A randomized, part A partial blinded and part B double blinded, placebo-controlled 24-week clinical study to evaluate the efficacy and safety of nomacopan therapy in adult patients with bullous pemphigoid receiving adjunct oral corticosteroid therapy (ARREST-BP)

Bullous pemphigoid (BP) is the most common subtype of autoimmune blistering
disease (AIBD). The pathogenesis of BP is not fully understood but it is likely
that there is an interaction between predisposing genetic factors and
environmental triggering factors.

BP treatment has 3 main goals: stopping blister formation and pruritus,
promoting healing of blisters and erosions, and improving quality of life.
First-line therapy consists of high potency topical or systemic
glucocorticosteroids.

Due to numerous AEs and symptoms associated with current therapeutic options
and the increased risk of morbidity and mortality, the need for a safe and
effective treatment of BP remains. Newer therapeutic agents targeting molecules
involved in the inflammatory cascade associated with BP represent future
alternatives to classical immunosuppressant drugs. There is currently no
approved targeted therapy for treatment of BP.

Nomacopan, a recombinant small protein therapeutic, is being developed as a
treatment for BP with the intention that it will have fewer adverse effects
than traditional corticosteroid therapies.
In Part A, a higher 45 mg once daily dose of nomacopan and a lower 15 mg once
daily dose of nomacopan will be compared. In Part B of the study, all patients
will receive either a 45mg or a 15mg once daily dose. The single dose to be
used for all patients will be selected based on the results seen in Part A.

A treatment period of 24 weeks will be used in Part A. Nomacopan will be
administered with adjunct oral corticosteroid therapy (OCS) tapered according
to disease response.

Primary Objective:
* confirm the dose of nomacopan and sample size for Part B and evaluate the
rank order of secondary endpoints

Other Objectives:
* compare nomacopan with adjunct OCS to placebo with adjunct OCS in achievement
of Complete Remission of disease on minimal OCS (CRon)
* test whether cumulative OCS is lower in the nomacopan than the placebo arm.
* assess steroid use testing whether fewer nomacopan than placebo treated
patients require rescue therapy during treatment.
* assess disease control by testing whether nomacopan arm is superior to
placebo arm in achieving Partial Remission of disease on minimal OCS (PRon).
* evaluate how long it takes to achieve initial CDA and full disease control
assessed by time to achievement of CRon or PRon.
* evaluate duration of CRon or PRon.
* evaluate the effect of treatment on disease intensity measured by bullous
pemphigoid disease area index (BPDAI)
* evaluate the effect of treatment on itch reported by the weekly average daily
peak pruritis Numerical Rating Scale (PP-NRS) and separately by the BPDAI
pruritus score.
* evaluate the effect of treatment on disease intensity measured by
Investigator Global Assessment (IGA).
* assess the safety and tolerability of nomacopan with adjunct OCS compared to
placebo and adjunct OCS.
* evaluate health-related quality of life (QoL) measures.
* characterize nomacopan PK and terminal complement activity in serum and total
LTB4 in plasma.
* record time taken until patient is receiving minimal OCS.
* evaluate time to relapse/flare from date that patient is first on minimal OCS.
* assess cumulative steroid use after treatment stops until week 28.
* evaluate BP180 and BP230 autoantibody titres.
* measure inflammatory markers associated with active BP disease by examining
cytokine profiles in serum.
* assess inflammation by skin tissue biopsy to measure leukotriene B4 (LTB4)
and cell infiltrate.
* assess the immunogenicity of nomacopan.

Study Design:
This is a randomized, placebo-controlled clinical study in two parts - Part A
and Part B. Part A is blinded for placebo/active but not for low/high dose;
part B is double blinded.

The objectives of the study are:

* In Part A: to confirm the dose of nomacopan and sample size for Part B and
also rank the order of secondary endpoints for Part B
* In Part A: to compare nomacopan with adjunct OCS to placebo with adjunct OCS
in achievement of Complete Remission of disease on minimal OCS (CRon)
* In Part A and Part B: to evaluate the safety of nomacopan with adjunct OCS
* In Part B: to test drug efficacy and in particular whether treatment with
nomacopan and adjunct oral corticosteroid (OCS), with steroid tapered (between
weeks 2 and 24) according to disease response, leads to a higher proportion of
patients in complete disease remission than treatment with placebo and adjunct
OCS.
* In Part B: to examine whether there is a reduction in cumulative OCS use and
fewer steroid related adverse events in the nomacopan than the placebo arm.

The primary endpoint of both Parts of the study is achievement of Complete
Disease Remission on (CRon) minimal OCS (0.1 mg/kg/day) for 8 weeks or more at
week 24.

The only OCS permitted in this trial is prednisone or prednisolone.

Part A (48 patients):
Part A will have four arms in which patients will be randomised to receive
either:

* high dose nomacopan (standard complement ablating doses on Day 1 followed by
45 mg qd) plus a starting dose of 0.5 mg/kg/day OCS, n = 16,
or
* low dose nomacopan (standard complement ablating doses on Day 1 followed by
15 mg qd) plus a starting dose of 0.5 mg/kg/day OCS, n = 16,
or
* placebo injections (matching standard complement ablating doses on Day 1 and
then matching injection volume of 45mg dose) plus a starting dose of 0.5
mg/kg/day oral corticosteroid (OCS) qd, n = 8,
or
* placebo injections (matching standard complement ablating doses on Day 1 and
then matching injection volume of 15mg dose) plus a starting dose of 0.5
mg/kg/day oral corticosteroid (OCS) qd, n = 8.

Randomisation in Part A will be stratified by newly presenting/relapsed
patients. Either 4 or 6 relapsing patients will be allowed into each of the
nomacopan treatment arms, and 2 or 3 relapsing patients will be allowed into
each of the placebo treatment arms, while maintaining the 2:2:1:1 randomization
scheme for high dose nomacopan: low dose nomacopan: placebo 45mg: placebo 15mg.
Twelve (12) or eighteen (18) relapsing patients will be recruited.

Part B (pivotal):
The dose of nomacopan and patient numbers in Part B will be determined
following completion and analysis of Part A, a Type A meeting with the FDA and
a Scientific Advice Meeting with the EMA. The sample size for Part B is
expected to be approximately 100 patients. Part B will have two arms.

* placebo plus oral corticosteroid (OCS), n = TBD,
or
* single selected dose of nomacopan (standard complement ablating doses on Day
1 followed by either 15 or 45 mg [TBD] qd) and OCS, n = TBD.

Randomisation in Part B will be stratified by moderate/severe disease based on
IGA score at Day 1 (Baseline) and by newly presenting/relapsed patients.

Part A and Part B will have a similar design and the same study periods:
In both Parts A and B patients will receive study drug once daily for 24
weeks. Both parts can each be considered to have three periods:

* Disease Control (Period 1): patients will remain on a fixed OCS starting dose
(0.5 mg/kg/day) for a minimum of 2 weeks until Control of Disease Activity
(CDA) is achieved, when OCS tapering begins. With CDA defined as the time at
which new lesions cease to form and established lesions begin to heal, or
pruritic symptoms start to abate.

* OCS Tapering (Period 2): OCS tapering will begin once CDA is achieved, and
after a minimum of 2 weeks of OCS study treatment. OCS tapering will continue
until the patient is on minimal OCS (0.1 mg/kg/day), at which point the patient
is eligible for assessment of the duration of disease remission. It is
important to note, that OCS tapering can begin once CDA is achieved and does
not require that the patient has 80% epithelialization of lesions. If CDA is
not maintained during tapering the OCS dose is kept constant if there are
transient lesions. If the disease is worsening the OCS dose may be increased,
to a maximum dose of 0.75 mg/kg/day, until disease control is re-established
when OCS tapering can be resumed. Rules for OCS taper and increase are
presented in the main body of the Protocol.

* Remission (Period 3): patients who remain in complete disease remission (no
lesions) will stay on minimal OCS (0.1 mg/kg/day) for the rest of the treatment
period (24 weeks). If there is onset of new disease activity (except transient
lesions) the OCS dose may be increased until disease control is re-established
when OCS tapering can be resumed. If patients are on 0.1 mg/kg/day and in
complete remission (CRon) for the entire period between weeks 16 to 24 they
meet the primary endpoint regardless of the patient*s OCS doses before week 16.

Definitions of disease worsening, and relapse/flare are provided in the main
body of the protocol.

In both Parts A and B there will be a follow-up period of four weeks, between
weeks 24 and 28, during this time patients will receive standard of care (SOC)
treatment without nomacopan.

Safety and Extension Study for Part B:
A separate one-year safety and extension study will be offered to patients from
either arm of the Part B study who have achieved the primary endpoint of CRon
or have achieved partial disease remission on (PRon) minimal OCS (0.1
mg/kg/day) for 8 weeks or more at the end of nomacopan treatment (week 24 of
the parent study AK802). If patients are in CRon when they enter the safety
and extension study or achieve CRon during the safety and extension study the
OCS dose may be gradually tapered to 0mg/kg/day OCS. The study will follow the
patients to assess total duration of CR on minimal or no OCS, PRon, cumulative
steroid use and safety after discontinuation of nomacopan. The study will also
monitor the response of patients to re-treatment with nomacopan if they
experience a relapse/flare. An interim analysis of safety will be undertaken
when all patients have reached six months in the extension study and a final
analysis at 12 months. Patients in CR or PRon who relapse/flare will be
treated with nomacopan (with the nomacopan dose used in Part B) plus a starting
dose of up to 0.5 mg/kg/day OCS determined by treating physician depending on
disease severity. Patients entering the safety and extension study will not be
receiving nomacopan but may do so at entry or anytime thereafter if they
exhibit relapse/flare. All patients, carers and staff treating the patients
who enter the safety and extension study will remain blinded to Part B
treatment allocation.

Study Procedures (Parts A and B):
Part A and B of the study will have similar study procedures. A patient who
has been in Part A of the trial cannot enter Part B.

Patients can be screened up to 10 days prior to randomization and should
generally not receive any treatment other than emollients until the
randomisation visit. For ethical reasons patients can be treated with 30-60g
potent topical corticosteroids (eg triamcinolone or mometasone furoate), but
not super-potent topical steroids, and no more than 0.3 mg/kg/day OCS during
the screening period. It is advised that the OCS dose is minimized during the
screening period to help ensure that healing does not begin before patients are
randomized to treatment. Patients will then be randomized on Day 1 to receive
study drug or placebo with OCS at a starting dose of 0.5 mg/kg/day. At
screening and on Day 1 subjects will have markers of disease activity measured
(including BPDAI, IGA, QOL, PP-NRS scores and BP180/BP230 antibody titres) to
gauge how their condition has changed between screening and trial entry.

Patients will have scheduled clinical visits for assessment (including disease
control and OCS dose assessment) at baseline (Day 1) and at Weeks 1, 2, 3 and 4
and then every four weeks thereafter until the end of treatment (Week 24). The
week 3 assessment may be either a clinical visit or a home assessment if the
patient has control of disease activity at the week 2 clinic visit. A safety
follow-up visit will be performed at the end of study (Week 28). Home
assessments (usually a televisit) will also be performed by trained staff at
Weeks 10, 14, 18, 22 and 26. Once a patient is in complete remission on
minimal OCS, a home consultation (by phone) will be undertaken once weekly
during the weeks that the patient is not having a full home assessment or being
seen at the clinic, to determine that disease control is being maintained
during the period of assessment of sustained disease remission. If during a
home assessment, it is considered that the patient may no longer be in disease
remission an unscheduled clinic visit will take place to confirm that the
patient is no longer in remission and to raise the OCS dose if required.

For the first 14 days of the study (minimum duration of period 1), the OCS dose
will usually remain the same (0.5 mg/kg/day), unless patients have severe
disease (IGA score of 4) and do not have CDA at their Week 1 assessment in
which case OCS may be raised to 0.75mg/kg/day at Week 1. If patients have
moderate disease at Week 1 (IGA score of 3) whether or not the disease has
worsened they should remain on 0.5mg/kg/day OCS until the Week 2 assessment.
At Week 2 and thereafter OCS taper can begin if there is CDA. At each
subsequent clinical or home assessment (ie on weeks 3, 4 and 6 and then every 2
weeks thereafter until week 24):

1. Dose decreased by one step if there is CDA.
2. Dose remains the same if there are transient lesions.
3. Dose increased by one step if there is Mild New Activity.
4. Dose increased by one or more steps if disease is exhibiting more than Mild
New Activity including Disease Relapse/Flare.

Any change in OCS dose can only be performed at a clinical assessment (either
at clinic or at home usually by televisit) from Week 1 onward (severe patients
only for dose increase * see above) or from Week 2 (all patients permitted dose
increase or decrease), and once weekly until Week 4, and then every two weeks
thereafter. If a home assessment is being performed and it is considered there
may be increased disease activity that mandates an increase of the OCS dose, an
unscheduled clinical visit should be arranged to assess disease activity and
whether there is a need to raise the OCS dose.

Once the patient is on minimal OCS (0.1 mg/kg/day), they are eligible for
assessment of duration of disease remission.

As described above, if patients do not achieve initial CDA on an OCS dose of
0.5 mg/kg/day their OCS dose can be raised to 0.75 mg/kg after one week if IGA
indicates they have worsening severe disease at Week 1 or at two weeks if they
have moderate disease. If CDA has not been achieved after three or four weeks
on the highest OCS dose of 0.75 mg/kg/day, the patient will be regarded as a
treatment failure and study treatment will be withdrawn. Whether the period is
three or four weeks depends on the timing of the shift to the highest dose of
OCS and the subsequent schedule of clinical assessments.

Stopping study IMP and use of rescue therapy does not constitute withdrawal
from the trial. The Investigator will start rescue therapy for treatment
failure according to their normal practice. Rescue therapy comprises any
therapy for treatment of BP administered because study treatment is considered
to have failed.

Patients who require rescue therapy for treatment failure will be requested to
attend clinic visits and have home assessments (usually televisits) as
described in Section 18.3 and 18.4 until week 28 or until complete remission
off steroid is achieved. In clinic visits will assess BPDAI, IGA, concomitant
medications (including all therapies for treatment of BP), cumulative OCS dose
and safety. Patients who are treatment failures will not be eligible to enter
the safety and extension study.

Topical emollients are permitted throughout the trial to relieve dry skin
(xerosis), which is not a symptom of BP, but is a very common cause of itch in
the elderly. The use of topical corticosteroids, even for a short period, is
not permitted after randomization.

Blood samples for assessment of blood chemistry, haematology, biomarkers of
inflammation, PKPD and anti-drug antibodies (ADA) will be taken throughout the
study.

Nasal and throat swabs will be taken neisseria sp. testing at screening. ECGs,
physical examinations and bullous pemphifoid related assessments will be
conducted throughout the study.

Biopsy sampling twice during the study is optional.

Treatment by daily subcutaneous injections, elaborate preparation of IMP,
several questionnaires adn daily diary entries as well as frequent efficacy
assessments are rather time consuming and in part painful. Treatment may also
be associated with the occurrance of side effects.
Different doses are accomplished by adapting the applied volume. For the higher
dose two injectiosn per application are necessary.

Nomacopan associated risks:
Nomacopan was well tolerated in normal volunteers, adults with paroxysmal
nocturnal hemoglobinuria (PNH), and severe allergic conjunctivitis and
keratoconjunctivitis, and an older adult BP population with many
comorbidities. The most commonly reported treatment emergent adverse events
(TEAEs) were injection site reactions of mild or very occasionally moderate
severity that required no specific treatment.

One serious adverse reaction of urinary tract infection caused by Escherichia
coli was reported in a PNH patient treated with nomacopan. This event was
assessed by the investigator as possibly related to nomacopan. The subject*s
medical history of urinary tract infection and cystitis potentially confounded
causality for the reported event making causality not related to nomacopan in
the opinion of the sponsor. There have been no other reports of
treatment-related serious infections.

There have been nine further serious infections reported in the nomacopan
clinical development program to date (August 2020); all of these were
considered unrelated to nomacopan by both the investigator and the sponsor. In
only a few instances were organisms cultured: Escherichia coli was cultured
from urine in a catheterised patient, and in another patient Staphylococcal
epidermis was cultured from a peripherally inserted central catheter.

There have been no treatment-related study withdrawals.

As Neisseria meningitidis has been reported as a risk with a C5 complement
inhibitor (Soliris®) all subjects have received meningitis prophylaxis either
by antibiotics or vaccine prior to nomacopan therapy. No events of
meningococcal infection have been reported to date.

Anti-Drug Antibodies
Nomacopan is a xenologous protein with the recombinant protein originally
derived from a cDNA encoding a tick salivary protein. In the AK577 dose
ranging study healthy volunteer study, anti-drug antibodies (ADAs) were
detected in two of four subjects dosed with nomacopan for 21 days and in none
of the 12 subjects dosed with nomacopan for 7 days. The antibodies were of low
titre and did not neutralise the complement inhibitory activity of nomacopan.
The eculizumab resistant PNH patient who received nomacopan for more than 21
months in Study AK578 first had detectable ADA at Day 16, which peaked at Day
60 and declined thereafter. All patients (n=8) in AK579 developed ADAs, which
were first detectable between Day 14 to Day 90. Again, the antibodies were of
low titre and did not neutralise the complement inhibitory activity of
nomacopan.

The appearance of ADA does not appear to be associated with an increase in the
rate or severity of injection site reactions.

The most compelling data supporting that the human ADA are non-neutralising is
that in PNH patients from trials AK578, AK579, AK581 and AK585, over a daily
dosing period of years, terminal complement activity has been found to be below
the lower limit of quantification at all time points after Day 1 of nomacopan
dosing. Furthermore, ADA are not associated with a decrease in the
concentration of unbound nomacopan in patients.

Experience with nomacopan to date appears similar to patient experience with
other parasite derived therapeutic molecules, such as the leech-derived
anticoagulant hirudin, where most patients develop detectable ADA which have no
effect on the inhibitory function of the protein.

Assessment/trial measure related risks:
Non-invasive measures like ECG, vital sign measurements and BPDAI assessments
do not pose any risk or burden to the subject.

Blood sampling during the trial poses the same small risk for pain through skin
puncture, hematoma, infection or venous inflammation as normally induced by
this technique. Risks will be mitigated by delegating this task to experienced
study personnel.

Biopsy sampling is associated with an increased risk of scaring, infection of
the wound, damage of superficial nerves with resulting insensitivity of
surrounding areal and discomfort or pain. Serious side-effects are rare and
biopsy sampling will only be performed by experienced medical trial team
members to reduce any risk.

Given the unmet need, efficacy observed in the Phase 2 study, and the benign
safety profile of nomacopan demonstrated to date - the benefit: risk of the
AK802 study is considered positive.

Participants my benefit by improvement of their conditions when being
randomized to active treatment. Overall, the study results will support insight
into the mechanism of pathogenisis of the diesase and the effectiveness and
side effects of the investigational medicinal product wihc will serve future
research and help mitigating the unmet needs for effective therapy.