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TOPIC: Mesoblast Delivers Good Phase II Renal Data

Mesoblast Delivers Good Phase II Renal Data 08 Jun 2015 21:57 #4641

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POSITIVE TRIAL RESULTS OF MESOBLAST CELL THERAPY IN PATIENTS
WITH DIABETES AND ADVANCED CHRONIC KIDNEY DISEASE
New York; USA; and Melbourne, Australia; 9 June 2015: Mesoblast Limited (ASX:MSB;
USOTC: MBLTY) today announced that results from the Company's Phase 2 trial in patients
with diabetic nephropathy showed that a single infusion of its intravenously delivered
allogeneic mesenchymal precursor cell (MPC) product candidate MPC-300-IV was safe,
reduced damaging inflammation, and preserved or improved renal function over at least 24
weeks.
The results were presented at the late-breaking scientific sessions of the 75th annual
meeting of the American Diabetes Association (ADA) currently being held in Boston. The ADA
annual meeting brings together approximately 14,000 participants, including clinicians and
researchers from 124 countries.
The trial's lead investigator, Associate Professor David Packham, Department of Medicine,
University of Melbourne, and Director of the Melbourne Renal Research Group, stated that:
“The results show that Mesoblast's allogeneic cell therapy was safe and may be particularly
useful in patients with moderate to severe diabetic nephropathy, a disease which, despite all
existing therapies, continues to have a high rate of progression to dialysis or transplantation,
and to portend a high risk of death from cardiovascular disease."
Diabetic nephropathy affects 40-50% of patients with type 2 diabetes and accounts for about
40% of all patients with end-stage renal disease (kidney failure). It is thought to be caused
by ongoing monocyte inflammation and endothelial dysfunction (abnormal blood vessels) in
the kidneys. Mesoblast's bone marrow-derived MPCs are potent modulators of monocyte
inflammation, and have been shown in preclinical studies to reduce monocyte infiltration in
diabetic kidneys and to reverse endothelial dysfunction. Consequently, Mesoblast is
developing MPC-300-IV for intravenous delivery in the treatment of diabetic nephropathy.
MPC-300-IV was evaluated in a double-blind, randomized, placebo-controlled, dose-
escalating Phase 2 trial of 30 patients with type 2 diabetes and moderate to severe renal
impairment, stage 3b-4 chronic kidney disease (CKD), who were already on a stable regimen
of the standard of care therapy for diabetic nephropathy (renin-angiotensin system inhibition
with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers). Patients
received a single infusion of 150 million MPCs, 300 million MPCs, or saline control.
The objectives of the trial were to evaluate safety and to explore potential efficacy signals of
MPC treatment on renal function. The pre-specified primary efficacy endpoint was to
evaluate effects of MPC treatment relative to placebo on renal functional decline at 12 weeks,
as defined by change in glomerular filtration rate (GFR) measured both by direct isotope scan
and by serum-creatinine based estimation, and then for an additional 48 weeks of follow-up.
Pre-specified secondary analyses included GFR differences between treatment and placebo
groups with baseline GFR>30ml/min/1.73m2 (stage 3b CKD, accounting for 60% of enrolled
patients), and treatment-related effects on the monocyte-derived cytokine interleukin-6 (IL-
6), a major inflammatory marker associated with renal failure progression and adverse
cardiovascular outcomes.
{JAPAN PATENT DRAFT ASX ANNOUNCEMENT v3 25 MARCH 2015 LM032515 - 1}

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Mesoblast Delivers Good Phase II Renal Data 08 Jun 2015 22:00 #4642

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The primary efficacy endpoint of decline or change in GFR was in line with the 2012 joint
workshop held by the United States Food and Drug Administration and the National Kidney
Foundation which recommended that time to 30%-40% decline in GFR is an acceptable
primary endpoint for evaluating potential benefits of new therapies for this patient population
(Levey et al. GFR decline as an endpoint in clinical trials for CKD. American Journal of Kidney
Disease 2014:64(6):821-835). This joint workshop recognized the significant unmet medical
need and urgency to make new therapies accessible to patients who may benefit from them.
This revised endpoint could make new treatments available earlier to patients with chronic
renal failure by reducing trial size and duration, compared with the previously accepted
composite endpoint of time to first occurrence of doubling of serum creatinine (equivalent to
a 57% reduction in GFR), renal replacement or death.
Key findings at 12 and 24 weeks in the MPC-300-IV trial were:
• Safety profile for MPC treatment was similar to placebo, with no treatment-related
infusion or other events.
• Efficacy testing showed that MPC-treated subjects had improved renal
function relative to placebo, as defined by preservation or improvement in GFR at
both 12 and 24 weeks; these effects were seen even though this trial was not
powered to show statistical significance of treatment.
• While all three groups had similar mean GFR at baseline, 34.6, 35.7 and
34.6 ml/min/1.73m2
, at 12 weeks the placebo group showed a decline in measured
GFR of 4.0 ml/min/1.73m2 and 3.9 ml/min/1.73m2 relative to the groups receiving a
single infusion of either 150M MPC or 300M MPC, respectively; the difference in
creatinine-based estimated GFR decline between placebo and the 150M group reached
significance (p=0.05).
• By isotope-measured GFR, in patients with GFR>30 ml/min/1.73m2 at baseline the
placebo group showed a GFR decline at 12 weeks of 6.2 ml/min/1.73m2 relative to the
pooled MPC-treated patients (p=0.07).
• By creatinine-based estimated GFR, the placebo group with
GFR>30 ml/min/1.73m2 at baseline showed a GFR decline at 12 weeks of
4.5 ml/min/1.73m2 and at 24 weeks of 4.6 ml/min/1.73m2 relative to the pooled MPC-
treated patients (p=0.04 and p=0.13, respectively).
• There was a correlation between increased baseline IL-6 levels and improvement at
12 weeks in both serum creatinine and GFR (r=0.57, p=0.008) in MPC-treated
patients.
• MPC treatment was associated with a dose-dependent inhibition of IL-6 increase over
12 weeks; serum IL-6 levels increased by 2.5 pg/dl at 12 weeks in the placebo group
compared to a reduction of 0.2 pg/dl in the 300M MPC group (p=0.01).
Key study conclusions were:
• The safety profile and the potential efficacy signals of allogeneic MPC therapy for
prevention or reversal of renal functional decline in diabetic nephropathy supports
advancing the clinical program in patients with the highest medical need, e.g. rapid
progression towards dialysis or renal transplantation, defined as an annual GFR
decline of >5ml/min/1.73m2
, and high risk of cardiovascular events.
• Positive response to MPC therapy may be enhanced by the presence of viable, but at-
risk, renal tissue and an aberrant pro-inflammatory milieu in the kidney.
• Baseline GFR>30 ml/min/1.73 m2 and high interleukin-6 (IL-6) levels may be
biomarkers that predict efficacy with MPC treatmewith
• Reduction in IL-6 levels suggests that the mechanism of action by MPCs may involve
reduction of pro-inflammatory M1 monocyte cytokines in the diabetic kidney.
• MPC therapy may have applications in diverse renal conditions where inflammation
plays a central role.
Mesoblast Chief Executive Silviu Itescu said: “We are very encouraged by the safety profile
and the sustained efficacy signal that we have seen over 24 weeks after a single intravenous
infusion of our allogeneic cell-based therapy in patients with diabetes and advanced chronic
kidney disease. The growing burden of diabetic nephropathy and its impact on healthcare
make this an important disease target for Mesoblast and our technology. We will specifically
evaluate whether MPC-300-IV can alter the natural course of the disease in patients with
rapid progression towards dialysis or renal transplantation, and will focus on early access
regulatory pathways for developing this product.”
Diabetic Nephropathy
Diabetic nephropathy is the single leading cause of end-stage kidney disease,
accounting for nearly half of all end-stage kidney disease cases in the United States
and over 40% of new patients entering dialysis treatment. There were almost 2
million cases of advanced diabetic nephropathy in 2013. With the current diabetes
population exceeding 20 million, over 6 million new patients are expected to develop
diabetic nephropathy in the United States alone. Staging of CKD is based on absolute
levels of GFR, and GFR decline is on the path of progression to kidney failure (stage 5,
GFR<15ml/min/1.73m2
). The current standard of care (renin-angiotensin system
inhibition with angiotensin converting enzyme inhibitors or angiotensin II receptor
blockers) only slows the rate of progression to kidney failure by 16-25%, leaving a
large residual risk for end-stage kidney disease. For patients with end-stage kidney
disease, the only treatment option is renal replacement (dialysis or kidney
transplantation) which incurs high medical costs and substantial disruptions to a
normal lifestyle. Due to a severe shortage of kidneys, in 2012 approximately 92,000
persons in the United States died while on the transplant list. For those on dialysis,
the mortality rate is high with an approximately 40% fatality rate within two years.
Mesoblast Limited
Mesoblast Limited (ASX: MSB; USOTC: MBLTY) is a global leader in regenerative medicine.
The Company has leveraged its proprietary technology platform, which is based on
specialized cells known as mesenchymal lineage adult stem cells, to establish a broad
portfolio of late stage product candidates. Mesoblast’s allogeneic or ‘off-the-shelf’ cell
product candidates target significantly advanced stages of diseases where there are highly
unmet medical needs, including cardiovascular conditions, orthopedic disorders,
immunologic/inflammatory disorders and oncology/hematology conditions. The lead
therapeutic product candidates under investigation include MPC-150-IM for chronic
congestive heart failure; MPC-06-ID for chronic discogenic low back pain, MSC-100-IV for
acute graft versus host disease, and MPC-300-IV for biologic refractory rheumatoid arthritis,
and diabetic nephropathy.
For further information, please contact:
Julie Meldrum
Global Head of Corporate Communications
Mesoblast Limited
T: +61 (0) 3 9639 6036
E: This email address is being protected from spambots. You need JavaScript enabled to view it.
{JAPAN PATENT DRAFT ASX ANNOUNCEMENT v3 25 MARCH 2015 LM032515 - 1}
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Mesoblast Delivers Good Phase II Renal Data 09 Jun 2015 10:17 #4643

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Thanks WST- to be honest, I do not have a clue what this all represents.

Maybe we should ask Camilo Ricordi for his opinion.

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Board moderator and Site-owner. I still regret the day I started analysing the prospects of MacroPore (now Cytori) back in 2004- a left-over from the tech-bubble at that time from the century change in my portfolio- and became addicted to Cytori´s fat cell technology. :cry:

Mesoblast Delivers Good Phase II Renal Data 09 Jun 2015 10:47 #4644

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Fas,

In a simplistic view, the strong Phase II p values represent a bright spot in an industry that has not shown much. Anyone who understands renal disease who could comment on the significance of the results would be appreciated.

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