dm+d

Unassigned

New Medicines

Relapsing multiple sclerosis (MS)

Information

New molecular entity
TG Therapeutics
TG Therapeutics

Development and Regulatory status

None
Pre-registration (Filed)
Pre-registration (Filed)
Dec 21Filed in EU via centralised procedure - assume for this indication [8].
Dec 21TG Therapeutics announces that the FDA has accepted the BLA for ublituximab as a treatment for relapsing forms of MS. The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date of September 28, 2022 [7]
Oct 21 TG Therapeutics are preparing to submit a MAA in EU [6].
Sep 21BLA submitted to US FDA for treatment of relapsing forms of MS [5].
Apr 21A Biologics License Application to FDA is planned for Q3 2021. [4]
Dec 20TG Therapeutics plan to submit a BLA to US FDA mid-21 [2].
Aug 17TG Therapeutics initiate PIII ULTIMATE I and II studies (NCT03277261, NCT03277248) in US [1].

Category

Third generation, chimeric, anti-CD20 monoclonal antibody. The specific glycosylation profile of ublituximab gives it potent antibody-dependent cell-mediated cytotoxicity against CD20-positive tumour cells.
MS estimated prevalence is 190 cases per 100,000 population. MS is more than twice as common in females than males. The highest prevalence for MS occurs in the 60 to 69 years age group for both sexes. The MS estimated incidence in England is between 8 and 11 new cases per 100,000 population [3].
Relapsing multiple sclerosis (MS)
Intravenous infusion

Trial or other data

Apr 22Additional pooled analyses of ULTIMATE I & II showed 95% of ublituximab treated pts who demonstrated 12-week Confirmed Disability Improvement sustained the improvement through the end of the study at week 96. 96% of pts completed their ublituximab infusions without interruptions. Infusion relate reactions were the prevailing adverse event with ublituximab in ULTIMATE I and II; the vast majority were mild to moderate in severity [9]
Apr 21Company announces additional positive topline results for its PIII trials- ULTIMATE I & II. For pts on ublituximab, the total number of T1 lesions in ULTIMATE I and II reduced by 97% and 96% vs teriflunomide. New/enlarging T2 lesions similarly reduced by 92% and 90%, respectively. Pts on ublituximab achieved No Evidence of Disease Activity in the two trials at rates of 44.6% and 43%, respectively, representing a 198% and 277% improvement vs pts on teriflunomide. [4]
Dec 20TG Therapeutics announce positive topline results from ULTIMATE I and II trials, of ublituximab in relapsing forms of multiple sclerosis (RMS). Both trials achieved primary endpoint, with ublituximab demonstrating a statistically significant decrease in annualised relapse rate (ARR) over a 96-week period (<0.10 in both) [2].

Chronic lymphocytic leukaemia (CLL) and small lymphocytic leukaemia (SLL) - in combination with umbralisib

Information

New molecular entity
TG Therapeutics
TG Therapeutics

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Yes
Apr 22US filing withdrawn and development of ublituximab for oncology indications discontinued. The decision came because of findings from the PIII UNITY-CLL trial (NCT02612311), which highlighted a growing imbalance in overall survival. Additionally, umbralisib has been withdrawn from sale in the US for its approved indications of marginal zone lymphoma following 1 or more prior anti-CD20 therapies and follicular lymphoma following 3 or more previous systemic therapies [17].
Mar 22Whilst an FDA decision is due March 25th, approval is unlikely as the trial for treatment of CLL was put on clinical hold in January for concerns that it increased death[16].
Nov 21TG Therapeutics is planning for expansion into certain European markets, but no specific timelines have been announced [13].
Nov 21The FDA is expected to decide on the combination by March 2022, but will hold a session of the Oncologic Drug Advisory Committee prior to examine questions regarding the benefit-risk ratio and safety profile [12].
Dec 20TG Therapeutics initiates rolling submission of NDA to US FDA for ublituximab in combination with umbralisib as a treatment for patients with CLL. The Company expects to complete the BLA rolling submission H1 2021 [10].
Oct 20US FDA grants Fast Track Designation based on data from UNITY-CLL phase 3 study(n=420) that met primary endpoint of PFS [9].
Jan 17US FDA grants orphan drug designation for the combination of ublituximab and umbralisib for treatment of patients with CLL [3].

Category

Third generation, chimeric, anti-CD20 monoclonal antibody. The specific glycosylation profile of ublituximab gives it potent antibody-dependent cell-mediated cytotoxicity against CD20-positive tumour cells.
CLL is the most common leukaemia in the Western world with an incidence of 4.2 per 100,000 per year. The incidence increases to >30 per 100,000 per year at an age of >80 years. The median age at diagnosis is 72 years [1].
Chronic lymphocytic leukaemia (CLL) and small lymphocytic leukaemia (SLL) - in combination with umbralisib
Intravenous infusion

Trial or other data

Feb 22In the US, the FDA is investigating a possible increased risk of death with umbralisib. This is following initial review of data from the PIII trial (UNITY-CLL) of the drug in combination with ublituximab in patients with chronic lymphocytic leukaemia (CLL). The FDA believes these findings have implications for umbralisib´s approved uses for marginal zone lymphoma (MZL) and follicular lymphoma (FL). In addition, clinical trials of other medicines in the same PI3 kinase inhibitor class have shown similar safety concerns (e.g. idelalisib). Healthcare professionals are advised to review patients’ progress on umbralisib and discuss with them the risks and benefits of continuing umbralisib in the context of other available treatments. Enrolment in ongoing clinical trials with umbralisib has been suspended [15].
Jan 22UNITY-CLL is no longer recruiting [14].
Jan 21PIII UNITY-CLL is ongoing and due to complete collection of primary outcome data in Nov 23. Recruitment had expanded to other countries including the UK and Europe [11].
May 20Manufacturers report interim analysis shows PIII UNITY-CLL trial has met primary endpoint of improved PFS (p<0.0001) and so will be stopped early. Regulatory submissions are planned H2 20 [8].
Dec 19In its latest quarterly report, TG Therapeutics states that in Mar 19, the UNITY-CLL DSMB conducted a pre-planned futility analysis of PFS. The DSMB determined that the trial was not futile and recommended the UNITY-CLL trial continue as planned. The pre-specified futility analysis of the UNITY-CLL trial did not allow for early stopping due to positive efficacy but only for lack of efficacy [7].
Dec 19Previously in Sep 18, TG Therapeutics announced that in a review by the independent Data Safety Monitoring Board the interim analysis of overall response rate (ORR) could not be conducted at this time as the data were not sufficiently mature to conduct the analysis. The company announced that instead of planned accelerated approval based on ORR data, the company intends to focus on obtaining full approval based on the progression free survival data. In the review, no safety concerns were identified. The DSMB recommended the trial continue without modification [6].
Dec 19PIII UNITY-CLL is on course to complete collection of primary outcome data in Nov 20 [5].
Jan 19NCT02612311 is ongoing but fully recruited. Estimated date for primary completion is Nov 19 and study completion Nov 20 [4].
Oct 17UNITY-CLL also recruiting in Poland and UK [2].
Oct 17Recruitment in UNITY-CLL study is complete. Collection of PFS data should complete Sep 18 [2].
Jan 16PIII UNITY-CLL trial to assess the combination of ublituximab plus umbralisib in patients with CLL starts (UTX-TGR-304; NCT02612311). The four treatment arm trial is enrolling front-line as well as previously treated 450 patients with CLL in the US. The primary outcome will evaluate the efficacy of each agent in the combination regimen and will also evaluate the superiority of progression free survival (PFS) of the combination regimen over the standard of care [2].

Non-Hodgkin lymphoma (NHL) - monotherapy or in combination with umbralisib

Information

Licence extension / variation
TG Therapeutics
TG Therapeutics

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Yes
Apr 22Development of ublituximab for oncology indications discontinued. The decision came because of findings from the PIII UNITY-CLL trial (NCT02612311), which highlighted a growing imbalance in overall survival. Additionally, umbralisib has been withdrawn from sale in the US for its approved indications of marginal zone lymphoma following 1 or more prior anti-CD20 therapies and follicular lymphoma following 3 or more previous systemic therapies. Umbralisib previously received accelerated approval from the FDA in February 2021 in the aforementioned MZL and follicular lymphoma indications [9].

Category

Third generation, chimeric, anti-CD20 monoclonal antibody. The specific glycosylation profile of ublituximab gives it potent antibody-dependent cell-mediated cytotoxicity against CD20-positive tumour cells. Umbralisib is an oral selective PI3K delta inhibitor.
The two most common types of NHL are DLBCL and follicular lymphomas. The overall annual incidence of DLBCL in Europe is 3.8/100,000 but the incidence increases with age and varies considerably across Europe. The annual incidence of follicular lymphomas has increased from 2-3/100,000 during the 1950s to 5-7/100,000 recently [1].
Non-Hodgkin lymphoma (NHL) - monotherapy or in combination with umbralisib
Intravenous infusion