A Phase 2, Prospective Study Of PRM-151 In Subjects With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (post-PV MF), Or Post-Essential Thrombocythemia MF (post-ET MF)

Pentraxin-2 (PTX-2), also called Serum Amyloid Protein (SAP) is an endogenous
protein that circulates in the bloodstream. Recent discoveries about the
biology of tissue repair and fibrosis have elucidated the important role that
PTX-2 plays biologically in regulating processes that relate to scar prevention
and healing. PTX-2 is an agonist that binds to Fc gamma receptors on monocytes
and promotes their differentiation into regulatory macrophages (Mreg), which
function to promote epithelial healing and resolution of inflammation and
scarring. PTX-2 also prevents the differentiation of monocytes into M2
pro-fibrotic macrophages and fibrocytes, preventing the formation of fibrosis.
Pre-clinical and clinical data exist to support the investigation of PRM-151 in
the treatment of fibrotic diseases. Myelofibrosis [including Primary
Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF and Post-Essential
Thrombocythemia (ET) MF] is a clonal myeloproliferative neoplasm, characterized
by progressive bone marrow fibrosis and subsequent ineffective erythropoiesis,
dysplastic megakaryocyte hyperplasia, and extramedullary hematopoiesis. The
typical clinical presentation includes marked splenomegaly, progressive anemia,
and constitutional symptoms. Bone marrow transplant is the only treatment that
can cure subjects with MF, but is associated with high morbidity and mortality
(Stewart, Pearce et al. 2010); (Ballen 2012) . Bone marrow fibrosis resolves
in subjects after successful transplant as early as one month (Przepiorka,
Giralt et al. 1998). Until recently, there was no approved medical therapy for
MF and most subjects were managed with various combinations of growth factors,
immunomodulatory agents, cytotoxic chemotherapy, and steroids. None of these
therapies produced significant responses in the majority of subjects. For this
reason, no medication has been approved for MF until recently. Ruxolitinib is
a Janus kinase inhibitor, recently approved in the US and EU for the treatment
of subjects with intermediate or high-risk myelofibrosis, including primary
myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF) and
post-essential thrombocythemia (postET MF) (JAKAFI® Full Prescribing
Information 2011). Treatment with ruxolitinib results in reduction in spleen
volume and improvement in constitutional symptoms, but does not appear to have
an effect on bone marrow fibrosis, and symptoms return within one week of
discontinuing the drug. (Verstovsek 2012) Other Janus kinase inhibitors are in
clinical development. There is a clear unmet medical need for new therapies
that could improve bone marrow fibrosis in subjects with myelofibrosis with a
resultant improvement in blood counts and other disease-related factors.

To determine the effect size of three different doses of PRM-151 on reduction
in bone marrow fibrosis by * 1 grade in intermediate-1, intermediate-2, and
high risk subjects with PMF, post-PV MF, or post ET-MF who are anemic or
thrombocytopenic and who are ineligible for, intolerant of, or have had an
inadequate response to ruxolitinib.

This is a randomized, double-blind Phase 2 study to determine the efficacy and
safety of three different doses of PRM-151 in subjects with PMF and post ET/PV
MF. Subjects will be randomized to one of three doses: 0.3 mg/kg, 3.0 mg/kg or
10 mg/kg of PRM-151. This is the second stage of an adaptive design study as
defined in FDA Draft Guidance for Industry: Adaptive Design Clinical Trials for
Drugs and Biologics, February 2010. Modifications to dose levels, schedule,
and regimen have been made in Stage 2 based on data from Stage 1. Approximately
84 subjects with intermediate-1, intermediate-2, or high risk MF who meet study
eligibility requirements will be enrolled and randomized to treatment with
single agent PRM-151 at doses of 0.3, 3, or 10 mg/kg IV on Days 1, 3, and 5 of
Cycle 1 and Day 1 of each subsequent 28 day cycle for nine cycles. All subjects
may switch to an open label extension and receive 10mg/kg every 4 weeks after
completing 9 cycles of the originally assigned treatment. After study
completion and data analysis, all subjects remaining on PRM-151 will switch to
the dose that has been selected for future development based on study results.
Enrolled subjects will be considered evaluable for response if they are on
study drug for at least twelve weeks.

All patients receive intravenous administration of PRM-151 on day 1 of every
28-day cycle for a total of 9 cycles. In the first cycle the patients will also
receive intravenous administration of PRM-151 on day3 and 5. Patient will
receive 0.3 mg/kg, 3 mg/kg of 10 mg/kg PRM-151, depending on to which group
they were randomised.

Burden for a patient may be that there are more visits to the hospital for the
investigation carried out, than for standard care and that the visits take
londer due to the additional exams and the intravenous administration of
PRM-151.

Patients have the following burden:
Keep transfusion diary (every visit)
ECG (once)
Physical exam (each visit)
Blood draws (each visit)
Bone marrow biopsy (4 times in 40 weeks)
Two quality of life questionnaires (each visit)
PET CT scan (4 times in 40 weeks)
Infusion of PRM-151 (11 times in 36 weeks)

Efficacy of PRM-151 in patients with MF must be proven.

Risks of PRM-151 (recombinant) may result in body's responses through the
development of anti-PRM-151, or by reaction to intravenous administration.