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BIOWORLD  Feb. 3  2020..
Australia’s Mesoblast submits final module of rolling BLA submission for pediatric GVHD stem cell therapy
By Tamra Sami....... Mesoblast submits final module of rolling BLA submission for pediatric GVHD stem cell therapy...
February 3, 2020
PERTH, Australia – Australian stem cell therapy company Mesoblast Ltd. has filed the final module of its rolling BLA submission for its allo- geneic mesenchymal precursor cell therapy, remestemcel-L (https://www.cortellis.com/intelligence/qsearch/"remestemcel-L"), after it showed strong survival rates in children with acute steroid-refractory graft-vs.-host disease (aGVHD).
Submitted Jan. 31, the final module covered quality control and manufacturing for the stem cell candidate, which is branded as Ryoncil. Mesoblast's allogeneic candidates are based on mesenchymal lineage cells col- lected from the bone marrow of healthy adult donors.
Mesoblast filed the first component of its rolling BLA submission for the pediatric aGVHD indication in April 2019. The product has received fast track designation for aGVHD, and Mesoblast intends to request a priori- ty review once its BLA filing is accepted by the FDA.
   A priority review would provide a six-month review period compared to 12 months for a regular review. Mesoblast CEO Silviu Itescu said he expects approval and launch by midyear.
The company reported in February 2018 that the phase III trial met the primary end- point (https://www.bioworld.com/articles/363853-mesoblast-poised-to-file-bla-clears- final-hurdle-in-phase-iii-gvhd-pediatric-trial), showing an overall response rate of 69% compared to a historical response rate of 45% at day 28 of treatment (p=0.0003).
The FDA had requested additional 180-day survival data (/articles/363853-mesoblast- poised-to-file-bla-clears-final-hurdle-in-phase-iii-gvhd-pediatric-trial), which showed a survival rate of 79% compared to an expected 30% survival rate in its pediatric phase
Silviu Itesco, CEO, Mesoblast
III trial in aGVHD.
The open-label phase III trial enrolled 55 children with steroid-refractory aGVHD between the ages of 2 months and 17 years in 32 sites across the U.S., with 89% of patients suffering from the most severe form of the disease (grade C/D).
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  Those outcomes are consistent with previous results in 241 children with steroid-refractory aGVHD who failed to respond to multiple biologic agents and were treated under an expanded access program that fol- lowed outcomes through 100 days. The multi-infusion regimen in both the expanded access program and the phase III trial was well-tolerated.
Roughly 12,000 bone marrow transplants are conducted each year in the U.S., and about half of those pa- tients will develop GVHD; one-fourth of all patients who receive transplants are children.
“The GVHD indication is a chance to launch our first product in the U.S. and retain full value,” Itescu said.
In November 2019, Mesoblast completed an AU$75 million (US$50.32 million) placement (/articles/429717- mesoblast-raises-au75m-to-prepare-for-us-launch-of-allogeneic-cell-therapy) to gear up to launch its first stem cell product into the U.S. market. The CEO is planning for a sales force of 10 to 20 people who will sell the allogeneic product to 15 or so transplant centers.
“We’re investing in manufacturing, so we have inventory ready to go. We don’t want to be surprised and not have enough to go around.” The company’s manufacturing facility is based in Singapore and is owned by Lonza. Itescu said the company is looking at bringing another facility online following approval. “We’d need a back-up facility, and whether that will be in the U.S. or elsewhere has yet to be decided.”
The company's goal is for Ryoncil to be the first commercially manufactured allogeneic cellular therapy avail- able in the U.S. The product also would be first out of the gate for children and the adult acute population with grade C or D aGVHD.
“We don’t have any competitors at all in children or those with the most advanced life-threatening compo- nent of the disease,” Itescu said.
Treatment is a four-week course, but, “effectively, the responder rate means this is a cure.”
The highest need in the U.S. is among the African American population, because it is hard to find matched donors due to the heterogeneity of the gene pool in the U.S., Itescu noted.
If the donor matching were improved, “we could increase transplants by 200 percent,” he said.
“This approval would have implications for our pipeline. The approval alone has the potential to be a major revenue stream. Beyond that, other areas of high unmet need where nothing works in inflammatory-related conditions would be a possibility.”
The CEO said he anticipates that the same data will satisfy European regulators.
The stem cell therapy is already approved in Japan for aGVHD (branded as Temcell) in both pediatric and adult indications. It was the first allogeneic regenerative medicine to receive full approval in Japan and was launched with partner JCR Pharmaceuticals Co. Under the terms of the partnership, Mesoblast receives roy- alties on Temcell product sales for all licensed indications.
In Japan, the product is priced at roughly $165,000 on average, Itescu said, noting that the cost of health care in the U.S. is about double that of Japan, and he would expect the price to reflect that difference.
The CEO said the size of the addressable market in the U.S is eight times the size of the Japan market due to the volume of patients and higher pricing.
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  Mesoblast has two other stem cell therapy candidates in phase III trials. Its MPC-150-IM is in two phase III tri- als for chronic heart failure – one for end-stage (class IV) heart failure patients with left ventricular assist de- vices (LVADs) and another larger trial in advanced (stage III) heart failure.
The FDA granted MPC-150-IM breakthrough therapy designation for the end-stage indication under the re- generative medicine advanced therapies (RMAT) designation under the 21st Century Cures Act.
The next trial to report is the larger end-stage heart failure trial, which Itescu said is on track to report midyear. Mesoblast previously reported that interim phase III data met the primary endpoint.
A phase III trial in chronic low back pain due to intervertebral disc degeneration is also underway.
Headquartered in Melbourne, Mesoblast also has facilities in New York, Singapore and Texas and is listed on the Australian Securities Exchange (ASX:MSB) and on Nasdaq (MESO).
Mesoblast shares (ASX:MSB) dipped slightly on the news, down 1.3% to AU$2.96 per share Feb. 3.
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