atl1103 successfully progresses towards phase

ATL1103 Successfully Progresses Towards Phase II Clinical Trial

? ATL1103 Phase I trial successfully meets primary endpoint – safe and well
tolerated
? Preliminary indication of drug activity shown with reduction of serum IGF-I
and other markers of drug activity
? Next step is a Phase II trial in patients with the growth disorder,
acromegaly
Antisense Therapeutics Limited (ASX:ANP) is pleased to report on the results of the Phase I
trial of the Company’s growth hormone receptor (GHr) targeting drug ATL1103. The primary
objective of the Phase I trial was to assess the safety, tolerability and pharmacokinetics (pK) of
ATL1103. The Company is pleased to advise that the study met its primary endpoint and that
ATL1103 was assessed as being safe and well tolerated at the doses employed in the study, with the
pK data as expected being in line with the general clinical experience with 2nd generation antisense
drugs.
The ATL1103 Phase I clinical trial also assessed certain markers of biological activity relevant to
ATL1103’s potential therapeutic action, including the drug’s effect on blood levels of the hormone
insulin-like growth factor 1 (IGF-I). While the Phase I trial was not primarily designed to assess the
efficacy of ATL1103, which will occur in larger and longer term clinical trials in patients, the results
achieved on these parameters in this trial in normal subjects indicate that ATL1103 demonstrated the
relevant pharmacological activity to support its further development as a potential treatment for
acromegaly and other growth hormone and IGF-I related disorders which include diabetic eye and
kidney complications and certain forms of cancer. As a consequence of these results, the Company is
now in planning for a Phase II clinical trial of ATL1103, initially in patients with acromegaly.
Principal Investigator for the ATL1103 Phase I trial, Professor Albert G Frauman, MD FRACP FACP
FACCP, Professor of Clinical Pharmacology & Therapeutics The University of Melbourne and Director,
Clinical Pharmacology & Therapeutics Co-Director Victorian Toxicology Service said “The safety and
tolerability profile of ATL1103 established in this clinical trial, along with preliminary indications of the
drug’s relevant pharmacological activity, are encouraging and support the ongoing development of
ATL1103 for a patient group such as those with acromegaly who would benefit from a new treatment
option.”
“There is a significant need for safer and more effective treatments for growth disorders, like
acromegaly. We are pleased with the Phase I clinical data generated on ATL1103 and are excited by
the drug’s longer term prospects and actively support its continued development,” commented
C. Frank Bennett, Ph.D., Senior Vice President, Research at Isis Pharmaceuticals Inc, ANP’s
technology partner and world leading antisense company.
The ATL1103 Phase I trial was a randomized, placebo controlled, double blind study of single
ascending doses and multiple doses of ATL1103 in healthy adult male subjects aged between 18 and
45 years. In the single ascending dose stage of the trial, 24 subjects were administered four dose
levels of ATL1103 as a single injection starting at 25mg and escalating to 75, 250 and 400mg or
placebo. The multiple dose stage was undertaken in 12 subjects, 8 who were to receive six ubcutaneous doses of 250mg of ATL1103 and 4 subjects who received placebo administered on
Days 1, 3, 5, 7, 14 and 21. Subjects were monitored out to Day 35.
Importantly, no serious adverse events were reported in this trial. Two subjects in the multiple dose
arm withdrew from the study for reasons not related to safety. All adverse events were reported as
“mild to moderate”. Injection site reactions represented the majority of all the adverse events
reported in the trial. There was one elevation in the liver enzyme ALT reported as an adverse event
in the multiple dose stage. Importantly, the ALT levels in this subject returned to normal during the
dosing phase, suggesting no residual or cumulative effect of the drug on this safety parameter.
A secondary objective of this study was to obtain data on the pharmacodynamic effects of ATL1103
on the IGF-I levels in the blood of the trial subjects. Reduction of elevated levels of serum IGF-I to
normal is the therapeutic endpoint in the treatment of the growth disorder acromegaly, and reducing
the effects of IGF-I has a potential role in the treatment of diabetic retinopathy, nephropathy and
certain forms of cancer.
As defined in the statistical analysis plan, the effect of ATL1103 on serum IGF-I was assessed as a
change in IGF-I levels versus baseline (starting point) readings for those subjects who received
treatment (ATL1103). Pre-dose baseline levels of IGF-I were recorded prior to the commencement of
dosing and then measured at weekly intervals until the end of the monitoring period. This treated
group showed a trend in reduction in IGF-I levels from Day 14 to Day 28, with a significant effect
(p=.034 one sided t-test) at Day 21 with a 7% reduction in mean IGF-I levels versus baseline.
Other exploratory objectives of the study investigated the drug’s mechanism of action and broader
pharmacological profile, including the pharmacodynamic effects on levels of growth hormone binding
protein (GHBP), insulin-like growth factor binding protein 3 (IGFBP-3), acid labile subunit of the
insulin-like growth factor binding protein complex (ALS), and growth hormone (GH), as well as in
vitro mitogenic and apoptotic parameters.
Notably, ATL1103 had a significant effect on reducing GHBP by 16% (p=0.007) at Day 21. As
circulating GHBP is produced by cleavage from the GHr receptor, the reduction of circulating GHBP
levels suggests that GHr expression is being reduced. This provides strong support for the drug
working via its intended, and unique, antisense mechanism of action. ATL1103 also significantly
reduced IGFBP-3 and ALS, both consistent with its effect on IGF-I and the fact that they are
regulated by GH. As expected, there was no effect on GH levels. Please refer to Appendix 1 for more
specific detail on the trial details and outcomes.
The mitogenic and apoptotic parameters, results of which are yet to be received, are part of the
ATL1103 cancer experimental program established with Dr Pinchas Cohen MD to look at ATL1103’s
effect on exploratory markers of cellular activity relevant to cancer in the serum of the subjects from
the multiple dose stage of the Phase I trial of ATL1103.
Next Steps for ATL1103
Based on the safety outcomes and the encouraging preliminary activity data reported from this
clinical trial, the Company is now planning to undertake a Phase II clinical trial, initially in
acromegalic patients. ANP expects the Phase I trial data to support the dosing of patients at the
doses already tested in the Phase I trial and possibly higher over a longer period (3 months), and
that this may result in a more pronounced effect on serum IGF-I that would be therapeutically
relevant to the treatment of acromegaly (i.e. a reduction of 25% or greater in the longer term Phase
II clinical trials being planned). The optimisation of dosage and the drug administration protocol
aimed at achieving this level of effect will be part of the planning for the Phase II trial.
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ANP also advises that subsequent to the Company’s trading halt, a Pharmaceutical Company that has
previously expressed an interest in ATL103 has indicated to ANP its desire to move into licensing due
diligence. While ANP is entertaining this interest from the Pharmaceutical Company, it has not
committed to partnering ATL1103 at this stage of the drug’s development and will continue its
planning to progress ATL1103’s development towards a Phase II clinical trial.
In concluding, the CEO and Managing Director of Antisense Therapeutics, Mark Diamond said “We
are very pleased to have successfully completed this Phase I clinical trial of ATL1103 on budget and
ahead of schedule. We are eager to move forward with the development of ATL1103 which we
believe has the potential to deliver much needed medical benefit to those people who suffer from
acromegaly and disorders where reducing the effects of IGF-I may lead to an effective treatment.”
Background Information
ATL1103 is a second generation antisense