by Manasi Vaidya in New York.
Mesenchymal stromal cell (MSC) therapies have experts noting that the field is still grappling with questions on the ideal source for MSCs and optimal dosing strategies. Hence, calling a potential winner between the three key players, Athersys, Mesoblast and Pluristem Therapeutics, is tough. Also, unlike biologics or antivirals being tested in Covid-19, the ability to scale-up manufacturing will be a critical component if MSCs are to be a panacea to all patients with Covid-related acute respiratory distress syndrome (ARDS).
While an ideal tissue source for the MSCs to be effective is not clear, each product may have to be weighed against supply constraints for the source material. In terms of dosing, a strategy that allows multiple dosing may be beneficial but could be logistically difficult given the critical nature of these ARDS patients. Furthermore, while companies are largely evaluating these therapies in patients with moderate-to-severe ARDS, the ideal timing for initiating treatment given the varying levels of lung damage still needs to be understood.
On 13 April, Athersys, which has a $353.7m market cap, received an IND approval for MultiStem, and the study is planned to start this quarter. Mesoblast received its IND approval for remestemcel-L on 6 April, sending its stock up 65%. Mesoblast’s market cap is ($694m). The company expects to initiate its study imminently, CEO Silviu Itescu told this news service. On 13 April, Pluristem said it intends to file for the initiation of a multinational clinical trial using its PLX cells, which resulted in the stock peaking at 37% on that day. Pluristem’s market cap is $150.8.
Other MSC-focused companies in the fray include Hope Biosciences, which has filed an IND for a therapeutic trial in Covid-19 patients and is initiating a Covid-19 prevention study, as reported by this news service on 10 April. Orbsen Therapeutics initiated a Phase IIa trial (NCT03042143) in the UK last week.
This news service reported that data from a clinical study in China and Pluristem’s compassionate use program were encouraging to support the exploration of MSCs in patients with ARDS due to Covid-19, but the data was to be interpreted cautiously due to small patient numbers and the nonrandomised nature of the data.
Athersys did not respond by press time, while Pluristem did not respond to a request for comment.
Answers needed on MSCs source and dosing specifics
The jury is out on whether cord blood, fat or bone marrow is the best source of MSCs, said Dr David Thickett, professor, Respiratory Medicine, Birmingham Acute Care Research Group, UK. The difficulty is unique to MSCs compared to other biologics being explored for Covid-19, noted Dr Daniel Weiss, professor, Critical Care Medicine, University of Vermont Medical Center, Burlington.
MultiStem and remestemcel-L are both bone marrow-derived, while PLX cells are prepared from placenta and all three are allogeneic therapies. MultiStem is derived from multipotent adult progenitor cells, while remestemcel-L comprises culture-expanded mesenchymal stem cells. PLX cells are described as mesenchymal-like stem cells.
Hope Biosciences’ HB-adMSCs are manufactured from adipose tissue, while Orbsen’s ORBCEL is made from umbilical cord tissue. As long as the MSCs are purified, the source should not matter, said Hope CEO Donna Chang. However, the source needs to be consistent, and getting MSCs from the bone marrow of older patients can be challenging, she noted on the rationale behind the company’s focus on fat cells, which are easier to obtain from any patient no matter how sick they are.
Yet, Dr Partow Kebriaei, professor, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, pointed out, MSCs are thought to have different properties based on which tissues they originate from, adding clinical experience has been the most with MSCs derived from bone marrow. Nonetheless, using the umbilical cord as a source is reasonable, said Dr Michael Matthay, professor of Medicine, University of California San Diego. Umbilical cord tissue also has the benefit of being in continuous supply, Thickett added.
Besides questions on the optimal source for MSCs, it is also not clear how many cells need to be used, and the dosing strategies with various approaches being explored in ARDS studies range from a single administration to four doses, said Weiss. While Pluristem has not divulged details for its planned trial or from use under compassionate use protocols, Athersys will evaluate two MultiStem doses in the open-label portion of its Phase II/III. The randomised part of its previous Phase I/II trial evaluated a 900-million-cell dose infusion. The Mesoblast study will assess two remestemcel-L infusions several days apart in the first week, this news service reported yesterday, with CEO Silviu Itescu noting the strategy is based on the company’s positive Phase III graft versus host disease trial, which tested two doses per week for four weeks.
Most MSC studies in various indications have assessed single infusions, but it is not clear whether one, high-dose infusion would be better than frequent, lower-dose infusions, said Thickett. There is rationale from non-ARDS studies using MSCs to give multiple infusions but that could be difficult considering the window for a severely ill patient may be narrow, he added. Hope’s proposed protocol for a study in Covid-19 patients is for multiple infusions of 100 million cells per dose, Chang said.
Additionally, the ideal administration time is not clear, said Weiss. Thus far, most clinical data with therapeutic interventions in Covid-19 patients, including cell therapies, has been in critically ill patients, who receive mechanical ventilation. But even for patients on a ventilator, lung damage is not uniform, Kebriaei explained. So the minimum oxygen requirement to determine patient eligibility or the maximum level that indicates fibrosis has taken place is not known, she said.
Manufacturing capacity for widespread use a potential hurdle
While companies seem to have enough capacity to manufacture their MSC products for clinical trial evaluation, the ability to produce the required number of doses if they get approved for widespread use is the real issue, Thickett added. Nonetheless, following the pandemic, there has been a strong ramp-up in activity in the US and Europe by cell therapy companies, according to Weiss. Also, in recent years, companies have improved their manufacturing protocols such that the final MSC product is uniform and that is no longer a limitation, said Kebriaei.
Orbsen can get 2,000 or more doses per umbilical cord and has a system set up for multiple sources of the tissue, said CEO Larry Couture. The company may consider conducting a Phase IIb ARDS study in the US, depending on strategic decisions taking into account its assets in other indications, Couture said. Yet, he pointed out, the FDA bans the import of cells from the UK due to a regulation put in place more than two decades ago in response to mad cow disease. That element of the manufacturing process would still need to be sorted before conducting a US study, he said.
Mesoblast has a strong supply chain to meet the expected demand and the ability to scale up as required, said Itescu. Proprietary technology on growth media that increases the yield and the ability to move from 2D to 3D bioreactors should address any increased demand, he added. As the company improves its technology, an increase in production is expected as well, said Itescu.
Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.