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GLPG0634 (Filgotinib)

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Omlaag ↓

[verwijderd] 28 september 2020 16:47

Flinke uitbreiding van locaties van Penguin studies!
Study to Evaluate the Efficacy and Safety of Filgotinib in Participants With Active Psoriatic Arthritis Who Are Naive to Biologic DMARD Therapy (PENGUIN 1)
Heeft nu 59 locaties. Vooral veel nieuwe in Polen
clinicaltrials.gov/ct2/history/NCT041...

Study to Evaluate the Efficacy and Safety of Filgotinib in Participants With Active Psoriatic Arthritis Who Have an Inadequate Response or Are Intolerant to Biologic DMARD Therapy (PENGUIN 2)
Heeft nu 55 locaties
clinicaltrials.gov/ct2/history/NCT041...

Lama Daila 3 oktober 2020 09:20

Jyseleca: Samenvatting van de productkenmerken (Nederlands):
www.ema.europa.eu/en/documents/produc...

Met een korte verwijzing naar spermatogenese:

Verstoorde spermatogenese en histopathologische effecten op mannelijke voortplantingsorganen (testes en epididymis) werden met filgotinib waargenomen bij ratten en honden. Bij de geen waargenomen bijwerkingsniveaus (‘no-observed-adverse-effect-levels’, NOAEL’s) bij honden (de gevoeligste soort) is de blootstellingsmarge 2,7 maal zo groot met de eenmaaldaagse dosis van 200 mg bij mensen. De ernst van de histologische effecten was dosisafhankelijk. De spermatogene en histopathologische effecten waren bij lagere blootstelling niet volledig reversibel en waren irreversibel bij blootstellingsmarges van ongeveer 7 tot 9 keer de blootstelling met de eenmaaldaagse dosis van 200 mg bij mensen.

Meer details in het Assessment report:
www.ema.europa.eu/en/documents/assess...

Op pagina 26 staat de info over “Male Reproductive Organs”

Lama Daila 3 oktober 2020 10:02

Typo gevonden:
“epididymides was observed from a dose of 45 kg/mg/day”
Voor een rat van 10 mg zou dat 450 kg Filgotinib per dag zijn. Dat lijkt me wat van het goede te veel :-)
In rest van het document wordt toch correct “mg/kg/day” vermeld.

Lama Daila 3 oktober 2020 10:18

Pagina 83:
“The indication initially proposed by the Applicant encompassed: monotherapy and combination with MTX = second line as well as monotherapy first line. In the approved indication, the first line indication has been omitted”

Op pagina 84 wordt hier verder op ingegaan:
“ Regarding DARWIN 2, it is noted that although this was considered as a monotherapy study, antimalarial DMARDs were included among the permitted medications. Given that a rather small proportion of subjects in the study were treated with antimalarials (approximately 10%), that this use was rather evenly distributed between the treatment groups and the known fairly modest treatment effect of antimalarials on RA, this condition is not expected to influence the overall conclusions to be drawn from this dose-finding study. However, as the Applicant indicated that the data from this study also supports the current monotherapy claim -and as this is actually the only study that provides data on monotherapy second line- the applicant was at Day 120 requested to re-analyse the data from this study (primary and key secondary endpoints with focus on endpoints reflecting low disease activity or remission) excluding subjects concomitantly treated with antimalarials (see outcome and discussion below)”

En ook op pagina 85/86 (FINCH3):
“First, antimalarials are included among the permitted concomitant medications and thus the treatment arm referred to as the Filgotinib monotherapy arm is actually not a monotherapy arm in the strictest sense. As in total, only 9.4% had concurrent antimalarials, since this use has a fairly even distribution among treatment groups and since the treatment effect of antimalarial DMARDs is known to be rather modest, this condition is not expected to have any major impact on the overall study results. However, to verify this preliminary view and to get a more precise view of the performance of Filgotinib given as true monotherapy (which is important given the proposed wording of the indication) the applicant was requested to re-analyse the data with regards to the primary and key secondary endpoints excluding subjects on concomitant anti-malarias (see outcome and discussion below).”

Lama Daila 3 oktober 2020 10:20

Pagina 84:
The duration of FINCH 2 (bDMARD-IR population) was only 24 weeks while the other two-phase III studies were of 52 weeks duration. In the initial submission, only data up to 24 weeks were included (in 24 week-CSRs). In the response to the Day 120 LoQ, the final CSRs with week 52-data were provided. Long-term safety and efficacy data from FINCH 4 Study, that enrols subjects from the three Phase 3 studies, will be submitted by 2Q 2021.

Lama Daila 3 oktober 2020 10:37

Pagina 89: Antimalarials waren toch geen issue !

“In response to the Day 120 LoQ, a re-analyse of important endpoints in DARWIN 2 excluding subjects concomitant antimalarials were conducted. The outcome in all study subjects vs subjects without antimalarials (FAS, NRI) were compared. The proportion of subjects with LDA at week 12 was similar in the three different treatment groups (Filgotinib 200 mg, Filgotinib 100 mg, placebo) for all subjects vs subjects without antimalarials. Such coherence was seen also for the other presented endpoints including ACR 20, which was the primary efficacy endpoint of this study and remission. The CHMP agreed with the applicant that the results in this monotherapy second line study were similar for subjects without antimalarials as compared to the overall study population.”

Lama Daila 3 oktober 2020 10:40

Pagina 89: Initieel wou GLPG/GILD enkel de 200mg gebruiken in Fase3

“Following the phase II studies, the applicant had initially selected only the 200 mgx1 dose to be tested in the phase 3 programme. As this was questioned by the SAWP/CHMP, both the 100 mg once daily and 200 mg once daily-doses were then ultimately chosen for the phase 3 studies. Overall, treatment with these doses conferred a clinically relevant effect vs placebo in the studied MTX-IR (second line) population both in the MTX add-on and monotherapy setting. Given the clinical efficacy data (including the dose-response observed) and the clinical safety data from this phase 2 studies, the selection of doses is considered acceptable. Of note, this would provide some support for the efficacy of filgotinib as monotherapy second line”

Lama Daila 3 oktober 2020 10:50

Pagina 89/90: EMA benadrukt dat 200mg “consistently numerically” beter is dan 100mg !

“Across endpoints, the short-term effect in the Filgotinib 200 mgx1 group (on top of MTX) was consistently numerically better than in the other treatment groups (Filgotinib 100 mgx1, adalimumab or placebo on top of MTX). This was noted for the proportion of subjects that achieved remission and disease activity, the most informative endpoints in this patient population, and for the radiological endpoint included among the key secondary endpoints (change from Baseline in mTSS). Numerically better improvements in the Filgotinib 200 mg group vs the other groups were finally seen for PROs and the CRP-independent outcome CDAI that were included as other endpoints in the study. Overall, not only the effect in the Filgotinib group 200 mgx1 (+MTX) group but also the effect in the Filgotinib 100 mgx1 (+MTX) group is of clinical relevance. There was a consistent and distinct difference for the Filgotinib 100 mgx1 (+MTX) group vs placebo (+MTX) and overall the observed magnitude of effect in the Filgotinib 100 mg (+MTX)-group was similar to what was observed in the active comparator adalimumab (+MTX) group”

Pagina 91:
Consistently, the results in the Filgotinib 200 mg arm were numerically better than in the Filgotinib 100 mg arm but the differences were not large. Relevant differences vs placebo was seen for both doses with regards to ACR response and LDA as presented above but also with regards to function as measured by HAQ and the ESR/CRP-independent measure CDAI. Consequently, the CHMP considered that both Filgotinib doses could be included in the recommended primary posology.

Lama Daila 3 oktober 2020 11:05

Pagina 94: Monotherapy

With regards to the observed monotherapy data, the following observations can be made:

-Regarding monotherapy first line: Although data are somewhat limited and although none of the comparisons between filgotinib 200 mg monotherapy and MTX in FINCH 3 resulted in an outcome that was considered statistically significant, it is noted that for the primary endpoint and all three key secondary endpoints (which included effect on structural progression and function as well as proportion of subjects in remission) numerically better outcomes were noted for filgotinib monotherapy vs MTX monotherapy (the active comparator). However, the CHMP questioned the initially proposed monotherapy indication in the D120 LoQ in the light of the totality of data on JAK-inhibitors that has so far become available also considering that such indication has not been approved for previous members in the class. As a consequence, the first line indication was withdrawn by the applicant during the application.

-Regarding monotherapy second line: In the phase 2 DARWIN 2-study, an effect of filgotinib 200 mg vs placebo was seen both for the primary and the secondary endpoints (including the proportion of subjects with remission/low disease activity). Although an active comparator would have been a more appropriate choice than placebo to better elucidate the effects of monotherapy in this MTX-IR population, the study included a rather limited number of patients and did not include a direct comparison between filgotinib monotherapy vs. filgotinib in combination, this data provides some support for monotherapy second line. Together with the support that can be retrieved through extrapolation from FINCH 3, data from DARWIN 3 (that supports maintenance of effect of filgotinib monotherapy second line although only pooled data from this study was provided without details on the exact dose regimen in each group ), it is considered sufficient to support the proposed monotherapy second line indication as it is currently worded (i.e. with no restrictions that monotherapy second line is only indicated when combination therapy is inappropriate- as the available data do not indicate a major efficacy advantage for the combination vs monotherapy and there are instead safety disadvantages associated with the combination, see safety section 2.6. ).

Lama Daila 3 oktober 2020 11:15

Pagina 139:
In addition, filgotinib was initially proposed to be given either in monotherapy or in combination with MTX or other csDMARDs. Since data supporting the combination with csDMARDs other then MTX were not presented, this was raised as a major objection in the D120 LoQ. As a consequence, the proposal for use in combination with csDMARDs was withdrawn by the applicant with their responses to the D120 LoQ.

Lama Daila 3 oktober 2020 11:32

Pagine 143: Benefit-risk discussion 200mg: CHMP agreed !!!

Finally, the applicant has presented a benefit-risk discussion for the filgotinib 200 mg dose. From the presented data, the CHMP agreed that additional benefit of filgotinib is observed at the 200 mg dose over the 100 mg dose. There is a small numerical difference in mortality point estimates; however, the relevance of this observation is difficult to assess taken into account that overall the differences between all the analyzed treatment groups are small with overlapping 95% CIs and that there are no dose-dependency observed for the most important AESIs of serious infections, MACE or malignancy. In conclusion, the CHMP considered that the data supports the approval of the 200 mg-dose.

Lama Daila 3 oktober 2020 11:36

Pagina 145:

Male fertility

In animal studies, decreased fertility, impaired spermatogenesis and histopathological effects on male reproductive organs were observed (see non-clinical Section 2.3). These effects are currently being investigated in ongoing studies in human males (MANTA [Study GS-US-418-4279] and MANTA-RAy [Study GLPG0634-CL-227]). The clinical consequences of these findings are currently uncertain. At the CHMP’s request, the applicant presented blinded interim data from the MANTA study. The applicant has also reported results of hormone levels from phase 2 studies, in which there were no clinically relevant changes in sex hormone levels. The CHMP agrees with the applicant that current data suggest there is no clinically relevant effect of filgotinib on male reproductive hormones, including testosterone, FSH, LH, and inhibin B.
Interim data from the MANTA and MANTA-Ray studies will be submitted in first half of 2021. The findings in pre-clinical studies are of great concern and has not been seen for other JAK inhibitors. No mechanistic explanation has been identified, and thus there is a potential risk for humans. At the CHMP’s request, a warning was included in section 4.4 of the SmPC and information on this risk in the proposed educational material.

[verwijderd] 3 oktober 2020 12:55

Dank Lama, AB!

Over die monotherapy first line: Dus Gilead en GLPG trokken die in tijdens de review.
Behoudens vergissing las ik dat Abbvie deze zelfs niet had aangevraagd had in hun submission.

Beide vergelijkend blijf ik wel bij mijn best in class profiel, zeker qua safety.

De documenten vergelijkende lijkt het wel dat Abbvie hun studies slimmer aanpakte waardoor hun data nuttiger is, als ik zo jou passages lees en die naast Rinvoq’s document leg. Pluim voor Abbvie in dat geval. Het is wel “onze” concurrent maar we kunnen niet ontkennen dat ze goed zijn. Zij kunnen behoudens vergissing wél in combinatie met csDMARDs werken omdat ze meer data hebben dan GLPG, dat niet voldoende data had hiervoor. Niet dat dat het verschil gaat maken, maar toch.
Misschien dat ze (Gilead en GLPG) dit bij Resubmission in US wel trachten te doen (extra data hiervoor).

Zoals gisteren gesteld mag van mij Abbvie marktleider blijven, toch in de race met Rinvoq vs Filgotinib.
Zolang ze maar die US markt opkunnen en een deel van de koek krijgen. Welgekomen inkomsten voor uitbouw en behoud pipeline.

[verwijderd] 3 oktober 2020 13:40

Hele dikke AB Lama. Dank andermaal voor je spitwerk!

[verwijderd] 3 oktober 2020 13:41

CORRECTIE - Sorry allen!

Ik lees dat uiteindelijk dat Rinvoq ook alleen met MTX en geen andere csDMARDs gebruikt mag worden:

From an efficacy-point-of view, the combination of upadacitinib and other csDMARDs could have been considered supported by the CHMP. However, from a safety perspective, the CHMP considered that it was not appropriate to conclude positively on an indication in combination with other csDMARDs. Indeed, the observed safety profile was less favourable with the combination of upadacitinib and other csDMARDs. Hence, the Applicant withdrew this claim from the indication during the assessment (see Safety section). The revised indication is as follows

Hadden wel genoeg data dus, in tegenstelling tot GLPG, maar owv safety issues niet weerhouden, tenminste Abbvie trok terug.

Lama Daila 4 oktober 2020 12:24

Vergelijking Rinvoq versus Jyseleca obv Package Leaflet:

Bijlage:

crulapagos 4 oktober 2020 16:13

Samenvatting van de productkenmerken Jyseleca hier beschikbaar in 23 verschillende talen waaronder NL:
ec.europa.eu/health/documents/communi...

[verwijderd] 9 oktober 2020 18:21

www.rheumatologytrainingacademy.com/

The Rheumatology Training Academy is a 12-month educational, non-promotional programme for certified rheumatologists with at least 3 years’ experience in actively treating patients with rheumatoid arthritis (RA) in routine clinical practice. It is open to rheumatologists from Europe, Australia, Canada and Japan.

The programme is organised and funded by Gilead Sciences and Galapagos with direction from a steering committee of leading independent expert rheumatologists.

www.jyseleca.eu/

Verder is JYSELECA (filgotinib) website live voor EU. Nu informatie beschikbaar voor RA-patiënten UK/Oostenrijk die JYSELECA gaan gebruiken. Andere selectie-landen zullen snel volgen.

Opstapelen 9 oktober 2020 18:33

UK/Oostenrijk klaar met prijsafspraak en kan worden verkocht.
Tenminste zo lees ik dit

Wall Street Trader 9 oktober 2020 19:30

Packaging design 100 mg / 200 mg

What JYSELECA is and what it is used for

JYSELECA contains the active substance filgotinib. It belongs to a group of medicines called Janus kinase inhibitors, which help reduce inflammation.

JYSELECA is used to treat adults with rheumatoid arthritis, an inflammatory disease of the joints. It can be used if previous therapy did not work well enough, or was not tolerated. JYSELECA can be used on its own, or together with another arthritis medicine, methotrexate.

JYSELECA reduces inflammation in your body. It helps to reduce pain, tiredness, stiffness and swelling in your joints, and it slows down damage to the bone and cartilage in the joints. These effects can help you to perform your normal daily activities, and improve your quality of life.

www.jyseleca.eu/en/download/Jyseleca-...

Bijlage:

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