A randomized, double-masked, placebo-controlled, efficacy and safety study of RV 001, an insulin-like growth factor-1 receptor (IGF-1R) antagonist antibody (fully human), administered every 3 weeks (q3W) by intravenous (iv) infusion in patients suffering from active thyroid eye disease (TED)

Thyroid eye disease (TED) also called Graves' orbitopathy or ophthalmopathy
(GO) and thyroid- associated ophthalmopathy (TAO), is an autoimmune condition
usually associated with Graves' disease (GD). In the US, the annual incidence
rate of TED has been estimated to be 16 cases per 100,000 population for women
and 2.9 cases for men.

Multiple lines of evidence indicate that IGF-1R is a major auto-antigen
responsible for triggering and driving TED. RV 001 is an antagonist mAb with
low nanomolar affinity for human IGF-1R. Binding of RV 001 to IGF-1R blocks
receptor activation by agonists and also causes direct inactivation of the
receptor through antibody-induced internalization. RV 001 has no agonist
activity at IGF-1R and is highly selective; in particular, it does not
recognize the insulin receptor. Systemic administration of RV 001 to patients
with moderate to severe active TED should therefore attenuate all disease
symptoms that are contingent on IGF-1R activation. This argument holds whether
the IGF-1R is being activated by GD-IgG or endogenous ligands IGF-1R and IGF2,
or whether the receptor function with an antibody may also attenuate signaling
through the TSHR, another autoantigen that has been implicated in TED, because
IGF-1R and TSHR are physically and functionally coupled. RV 001 therefore has
the potential to treat TED at multiple different molecular and cellular levels
and administering RV 001 early in the active phase of TED will potentially
minimize the severity and duration of the active phase, have a beneficial
effect on long-term outcome, and minimize the need for corrective surgeries.
Previous preclinical and clinical experience indicates that RV 001 has an
acceptable safety profile following iv infusion and is therefore a suitable
drug candidate to be investigated in the TED indication.

The primary objective is to investigate the efficacy, safety and tolerability
of RV 001 (a fully human anti-IGF-1R antibody) administered q3W for 6 months,
in comparison to placebo, in the treatment of patients suffering from active
TED.

Secondary objectives:
- to assess clinical measures of severity
- to assess the effect of treatment on quality of life (QOL)

Exploratory objectives:
- to explore the effects of RV 001 over time on candidate plasma biomarkers, to
assess the correlation between changes for baseline in plasma biomarkers and
efficacy, and to evaluate the effects of treatment on markers of inflammation
an immunity considered related to the disease pathophysiology, relative to pre-
and post-treatment profiles.
- to evaluate pharmacokinetic (PK) parameters to estimate exposures and
understand PK-pharmacodynamic (PD) relationships.
and understand PK-pharmacodynamic (PD) relationships.

This multicenter study has a randomized, double-masked, placebo-controlled,
parallel-group, design.

The study consists of three parts:

1) A screening phase of 4 weeks duration (+/- 2 weeks) within no treatment.
Patients will attend the clinic on 1-2 occasions or as required during the
screening period.
2) A double-masked treatment phase of 6 months. Patients will attend clinic
visits at week 0 (1st infusion, baseline visit), week 1, 3 ( 2nd infusion),
4,6 (3rd infusion), 9 ( 4th infusion), 12 (5th infusion), 15 (6th infusion), 18
(7th infusion),21 (8th infusion) and 24 (final assessment visit). Phone contact
by research staff focusing on safety and tolerability aspects will be made the
day after infusion for the first and second infusions, and thereafter as
required. Patients experiencing an infusion associated event will also be
contacted by phone by research staff after the infusion.
3) A follow-up phase of 12 months with no additional treatment during at least
the first 3 months. Patients will attend clinic visits at months 7,9,12,15 and
18.

During the screening period patients will complete eligibility criteria
assessments; eligible patients meeting the study criteria will be randomly
assigned to the double-masked treatment phase, using a 1:1 ratio, to receive a
starting dose of 10 mg/kg of RV 001 or placebo q3W by iv infusion. At week 3,
the dose will be escalated to 20 mg/kg iv q3W. Following dose escalation,
patients will continue at this dose level for all subsequent infusions. The
active treatment phase of the study has a duration of 6 months ( 8 infusions).
Randomization will be stratified by smoking status. During the treatment period
patients will be evaluated at clinic visits every 3 weeks and, if appropriate,
by phone contact by research staff. Measurements for efficacy, tolerability,
safety, biomarkers and PK will be performed according to the assessment
schedule.

Patients must be withdrawn if optic neuropathy or any condition requiring
surgical intervention develops or if the clinical activity score (CAS)
increases by 2 or more points.

Data and Safety Monitoring Board (DSMB): a DSMB will be assembled to review
data on a regular basis. All details relating to the constitution of the DSMB,
the scope of the data review, and timing of the meetings, are described
separately in the DSMB Charter.

RV 001 or placebo will be administered q3W by iv infusion over 6 months for a
total of 8 infusions. All patients will start RV 001 treatment at a dose of 10
mg/kg. At week 3, the dose will be escalated to 20 mg/kg and then kept constant
for the remaining period of the trial. In case of intolerable AEs, patients
should be withdrawn from the study. To maintain the mask, placebo patients will
similarly have the "dose" doubled at week 3. The duration of the infusion can
be adjusted if infusion related AEs emerge.

Patients will have to return to the clinic up to a maximum of 19 times and will
have to undergo the following procedures:

- Administration of RV 001 or placebo every three weeks by iv infusion over 6
months for a total of 8 infusions
- Medical history assessment (questions about health, current medications, and
any allergies).
- Physical examination, vital signs (respiratory rate, pulse rate, blood
pressure and body temperature), height and weight. - every visit
- Electrocardiograms (ECG) - at weeks 0, 3, 6, 12, 24, 72
- Blood samples will be drawn for blood chemistry, blood cell counts, biomarker
assessment - every visit
- Patients need to fasten 8 hours before blood sample is drawn at week 1 and 4
- Urine test for chemistry and cells - every visit
- Serum (at screening) and urine pregnancy tests (every three weeks) will be
performed, for women able to have children, or who's onset of menopause was
within the past 2 years
- Eye examinations to assess the Clinical Activity Score/ Clinical Measures of
Severity Score: Assessment of pain, swelling, redness, space between eyelids,
range of eye movement and any protrusion of the eyes - every visit
- Completion of a short questionnaire to show how the eye problems affect the
daily life (a quality of life assessment) - at weeks 6 and 12, 24, 28, 48, 72
- Color eye photos will be taken - at weeks 0, 6, 12, 18, 24, 28, 72

The main ethical concerns with study design are the potential risks imposed by
exposure to the investigational drug RV 001. RV 001 is a fully human IgG
monoclonal antibody that is a high potency, high specificity antagonist of the
insulin like growth factor type 1 receptor (IGF1R).
Unlike some first generation antiIGF1R monoclonal antibodies, RV 001has no
partial agonist activity and does not interact with insulin receptors, to which
IGF1R is most closely related. RV 001 does not stimulate antibody dependent
cell mediated cytotoxicity and is not immunogenic. Good laboratory practice
toxicology studies in cynomolgus monkeys showed that RV 001, dosed to 75
mg/kg/week IV for up to 39 weeks, produced no target organ histopathology or
adverse safety pharmacology.
Most importantly from a risk assessment perspective, RV 001 has been previously
administered to greater than 730 human cancer patients in trials for a number
of oncology indications. The doses used in the oncology studies are comparable
to the dose that is being used in the TED study. The extensive clinical safety
database generated from these previous trials confirms that RV 001 is generally
well tolerated. The safety data from a RV 001 monotherapy study conducted in
310 late stage sarcoma patients indicated the only potentially drug related
SAEs (Grade > 3) anticipated in the TED patients are hyperglycemia (< 3 %),
thrombocytopenia (< 1 %) and infusion related side effects (< 1 %).
These AEs were all reversible and will be specifically monitored for, and
managed, if observed in TED patients.
Multiple procedures have been put in place to ensure the safety of patients in
the TED01RV study. These include:
(i) Patients with potential risk factors for RV 001 therapy are excluded from
the study. This covers poorly controlled diabetics (i.e. change in the diabetes
medication * oral or insulin * greater than 10% over the past 60 days) and
subjects with platelet count less than 100 x 109/L at screening or baseline, or
hemoglobin values greater than 2 gr/dL below the lower limit of the reference
range.
(ii) Ongoing assessment of adverse events (AEs), including serious adverse
events (SAEs), premature withdrawals for AEs and rates of AEs (severity,
relationship) and regular measurement of ECGs, vital signs, and laboratory
parameters (hematology, biochemistry, urinalysis), together with physical
examinations. The assessment of AEs and SAEs will be conducted by an
independent Data and Safety Monitoring Board (DSMB) who meets monthly during
the duration of the trial.
iii) Immediate withdrawal of patients from the study in cases of unacceptable
AEs within 2 weeks of the next scheduled dose (defined as inability to work or
perform daily activity), or if optic neuropathy (defined by a decrease in
vision of two lines of Snellen chart, new visual field defect or color defect
secondary to optic nerve involvement), or any condition requiring surgical
intervention develops, or if the clinical activity score (CAS) increases by 2
or more points.
(iv) Non fasted blood glucose levels will be evaluated prior to each RV 001
infusion and under fasting conditions at weeks 1, 4, 15, and 21. In the event
of hyperglycemia, the decision whether to withdraw a patient from the trial is
at the discretion of the investigator. If hyperglycemia is mild and the patient
remains in the study the investigator can control the condition by modifying
the patient*s diet or by treatment with standard antidiabetic drugs such as
metformin and sulphanylureas. Since a referral for treatment of hyperglycemia
may take some time, if the investigator considers it appropriate to continue
the patient in the study, the next scheduled infusion visit may be skipped to
allow anti-diabetic treatment to show its activity and hyperglycemia to return
to mild/moderate level before dosing. The patient would then be dosed at the
next scheduled visit (i.e. 6 weeks after the previous infusion). Fasting blood
glucose levels must return to mild/moderate severity before the next scheduled
infusion. The above process of withholding a scheduled infusion will be
permitted only twice during the study.
(v) Platelet levels will also be assessed by the investigator prior to each RV
001 infusion. Patients with severe thrombocytopenia (i.e. < 35 x 109/l
platelets) will be withdrawn from the study and treated, for example with
corticosteroids, or blood / platelet transfusions.
(vi) If adverse events develop during an infusion (e.g. nausea, injection site
pain), the rate of infusion may be slowed, or stopped, as required. Symptomatic
treatment, e.g. antipyretics, antihistamines, beta agonists, oxygen, IV fluid,
will be administered as needed. Following an immediate infusion associated
event, vital signs (temperature, blood pressure, pulse and respiratory rate)
will be determined every 5 minutes until stable, and then every 15 minutes for
two additional determinations. The infusion may be restarted upon complete
resolution of symptoms, except for patients who experienced an anaphylactic
reaction assessed to be severe in intensity. Patients experiencing an immediate
infusion associated event will also be contacted by phone by a research nurse
the day after the infusion.
(vii) To monitor for delayed infusion reactions, phone contacts by a research
nurse focusing on safety and tolerability will be made the day after infusion
for the first and second infusions, and thereafter as required. Patients with a
skin rash which worsens following repeated infusions of study drug, or who
present other signs of serum sickness (e.g. delayed fever, myalgias,
arthralgias), will be withdrawn.
(viii) The first infusion for all patients is a * dose (10 mg/kg IV). This is
an additional safety measure included to take account of the fact that only
cancer patients have previously been exposed to RV 001.
(ix) To obviate risk to a developing fetus, women of childbearing age
(including women with onset of menopause of < 2 years) must be willing and able
to use two different methods of contraception, one of which must be an oral (or
depot) contraceptive. Assurances of abstinence will not be acceptable.
Pregnancy tests will be performed at screening, baseline, all visits during
dosing and at follow up visits 1 and 2. If pregnancy occurs the patient will be
withdrawn from the study. Male patients must agree to use a barrier
contraceptive method or must be surgically sterile.
(x) Samples for measuring anti RV 001 antibodies will be taken at baseline and
at weeks 0, 3, 9, 24, 36, and 72.
Analysis will only be performed at week 72 (study completion), but any patient
with treatment emergent antidrug antibodies will be followed up.
Note, treatment induced anti RV 001 antibodies were not detected in previous
oncology studies.


Several lines of evidence suggest that IGF1 is involved in the pathophysiology
of thyroid eye disease.
RV001 is specifically blocking the IGF1 receptor therefore the study has been
designed to answer the question: Is RV 001 superior to placebo in treating
active thyroid eye disease and what is RV 001*s safety profile in the TED
population? In addition, positive efficacy results would indicate that:
(i) IGF1R plays important roles in regulating the autoimmune response in TED.
This could have implications for other autoimmune conditions, such as
rheumatoid arthritis, Crohn*s disease and multiple sclerosis, raising the
possibility that these diseases may likewise be successfully treated with IGF1R
antagonists (Smith 2010). The result would also promote the discovery and
development of orally active IGF1R antagonists as 2nd generation therapies for
TED.
(ii) Blocking the underlying autoimmune pathophysiology of TED is a viable
means of treating the disease. This would strengthen arguments that other
targets believed to be important in TED autoimmunity, in particular thyroid
stimulating hormone receptor (TSHR), may also be viable targets for treating
TED (Bahn, 2010).

In addition, irrespective of the efficacy outcome, TED01RV will provide
valuable information about the time course of TED by following disease
progression in 42 placebo treated patients over 18 months, starting within 9
months of the first diagnosis of eye symptoms. Moreover, thyroid biomarker
analysis may provide useful data about TED disease mechanism at both the
molecular and cellular levels.