dm+d

Unassigned

New Medicines

BrukinsaWaldenström’s macroglobulinaemia (WM) in adults after at least one prior therapy, or first line if unsuitable for chemo-immunotherapy

Information

Brukinsa
New molecular entity
BeiGene
BeiGene

Development and Regulatory status

Launched
Approved (Licensed)
Launched
August 2022
Yes
Yes
Aug 22Stock of Brukinsa capsules is now available to order in the UK [20].
Jul 22NHS price announced for Brukinsa, so presume UK launch imminent. Price for 120 x 80mg capsules = £4928.65 [19].
Dec 21Brukinsa 80mg capsules approved by MHRA for same indication as EU [16].
Nov 21Approved in EU [15].
Sep 21Recommended for EU approval by CHMP “for the treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy”. Brukinsa will be available as 80mg hard capsules [14].
Sep 21Approved in US [13].
Feb 21US FDA accept sNDA for treatment of Waldenstroms macroglobulinaemia [12].
Jun 20Has orphan drug status in EU (EU/3/19/2167) for treatment of lymphoplasmatic lymphoma. WM is the most common type of lymphoplasmatic lymphoma [10].
Jun 20Filed in EU [9].
Nov 19Beigene plans to file a sNDA in the US in early 2020 [8].
Nov 19Beigene has commercial teams in China and the US. In the EU, it is evaluating its commercialisation strategy including potential collaborations [8].
Jul 18Granted Fast Track designation by the US FDA. Company announce plans to submit a New Drug Application in the H1 2019 [5].
Jan 17BeiGene announces that it will start a global PIII trial in WM, for which the drug has Orphan Status in the US; the trial will compare BGB3111 to ibrutinib as the company believe it will have a better adverse effect profile due to greater selectivity [1].

Category

Brutons tyrosine kinase (BTK) inhibitor
WM is a rare chronic B-cell lymphoproliferative disorder, classed as a low-grade NHL. Age-standardised annual UK incidence is 0.55 per 100,000 with male predominance. Median age at presentation is 71 years & median overall survival is 60 months; there is an association with multiple auto-immune disorders. A significant minority of pts remain asymptomatic & never require therapy while others have advanced lymphoma requiring therapy.
Waldenström’s macroglobulinaemia (WM) in adults after at least one prior therapy, or first line if unsuitable for chemo-immunotherapy
Oral

Further information

Yes

Trial or other data

Jul 21PIII ASPEN trial recruited 229 participants; collection of primary outcome data due to complete Jan 22 [18].
May 21Beigene releases updated efficacy and safety data from the PIII ASPEN trial. In the relapsed or refractory cohort after a median follow up of 19.4 months in the overall intention-to-treat (ITT) population there was a CR+VGPR rate of 28.4% and 19.2% in zanubrutinib and ibrutinib arm, respectively as assessed by independent review committee (IRC) (2-sided descriptive p = 0.0921). Similarly, as assessed by investigators for the overall ITT population the CR+VGPR rate was observed to be 28.4% and 17.2% in the zanubrutinib and ibrutinib arm respectively (2-sided descriptive p=0.0437). In the additional five month follow up with 24.2 months median follow up, the CR+VGPR rate as assessed by investigator for zanubrutinib and ibrutinib was observed to be 30.4% and 18.2% respectively (exploratory analysis; 2-sided descriptive p=0.0302). The major response rate (MRR) as assessed by IRC was found to 78.3% and 80.2% in the zanubrutinib arm the ibrutinib arm, respectively. In the zanubrutinib and ibrutinib arm, the 12-month PFS rate was found to be 92.4% and 85.9%, respectively. The 12-month OS rate was 98.8% for the zanubrutinib arm as compared with 92.5% in the ibrutinib arm. The MRR was found to be 77.5% in the zanubrutinib arm as compared to 77.8% in the ibrutinib arm. In the zanubrutinib and ibrutinib arm, the 12-month PFS rate was found to be 78.0% and 87.2%, respectively. The 12-month OS rate was 97.0% for the zanubrutinib arm vs. 93.9% in the ibrutinib arm [17].
Apr 20PIII ASPEN continues to follow-up recruited patients [11].
Dec 19Results from cohort 1 of PIII ASPEN trial (median follow-up of 19.4 months) announced. In the overall pt population, the VGPR rate was 28.4% in the zanubrutinib arm vs. 19.2% in the ibrutinib arm (p=0.0921) with no pts achieving a CR in either arm. While the trial was not powered to detect a statistically significant improvement in progression free survival (PFS), the 12-month PFS rate was 89.7% in all pts in the zanubrutinib arm vs. 87.2% in the ibrutinib arm. The 12-month OS rate was 97% for all pts in the zanubrutinib arm vs. 93.9% in the ibrutinib arm. Grade >3 adverse events (AEs) were 58.4% in the zanubrutinib arm and 63.3% in the ibrutinib arm (atrial fibrillation/flutter; 2% vs. 15.3% with zanubrtinimab vs. ibrutinib, minor bleeding 48.5% vs. 59.2%, major haemorrhage; 5.9% vs. 9.2%, diarrhea; 20.8% vs. 31.6% and neutropenia; 29.7% vs. 13.3%. [7]
Jan 19NCT03053440 is ongoing but fully recruited. Estimated date for primary and study completion is Jun 21 [6]
Jan 17PIII trial started comparing zanubrutinib with ibrutinib (NCT03053440). The first cohort of approximately 150 patients with MYD88 mutations will be enrolled while the patients with MYD88 wildtype status will be enrolled in a second cohort and will receive zanubrutinib 160mg BID until progression. Primary completion date Jun 2021 [3,4]

Evidence based evaluations

BrukinsaChronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) - first-line

Information

Brukinsa
Licence extension / variation
BeiGene
BeiGene

Development and Regulatory status

Phase III Clinical Trials
Recommended for approval (Positive opinion)
Pre-registration (Filed)
Yes
Oct 22Recommended for EU approval by CHMP – the new indication is use “as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL)” [10].
Jun 22FDA issue a three-month extension to PUFDA date, a decision is now anticipated by 20 January 2023 [22].
Feb 22Filed in US [9].
Feb 22BeiGene announces EMA acceptance of sMAA for treatment of CLL in both treatment-naïve and relapsed or refractory patient populations. Filing is based on data from PIII ALPINE (NCT03734016) and SEQUOIA (NCT03336333) trials [7].
Aug 16Zanubrutinib received orphan drug designation from the US FDA for the treatment of CLL [5]

Category

Selective next-generation Bruton tyrosine kinase inhibitor
CLL is the most common form of leukaemia in adults, with a global incidence of approximately 114,000 new cases in 2017. SLL shares many similarities to CLL but with cancer cells found mostly in lymph nodes. The incidence of del(17p) is approximately 5% to 8% of patients with CLL at diagnosis and increases with each relapse [3,4].
Chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) - first-line
Oral

Further information

Yes

Trial or other data

Jul 22PIII SEQUOIA study (n=590) found zanubrutinib was associated with superior progression-free survival to bendamustine rituximab (median not reached in either group; HR 0.42; 95% CI 0.28 to 0.63; two-sided p<0.0001) [8].
Nov 21PIII SEQUOIA trial is recruiting, including in the UK, other European countries and US; collection of primary outcome data now expected to complete Jan 22 [6].
Sep 21Results from participants with del(17p) (Arm C) of the PIII SEQUOIA trial published in Haematologica. A total of 109 patients (median age 70 years) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), 12 patients had discontinued study treatment. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete haematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhoea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%) [4].
Nov 17Enrolment started for the PIII SEQUOIA trial (NCT03336333; EudraCT2017-001551-31). The open-label, randomised trial aims to enrol 710 participants worldwide, including participants without del(17p) [Cohort 1] and participants with del(17p) [Cohort 2 and Cohort 3], to compare the efficacy and safety of zanubrutinib, with bendamustine plus rituximab in treatment-naive patients with CLL or SLL. Participants in Cohort 1 will be randomised 1:1 to zanubrutinib (Arm A) or bendamustine plus rituximab (Arm B). Participants in Cohort 2 will receive treatment with zanubrutinib. Participants in Cohort 3 will receive treatment with zanubrutinib and venetoclax. Primary outcome measure will be for Cohort 1: Progression-free survival (PFS) between treatment groups (Zanubrutinib vs. B+R) as determined by independent central review (ICR). Estimated primary completion date is Oct 2021 [1,2].

Evidence based evaluations

BrukinsaRelapsed or refractory marginal zone B-cell lymphoma

Information

Brukinsa
Licence extension / variation
BeiGene
BeiGene

Development and Regulatory status

Phase II Clinical Trials
Recommended for approval (Positive opinion)
Launched
Sep 22Recommended for EU approval by CHMP – the extension to the existing indication is “for the treatment of adult patients with marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based therapy” [8].
Feb 22Biogene announces EMA acceptance of sMAA for treatment of MZL; filing is based on efficacy results from MAGNOLIA (NCT03846427 and BGB-3111-AU-003 (NCT02343120) trials [7].
Sep 21Zanubrutinib receives accelerated approval from the US FDA for the treatment of adults with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen. Approval is based on overall response rate (ORR) from two single-arm clinical trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.[2]

Category

BTK inhibitor
There are around 14,100 new non-Hodgkin lymphoma cases in the UK every year [1]. Marginal zone lymphomas (MZLs) account for between 5% and 17% of all NHL. MZLs consist of 3 different subtypes with extranodal being the most commonly reported, representing 50-70% of MZL, followed by splenic (20%) and nodal (10%) [1].
Relapsed or refractory marginal zone B-cell lymphoma
Oral

Further information

Yes

Trial or other data

Dec 21Single-arm PII MAGNOLIA trial is due to complete this month. It enrolled a total of 68 participants. Primary outcome is overall response rate (ORR) determined by independent central review. Zanubrutinib was dosed at 160mg twice daily [6].
Jun 21In the multicentre, pivotal PII MAGNOLIA trial (NCT03846427) in 66 pts who received >1 anti-CD20-based regimen (n=26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, 4 with unknown subtype). Based on CT scan assessment, the ORR was 56% (95% CI: 43, 68) with a complete response (CR) rate of 20%; based on PET-CT scan assessment, the ORR was 67% (95% CI: 54, 78) with a CR rate of 26%. The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months (95% CI: 67, 93). Responses were observed in all MZL subtypes. [2-4]
Mar 21Single arm PI/II trial (NCT02343120) completes. It was designed to evaluate the safety, tolerability, pharmacokinetic profile and treatment effect of BGB-3111 (zanubrutinib) in patients with B-Cell Lymphoid Malignancies, and enrolled 397 adults in countries such as the UK, US and Italy. Safety was the primary outcome [6].
Jun 20In the global PI/II trial of BGB-3111-AU-003 (NCT02343120), 20 pts (9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype) were assessed using CT scan. The ORR was 80% (95% CI: 56, 94) with a CR rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months (95% CI: 40, 88). [5,6]

Evidence based evaluations

BrukinsaRelapsed or refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL)

Information

Brukinsa
Licence extension / variation
BeiGene
BeiGene

Development and Regulatory status

Phase III Clinical Trials
Recommended for approval (Positive opinion)
Pre-registration (Filed)
Yes
Oct 22 Recommended for EU approval by CHMP – the extension to the existing indication is use “as monotherapy is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL)” [11].
Jun 22FDA issue a three-month extension to PUFDA date, a decision is now anticipated by 20 January 2023 [9,10].
Feb 22BeiGene announces EMA acceptance of sMAA for treatment of CLL in both treatment-naïve and relapsed or refractory patient populations. Filing is based on data from PIII ALPINE (NCT03734016) and SEQUOIA (NCT03336333) trials [].
Feb 22Filed in US [10].
Aug 16Zanubrutinib received orphan drug designation from the US FDA for the treatment of CLL [6]

Category

Brutons tyrosine kinase (BTK) inhibitor
CLL/SLL is the most common leukaemia in the Western world with an incidence of 4.2/100,000/year. Incidence increases to >30/100,000/year at an age of >80 years [1].
Relapsed or refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL)
Oral

Further information

Yes

Trial or other data

Dec 21PIII ALPINE study is no longer recruiting, having enrolled 652 participants. Collection of primary outcome data now expected to complete Jan 23 [7].
Jun 21BeiGene presented results from the interim analysis of the PIII ALPINE trial at the European Haematology Association virtual conference. Zanubrutinib demonstrated superiority vs ibrutinib in the primary endpoint of investigator-assessed overall response rate (ORR), achieving an ORR of 78.3% (95% CI: 72.0, 83.7), vs 62.5% (95% CI: 55.5, 69.1) with ibrutinib (p=0.0006). However, as assessed by independent review committee, zanubrutinib achieved an ORR of 76.3%, numerically higher but not statistically significant compared to 64.4% with ibrutinib (p=0.0121). Zanubrutinib also demonstrated superiority vs ibrutinib in a key secondary endpoint of atrial fibrillation or flutter. 195 patients (95.6%) in the zanubrutinib arm experienced at least one adverse event (AE) of any grade, vs 205 patients (99.0%) in the ibrutinib arm. The most common (≥10%) AEs included anaemia (zanubrutinib vs. ibrutinib: 13.2% vs. 15.0%), arthralgia (9.3% vs. 14.0%), contusion (10.3% vs. 8.7%), cough (12.7% vs. 6.3%), diarrhoea (16.7% vs. 19.3%), hypertension (15.7% vs. 13.0%), muscle spasm (2.9% vs. 11.1%), neutropenia (19.6% vs. 15.5%), upper respiratory tract infection (21.6% vs. 14.0%), and urinary tract infection (10.8% vs. 8.2%) [4,5].
May 21Estimated primary completion date of NCT03734016 is Aug 22 [2].
Apr 21Beigene announce positive results from planned interim analysis of PIII ALPINE study (n=415 of 652 followed for ≥12 months). Zanubrutinib, met primary endpoint of non-inferiority in objective response rate (p<0.0001). Data pertaining to PFS in the 652 patients (a secondary endpoint), were immature at the data cut-off [3].
Nov 18Recruitment to PIII ALPINE study (NCT03734016) comparing overall response rate of oral zanubrutinib 160mg BD vs ibrutinib 420mg OD in adults with relapsed or refractory CLL or SLL begins [2].

Evidence based evaluations

Mantle cell lymphoma (MCL) - second-line or greater

Information

Licence extension / variation
BeiGene
BeiGene

Development and Regulatory status

None
Phase III Clinical Trials
Launched
Yes
Nov 21No plans for filing to the EMA described in latest company quarterly report [6].
Oct 21As of this date, Brukinsa has been approved for treatment of adults with MCL who have received at least one prior therapy in 10 countries, including Russia, Australia, China, Israel, Canada, UAE and Brazil. Marketing approval has generally been based on results from two single-arm clinical trials. Across both trials, as assessed by independent review committee (IRC) per 2014 Lugano Classification, Brukinsa achieved an overall response rate of 83.7% [5].
Nov 19Launched in the US [4].
Nov 19Zanubrutinib receives accelerated approval in US for MCL, contingent upon verification and description of clinical benefit in a confirmatory trial [4].
Aug 19Filed in the US [4].
Jan 19Has orphan drug status in US [4].
Jan 19FDA awards zanubrutinib Breakthrough Therapy designation [1].

Category

Small molecule inhibitor of Bruton’s tyrosine kinase (BTK).
MCL is a rare, aggressive type of non-Hodgkin lymphoma that mostly affects men over the age of 60. There are about 3,000 to 4,000 new diagnoses in the U.S. each year [1].
Mantle cell lymphoma (MCL) - second-line or greater
Oral

Trial or other data

Jan 22Two supportive trials are PI/II (BGB-3111-AU-003; NCT02343120) study and PII (BGB-3111-206, NCT03206970) study [5].
Jun 21BeiGene releases long term safety and efficacy results from PII (NCT03206970) trial, from a follow-up time of 35.3 months and a median duration of exposure of 27.6 months. Zanubrutinib demonstrated high, deep, and sustained efficacy in patients with R/R MCL, and responses were generally consistent across patient subgroups. The investigator-assessed ORR was 83.7% (95% CI: 74.2, 90.8), including 67 patients who achieved a CR (77.9%). Median duration of response was not reached; 57.3% (95% CI, 44.9-67.9) of responders were estimated event (PD/death)-free at 30 months. The median PFS was 33.0 months (95% CI: 19.4, NE) and the estimated 36-month PFS rate was 47.6% (95% CI: 36.2, 58.1) [5].
Nov 19Results from a single arm, PII trial (NCT03206970) of Brukinsa (n=86) with mantle cell lymphoma who have received at least one prior treatment demonstrated that 84% of patients had tumour shrinkage, with a median duration of response of 19.5 months. Common side effects were decreased neutrophils and platelets, upper respiratory tract infection, decreased white blood cell count, decreased haemoglobin, rash, bruising, diarrhoea and cough [2,3].

BrukinsaMantle cell lymphoma (MCL) in treatment naive patients - first-line with rituximab

Information

Brukinsa
Licence extension / variation
BeiGene
BeiGene

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes

Category

Small molecule inhibitor of Bruton’s tyrosine kinase (BTK).
MCL is a rare, aggressive type of non-Hodgkin lymphoma that mostly affects men over the age of 60. There are about 3,000 to 4,000 new diagnoses in the U.S. each year [1].
Mantle cell lymphoma (MCL) in treatment naive patients - first-line with rituximab
Oral