Study of BEGEDINA® vs "Conventional Treatment" for Treating Steroid-Resistant Acute GvHD

This is a prospective, phase II/III, randomized clinical study to compare the efficacy and
safety of BEGEDINA® (Begelomab) versus "conventional treatment" for treating
steroid-resistant acute graft versus host disease (GvHD). Despite prophylactic treatment,
GvHD still develops in up to 30% of allogeneic hemopoietic stem cell transplant (HSCT)
recipients. GvHD is a life-threatening and complex immunological disease that may be acute or
chronic. Acute GvHD affects mainly the skin, liver and gastrointestinal (GI) tissues with
long-term survival directly related to the severity of skin, liver and gut involvement. First
line treatment for patients with acute GvHD (Grade II or higher) is the immunosuppressive
corticosteroid methylprednisolone. Although effective in over 50% of patients, durable
responses are observed in only a third of patients and it also confers a risk of severe
infection. Steroid-resistant acute GvHD is associated with a high rate of morbidity and
mortality, primarily from infections and/or multi-organ failure. Despite this, there are no
authorized treatments for non-responders and GvHD remains largely an untreatable disease with
limited survival and thus a great unmet therapeutic need. BEGEDINA® (Begelomab) is a murine
immunoglobulin G (IgG) 2b monoclonal antibody against CD26 (dipeptidyl peptidase-4; DPP4) and
is produced by biotechnological means and is a new potential therapeutic approach. BEGEDINA®
has been shown to bind to CD26 which is present on a subset of CD4+ T helper lymphocytes
leading to down-regulation of CD26 signaling and inhibition of immune response and thus
therapeutic improvements. BEGEDINA has been investigated in two completed clinical studies: a
pilot study and a dose-finding study and so far showing promising efficacy, safety and
tolerability.

The primary objective for this study is therefore to determine the efficacy of BEGEDINA®
versus conventional therapy in steroid-resistant acute GvHD. To satisfy this objective, two
co primary hypothesis will be tested. The first is that the overall response rate consisting
of the Complete Responders and the Partial Responders (CR+PR) at Study Day 28 will be higher
in the BEGEDINA® treated subjects. The second is that the incidence of transplant-related
mortality (TRM) at 6 months will be reduced in those subjects treated with BEGEDINA® versus
those treated with conventional therapy. Additional secondary efficacy endpoints will also be
assessed as a measure of effectiveness. In addition, some pharmacokinetics assessments will
be performed. Adverse events (AEs) will be coded using MedDRA and the frequency, causality
and intensity of AEs will be compared to conventional therapies. Further safety analysis will
also include laboratory findings, vital signs, immunogenicity and other assessments. Finally,
some exploratory analysis will also be performed.

This will be a prospective, multicenter, randomized, open-label, phase II/III clinical study
in which subjects will be randomly assigned in a 1:1 ratio to receive BEGEDINA® treatment or
the best conventional treatment available in their territory as no second line therapy is
currently approved. It is planned to enroll 184 male or female adult subjects with an upper
age limit of 65 years with steroid-resistant acute GvHD. BEGEDINA® will be administered at a
dose of 2.7 mg/m2/day for 5 consecutive days from Study Day 1 through to Study Day 5, and on
Study Days 10, 14, 17, 21, 24, and 28. Thus, the expected duration for each subject will be
approximately 12 months. The final statistical analysis plan (SAP) will be finalized prior to
database lock. Baseline characteristics of the subject sample will be described using summary
statistics. All statistical tests will be conducted at a 2-sided significance level of 5%
unless specifically specified. Multiple Imputation methods will be used as the primary method
for accounting for missing data.

Inclusion Criteria:

Male or female subjects may be entered in the study only if they meet all of the following
criteria:

1. Age ≥18 and ≤65 years of age.

2. Recipient of an allogeneic hematopoietic stem cell transplantation.

3. Steroid-resistant acute GvHD, Grade II-IV, defined as: progressive disease after 3
days of primary treatment with methylprednisolone 2 mg/kg, or equivalent; or lack of
at least a partial response after 7 days of primary treatment with methylprednisolone
2 mg/kg or equivalent; or lack of a complete response after 14 days of primary
treatment with methylprednisolone 2 mg/kg or equivalent. Note: Subjects who may have
received an increase in their steroid dose treatment prior to randomization will be
eligible for enrolment.

4. Evidence of myeloid engraftment (absolute neutrophil count ≥0.5 x 10E9/L).

5. Karnofsky Performance Status score ≥50%.

6. Adequate renal function as defined by serum creatinine ≤2 × ULN or calculated CrCl of
≥30 mL/min using the Cockroft-Gault equation: Calculated CrCl= ([140-age in years] x
[ideal body mass {IBM} in kg])/72 x (serum creatinine value in mg/dL), where IBM = IBM
(kg) = ([height in cm-154] × 0.9) + (50 if male, 45.5 if female).

7. Subject must be willing and able to comply with study requirements, remain at the
clinic, and return to the clinic for the follow-up evaluation, as specified in this
protocol during the study period.

8. Able and willing to provide signed informed consent.

Exclusion Criteria:

Subjects will not be entered in the study for any of the following reasons:

1. Prior second-line systemic treatment for GvHD.

2. Received agents other than steroids for primary treatment of acute GvHD.

3. Stage 1-2 skin acute GvHD alone (with no other organ involvement).

4. Acute steroid resistant GvHD beyond 28 days from first-line therapy (primary
treatment).

5. Evidence of severe hepatic veno-occlusive disease or sinusoidal obstruction.

6. Evidence of encephalopathy.

7. Life expectancy <3 weeks.

8. Presence of chronic GvHD.

9. Second or subsequent allogeneic transplant.

10. Received a solid organ transplant (with the exception of a corneal transplant >3
months prior to screening).

11. Relapsed disease after last transplant.

12. HIV positive.

13. Evidence of lung disease that is likely to require more than 2L of O2 via face mask or
an estimated FiO2 of 28% via other delivery methods in order to sustain an O2
saturation of 92% within the next 3 days.

14. Any underlying or current medical or psychiatric condition that, in the opinion of the
Investigator, would interfere with the evaluation of the subject including
uncontrolled infection, heart failure, pulmonary hypertension. Any other serious
medical condition, as judged by the investigator, which places the subject at an
unacceptable risk if he or she were to participate in the study or confounds the
ability to interpret data from the study.

15. Administration of any other investigational agents (not approved by the FDA/EMA for
any indication) within 30 days of randomization. Participated in any interventional
clinical trial for an acute GvHD therapeutic agent or for an immunomodulatory drug,
within the past 30 days or within 5 half-lives of the study treatment, whichever is
the greater. Participated or is currently participating in any bone marrow derived
autologous and allogeneic stem cell or gene therapy study.

16. Known allergy to murine proteins.

17. Women who are pregnant, breastfeeding or at risk to become pregnant during study
participation. Female subjects of childbearing potential who have not been started on
an anti-ovulatory regimen prior to initiation of chemo-inductive regimen must test
negative for pregnancy (serum) at the time of enrollment.

18. Male and female subjects who do not agree to take adequate measures to avoid pregnancy
(including abstinence) prior to study entry and for the duration of participation in
the study (or for at least 3 months following the last dose of study drug, whichever
is longer).