Author: Chowdary, Pratima ; Gil, Lidia ; Lentz, Steven R ; Matytsina, Irina ; Mahlangu, Johnny ; Nielsen, Anne Louise ; Lopez-Jaime, Francisco J ; Windyga, Jerzy

BACKGROUNDMim8 (denecimig) is a factor VIII (FVIII) mimetic bispecific antibody in development for the treatment of hemophilia. Data from the phase 1 part of FRONTIER1 (EudraCT: 2019-000465-20, NCT04204408, and NN7769-4513) suggested that Mim8 was well tolerated in healthy participants and exhibited pharmacokinetic (PK) properties consistent with dose proportionality.OBJECTIVESThe partially randomized, phase 2, multiple ascending dose (MAD) part of FRONTIER1 aimed to evaluate the safety, PK, pharmacodynamics (PD), and exploratory efficacy of Mim8 in participants with hemophilia A with or without FVIII inhibitors.METHODSThe MAD part of FRONTIER1 consisted of 42 participants, assigned to 5 cohorts, with participants in cohorts 3 and 4 randomized 1:1 to dosing weekly or every 4 weeks, respectively. Four of the 42 participants (9.5%) had FVIII inhibitors prior to study enrolment. The primary endpoint was treatment-emergent adverse events (TEAEs). PK and PD were evaluated by Mim8 plasma concentration and thrombin generation, respectively. Exploratory efficacy was assessed via the number of treated bleeds. Safety and PD parameters were also evaluated from an exploratory cohort treated with emicizumab.RESULTSMim8 was well tolerated, with 1 serious TEAE (anxiety-related chest pain) deemed unrelated to Mim8. There was no dose dependency on the number, causality, type, or severity of TEAEs. PK/PD properties supported weekly to monthly dosing approaches, and few participants experienced treated bleeds beyond the lowest dose cohort (1 in cohorts 2 and 3, and 3 in cohort 5).CONCLUSIONThese data support the continued clinical development of Mim8, and FRONTIER1 has proceeded onto an extension phase.

01 Nov 2023·The Lancet Haematology

Emicizumab prophylaxis in patients with acquired haemophilia A (GTH-AHA-EMI): an open-label, single-arm, multicentre, phase 2 study

Article

Author: Hart, Christina ; Knöbl, Paul ; Weigt, Carmen ; Schindler, Christoph ; Pilch, Jan ; Miesbach, Wolfgang ; Pfrepper, Christian ; May, Marcus ; Klamroth, Robert ; Tiede, Andreas ; Schipp, Dorothea ; Greil, Richard ; Holstein, Katharina ; Dobbelstein, Christiane ; Trautmann-Grill, Karolin ; Möhnle, Patrick ; Sachs, Ulrich J ; Werwitzke, Sonja ; Oldenburg, Johannes ; Pelzer, Fabius J

BACKGROUNDAcquired haemophilia A is caused by neutralising autoantibodies against coagulation factor VIII, leading to severe bleeding. Standard treatment involves immunosuppressive therapy, which is associated with adverse events and mortality in the frail population of patients with acquired haemophilia A. This study investigated whether emicizumab, a factor VIIIa mimetic antibody, protects patients with acquired haemophilia A from bleeding and allows deferral of immunosuppression during the first 12 weeks after diagnosis.METHODSWe report final results of an open-label, single-arm, phase 2 clinical trial. Adult patients with acquired haemophilia A from 16 haemophilia treatment centres in Germany and Austria were eligible if they had not previously received immunosuppression. Patients received emicizumab subcutaneously (6 and 3 mg/kg on days 1 and 2, 1·5 mg/kg weekly until week 12), but no immunosuppression. Follow-up was until week 24. The primary endpoint was the number of clinically relevant bleeds per patient-week until week 12. Emicizumab was considered effective if the mean bleeding rate was significantly below 0·15 bleeds per patient-week, the rate observed in a previous study of patients with acquired haemophilia A treated with bypassing agents and immunosuppression but no emicizumab. The study is registered with clinicaltrials.gov, NCT04188639 and is complete.FINDINGSOf 49 patients screened from March 25, 2021, to June 10, 2022, 47 were enrolled (23 women, 24 men). Median age was 76 years (IQR 66-80), 46 (98%) of 47 patients were White, median factor VIII activity was 1·4 IU/dL (0·3-5·6), and median inhibitor concentration was 11·4 Bethesda units per mL (3·9-42·7). Mean breakthrough bleeding rate was 0·04 bleeds per patient-week (upper 97·5% CI 0·06). 33 (70%) of 47 patients had no bleeding events, seven patients (15%) had one bleed, six patients (13%) had two bleeds, and one patient (2%) had three bleeds. Adverse events of grade 3 or worse included COVID-19 (n=2), acute kidney injury (n=2), and stroke (n=1). Four of 47 patients died, including two deaths related to bleeding, one from COVID-19, and one from cardiac arrest (none were judged as related to emicizumab).INTERPRETATIONThis study suggests that emicizumab prophylaxis prevents bleeding in patients with acquired haemophilia A and that immunosuppressive therapy can be deferred while patients are receiving this treatment. The low number of thromboembolic events, severe infections, and fatalities observed in this study are promising.FUNDINGThis study was supported by funding from Hoffman-La Roche.

01 Nov 2023·Haemophilia

A next generation FVIII mimetic bispecific antibody, Mim8, the impact on non‐factor VIII related haemostasis assays

Article

Author: Kitchen, Steve ; Bowyer, Annette Elizabeth ; Hickey, Kieron ; Ezban, Mirella

AbstractIntroduction and aimsMim8 is a next generation bispecific antibody developed for the treatment of haemophilia A (HA). Mim8 has an increased potency compared to first generation molecules. The impact on Mim8 on non‐FVIII measuring haemostasis assays was assessed in plasma containing Mim8.MethodsCongenital severe HA plasma was spiked with increasing concentrations of Mim8 (0–20 μg/mL). 28 routine and specialist haemostasis assays were used to measure activities. These included tests for prothrombin time (PT), fibrinogen, thrombin, D‐dimer, anti‐Xa, heparin induced thrombocytopenia (HIT), clotting factors II–XII, factor XIII, von Willebrand factor (VWF), thrombophilia and DRVVT.Results and conclusionsLess than 10 % difference was calculated between plasma without Mim8 and plasma spiked to 15 μg/mL Mim8 in all assays except thrombin time (−10.5%), APTT‐based factor IX, XI and XII, Werfen VWF:RCo (10.6%) and Siemens LA1 (−26.4%) and LA2 (−16.9%). At the expected therapeutic steady state levels of Mim8 (5–8 μg/mL), less than 10% difference was calculated for thrombin time and Werfen VWF:RCo.APTT‐based assays of FIX, XI and XII are significantly elevated in the presence of Mim8 and should not be performed. A chromogenic FIX assay could be used to accurately measure FIX activity in the presence of Mim8. There was some interference in the DRVVT method we used so local assessment of other DRVVT methods is advised. Differences in all other tests would not be predicted to affect patient management.

News (Medical) associated with Mim8

26 Jun 2024

·pmlive.com

Novo Nordisk shares positive results for Mim8 in late-stage haemophilia A trial

Novo Nordisk has shared positive results from a late-stage study of its haemophilia A therapy, Mim8, in adults and adolescents aged 12 years and older. The rare inherited bleeding disorder is caused by a missing or defective clotting factor VIII and accounts for up to 85% of the 1,125,000 global haemophilia cases. The phase 3 FRONTIER 2 trial has been evaluating the safety and efficacy of a once-weekly and once-monthly dose of Novo’s subcutaneously administered therapy to prevent prolonged and spontaneous bleeding in patients with or without inhibitors. It is estimated that up to 30% of haemophilia A patients have inhibitors, an immune system response to the clotting factors in replacement therapy that cause treatment to stop working. According to the results presented at this year’s International Society of Thrombosis and Haemostasis Annual Congress, Mim8 demonstrated a superior reduction in the estimated mean annualised bleeding rate (ABR) of treated bleeds by 97.1% with once-weekly and 98.7% with once-monthly Mim8 in the trial population with no prior prophylaxis treatment. Once-weekly and once-monthly Mim8 prophylaxis also demonstrated a superior reduction in treated bleeds compared to no prior prophylaxis treatment, and zero bleeds were observed in 85.7% of patients treated with once-weekly Mim8 and in 95% of those receiving a once-monthly dose of the therapy. In the study cohort with prior coagulation factor prophylaxis, Mim8 demonstrated a superior reduction in the estimated mean ABR by 48% for once-weekly and 42.6% for once-monthly treatment, and also showed a superior reduction in treated bleeds compared to prior coagulation factor prophylaxis. Zero bleeds were observed in 66.3% of patients in the once-weekly Mim8 treatment arm and 65.3% of those receiving once-monthly Mim8. Novo said it aims to submit Mim8 for the first regulatory approval towards the end of this year. Martin Holst Lange, executive vice president of development at Novo, described the data as “very encouraging”. “With Mim8, we have the potential of offering a substantial proportion of patients the prospect of zero bleeds and convenient dosing flexibility to fit their lifestyles and needs,” he said.

Clinical ResultPhase 3Phase 2

24 Jun 2024

·www.biopharmadive.com

Novo fills in positive picture for preventive hemophilia drug

Dive Brief:Novo Nordisk on Sunday disclosed detailed clinical trial results for an experimental hemophilia treatment dubbed Mim8, showing once-weekly and once-monthly doses of the antibody drug controlled bleeding in people with the more common A form of the disorder.The data, which were presented at the International Society on Thrombosis and Haemostasis Annual Congress in Thailand, fill in a positive picture for Mim8s effectiveness and safety. Novo had said in May that the Phase 3 trial, called Frontier-2, succeeded and shared topline findings.Among people who had not previously been on preventive treatment, researchers reported zero bleeds in 86% of study participants who received once-weekly Mim8, and 95% of those given the once-monthly dose. Those figures were 66% and 65%, respectively, among people in the trial who had prior preventive treatment.Dive Insight:The success of Ozempic and Wegovy, Novos drugs for diabetes and weight loss, have transformed the Danish drugmaker into the pharmaceutical industrys second largest. Not surprisingly, analysts and Wall Street investors are now laser focused on that portion of the companys business.But Novo continues to develop drugs for rare blood disorders, and has placed emphasis on the potential of Mim8. Its also invested in sickle cell disease, acquiring Forma Therapeutics two years ago and advancing another drug it licensed in 2018.The recent results for Mim8 are the first from a Phase 3 trial program that includes three other studies beyond Frontier-2.Novo enrolled 254 people with hemophilia A into Frontier-2, including those with and without inhibitors, which can prevent standard drugs from effectively clotting blood. The one-year study compared Mim8 to either no prophylaxis among those not on preventive treatment, or to prior coagulation factor prophylaxis among those who were.In the former group, a once-weekly dose of Mim8 reduced the average annualized bleeding rate by 97%, while the once-monthly dose led to a 99% reduction. That translated to an average of 0.45 treated bleeds per patient year among the once-weekly group and 0.20 among the once-monthly patients. In the control arm of people who did not receive preventive treatment, the average rate was 15.75 treated bleeds per patient year.Patients in the study who previously were on preventive treatment went through a run-in phase of the study, and then were given one of the two Mim8 doses. The average rate of treated bleeds was 2.51 per patient year for those on once-weekly dosing, versus 4.83 on their prior prophylaxis, and 1.78 for those on the once-monthly, versus 3.10 on their prior treatment.There were no thromboembolic events or related serious side effects reported in the trial, Novo said.With Mim8, we have the potential of offering a substantial proportion of patients the prospect of zero bleeds and convenient dosing flexibility to fit their lifestyles and needs, said Martin Holst Lange, head of development for Novo, in the companys Sunday statement.Novo plans to submit an approval application for Mim8 toward the end of the year, and will disclose more trial data for the drug at upcoming medical meetings.A bispecific antibody, Mim8 is designed to bridge Factors IXa and X to replace the Factor VIII thats missing in people with hemophilia A.If approved, Mim8 would likely compete with Roches Hemlibra, which is also a bispecific anitbody and holds approval in the U.S. as a routine preventive treatment for people with hemophilia A. Dosing is flexible to either once-weekly, bi-weekly or once-monthly. Roche reported sales of 4.1 billion Swiss francs last year, or about $4.6 billion, using an average U.S. dollar exchange rate for 2023. '

Clinical ResultPhase 3

23 Jun 2024

·pipelinereview.com

Novo Nordisk A/S: Mim8 demonstrated superior reductions in annualised bleeding rate (ABR) compared to on-demand and prior prophylaxis treatment in people with haemophilia A

FRONTIER2 data presented at ISTH 2024 showed that up to 95% of people, who had no prior prophylaxis treatment, experienced zero treated bleeds while on Mim8 BAGSVAERD, Denmark I June 23, 2024 I Novo Nordisk announced results from the phase 3 FRONTIER2 trial of 254 adults and adolescents aged 12 years and over with haemophilia A, with and without inhibitors. The trial assessed both once-weekly and once-monthly prophylactic treatment (regular treatment to prevent prolonged and spontaneous bleeding) with the investigational treatment Mim8. The data were presented at the International Society of Thrombosis and Haemostasis Annual Congress (ISTH 2024) in Bangkok, Thailand. In the trial population with no prior prophylaxis treatment: In the trial population with prior coagulation factor prophylaxis: “Despite treatment advances, there are still many unmet needs for people living with haemophilia A,” said FRONTIER2 lead investigator Dr Maria Elisa Mancuso, Senior Consultant in Haematology, Centre for Thrombosis and Haemorrhagic Diseases, IRCCS Humanitas Research Hospital, Milan, Italy. “The FRONTIER2 data demonstrated superiority of Mim8 prophylaxis over both on demand treatment and prior clotting factor prophylaxis with respect to the number of treated bleeding episodes in people living with haemophilia A, regardless of their inhibitor status. It is also encouraging to see that in some subgroups in the study, up to 95% of people treated with Mim8 experienced zero bleeds.” Mim8 is a next-generation Factor VIIIa (FVIIIa) mimetic bispecific antibody designed with the potential to deliver sustained haemostasis. It is currently in development for once-weekly or once-monthly prophylaxis treatment for people living with haemophilia A, with and without inhibitors. Administered subcutaneously, Mim8 bridges Factor IXa/X (FIXa/FX), thereby replacing missing FVIII. This restores the body’s thrombin generation capacity, helping blood to clot. 1 In this trial, Mim8 was well-tolerated, and no safety concerns (thromboembolic events or related serious adverse events) were observed, in line with previous findings. “The FRONTIER2 efficacy and safety data is very encouraging,” said Martin Holst Lange, Executive Vice President of Development at Novo Nordisk. “With Mim8, we have the potential of offering a substantial proportion of patients the prospect of zero bleeds and convenient dosing flexibility to fit their lifestyles and needs. We look forward to discussing these data with regulatory authorities.” Contingent on regulatory interactions, Novo Nordisk aims to submit Mim8 for the first regulatory approval towards the end of 2024. Data from the ongoing phase 3 FRONTIER programme will continue to be disclosed at upcoming congresses and in publications in 2024 and 2025. About Haemophilia Haemophilia is a rare inherited bleeding disorder that impairs the body’s ability to make blood clots, a process needed to stop bleeding. It is estimated to affect approximately 1,125,000 people worldwide, and haemophilia A is estimated to account for 80-85% of all haemophilia cases. 2 Due to the nature of haemophilia being a rare x-linked recessive disorder, it often presents differently in males compared to females, with ~ 88% of people diagnosed with haemophilia worldwide being male. 3,4 There are different types of haemophilia, which are characterised by the type of clotting factor protein that is defective or missing. Haemophilia A is caused by a missing or defective clotting Factor VIII (FVIII). Some people with haemophilia may also develop inhibitors, which are an immune system response to the clotting factors in replacement therapy that cause treatment to stop working. Currently, it is estimated that up to 30% of people living with severe haemophilia A have inhibitors. 5 About the FRONTIER2 clinical trial The FRONTIER phase 3 clinical development programme investigates Mim8 as a prophylactic treatment for people with haemophilia A, with or without inhibitors. The phase 3 programme includes FRONTIER2 6 , FRONTIER3 7 , FRONTIER4 8 , and FRONTIER5 9 . FRONTIER2 is a 52-week efficacy and safety phase 3 trial, comparing once-weekly and once-monthly Mim8 versus no prophylaxis and versus prior coagulation factor prophylaxis (26-52-week run-in period) in people aged 12 years and over with haemophilia A, with or without inhibitors. The 26-week main phase of the trial is completed, a 26-week extension phase is ongoing. Participants were randomised into five treatment arms: Those who had received on-demand treatment prior to trial enrolment: Those who had received prophylaxis treatment prior to trial enrolment: About Novo Nordisk Novo Nordisk is a leading global healthcare company, founded in 1923 and headquartered in Denmark. Our purpose is to drive change to defeat serious chronic diseases, built upon our heritage in diabetes. We do so by pioneering scientific breakthroughs, expanding access to our medicines, and working to prevent and ultimately cure disease. Novo Nordisk employs about 66,000 people in 80 countries and markets its products in around 170 countries. Novo Nordisk’s B shares are listed on Nasdaq Copenhagen (Novo-B). Its ADRs are listed on the New York Stock Exchange (NVO). For more information, visit novonordisk.com , Facebook , Instagram , X , LinkedIn and YouTube . References 1 Østergaard H, Lund J, Greisen PJ, et al. A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice. Blood. 2021;138(14):1258-1268. doi:10.1182/blood.2020010331 2 Iorio A, Stonebraker JS, Chambost H, Makris M, Coffin D, Herr C, Germini F; Data and Demographics Committee of the World Federation of Hemophilia. Establishing the Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach Using National Registries. Ann Intern Med. 2019 Oct 15;171(8):540-546. doi: 10.7326/M19-1208. 3 Centers for Disease Control and Prevention. What is Hemophilia? Available at: https://www.cdc.gov/ncbddd/hemophilia/facts.html Accessed: June 2024 4 Statista. Distribution of people with bleeding disorders worldwide in 2020, by gender. Available at: https://www.statista.com/statistics/495675/percentager-of-people-with-bleeding-disorders-in-worldwide-bygender/#:~:text=This%20statistic%20displays%20the%20percentage,with%20hemophilia%20A%20were%20males Accessed: June 2024 5 Kim JY, You CW. The prevalence and risk factors of inhibitor development of FVIII in previously treated patients with hemophilia A. Blood Res. 2019 Sep;54(3):204-209. doi: 10.5045/br.2019.54.3.204. 6 ClinicalTrials.gov. A Research Study Investigating Mim8 in Adults and Adolescents With Haemophilia A With or Without Inhibitors. Available at: https://clinicaltrials.gov/study/NCT05053139 Last accessed: June 2024. 7 ClinicalTrials.gov. A Research Study Looking at Mim8 in Children With Haemophilia A With or Without Inhibitors. Available at: https://clinicaltrials.gov/study/NCT05306418 Last accessed: June 2024. 8 ClinicalTrials.gov. A Research Study Looking at Long-term Treatment With Mim8 in People With Haemophilia A (FRONTIER 4) (FRONTIER4). Available at: https://classic.clinicaltrials.gov/ct2/show/NCT05685238?term=NCT05685238&rank=1 Last accessed: June 2024. 9 ClinicalTrials.gov. A Research Study Looking at How Safe it is to Switch From Emicizumab to Mim8 in People With Haemophilia A (FRONTIER 5) (FRONTIER 5). Available at: https://clinicaltrials.gov/study/NCT05878938#xd_co_f=ZDM2YmY4ZmMtMmRhNi00YTI1LWI4YmItNTBjOWE4Yjg4NGI1~ Last accessed: June 2024. SOURCE: Novo Nordisk

Clinical ResultPhase 3

100 Deals associated with Mim8

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Hemophilia A	Phase 3	TW	Novo Nordisk A/S	02 Dec 2021
Hemophilia A	Phase 3	CH	Novo Nordisk A/S	02 Dec 2021
Hemophilia A	Phase 3	DE	Novo Nordisk A/S	02 Dec 2021
Hemophilia A	Phase 3	IN	Novo Nordisk A/S	02 Dec 2021
Hemophilia A	Phase 3	RU	Novo Nordisk A/S	02 Dec 2021
Hemophilia A	Phase 3	RS	Novo Nordisk A/S	02 Dec 2021
Hemophilia A	Phase 3	MY	Novo Nordisk A/S	02 Dec 2021
Hemophilia A	Phase 3	AT	Novo Nordisk A/S	02 Dec 2021
Hemophilia A	Phase 3	SA	Novo Nordisk A/S	02 Dec 2021
Hemophilia A	Phase 3	CA	Novo Nordisk A/S	02 Dec 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05053139 (Frontier 2, Corporate Publications) Manual	Phase 3	Hemophilia A	254	Mim8 once-weekly prophylaxis (no prior prophylaxis treatment)	(qqknjhtkdu) = xgryitfbus tvigoxzavb (wusatklzbd ) View more	Positive	23 Jun 2024
				Mim8 once-monthly prophylaxis (no prior prophylaxis treatment)	(qqknjhtkdu) = jjhrwwjwbb tvigoxzavb (wusatklzbd ) View more
FRONTIER 2 (GlobeNewswire) Manual	Phase 3	Hemophilia A	254	Mim8 once-weekly	pmeujskccm(gxyyuajhzk) = lulhspcoci yryevyooyu (gncoaayhiu ) Met View more	Positive	13 May 2024
				Mim8 once-monthly	pmeujskccm(gxyyuajhzk) = lnsxkedmem yryevyooyu (gncoaayhiu ) Met View more
ASH2023	Not Applicable	Hemophilia A	-	AAV-Mediated Expression of a Single-Chain FVIII Mimetic Antibody (AAV-Bi8 vector)	qvlxgcwnyj(yytfcasdmc) = ldgykvwkvs uiilcpxurc (zwfqoaaokx ) View more	-	10 Dec 2023
EUCTR2019-000465-20-AT \| NCT04204408 (FRONTIER 1, ASH2022) Manual	Phase 1/2	Hemophilia A	42	Mim 8	(rehnzskkti) = ftcpbpuskp xyhnkgcqsz (ebrfmpxwcq ) View more	Positive	15 Nov 2022
NCT04204408 (EudraCT:2019-000465-20, ISTH2022) Manual	Phase 1/2	-	-	Mim 8 (SAD phase)	(ftxnmapqbr) = Mim8 was well tolerated following both single and multiple dosing, and no thromboembolic events or related serious adverse events were reported karilikiol (qjmasbzmus )	Positive	11 Jul 2022
				Mim 8 (MAD phase)

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