XanaMIA Phase IIb/III study continues to advance
Actinogen is continuing to advance its ongoing 36-week XanaMIA Phase IIb/III study assessing Xanamem in patients with biomarker-positive AD (as determined through elevated
levels of phosphorylated Tau-181 (p-Tau 181) biomarker at baseline). The primary endpoint is the drug’s effect on AD progression using
the FDA-recognised Clinical Dementia Rating – Sum of Boxes (CDR-SB), a comprehensive
scale of functional capacities. The CDR-SB scale was used as the primary endpoint
to support lecanemab’s FDA approval in AD. We note that XanaMIA’s study design was
supported by a subset analysis reported in Q422 among patients with elevated p-Tau 181 biomarker at baseline from
Actinogen’s XanADu AD study. This showed statistically significant improvements versus placebo on the
CDR-SB scale in this group.
Actinogen made certain study protocol and data management revisions in H2 CY24, which
the company expects will enable the trial to meet the statistical and quality standards
required to achieve ‘pivotal’ status with US regulators (the FDA), thus permitting
the study potentially to serve as one of the two anticipated trials required for marketing
approval in the US (and other regions, such as Europe) for the treatment of AD.
This Phase IIb/III study is designed to enrol c 220 mild-to-moderate AD patients (with
elevated blood levels of pTau-181 at baseline) predominantly across sites in the US
and Australia. Study patients are being randomised to take Xanamem 10mg or placebo
once daily for 36 weeks.
Interim results now expected in Q4 CY25
Actinogen aims to perform an interim study analysis on the first c 100 subjects, whereby
initial efficacy (futility analysis) and safety results will be analysed when patients
reach 24 weeks of treatment. While the company previously expected to report interim
results in Q3 CY25, given the pace of study recruitment to date, in its Quarterly 4C statement (for the period ending 31 December 2024) Actinogen said it now anticipates it will
report these results in Q4 CY25.
The XanaMIA study started enrolment in late CY23 and has since opened 15 clinical trial study sites in Australia and 10 US sites,
with the first US patient having been randomised on 9 December 2024. The company reports
that patient recruitment and randomisation activities have recently accelerated, with
approximately 40 patients randomised and treated in the study and more than 20 in
the intermediate stage of the screening process (to date, more than 300 patients have
been pre-screened for the study). To meet Actinogen’s target of reporting interim
data by Q4 CY25, we estimate the company will need to recruit and initiate treatment
of another c 60 patients (ie on top of the 40 who have been treated to date) by early
to mid-June 2025.
Actinogen reports that it has made good progress and learned valuable insights about
recruitment and trial logistics since starting the study. The company remains actively
involved with the XanaMIA study, with key Actinogen staff, including CMO Dr Dana Hilt,
regularly visiting the clinical trial sites and meeting with study investigators.
We expect that the pace of recruitment should be faster in the coming months now that
more study sites are open, and given that the US study sites have only been active
for XanaMIA since Q3 CY24. We anticipate that the US study sites will have access
to broader pools of patients for recruitment (than the Australian study sites), and
we expect there is a strong likelihood that the majority of the 220 patients for this
study will come from US study sites (we previously assumed a 50:50 split).
Actinogen aims to report full 36-week study data in H2 CY26. We believe this target
is achievable provided the company completes enrolment for the first c 100 patients
by early to mid-June and maintains a steady pace of recruitment (completing total
enrolment close to year-end CY25).
Emestedastat name granted for Xanamem by WHO
The WHO has granted the nonproprietary name ‘emestedastat’ to Actinogen for Xanamem,
in line with the agency’s processes for the selection of International Nonproprietary
Names (INN) for active pharmaceutical ingredients. The INN becomes a unique and globally
recognised name for the active molecule of Xanamem and, importantly, Xanamem becomes
the first recognised molecule with the unique suffix of ‘-stedastat’ relating to its
distinct mechanism of action on inhibition of the 11β-HSD1 enzyme. Xanamem’s intended
mechanism of action is to penetrate the brain and inhibit this enzyme. As discussed
in detail in our Outlook report, the naturally present enzyme 11β-HSD1 normally converts cortisone to cortisol inside
cells, and thus Xanamem is designed to reduce excessive cortisol production in the
brain. Much scientific literature suggests that excessive cortisol is associated with
chronic neurological conditions, including age-related AD.
The granting of the INN for Xanamem reflects the unique mechanism of its 11β-HSD1
inhibition drug class and the company’s intellectual property surrounding this molecule.
In addition to the protection provided by its patent portfolio globally, Actinogen
expects to have a minimum of five years of market exclusivity for Xanamem in the US
and 10 years in Europe following regulatory approval (given the relevant term extension
and data protection provisions in each region), with market exclusivity in these and
other major regions (including Australia) not expected to expire before 2036 (given the relevant composition of matter patents).
Meetings with regulators in Q1 CY25 to inform the development path in MDD
Following the positive signals for Xanamem in treating depression symptoms shown in
the Phase IIa XanaCIDD study in major depressive disorder (MDD), Actinogen plans to meet with the FDA in Q1 CY25
to determine the parameters for future clinical studies in depression that would potentially
fulfil the registration requirements for Xanamem as a potential treatment for this
indication. As a reminder, while this six-week study (n=165) assessing 10mg Xanamem
once daily versus placebo did not meet its primary efficacy endpoint of demonstrating
a cognitive improvement over placebo, the top-line data did show separation in terms of treatment effect in resolving depression symptoms,
including a statistically significant improvement at 10 weeks (four weeks following
the end of the six-week treatment period). In all patients, a trend towards benefit
was seen at the six-week end-of-treatment (EOT) visit in the recognised Montgomery-Åsberg
Depression Rating Scale (MADRS) versus placebo (two-sided p=0.23, not reaching statistical
significance). A meaningful and statistically significant 2.7 point difference in
the MADRS score (two-sided p<0.05) was shown at four weeks after the EOT visit (week
10 of the study). Subsequent data reported in August 2024, which include findings using the Patient Global Impression of Severity score in
depression, confirmed that maximal treatment effects on depression on all endpoints
occurred at week 10. The results appear to be consistent with the molecule having
a durable clinical effect in terms of controlling brain cortisol and potentially exerting
anti-depressant activity.
If improvements in addressing depression symptoms are consistently shown in future
trials, Xanamem has the potential to be differentiated from existing approved drug
treatments for depression due to its unique mechanism of action involving the suppression
of cortisol formation in the brain.
Actinogen expects that, following its meetings with regulators, it will have clarity
on the pathway for future Xanamem Phase IIb and/or pivotal studies in depression.
Nonetheless, based on our discussions with management, the company’s capital allocation
and strategic priority is to fund and complete its XanaMIA Phase IIb/III study in
AD. Actinogen does not intend to independently fund or start future Xanamem studies
in depression prior to the conclusion of the XanaMIA study. We understand that, prior
to the conclusion of XanaMIA (H2 CY26), the company would only start the next Xanamem
depression clinical trial if it obtains specific non-dilutive funding to support this
study, such as from research agencies or grants, or from arrangements and/or licensing
transactions covering Xanamem in the depression indication with interested parties
(eg pharma companies).
Emestedastat 10mg daily dose selection validated in journal article
Actinogen reported in February that a journal article discussing the utility and selection of the 10mg daily dose
level of emestedastat was published in Clinical Pharmacology in Drug Development,
the journal associated with the American College of Clinical Pharmacology. The article summarises how central pharmacodynamics, including PET and computerised cognitive
testing, as applied within multiple clinical trials assessing Xanamem, determined
that daily doses of 10mg, or even 5mg, may be sufficient to adequately inhibit 11β‐HSD1
and exert the desired therapeutic effect of cortisol inhibition. The article reviewed
findings, including cognitive testing results from multiple completed Xanamem trials,
such as the XanaHES (n=42) and XanaMIA-DR studies (n=107) in cognitively normal, older volunteers, and the XanADu study (n=185) in patients with AD.
Taken collectively, the data suggest that once-daily doses of 5–20 mg in cognitively
normal, older volunteers, provided a consistent pattern of pro-cognitive benefit,
without a dose-response, and as seen by an improvement in attention and working memory.
The authors determine that these results, along with PET imaging data from a separate
Phase I study, suggest the target dose range for Xanamem therapeutic is activity is
at or below 10 mg daily and not higher. This data, combined with results showing clinical
activity at 10mg daily dosing from XanaCIDD in MDD, are supportive of the 10mg daily
dose level chosen from the ongoing XanaMIA Phase IIb/III study in patients with biomarker-positive
AD.
Revising potential launch timelines in depression
We have adjusted our base-case scenario to now assume that Actinogen will not start
its next clinical study in MDD until CY27 (ie after the conclusion of XanaMIA). This
pushes back our commercialisation timing assumption for Xanamem in MDD to CY29 (vs
CY28 previously). We maintain our CY29 timeline for potential commercialisation of
Xanamem in AD. While it is possible the company may obtain non-dilutive funding and/or
enter into a licence agreement for Xanamem before the conclusion of XanaMIA (which
would provide the funding needed to start the next MDD study), we believe the more
likely scenario is that Actinogen would only secure a material Xanamem licensing transaction
(covering AD and other indications such as MDD) following the conclusion of the XanaMIA
study (in H2 CY26). We believe it is unlikely the company would even consider a licensing
deal covering the major markets (the US and Europe) prior to the release of interim
data (now expected in Q4 CY25), given that the economic benefits (the potential upfront
and milestone payments and royalty rates) are likely to be much more substantial if
a transaction is realised after the release of positive interim XanaMIA data (assuming
it would be consistent with the treatment effect shown in the XanADu subset analysis).
If XanaMIA Phase IIb/III results are positive, which would be a substantial positive
catalyst that could unlock material value-enhancing partnerships and/or licensing-type
transactions for Actinogen, we would still estimate that an additional 500–1,500 patients
would need to be treated in a Phase III programme to support a US regulatory approval
application.
