Other notable FY25 highlights include the completion of the XanaCIDD Phase IIa study in MDD and the company holding a Type C meeting with the US FDA to clarify the steps needed and study endpoints required for future
MDD studies in order to seek marketing approval in depression.
The company reported that it had reached a common understanding with the FDA in terms
of what additional clinical trials, clinical pharmacology and non-clinical study data
are required to potentially file for marketing approval for Xanamem in MDD. The company
plans to use the agreements reached with the FDA in discussions with potential partners
and granting agencies.
We expect the company to focus its R&D efforts on the development of Xanamem for AD,
as it does not intend to independently fund or start future Xanamem studies in depression
(prior to the conclusion of the XanaMIA study), although it continues to explore grants
or other non-dilutive forms of capital to help fund the next depression study.
FDA Type C meeting on AD programme confirms the way forward
Actinogen in September reported that, following a successful Type C meeting with the Neurology-I division of the
FDA, it reached agreement from the agency on the pathway towards a potential future
regulatory approval for Xanamem in AD. Specifically, the FDA agreed that if XanaMIA
results are positive, only one additional pivotal study and a limited number of ancillary
clinical pharmacology studies and non-clinical trials will be required. Importantly,
the Type C meeting confirmed that the XanaMIA study would therefore qualify as one
of the two pivotal trials required for marketing approval in AD. The additional pivotal
trial will, like XanaMIA, be a well-controlled two-arm study assessing 10mg Xanamem
versus placebo. The non-clinical studies requested by the FDA are intended to further
assess the metabolism and excretion pathways of the drug. Actinogen also received
clarification and a common understanding on manufacturing considerations (such as
the regulatory starting materials in drug substance synthesis).
Altogether, the information and agreements received from the FDA provide clarity on
the regulatory steps needed for approval, which could solidify and support the company’s
position as it engages with potential development and marketing partners. Further,
Actinogen expects to engage in a similar regulatory meeting with the European Medicines
Agency (EMA) in CY26, and subsequently with other regulators including the UK’s Medicines
and Healthcare products Regulatory Agency (MHRA).
Next key clinical milestone: Interim (futility) analysis in Q1 CY26
The company is on track to report a pre-planned interim efficacy (futility) analysis
in early Q126, as this assessment will begin once the 100th study participant reaches
24 weeks of treatment. With the enrolment of the 100th patient now complete, the 24-week
visit ‘trigger’ to commence the interim data analysis will occur in late December
2025, with the resulting review from the trial’s independent data monitoring committee
(DMC) expected to occur in January 2026. The XanaMIA interim analysis is a key catalyst
for Actinogen as it will be the first major clinical readout for Xanamem in AD since
the subset analysis from the XanADu study first reported in Q422.
The DMC is expected to review all unblinded interim safety and efficacy data from
all available participant visits (in both the treatment and placebo arms) up until
that point (including many subjects who would have completed the full 36-week treatment
period) and perform the required statistical and data analyses. The DMC will make
a recommendation on whether the study should be permitted to continue as planned,
and without disclosing details of its data review. The DMC will not comment on any
possible positive signals of efficacy, as its pre-specified futility analysis is limited
to determining whether the study should be terminated early in the event either:
- of the identification of major safety concerns (which we believe is highly unlikely
given that more than 400 patients have already treated with the drug across multiple
trials), or
- it is determined that the likelihood of the study meeting the primary efficacy endpoint
is near nil (ie if ‘futility’ criteria are met).
Subsequently, the results of the interim (futility) analysis will be reported by the
company. If, as we anticipate is highly probable (given the positive signals from
the XanADU subset analysis), the interim results surpass the futility thresholds,
investors and market participants may react favourably to this critical test milestone.
Pharmacokinetics data supportive of new tablet formulation
Actinogen recently completed a pharmacokinetics (PK) study that confirmed that the new tablet formulation (also
currently employed in the XanaMIA study) of Xanamem, when taken both with and without
food, demonstrates the expected blood plasma levels of drug exposure or PK, and is
comparable with the PK data from prior human studies of the drug (including the XanADU
study, XanaCIDD, XanaHES and XanaMIA-DR study in healthy subjects). This supports the company’s current plan to use the 10mg
once-daily dose as the targeted therapeutic dose in the AD and MDD indications.
The PK study involving 16 healthy individuals was conducted at the CMAX Clinical Research
centre in Adelaide. The subjects were assessed on two occasions, one week apart. Each
subject received a 10mg tablet of Xanamem, once while fasting and once after a high
fat meal. Blood levels of Xanamem were then measured repeatedly over the subsequent
48 hours.
Key PK results include the median time to maximum blood concentration of four to six
hours (four hours fasted, six hours after a high fat meal), and very similar Xanamem
drug exposures (area under the concentration-time curves) and elimination half-lives
of 15 hours in both the fasted and fed scenarios. The comparability of the drug exposures
for both the fasting and fed arms suggest that in a commercial setting, Xanamem should
provide full flexibility for patient dosing (meaning that the patient would likely
have the option to choose to take the drug either with or without food).
This new tablet formulation is expected to be the dosage form that the company commercialises
and brings to market. Actinogen reported that in FY25 its contract manufacturer, Asymchem,
completed production of a 15kg scale-up batch of drug substance, which will be manufactured
in the US into Xanamem tablets for use in current and future trials. Completion of
the manufacturing batch also indicates that the company is ready or future commercial-scale
production, should Xanamem obtain regulatory approval.
Recap of recent developments in the AD treatment space
One of Xanamem’s commercial advantages, given its convenient once-daily oral-dosing
form and its attractive safety profile to date, is that if approved it can potentially
be used in combination with other AD treatments. That said, its overall commercial
competitiveness will still depend on how its efficacy compares with other AD treatments
that may be on the market. To that end, below we highlight some recent events in the
AD drug treatment space.
The most recent FDA drug approvals in AD have been Biogen/Eisai’s Leqembi (lecanemab)
(in January 2023) and Eli Lilly’s Kisunla (donanemab) (in July 2024); both are anti-amyloid
drugs requiring systemic administration. While initial expectations for such anti-amyloid drugs were in the multibillion dollar range, sales trends since
launch have been more modest but are now growing at a strong clip, with Leqembi reporting
sales of JPY23.1bn (c
US$157m) in Q2 CY25, up 369% y-o-y, including JPY7.7bn in China (much of this was due to a one-time stockpiling
effect due to tariff risks) and JPY9.1bn in the Americas (up 98% y-o-y). Kisunla’s
Q225 sales reached $49m (vs $21m in Q125). Leqembi sales may receive a longer-term boost with
the FDA approving in August 2025 a sub-cutaneous autoinjector form of the drug for maintenance dosing. Currently,
both Leqembi and Kisunla must be administered via repeated intravenous infusion (typically
once every four weeks) at a healthcare facility. This new approval will allow a once-weekly
at-home injection option to patients who have taken Leqembi for 18 months and thereby
potentially eliminates the need for such patients to continue to regularly visit an
infusion centre for treatment.
Roche in July announced an update on its development plans for its proprietary anti-amyloid development bispecific
antibody candidate, trontinemab. Trontinemab is differentiated from existing approved
anti-amyloid drugs in that it is based on Roche's proprietary Brainshuttle technology,
which combines an amyloid beta-binding antibody with a transferring receptor (TfR1)
shuttle module. The TfR1 shuttle molecule is designed to facilitate enhanced access
of the drug past the blood-brain barrier (BBB) to enable high central nervous system
(CNS) drug exposure at relatively low doses, with the aim of delivering effective
and rapid amyloid clearance with potentially a lower risk of Amyloid-related imaging
abnormalities-edema/effusion (ARIA-E). Results from the ongoing Phase Ib/IIa Brainshuttle AD study showed that in the 3.6mg/kg cohort, trontinemab reduced amyloid levels below the
24 centiloid positivity threshold in 91% of participants (n=49/54) after 28 weeks
of treatment, and the company also reported early and significant reductions in fluid
AD biomarkers including total tau and pTau-181. ARIA-E was only observed in <5% of
participants (n=149 across both dose cohorts). Roche plans to start two Phase III
studies (TRONTIER 1 and TRONTIER 2) in H225, which will use Roche’s Elecsys pTau217
companion blood-based biomarker diagnostic test.
One key data point expected in H2 CY25 will be the top-line 104-week data from both
of Novo Nordisk’s ongoing Phase III studies (EVOKE and EVOKE PLUS) assessing oral semaglutide versus placebo in patients with early AD. Each of the
two placebo-controlled studies have enrolled c 1,840 patients (total n=3,680) and will assess the CDR-SB score from baseline to 104 weeks as the
primary endpoint. Novo Nordisk reports that its Phase III programme for semaglutide
was supported by four real-world evidence trials that have suggested materially lower risks or odds of dementia in patients with GLP-1
drug exposure. One of the suggested mechanisms why GLP-1 drugs such as semaglutide
may be protective in AD is that they may improve glucose metabolism in brain cells as well as reduce oxidative stress and inflammation. GLP-1 drugs have
an established record of safety and their oral dosage form, like Xanamem, provides
key differentiation versus the anti-amyloid drugs on the market that require more
invasive intravenous administration (or injection after 18 months in the case of Leqembi).
We also note that Johnson & Johnson (JNJ) continues to advance two Phase II AD programmes,
both with FDA Fast Track Designations, and both targeting the formation of disease-associated tau proteins. JNJ has completed enrolment (n=523) of its Phase IIb Autonomy study assessing posdinemab, its monoclonal antibody candidate directed against tau protein,
in patients with AD, and it expects to report top line primary efficacy data (the
change from baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) Total
Score at Week 104) in H1 CY26. The Phase IIb Retain study is ongoing and assessing JNJ’s anti-Tau active immunotherapy candidate, JNJ-2056
(in-licensed from AC Immune), in up to 500 patients with preclinical (pre-symptomatic)
AD. This immunotherapy candidate is designed to prime the immune system to target
tau protein and patients will receive up to nine injections for the first three years
of the study. A readout for this trial may not occur until after 2030.
A relatively less encouraging development in the AD space is that Alzheon’s Phase
III APOLLOE4 study for oral valiltramiprosate/ALZ-801 in patients with early AD did not meet the primary endpoint.
