Phase IIb study on the safety and efficacy of BM32, a recombinant hypoallergenic vaccine for immunotherapy of grass pollen allergy

Specific immunotherapy (SIT) is the only allergen-specific and
disease-modifying therapeutic modality for IgE-mediated allergies. However, the
current clinical use of extracts from allergy causing agents (pollen, mites,
animal dander) is limited by many problems caused by the poor quality of
natural allergen extracts, including poor characterization, lack of important
allergens and contaminations of the API. Because this results in inconvenient
dosing schemes and occurrence of side effects, in the worst case severe and
life-threatening anaphylactic side effects, the use of SIT is limited. It is
therefore highly desirable to develop products for SIT, which overcome these
problems and provide a safe and convenient treatment so that a larger number of
patients can benefit from it. This promise is approaching reality with improved
understanding of the molecular nature of the disease-causing allergens and the
disease process itself. Pure allergens can now be obtained by recombinant
expression and molecular modifications of the allergens allow development of
vaccines with reduced side effects and enhanced efficacy.
The recombinant proteins constituting the grass pollen vaccine BM32 are the
first members of a new generation of allergy vaccines, which have been designed
to minimize side effects and to allow establishment of a convenient
immunotherapy schedule for all major seasonal and perennial allergies. They
have been engineered to reduce IgE reactivity and T cell reactivity but to
retain the ability to induce protective IgG antibody responses against the
natural allergens upon vaccination. Their safety has been studied in grass
pollen allergic patients by skin testing showing almost complete lack of
allergenic activity. Currently, a study (CS-BM32-002) is investigating safety
and dose dependent effects of 3 subcutaneous injections of BM32 on
immunological and clinical responses to grass pollen allergens in patients
suffering from grass pollen-induced rhinoconjunctivitis. In this study,
antibody responses to grass pollen allergens are studied in patients treated
with 3 different doses of BM32 or placebo. Clinical effects are evaluated by
respiratory exposure to grass pollen allergens in an environmental exposure
chamber and by titrated skin prick testing. The aim is to determine a safe dose
of BM32 which affects grass pollen-specific allergic reactions in the skin and
upon exposure in the pollen chamber and induces immunological changes expected
to be associated with clinically effective SIT. The study has started in
October 2011 and will be carried out until the end of February 2012; data will
be available in the second quarter of 2012.
The present study CS-BM32-003 is designed to evaluate the safety and efficacy
of a treatment with BM32 during 2 grass pollen seasons under natural pollen
exposure. 180 grass pollen allergic individuals will be randomized into 3 study
arms (2 dose levels BM32 + placebo). After patient assessment during the first
grass pollen season for screening purposes, subjects will be randomized to
receive 3 monthly injections before each of the next 2 grass pollen seasons and
a boost injection between the seasons to maintain the desired allergen-specific
IgG response. The dose levels of BM32 will be 20 mcg and 40 mcg per protein
component, unless safety and efficacy assessment of study CS-BM32-002 suggest a
different dose selection.
In December 2013, after reviewing unblinded safety and efficacy data, the DMC
recommended to continue with the study with the lower dose of BM32 only and
switch patients, who have received high dose in the first treatment year to the
lower dose in the second treatment year.

Objectives
Primary Efficacy Objective
• To assess the sustained clinical effect of BM32 during 2 consecutive
treatment years compared to placebo. The clinical effect of BM32 is evaluated
by a combined Symptom-Medication-Score (SMS) which is recorded during the peak
of the grass pollen season of each treatment year.

Secondary Efficacy Objective(s)
• To assess the sustained clinical effect of BM32 during 2 consecutive
treatment years
compared to placebo. The clinical effect of BM32 is
evaluated by a combined Symptom-Medication-Score (SMS) which is recorded during
the whole grass pollen season of each treatment year.
• To assess separately, the effect of BM32 on the level of allergy symptoms and
the
amount of stand-by-medication needed during the peak of the pollen season as
well
as during the whole grass pollen season of each treatment year. The recorded
Symptom-Scores (SS) and Medication-Scores (MS) of subjects treated with BM32
are compared to those of subjects having received placebo.
• To assess the effect of BM32 on individual allergy symptoms by comparing
scores of
BM32-treated subjects and subjects having received placebo for each individual
symptom.
• To assess the effect of treatment with BM32 on the *Well-being* of subjects
during
the grass pollen season as measured via a visual analogue score (VAS).
• To assess the effect of treatment with BM32 vs. placebo on the severity of
grass
pollen allergy by evaluation of the
- Number of *bad days* and
- Number of *symptom-free* days
during the pollen season.
• To assess the effect of treatment with BM32 vs. treatment with placebo on the
skin
reactivity to a commercially available grass pollen extract. The change from
baseline
in skin reactivity of each individual subject is measured by titrated SPT.
• To assess the effect of treatment with BM32 on the quality of life of grass
pollen
allergic individuals via a Rhinoconjunctivitis-Quality-of-Life-Questionnaire
(RQLQ).
• To explore a potential effect of treatment with BM32 on asthma symptoms.
Primary Safety Objective
• To evaluate the relative safety and tolerability of BM32
compared to placebo.
Secondary Safety and Immunogenicity Objective(s)
• To assess the development of Immunological parameters during treatment by
measuring grass pollen allergen-specific IgG and IgE, de-novo IgE, carrier
specific
antibodies in serum samples collected from subjects at different time points.
Comparison of BM32-treated vs. placebo and intra-group comparison of treatment
years with baseline.
• To assess effects of subcutaneous administration of BM32 on parameters of
vital
signs and safety laboratory parameters.

The study will be performed over 3 years (baseline year + 2 treatment years) as
a
randomized, double-blind, and placebo-controlled multi-center study. 250-270
individuals
with sensitivity to grass pollen will be screened and 180 will be randomized
into 2 study arms
(BM32 and placebo). The study will consist of 17 visits.

7 subcutaneous injections: 3 in the first treatment year and 3 in the second
treatment year with a distance of 4 weeks before the grass pollen season and in
between 1 boost injection.

No information is yet available about potential side effects of BM32
hyposensitization therapy. BM32 hyposensitization therapy is currently
investigated in another study, but the study is still ongoing and results are
not yet available. Safety results are available from a first study with 60
subjects with grass pollen allergy where BM32 or components of BM32 were
applied on the skin, but not injected under the skin as it is being done in
this study. Only one adverse event (skin rash and itching on the neck) was
observed in this study, which was considered as possibly related to the
application of BM32. The rash resolved within the same day.

Because allergies can never be definitely foreseen in individual cases, there
is always the possibility that the patient may experience local allergic
reactions such as redness of the skin, itching or wheals at the injection site
that usually resolve within a few days. There is also a risk of more severe
allergic reactions such as skin rash, blistering, swelling of the mucous
membrane, difficulty in breathing, inflammation, fever or very seldom an
anaphylactic shock (allergic circulatory collapse) that may become
life-threatening. In addition to an immediate allergic reaction, allergy
symptoms may present after several hours or days (delayed allergic reaction).
In case of extreme allergic reactions, medical equipment for an emergency and
study personnel trained in emergency measures are available at the study site.

Subcutaneous injection
A subcutaneous injection can lead to transient redness of the skin and swelling
at the injection site.

Blood sampling
Blood sampling could lead to bleeding/bruising or irritation at the puncture
site and in rare cases to inflammation or closure of the relevant vein,
faintness/collapse or damage to a nerve.

Skin allergy test (Skin Prick Test)
The skin allergy test may cause allergy symptoms as described above