A multi-centre, open-label, follow-on study to assess long-term safety and tolerability of intracerebroventricular administration of sNN0029 in patients with amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig*s disease,
Maladie de Charcot and motor neuron disease, is one of the most devastating
diseases of the central nervous system (CNS).
Although precise figures are lacking, the general incidence of ALS is
approximately 2 per 100,000 with onset typically between 40 to 70 years of age.
The disease is characterised by progressive muscle weakness, stiffness and
fasciculation (muscle twitching) most commonly affecting muscles of the limbs.
Upon histological examination, the most striking feature is a loss of upper
motor neurons in the cerebral cortex and lower motor neurons in brain stem and
spinal cord. In some cases muscles involved in speech and swallowing are the
ones primarily affected and this variant of the disease is called Progressive
Bulbar Palsy or ALS with *bulbar onset*. More commonly, symptoms first appear
from the limbs (ALS with *limb onset*), which represents approximately 75% of
total ALS cases. Over time, patients with both major forms of ALS lose the
ability to breathe spontaneously and to swallow. The patients become
immobilised and finally completely dependent on assisted ventilation and
feeding. Death is often caused by untreatable infections due to the respiratory
failure and cachexia. The median survival time from onset of symptoms for
bulbar onset cases is 2-3 years and 3-5 years for limb onset cases (see review
Wijesekera and Leigh 2009). The mean survival time after diagnosis is 30 months
(Régal et al. 2006).
For the majority of ALS cases (90%, sporadic ALS), there is no known cause for
the disease, but as for other neurodegenerative diseases, familial forms have
been identified. The most common form of familial ALS (2-5%) is caused by a
mutation in the superoxide dismutase (SOD) gene. Although the mechanism is not
fully understood, this mutation is believed to make the SOD enzyme
dysfunctional and as a consequence the micro environment for motor neurons is
not cleared from e.g. toxic free oxygen radicals. Mice and rats expressing the
human SOD-1 mutation develop ALS like symptoms; muscle weakness and premature
death, paralleled with a progressive loss of motor neurons. The SOD-1 rodent
models are considered state of the art models in ALS research, although there
is a recognised need for additional models with a clearer relevance for
sporadic ALS.
There is currently no effective treatment available for ALS. The only
registered drug with ALS as its therapeutic indication is Rilutek (Riluzole),
which increases survival by an average of approximately 3 months. The effects
appear to be more pronounced in patients presenting the bulbar onset form of
sporadic ALS (Bensimon et al. 1994). The medical need for new therapeutics in
this field is enormous.

The objective of the trial is to assess the long-term safety and tolerability
of intracerebroventricular administration of sNN0029 infusion solution at a
dose of 4 µg/day delivered via a Medtronic SynchroMed® II Infusion System.

Shortly before the end of trial treatment administration in study sNN0029-003
(Visit 9, Day 85), patients will be asked whether they would like to continue
sNN0029 treatment after end of study. Information on the content of the
follow-on study will be given and an informed consent signed for the follow-on
study. Eligible patients will roll over to study sNN0029-004 immediately after
completion of study sNN0029-003, i.e. the last day of the sNN0029-003 study
will constitute the first in the sNN0029-004 study.

The assessments performed at the last visit in study sNN0029-003 will serve as
the baseline values for patients included in study sNN0029-004 and be the start
of sNN0029 treatment for all patients (Study Day 1; Visit 1). Patients who have
received placebo in the previous sNN0029-003 study will start administration of
IMP at a higher flow rate than those who have received active treatment (see
Section 10.4.9). In order not to reveal the blind, an unblinded study nurse
will be specifically assigned to handle pump refill and programming in the
sNN0029-004 study. For the same purpose, all patients, and not only those who
have previously received placebo, will return to hospital on Day 3 and stay to
Day 6 (Visit 2). During these days, the sNN0029 begins to exit the i.c.v.
catheter tip in the ventricle of the brain for patients who have previously
received placebo.
Patients will return to the hospital on Day 11 (Visit 3) for a refill of
sNN0029 and adjustment of the infusion pump flow rate. After this, the patient
will return to the clinic on Day 39 (Visit 4) for a sNN0029-refill and
assessments. Thereafter the patients will visit the hospital on a monthly basis
(every 28 days ± 2) to perform refills and every 3 months for the assessment of
clinical parameters.
Treatment in study sNN0029-004 may continue unless safety concerns warrant
discontinuation of therapy, until patients choose to withdraw from the study,
experience treatment related toxicity or intolerance, are deemed to be
unsuitable to continue treatment by the investigator, or die.

Intercerebrovascular administration of sNN0029 infusion solution at a dose of 4
µg sNN0029 per day delivered via a Medtronic SynchroMed® II Infusion System.

The patient will be hospitalized once during the study for observation of the
first administration of the study drug into the cavity of the brain.
Further, the following items will be performed/requested with the possible side
effects:
- Blood drawing can be unpleasant, painful and might cause bruising, swelling
or inflammation.
- Stickers used to adhere the ECG electrodes may cause sensitive and red skin
after removal.
- There is a possible risk that the intracerebrovascular catheter tip may move
from its intended position within the cavity of the brain. The possible
administration of the study drug in a location other than the ventricle is
considered to be associated with minor risks due to the low dose administered.
Regular MRI scans during the study ensures close monitoring of this.
- A potential risk of infection assocatied with refilling of the infusion
system exists. The risk is minimized by conducting the refill procedure under
aseptic conditions.
- Not all side effects of the study drug may be known at this moment.
- It cannot be excluded that already existing tumors may grow more quickly
because VEFG may stimulate cell division. Patients with history of tumors will
therefore be excluded from the study. MRIs performed regularly during the study
will monitor for any signs of tumor formation.
- The local anesthetics used for lumbar puncture may cause headache of mild
intenstiy, and dizziness, stiff neck or buzzing in the ears can occur.
- Two questionnaires have to be completed (4 times in the first year and then 2
times per year).