Remestemcel-L

Unassigned

New Medicines

RyoncilAcute steroid-refractory graft versus host disease (GvHD) in children - second-line following allogeneic bone marrow transplant (BMT)

Information

Ryoncil
New molecular entity
Mesoblast
Mesoblast

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Not approved
Yes
Yes
Nov 20On November 17, a Type A meeting was held with the FDA to discuss the review of the Biologics License Application for remestemcel-L and a potential pathway for accelerated approval with a post-approval requirement to conduct an additional RCT in patients 12 years and older. Mesoblast reports in its Q1 FY 2021 report, that at the current time it appears that the FDA review team will not agree to accelerated approval. However, the definitive outcome of the Type A meeting will not be known until Mesoblast receives the formal minutes which are expected within 30 days of the meeting. If the current review team does not agree to accelerated approval, Mesoblast will request a further Type A meeting to initiate the well-established FDA dispute resolution pathway. Under the terms of the license and collaboration agreement, Novartis has an option to become the commercial distributor for remestemcel-L in SR-aGVHD outside of Japan [27].
Oct 20In its Complete Response Letter rejecting Ryoncil, the FDA asked for at least one more RCT in adults and/or children to provide further evidence of efficacy. The company thinks it could ask for accelerated approval pending confirmatory data from a late-stage trial. The FDA needs further information showing the relationship of potency measurements to the product ’s biologic activity [26].
Oct 20FDA requires results from an additional trial before granting full authorisation. This decision is counter to the earlier briefing advise from the Oncologic Drugs Advisory Committee (ODAC) to approve the drug. Accelerated approval based on existing data and unmet clinical need is being explored by the company [25].
Aug 20US FDA Oncologic Drugs Advisory Committee votes in favor that available data support efficacy of remestemcel-L in pediatric patients with SR-aGVHD [24].
Apr 20US FDA accepts BLA for treatment of children with steroid-refractory acute GVHD for priority review with PDUFA action date of 30/09/20. If approved, Mesoblast will make RYONCIL immediately available in the US [21].
Aug 19Remestemcel-L is approved in Canada for the treatment of acute, steroid-refractory GvHD in paediatric patients, and for the acute form of the disease in paediatric patients in New Zealand [20].
Aug 19Preregistration for Graft-versus-host disease (Treatment-experienced, In children) in USA [20]
Aug 19US FDA granted fast track designation for the treatment of children with steroid refractory acute GVHD [20]
May 19Initiated a rolling Biologics License Application to the FDA for children with steroid-refractory acute GVHD
Dec 16Mesoblast and Mallinckrodt Pharmaceuticals enter into an equity purchase agreement to negotiate development and commercialisation rights for remestemcel-L for acute GvHD in all territories outside of Japan and China [18].
Aug 14Mesoblast announces it intends to submit a registrational filing for paediatric GvHD in 2016 and is aiming for a 2017 launch in the US [17].
Apr 14Expanded access to Prochymal is no longer available in the US for adults, but is for children [16].
Feb 13EMA grants orphan drug designation to remestemcel-L (Prochymal™) for acute GvHD [13].
Jun 12Approved in New Zealand for the treatment of acute graft-vs-host disease (GvHD) in children [11].
May 12Approved in Canada for use in children with GvHD whose disease is not controlled with corticosteroids. First global approval of a stem cell drug [10].
Apr 11Filed in Canada July 2010 with priority review status. In January 2011 requested additional information. In November 2010, the company met with the FDA to discuss a US application where it is available in an expanded access programme for paediatric patients [7].
Jan 10US approval was anticipated by the end of 2009, and EU approval was expected in 2010. Disappointing interim results from PIII trials (Studies 280 and 265) reported in September 2009 has forced the company to questions Prochymal’s future for this indication (5)
Jan 09Orphan status and fast-tracked in both the Eu and US (1)

Category

Culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor. It is administered to patients in a series of intravenous infusions.
Immunosuppressed patients who receive white blood cells from another person are at risk of GVHD [9]. There are approximately 25,000 HSCTs globally per year. Nearly 50% of these develop acute GVHD and a fraction of these will progress to severe GVHD which is steroid refractory. In patients that fail to respond to steroids, mortality can reach 85%. There are no approved therapies for acute GVHD. Standard of care is corticosteroids as a first line agent [15].
Acute steroid-refractory graft versus host disease (GvHD) in children - second-line following allogeneic bone marrow transplant (BMT)
Intravenous

Further information

Yes
Has been prioritised

Trial or other data

Apr 20Remestemcel-L has been prioritised for potential TA guidance production. Topic has been passed to scoping team to prepare for a consultation exercise [23].
Apr 20Aggregated results from 309 children treated with RYONCIL were presented at the 2020 annual meeting of the American Society for Transplantation Cellular Therapy and the Center for International Blood & Bone Marrow Transplant Research (TCT). The data showed that treatment with RYONCIL across three separate trials resulted in consistent treatment responses and survival outcomes in children with steroid-refractory acute graft versus host disease (SR-aGVHD). Key findings and conclusions were: Consistent safety and efficacy were observed across the continuum from first-line treatment after steroid failure through the most challenging patients who received RYONCIL as salvage after exhausting all other options. In the aggregated dataset, 204 of the 309 (66%) patients achieved an overall response at Day 28 following a four-week course of RYONCIL. Results were consistent across all grades of disease, including most severe (IBMTR Grade C/D or Glucksberg Grade 3/4). In the most severe patients (Grade C/D), who accounted for 82% of all treated patients, Day 28 overall response was 65%. Overall response at Day 28 was strongly predictive of survival at Day 100 and Day 180. Day 28 responders were more than twice as likely to survive as non-responders (84% vs 39% at Day 100, and 83% vs 38% at Day 180). RYONCIL was well tolerated with no infusion-related toxicity and no identified safety concerns [22].
Apr 18NCT02336230 completed.[21]
Dec 17Available data from clinical dose ranging studies identified an effective dose to be 2 x 10-6 MLCs/kg, body weight, to be administered repeatedly for at least four weeks after diagnosis of aGVHD. For the U.S. market, the unit packaging is 25 million cells per vial for intravenous infusion [19].
Dec 17Enrolment in a PIII trial (NCT02336230) completes. Interim results show the study met its primary endpoint of Day 28 overall response. The study was initiated in collaboration with Quintiles in Jan 15, to assess the efficacy and tolerability of remestemcel-L in patients with acute GvHD, following allogeneic haematopoietic stem cell transplant (HSCT) that failed to respond to systemic corticosteroid therapy. The trial enrolled 60 paediatric patients in the US. Positive data from the study will support the accelerated approval filling in the US. Mesoblast intends to expand use of the drug in adult patients with high-risk steroid-refractory aGVHD [18].
May 14Acute GVHD with liver or low gut involvement is a life-threatening complication of HSCT with a poor prognosis. In a PIII study involving patients with liver GVHD, Prochymal improved response by 76% vs 47% in controls (p=0.026, n=61) and durable complete response in 29% versus 5% (p=0.046). Mesoblast plans to engage with regulatory authorities regarding a new, more targeted PIII study in this subset of pts [15].
Oct 13Osiris has entered into an agreement with a subsidiary of Mesoblast Limited for the sale of Osiris’ culture-expanded mesenchymal stem cell business, including Prochymal [14]
Oct 12The collaboration between Osiris and Genzyme has concluded and all rights to Prochymal (and Chondrogen) worldwide revert back to Osiris. Prochymal is currently available in 7 countries including the US under an Expanded Access Programme [12].
Mar 12Sanofi (which acquired Genzyme in 2011) has discontinued PIII studies in paediatric GvHD. Osiris, a US stem cell therapy firm which was collaborating with Genzyme, now have the rights to Prochymal and will continue development and commercialization [8].
Feb 10Company report results from the study (Protocol 275) that evaluated Prochymal as a rescue therapy in 59 paediatric patients with severe, treatment resistant GvHD. Patients were evaluated for response to Prochymal at day 28 of therapy and survival through day 100. Patients who experienced a partial response by day 28 were eligible for continued treatment. At study entry, 6 patients had Grade B, 18 patients, Grade C and 35 patients Grade D GvHD. Grades C and D represent the most severe forms. Included patients were unresponsive to an average of 3 previous therapies (failed steroids and other immunosuppressive agents) for an average of 46 days. Overall response to treatment with Prochymal at 28 days was 63%. Response to Prochymal at day 28 significantly improved survival over patients who progressed (78% vs. 9%, p<0.05). Full study results are published in a Feb supplement of the journal, Biology of Blood and Marrow Transplantation [6].
Sep 09Prochymal failed both GVHD PIII trials. In one of the studies (protocol 280, n=260) for steroid refractory GVHD, 35% of the patients on Prochymal responded to the therapy vs 30% on placebo. And in a second study (protocol 265, n=192) for first-line GVHD patients, the respective response rates were 45% vs 46%. Positive outcomes from the trials noted by the company include: the primary endpoint for the steroid-refractory GvHD trial (durable complete response) for the per-protocol population approached statistical significance (40% vs. 28%, p=0.087, n=179);in patients with steroid-refractory liver GvHD, there was a significantly improved response (76% vs. 47%, p=0.026, n=61) and durable complete response (29% vs. 5%, p=0.046); response rates in patients with steroid-refractory gastrointestinal GvHD were 88% (vs. 64%, p=0.018, n=71); and in paediatric patients, there was a trend to improved response rates (86% vs. 57%, p=0.094, n=28). The company state that: in protocol 265 the majority of patients were suffering from skin GvHD, which responded significantly better to steroids expected; in protocol 280, the Prochymal cohort had more severe GvHD (27% had grade D GvHD vs. 16% of placebo patients, p=0.05). Based upon the results of the steroid-refractory GvHD trial, the company plans to file an amendment with the FDA to the current expanded access programme, broadening the entry criteria to include patients with severe GvHD of the liver [4].
Apr 09Enrollment in PIII trial complete. The study will assess the safety and efficacy of Prochymal in conjunction with steroid therapy in patients with newly diagnosed acute GvHD (grades B-D). The study enrolled 190 patients from 52 leading transplant sites in the US, Canada and Australia. The main outcome is the number of patients surviving at least 90 days that achieve a Complete Response (CR) when Prochymal is added to steroid therapy vs. those receiving steroids alone. Patients are considered treatment failures if they do not achieve a CR within 28 days of commencing therapy, if the steroid dose is increased or other immunosuppressive agents are added, or if the patient does not survive 90 days after initial therapy. (3)
Jan 09A pivotal phase III trial in approximately 244 patients with steroid refractory GvHD (NCT00366145) in 244 patients in the US, Canada, Europe and Australia (including 27 paediatric patients) completed enrollment in Dec 2008. The company expects to file for regulatory approval in the US, Canada and Europe, following completion of this phase III trial (1)
Jan 09Expanded access programme approved by the FDA for paediatric GvHD pt in May 2008, and in adults with life-threatening GvHD in Jan 09 (2).

Evidence based evaluations

RyoncilAcute, steroid-refractory graft versus host disease (GvHD) in adults

Information

Ryoncil
Licence extension / variation
Mesoblast
Mesoblast

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes
Yes
Dec 20There is no information available from the company website re: active development, although still listed in company pipeline. Remestemcel-L, as TEMCELL HS, has been available for aGvHD in adults and children in Japan since Mar 16 [6].
Apr 20Has orphan drug status in EU and US [4].
Apr 20According to company pipeline, remestemcel-L is not yet in PIII trials. Mesoblast is planning to pursue a licence for aGvHD in adults, after successful launch for paediatric aGvHD [3].

Category

Culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor. It is administered to patients in a series of intravenous infusions.
The number of allogeneic bone marrow and stem cell transplants is increasing worldwide. Graft-versus-host disease (GvHD) is a serious complication of this type of transplant. The incidence of acute GvHD varies widely, ranging from 10-80% depending on risk factors [1].
Acute, steroid-refractory graft versus host disease (GvHD) in adults
Intravenous infusion

Trial or other data

Dec 20There are currently no active trials investigating remestemcel-L in adults with aGvHD registered with the US clinical trials registry [5].
Sep 09PIII trial (NCT00366145) did not meet its primary endpoint according to preliminary results reported [4].
Aug 06Pivotal PIII trial of remestemcel-L in 260 patients aged 6 months to 70 years with steroid-refractory GvHD starts (Study 280; NCT00366145). The trial will assess remestemcel-L in conjunction with standard-of-care second-line therapy. The primary endpoint is durable, complete response defined as complete resolution of GvHD for a duration of at least 28 days. The trial will enrol patients in the US, Canada, Australia, the UK, Italy and Switzerland [2].

Evidence based evaluations

Treatment refractory, moderate to severe Crohn's disease in adults - second-line

Information

Licence extension / variation
Mesoblast
Mesoblast

Development and Regulatory status

None
None
Phase III Clinical Trials
Dec 20Has been awarded fast track status in US [13].
Apr 20Mesoblast is planning to pursue a licence for Crohns disease, according to its lifecycle extension strategy [11].
Aug 19Development is continuing [10].
Dec 18In PIII in US, however UK/EU licensing plans are uncertain.

Category

Adult human stem cells are manufactured from healthy, volunteer donors. They may have immunosuppressive and healing benefits
In 2010, there were around 79,115 adults in England with Crohn’s disease, of whom ~50% (39,557) are resistant or intolerant to conventional therapies [7].
Treatment refractory, moderate to severe Crohn's disease in adults - second-line
Intravenous infusion

Trial or other data

Dec 20No trial results seem to be have been announced for the completed PIII trials [11-13].
Oct 20The Cleveland Clinic in collaboration with Mesoblast initiate a PIb/IIa trial to evaluate the safety and efficacy of remestemcel-L in patients with refractory Crohn ´s disease (CCF-Stem-Cells-IBD004; NCT04548583). The randomised, placebo-controlled trial intends to enrol 24 patients in the US. Primary outcome is safety. The trial is due to complete Oct 23 [12].
Sep 14PIII Osiris 603 trial (NCT00482092) and PIII Osiris 611 trial (NCT01233960) completed. PIII Osiris 603 trial (NCT00543374) completed in Apr 11. Another PIII trial, Osiris 610, was discontinued to remove the potential for bias in Osiris 603 [12].
Oct 13Osiris has entered into an agreement with a subsidiary of Mesoblast Limited for the sale of Osiris’ culture-expanded mesenchymal stem cell business, including Prochymal [6]
Nov 10NCT01233960 is a multicenter, open-label study (protocol 611) to evaluate the safety of Prochymal® (remestemcel-l) in 120 subjects who have received previous remestemcel-l induction treatment (in Protocol 603) for treatment-refractory moderate-to-severe Crohn´s disease. The primary outcome is disease remission at 180 days after first infusion in Protocol 603 (CDAI ≤150 and increase in IBDQ). The study started Sep 10 and is due to complete Jan 13 [4].
Apr 10Protocol 603 trial enrolment restarting following interim analysis demonstrating that main outcome (disease remission) was reaching statistical significance in ITT population and has reached statistical significant in PP population. Despite the initial concerns that the study design would make it difficult to detect a treatment effect, the effect size, or difference between the Prochymal and placebo response rates, of one dose arm of Prochymal is consistent with the original statistical assumptions of the protocol and is significantly outperforming placebo. (3)
Mar 09The Prochymal Crohn´s PIII programme consists of two separate but related double blinded trials; the first (NCT00482092) to evaluate patients´ initial response to two dose levels of Prochymal (600 or 1200 million cells total over four infusions in two weeks) vs. placebo, and the second, an extension study (NCT00543374) enrolling subjects who successfully achieved clinical benefit (reduction in CDAI of at least 100 points) in the first study. The first trial was to enroll 270 subjects and the second, around 200. However enrollment was discontinued in March 2009 after 210 subjects had been enrolled because of a suspected design flaw resulting in significantly higher than expected placebo response rates; an interim showed that one of the two Prochymal dose arms had crossed a futility boundary. Because the current standard for determining response of Crohn´s patients to therapy is largely subjective, there may have been response bias to meet the eligibility requirements for continuation of therapy in the longer-term maintenance trial (1,2)