abnormal growth of the face,
hands and feet, and enlargement of body organs including liver,
kidney and heart. The primary treatments for acromegaly are to
surgically remove the pituitary gland and/or drug therapy to
normalize GH and serum IGF-I levels. In North America and Europe there are approximately 85,000
acromegaly patients with about half requiring drug therapy. Cost of
drug therapy ranges from approximatelyA$30,000/annum to over
A$60,000/annum depending on the
treatment.
Antisense Therapeutics Limited (ASX: ANP) is an
Australian publicly listed biopharmaceutical drug discovery and
development company. Its mission is to create, develop and
commercialise second generation antisense pharmaceuticals for large
unmet markets. ANP has 4 products in its development pipeline that
it has in-licensed from Isis Pharmaceuticals Inc. (NASDAQ:ISIS),
world leaders in antisense drug development and commercialisation -
ATL1102 (injection) which has successfully completed a Phase II
efficacy and safety trial, significantly reducing the number of
brain lesions in patients with multiple sclerosis, ATL1103 a
second-generation antisense drug designed to block GHr production
and thereby lower blood IGF-I levels and is in clinical development
as a potential treatment for growth and other GH-IGF-I disorders,
ATL1102 (inhaled) which is at the pre-clinical research stage as a
potential treatment for asthma and ATL1101 a second-generation
antisense drug at the pre-clinical stage being investigated as a
potential treatment for cancer.
SOURCE Antisense Therapeutics Limited
