A randomized, subject and investigator blinded, placebo controlled and multi-center platform study, to assess efficacy and safety of different investigational drugs in patients with moderate to severe hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic, recurrent, and debilitating
inflammatory skin condition that typically presents with deep, inflammatory,
painful lesions in apocrine gland-bearing parts of the body. This disease
results in a strong decrease in the quality of live and there is an unmet need
for systemic therapies that effectively reduce inflammation while having a
favorable safety profile for patients suffering from moderate to severe HS.
This study uses a platform study design to investigate multiple targeted
investigational treatments in the context of a single disease and consequently
limiting exposure to placebo.
CFZ533 (iscalimab) is a non-agonistic, fully human, Fc-silent, antagonistic
IgG1 anti-CD40 antibody that binds to CD40 and prevents the binding of CD40L to
CD40, thereby inhibiting cellular proliferation and other effector functions.
This is an interesting therapeutic inetervention since the presence and
upregulation of B cells in HS lesion has been observed previously.
LYS006 is a highly potent and selective oral inhibitor of the enzyme
leukotriene A4 Hydrolase (LTA4H). LYS006 inhibits the biosynthesis of
pro-inflammatory leukotriene B4 (LTB4) and increases the generation of
anti-inflammatory, resolution-enhancing lipoxin A4 (LXA4). Both lipid mediators
are known to play an important role in the orchestration of neutrophilic
inflammation.
MAS825 is an IgG-like bispecific monoclonal antibody (mAb) containing a
heterodimeric Fc part that simultaneously neutralizes the key inflammasome
effector cytokines interleukin-1 beta (IL-1ß) and interleukin-18 (IL-18).
Remibrutinib (LOU064) is a selective, potent, covalent inhibitor of BTK.

Secondary objective
To assess the safety and tolerability of the investigational treatments in
patients with moderate to severe hidradenitis suppurativa (HS) by:
• Number and severity of AEs
• Physical examination, vital signs, safety laboratory measurements, ECGs at
baseline and repeatedly until study completion visit

This is a non-confirmatory, randomized, subject and investigator-blinded,
placebo-controlled, multi-center and parallel-group study to assess efficacy,
safety and tolerability of several active investigational drugs, iscalimab,
LYS006, MAS825, and remibrutinib, in subjects with moderate to severe
hidradenitis suppurativa. The maximum duration of any subject's participation
in a single cohort may not exceed 33 weeks (25 weeks for remibrutinib) and will
consist of a 35 day screening period, a 16 week treatment period and will be
concluded by a 12 week safety follow-up (4 week safety follow up for
remibrutinib). Subjects will be allocated to either of the cohorts (based on
the eligibility criteria for each cohort). Within each cohort, subjects will be
randomized 2:1 (Cohort A and B) or 3:1 (Cohort C), or 3:3:1 (Cohort D) to
either investigational treatment or matching placebo. The study will be set up
as a platform study to allow early discontinuation of cohorts and inclusion of
new cohorts.

Cohort A:
Iscalimab (CFZ533) 600 mg in a 150 mg/ml solution for s.c. injection (2
injections of 2 ml).
Placebo-solution for s.c. injections (2 injections of 2 ml).

Cohort B:
LYS006 capsules (5mg/capsule) taking four capsules orally twice a day.
Placebo capsules taking four capsules orally twice a day.

Cohort C:
MAS825, 300 mg, s.c. or matching placebo as follows:
Bi-weekly (Q2W) from Day 1 (week 1) to Day 29 (Week 5) and then monthly (Q4W)
until Day 85 included (Week 13).

Cohort D:
LOU064 (remibrutinib), 100 mg b.i.d. p.o or 25 mg b.i.d. p.o or
placebo from Day 1 (Week 1) to Day 113 included (Week 17).

Possible side effects of the study treatments include:

Potential risks of iscalimab:
Infections: Iscalimab can suppress part of the immune system, which could
increase your risk for infections, including serious infections.
Patients who have active infections or latent infections at risk of
reactivation may be at increased risk, and should therefore not join this
study. Before and during this study, your Study Doctor will check for signs and
symptoms of infection such as fever, chills, cough, loss of appetite, diarrhea
or sore throat. Please let him or her know if you experience any such signs or
symptoms. In order to minimize risk of infection, your blood will be checked
for signs of certain infections at screening. If the lab results show that you
have certain infections and/or if your Study Doctor detects certain signs of
infection at screening, you will not be able to take part in the study. If
signs of infection are detected during the study, the Study Doctor may consider
discontinuing your study treatment.
Patients who take strong immunosuppressive drugs also should not join the
study. The risk of infection may be increased when these drugs are taken
together with iscalimab, as this combination increases suppression of the
immune system. In liver and kidney transplant patients given iscalimab in
combination with other strong immunosuppressive medications, an increased risk
for infections has been observed, and fatal infections of cytomegalovirus (CMV)
have occurred. In patients given iscalimab without additional strong
immunosuppressive medications (such as in this study), no increased risk for
infection has been seen.
Systemic inflammation and potential kidney injury: There may be a risk of
infections that lead to inflammation and kidney injury when taking iscalimab.
Injection related reactions: Signs may occur around the area where you received
the treatment (for example infusion site pain, bleeding, and redness) or you
may experience symptoms in other parts of your body (for example, nausea,
vomiting, headache, chills, fever, muscle aches, or rash).
Vaccination failure: Vaccination success is expected to be reduced while taking
iscalimab. You should therefore complete all pre-planned vaccine immunizations
(*shots*) prior to starting treatment in Cohort A.
Thrombosis: There might be an increased risk of blood clotting while taking
iscalimab.
Immunogenicity: Your body may develop antibodies (a type of immune system
protein) against iscalimab which may make it ineffective or lead to allergic
reactions.
Lymphadenopathy: Iscalimab may increase the risk for swollen and painful lymph
nodes.
Teratogenicity: is not known if iscalimab may cause harm to an unborn child

Potential risks of LYS006:
Kidney or bladder injury: Crystalluria (presence of crystals in the urine),
leading to blockages in the kidneys or bladder may be a potential risk of
taking LYS006. To reduce these risks, it is important to take LYS006 (or its
placebo) during or shortly after a meal with a glass of fluid (ideally water).
See the section titled *What are my responsibilities and are there any costs
for me if I agree to join this study?* below for further details
Increased pancreatic enzymes: temporary increases in proteins secreted by the
pancreas (an organ involved in digestion) without clinical signs were observed
in earlier clinical studies. The relevance of these increases is still unknown.
Teratogenicity: is not known if LYS006 may cause harm to an unborn child.
Live vaccinations: Receipt of certain vaccines (known as *live* or *attenuated*
vaccines) while taking iscalimab could lead to risk of infection. Therefore, in
Cohort A, live and attenuated vaccines should be avoided for 2 months prior to
your first dose and for 14 weeks after your last dose of study treatment.
Note: there is currently no clear evidence that the effects of LYS006 would
significantly affect vaccination response. Thus, the impact of LYS006 on
vaccine response is expected to be low. However, studies investigating vaccine
response in the presence of LYS006 have not been conducted.

Potential risks of MAS825:
Infections: MAS825 can suppress part of the immune system, which could increase
your risk for infections, including serious infections.
Patients who have active infections or latent infections at risk of
reactivation may be at increased risk, and should therefore not join this
study. Before and during this study, your Study Doctor will check for signs and
symptoms of infection such as fever, chills, cough, loss of appetite, diarrhea
or sore throat. Please let him or her know if you experience any such signs or
symptoms. In order to minimize risk of infection, your blood will be checked
for signs of certain infections at screening. If the lab results show that you
have certain infections and/or if your Study Doctor detects certain signs of
infection at screening, you will not be able to take part in the study. If
signs of infection are detected during the study, the Study Doctor may consider
discontinuing your study treatment.
Injection related reactions: Signs may occur around the area where you received
the treatment (for example infusion site pain, bleeding, and redness) or you
may experience symptoms in other parts of your body (for example, nausea,
vomiting, headache, chills, fever, muscle aches, or rash).
Live vaccinations: Receipt of certain vaccines (known as *live* or *attenuated*
vaccines) while taking iscalimab could lead to risk of infection. Therefore, in
Cohort C, live and attenuated vaccines should be avoided for 2 months prior to
your first dose and for 14 weeks after your last dose of study treatment.
Changes in blood lipids/cholesterol and blood sugar values: constitute a
theoretical risk, but have not been reported to cause any symptoms in healthy
volunteers.
Immunogenicity: Your body may develop antibodies (a type of immune system
protein) against MAS825 which may make it ineffective or lead to allergic
reactions.
Teratogenicity: It is not known if MAS825 may cause harm to an unborn child.

Possible side effects of remibrutinib
- Remibrutinib may reduce the body's defenses against infections. This may make
you more susceptible to infections, which can be serious. This has been seen
before with other drugs that work in a similar way to remibrutinib. So far,
most infections seen when using remibrutinib in a clinical trial are mild to
moderate in severity and are no more common than in patients taking placebo.
- Remibrutinib is expected to have an effect on vaccinations. Vaccinations may
be less effective when administered during treatment with remibrutinib.
Therefore, you should have received all scheduled vaccinations at least 2 weeks
before starting remibrutinib.
- Certain vaccines (called "live" or "weakened" vaccines) may lead to a risk of
infection during remibrutinib use. Therefore, live and attenuated vaccines
should be avoided in the 2 months before the first intake and up to 4 weeks
after the last intake of your study treatment. Consult your research physician
before receiving any vaccination while participating in this study.
- Based on what is known from similar treatments, there is a risk of bleeding
when using remibrutinib. Only mild to moderate bleeding has been reported in
previous studies with remibrutinib. If you have an increased risk of bleeding
due to a condition or use of certain medications, you may not be allowed to
participate. Medications that increase the risk of bleeding (e.g., higher doses
of aspirin) should be avoided. Report any medication you are taking, even if it
is an occasional one, and any unusual bleeding you experience to your research
physician. Please inform
your research physician about any planned surgeries as this may be important
for treatment. - Remibrutinib may cause a decrease in certain blood cells such
as neutrophils (a type of white blood cell), platelets or red blood cells.
Subjects with an insufficient blood cell count should therefore not participate
in this study. The blood draws during the study are partly to monitor the blood
cell count.
- In some people, remibrutinib can lead to heart rhythm abnormalities.
Therefore, heart sounds will be taken regularly during the study.
- Remibrutinib is broken down in the liver by specific proteins (called CYP3A).
It is possible that it may interact with other medications that are also broken
down by these proteins, which may lead to side effects. It is therefore
important that you tell your research physician what other medications you are
taking during the study.
- Studies with animals have shown that remibrutinib during pregnancy can
potentially lead to problems in an unborn child. It is not clear if this also
applies to humans. Fertile women should therefore only participate if they are
using an effective form of contraception. The research physician can give you
more clarification.

Additionally, allergic reactions may occur when any drugs are administered.
Possible symptoms of an allergic reaction include: rash, itching, swelling in
the face or throat, difficulty breathing, decreased blood pressure, increased
pulse, and sudden sweating or cold sweat. If these symptoms occur soon after
the intake of study treatment and are strong, this may be a very rare but
potentially life threatening reaction which must be treated immediately.
Iscalimab, LYS006, and MAS825 are investigational drugs being tested and thus
not all of the possible side effects that may occur from taking them are known
at this time.