Candidate: RYONCIL™ (Remestemcel-L)

Type: Allogeneic mesenchymal stem cell (MSC) product candidate, now under FDA priority review for treating pediatric steroid-refractory acute graft versus host disease (SR-aGVHD), with a Prescription Drug User Fee Act (PDUFA) action date of September 30, 2020. On August 13, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 9-1 to recommend approval of RYONCIL in children pediatric patients with SR-aGVHD.

2021 Status: Mesoblast on April 30 announced 60-day results from a randomized controlled trial of remestemcel-L in 222 ventilator-dependent COVID-19 patients with moderate/severe acute respiratory distress syndrome (ARDS), which had been halted after the third interim analysis, as previously announced. Remestemcel-L reduced mortality through day 60 by 46% compared with standard of care (26% vs 42%) in the prespecified group of 123 treated patients below age 65, but not in patients 65 or older. However, Remestemcel-L reduced mortality by 75% (14% vs. 45%) and increased days alive off mechanical ventilation in patients under age 65 when combined with dexamethasone, in comparison with controls on dexamethasone, the company said.

2020 Status: Novartis Secures Exclusive Remestemcel-L Rights—Novartis said November 19 that it entered into an exclusive worldwide license and collaboration agreement with Mesoblast to develop, commercialize and manufacture remestemcel-L for the treatment of acute respiratory distress syndrome (ARDS), including that associated with COVID-19.

Novartis agreed to pay Mesoblast $25 million upfront and invest $25 million in Mesoblast equity, as well as additional payments and royalties tied to achieving development, regulatory and commercial milestones. Also, Novartis also agreed to support commercial manufacturing scale-up.

The companies’ agreement gives Novartis the option to distribute remestemcel-L for graft versus host disease (GVHD) outside Japan, while both companies have rights to co-fund development and commercialization for other non-respiratory indications.

Novartis said it intended to begin a Phase III study in non-COVID-19-related ARDS after the anticipated closing of the license agreement and successful completion and outcome of the current study.

Mesoblast said September 4 that the independent Data Safety Monitoring Board (DSMB) recommended continuation of the company’s randomized controlled Phase III trial (NCT04371393) of remestemcel-L in COVID-19 infected patients with moderate to severe acute respiratory distress syndrome (ARDS) on ventilator support. The recommendation followed completion of trial’s first interim analysis, which was performed on the first 30% of the total target of randomized patients.

The DSMB reviewed the trial’s primary endpoint, all-cause mortality within 30 days of randomization and all safety data. The key secondary endpoint is the number of days alive off mechanical ventilatory support within 60 days of randomization. Up to 300 patients are set to be randomized 1:1 to receive either two intravenous infusions of remestemcel-L within five days, or placebo, on top of maximal care. Enrollment is expected to be completed by the fourth quarter of 2020.

Two days earlier, Mesoblast received ethics approval to include Australian hospitals in the Phase III trial. Participating hospitals in Melbourne and Sydney have been granted approval by the Human Research Ethics Committee of Monash Health and will join more than 17 leading U.S. medical centers already in the trial.

“As an Australian company developing a potential treatment for COVID-19 ARDS, the primary cause of death in patients infected with COVID-19, we have a responsibility to evaluate remestemcel-L in Australian patients as the country continues to grapple with COVID-19,” said Mesoblast CEO Silviu Itescu, MBBS, FRACP.

The study is being conducted by the NIH-funded Cardiothoracic Surgical Trials Network, and cleared by the FDA.

In July, Mesoblast initiated an expanded access protocol (EAP; NCT04456439) in the U.S. for compassionate use of its allogeneic mesenchymal stem cell (MSC) product candidate remestemcel-L in the treatment of COVID-19 infected children with cardiovascular and other complications of multisystem inflammatory syndrome (MIS-C). Patients aged 2 months to 17 years may receive one or two doses of remestemcel-L within five days of referral under the EAP. The protocol, filed with the FDA, provides physicians with access to remestemcel-L for an intermediate-size patient population under Mesoblast’s IND application.

Mesoblast said in May that the first patients have been dosed in the Phase II/III trial. The clinical protocol was based on results from a pilot study using remestemcel-L under emergency compassionate care at Mt Sinai Hospital in New York, with 75% (9 of 12) of patients with moderate to severe ARDS successfully taken off a ventilator and discharged from hospital within a median of 10 days.

In April, Mesoblast received FDA clearance for its IND application to treat patients with ARDS caused by COVID-19 with intravenous infusions of remestemcel-L, nearly a month after disclosing March 10 it was in active discussions with government and regulatory authorities, medical institutions and biopharma companies about assessing remestemcel-L in that indication.

The company has cited a clinical study published in February which reported that allogeneic MSCs cured or significantly improved functional outcomes in all seven treated patients with severe COVID-19 pneumonia. Mesoblast also cited post-hoc analyses of a study in 60 chronic obstructive pulmonary disease (COPD) patients submitted for presentation at a future conference, showing significantly reduced inflammatory biomarkers, and significantly improved pulmonary function in patients with elevated inflammatory biomarkers. The same inflammatory biomarkers are also elevated in COVID-19.

“Consequently, remestemcel-L could be an effective treatment to reduce the high mortality in patients with COVID-19 who are older, have elevated inflammation biomarkers, and develop moderate to severe ARDS,” Mesoblast CEO Silviu Itescu told GEN. “Clinical trials using remestemcel-L in ARDS associated with COVID-19 disease are expected to be initiated shortly.”


COVID-19: 300 Candidates and Counting

To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:

FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.

DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data

KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.

TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.

GEN has also tagged the most common treatment types:

● ANTIVIRAL
● VAX
● ANTIBODY
● RNA