A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTINATIONAL, MULTICENTER STUDY WITH OPEN-LABEL TREATMENT EXTENSION TO ASSESS THE EFFECT OF MIN-102 ON THE PROGRESSION OF ADRENOMYELONEUROPATHY IN MALE PATIENTS WITH X-LINKED ADRENOLEUKODYSTROPHY

The two main clinical phenotypes of Adrenoleukodystrophy (ALD) are the
predominantly neurodegenerative adrenomyeloneuropathy (AMN) and inflammatory
cerebral ALD (cALD). There is no authorized treatment for AMN. Hematopoietic
(blood) stem-cell transplantation is used in some patients with cALD but no
therapy is available for AMN patients. Corticosteroids are used to treat the
adrenal insufficiency. Therapies for ALD generally aim to either reduce
hyperlipidemia or lower dietary Very long chain fatty acid (VLCFA) intake;
however this approach fails to achieve a clinically relevant effect in terms of
slowing ALD progression. This apparent disconnect between reduced VLCFA levels
and functional outcome could result from the pathogenic cascade in ALD having
already been triggered by the time of VLCFA increase. This would support the
idea of targeting downstream events in the ALD pathologic cascade to stop
disease progression. As neuroinflammation is a hallmark of cALD, MIN-102 may be
effective at modulating this phenotype.
MIN-102, the M4 metabolite of pioglitazone, is an optimized peroxisome
proliferator-activated receptor γ (PPARγ) agonist for the treatment of
neurodegenerative and neuroinflammatory disorders that is able to achieve
exposure levels sufficient to unfold the full spectrum of beneficial effects at
safe and well tolerated doses. MIN-102 and other PPARγ agonists have
demonstrated to decrease oxidative stress, promote neuronal survival,
regeneration and growth, promote oligodendrocyte differentiation and myelin
synthesis, and decrease inflammation.
MIN-102 has a simpler metabolic profile than pioglitazone with a lower risk for
drug-drug interactions, shows higher blood-brain barrier penetration and was
validated in several non-clinical experiments as a promising candidate to treat
both phenotypes of ALD with a level of PPARγ engagement that cannot be achieved
with pioglitazone

Main Study
Primary efficacy objective: To evaluate the efficacy of MIN-102 on the
progression of
adrenomyeloneuropathy (AMN) in male patients as determined by the change from
baseline in Six-Minute Walk Test (6MWT) compared with placebo after 96 weeks of
treatment.

Secondary efficacy objectives: To evaluate the effects of MIN-102 after 96
weeks of treatment on:
• Change from baseline in body sway amplitude (in four states: eyes closed/feet
apart, eyes open/feet apart, eyes closed/feet together, eyes open/feet together)
• Comprehensive clinical rating scales (Severity Score System for Progressive
Myelopathy [SSPROM] and Expanded Disability Status Scale [EDSS])
• Clinician and patient global impression of symptom severity and change
• Muscle strength
• Quality of life
• Incidence of progression of cerebral lesions.
• Loes severity score

Exploratory objectives- To evaluate the effects of MIN-102 on various
biochemical markers in plasma and cerebrospinal fluid (CSF), and spinal cord
imaging parameters

Safety objectives- To evaluate the safety and tolerability of MIN-102 compared
with placebo.

Extension Study
Primary objective- To assess the safety and tolerability of MIN-102 upon
long-term treatment.

Secondary objectives- To evaluate the long-term effects of MIN-102 on:
• Change from baseline in 6MWT and body sway (in four states: eyes closed/feet
apart, eyes open/feet
apart, eyes closed/feet together, eyes open/feet together)
• clinical rating scales (SSPROM and EDSS)
• Quality of life
• Incidence of progression of cerebral lesions.

Exploratory objectives- To assess the long-term effects of MIN-102 on various
biochemical markers in
plasma.

Main Study
This is a Phase II/III, randomized, double-blind, placebo-controlled,
multicenter, two parallel-group study in male patients with the AMN phenotype
of X-linked adrenoleukodystrophy (X-ALD), to assess the efficacy and safety of
MIN-102 treatment. Study sites will consist of specialist referral centers
experienced in the management of adrenoleukodystrophy (ALD).

Extension Study
This is an open-label treatment extension study starting immediately after the
day of last treatment in the double-blind period at V6, after the patient signs
the extension part ICF. Visit 6 after 96 weeks of double-blind treatment will
simultaneously be the baseline visit of this treatment extension study part.
All patients included in the extension study will receive a MIN-102 dose to
achieve the pre-defined target plasma exposure. Dose adjustments to achieve the
target plasma exposure will be allowed until informed by PK parameters obtained
at week 12 (V8); after this, no further dose adjustments will be allowed.
Patients who, at the end of the previous double-blind part (at V6) are on a
dose of <=10 mL will start Part 2 with the same dose. All other patients will be
reverted to a starting dose of 10 mL.

Main Study:
MIN-102 (study drug): A liquid suspension that will be taken orally, preferably
after breakfast at the same time of the day once-daily at a dose of 150 mg
MIN-102, with the option for dose modification based on plasma exposure data
obtained 4 weeks and 12 weeks after first dose to achieve the target exposure
of 200 µg.hr.mL-1.
Placebo: A liquid suspension with 1 dose per day to be taken orally at the same
time of day, preferably after breakfast.

Extension Study:
MIN-102 (study drug): Starting dose is 10 mL for all patients on a dose of >10
mL at V6. Patients on a dose of <=10 mL at V6 will continue with the same dose,
with the option of dose modification based on plasma exposure data obtained
until Week 12 (V8) to achieve the pre-defined target plasma exposure of 200
µg.hr.mL-1.

Patients are asked to undergo procedures described in the tables on pages 15 -
18 of the study protocol. These
procedures include physical examination, vital signs, ECG, cerebral/spinal
cord MRI, lumbar puncture for CSF, blood draw, 6 minutes walking test,
dynamometry, completing questionnaire and diaries, answer questions of
investigator and study team, administration of study drug.
Additionally, fertile patients who are sexuallyactive must consent to use total
abstinence or an effective form of contraception with their sexual partners
throughout participation in the study. Patients are also asked to inform their
study doctor on their medication usage and change in health status.
MIN-102 is a metabolite of pioglitazone, an approved treatment for type II
diabetes. The safety profile of MIN-102 can be considered to have been
evaluated directly or indirectly during pioglitazone development. It is
expected that the safety profile of MIN-102 is similar to that of pioglitazone.
Known side effects of pioglitazone are fluid retention and weight increase.
There are some suggestions that bladder cancer may be associated with long-term
administration of pioglitazone; however, there were too few events of bladder
cancer to establish causality to pioglitazone. Nonetheless, even if the
potential risk is considered to be very low, patients urine samples during the
study will be carefully investigated for the presence of abnormal cells. One
other clinical study with MIN-102 has been conducted. This was a study in
healthy male volunteers. Only one related adverse event (side effect) of mild
severity, dysphagia (difficulty in swallowing), was reported with MIN-102 at
the 90-mg dose in fasting (non-eating) condition. Four related events of mild
headache and one event each of mild nausea and somnolence occurred at the
270-mg dose level in the fed condition (when MIN-102 was administered after a
meal). All adverse events resolved completely. Patient may also experience
discomfort while performing blood draw (i.e. pain swelling, bruising, risk of
infection, etc.), lumbar puncture (i.e. pain in lower back, temporary pain or
numbness to the legs, etc.), ECG (i.e. adhesive used for the electrodes from
the ECG may irritate patient*s skin) and MRI scans