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Morphosys – fachliche Überlegungen zur Entwicklungspipeline (Seite 77)


ISIN: DE0006632003 | WKN: 663200 | Symbol: MOR
93,00
21.09.18
Hamburg
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+0,45 EUR

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Antwort auf Beitrag Nr.: 57.374.294 von Joschka Schröder am 23.03.18 22:03:06Jetzt müsste ich nur noch verstehen, wie die Werte einzuschätzen sind und warum es bei Männern (soweit ich es verstanden habe) keinen Effekt gegeben hat.

Kannst mir das jemand so erklären, dass ich das auch verstehe? :confused:
Ach ja, die alte Amyloid-Hypothese ....



https://endpts.com/merck-study-may-signal-doom-for-a-broad-g…

Merck study may signal doom for a broad group of pivotal Alzheimer’s studies

by john carroll — on May 3, 2018 08:53 AM EDT
Updated: 09:17 AM


The BACE the­ory in Alzheimer’s R&D is sim­ple. Cut off the flow of amy­loid beta to the brain and you can elim­i­nate what is widely be­lieved — though not proven — to be a cause of the dis­ease. Do that, and you could bend the course of this dev­as­tat­ing ill­ness in mil­lions of peo­ple with mild to mod­er­ate forms of the dis­ease.

And Merck $MRK just spent a for­tune to demon­strate that it may well be com­pletely wrong.

To be sure, Merck ran a clean study for verube­ce­s­tat, the lead­ing BACE drug in the clinic, and dis­played the data on 1,958 pa­tients for all to see today in the New Eng­land Jour­nal of Med­i­cine. In­ves­ti­ga­tors care­fully tracked amy­loid beta flows in cere­brospinal cords and found that the drug did what it was in­tended to do, with a dra­matic re­duc­tion of the toxic pro­tein. 

It had no ef­fect, with pa­tients in the two dosage groups track­ing in par­al­lel de­cline on both cog­ni­tion and func­tion, the two clas­sic mea­sures for Alzheimer’s. 

The con­clu­sion they reached is that the dam­age al­ready pre­sent in the brains of pa­tients with Alzheimer’s may be too ex­ten­sive to treat with any BACE drug. And they also con­cede that the amy­loid the­ory it­self may be just flat wrong.

This sug­gests that once de­men­tia is pre­sent, dis­ease pro­gres­sion may be in­de­pen­dent of Aβ pro­duc­tion or, al­ter­na­tively, that the amy­loid hy­poth­e­sis of Alzheimer’s dis­ease may not be cor­rect. Be­cause Aβ de­po­si­tion takes place years be­fore clin­i­cal symp­toms be­come ap­par­ent, it has been pro­posed that treat­ments tar­get­ing amy­loid should be im­ple­mented early in the dis­ease process, be­fore the onset of clin­i­cal symp­toms.

Soon after this study failed, Merck also threw in the towel on their sec­ond piv­otal trial, not­ing it too was a flop. Those data are still being eval­u­ated, but it un­der­scores the be­lief that all of the BACE stud­ies — in­clud­ing those at Eli Lilly $LLY, part­nered with As­traZeneca$AZN, or Bio­gen $BIIB, al­lied with Eisai — are headed straight to fail­ure.

Bio­gen is also rolling the dice on ad­u­canumab, which the com­pany has touted as a lead­ing amy­loid beta ther­apy. But with in­ves­ti­ga­tors in the field openly won­der­ing whether the amy­loid the­ory has lured a long lineup into a clin­i­cal dis­as­ter zone, it’s likely to face grow­ing skep­ti­cism that it can de­velop a safe, ef­fec­tive ther­apy with just one drug.

This doesn’t by any means elim­i­nate work in the area. True, Pfizer re­cently pulled out after spend­ing hun­dreds of mil­lions of dol­lars on their pro­grams. But star­tups like De­nali be­lieve that new and bet­ter tech­nol­ogy can give them bet­ter odds at suc­cess, while Cel­gene is jump­ing in with its own new pipeline. Oth­ers want to see if com­bi­na­tion ap­proaches using tau and amy­loid beta to­gether could work. 

Merck’s sug­ges­tion about going even ear­lier in the dis­ease process has also prompted a range of stud­ies in pre-symp­to­matic pa­tients, while the FDA has sig­naled its in­ter­est in com­ing up with bio­mark­ers to help speed new stud­ies.

After more than 200 R&D pro­jects ended in dis­as­ter, though, Alzheimer’s is look­ing like an in­creas­ingly daunt­ing chal­lenge, with no clear path for­ward that would in­spire con­fi­dence among pa­tients with the dis­ease.
Betrifft Guselkumab:


Ich habe mir heute diverse Studiendaten von UCBs Bimekizumab (anti-IL-17A/F) angesehen. In der Indikation "Psoriatische Arthritis" toppen die Phase 2b-Daten die Daten der Konkurrenz deutlich. Nach dreimaliger Gabe in Woche 2, 3 und 6 wurden in Woche 8 bereits 89 % PASI90 (Placebo 1%) und in Woche 20 sogar 93 % PASI90 (Placebo abermals 1 %) erzielt Die ACR50-Werte in Woche 8 bzw. 20 wurden von 40 % bzw. 57 % der Patienten erreicht.

Man darf gespannt sein, zu welchen Ergebnissen der multispezifische Antikörper UCB0159 führen wird, der außer IL-17A/F noch TNF adressiert und zusätzlich (zwecks Verlängerung der Halbwertszeit) an Albumin bindet.
Bei diesjährigen EULAR Meeting wird GSK wohl keine Ergebnisse zu MOR103 berichten, konnte in der Abstracts-Übersicht jedenfalls nichts dergleichen finden.
Antwort auf Beitrag Nr.: 57.705.709 von Joschka Schröder am 06.05.18 23:27:52
Zitat von Joschka Schröder: Betrifft Guselkumab:

Ich habe mir heute diverse Studiendaten von UCBs Bimekizumab (anti-IL-17A/F) angesehen. In der Indikation "Psoriatische Arthritis" toppen die Phase 2b-Daten die Daten der Konkurrenz deutlich. Nach dreimaliger Gabe in Woche 2, 3 und 6 wurden in Woche 8 bereits 89 % PASI90 (Placebo 1%) und in Woche 20 sogar 93 % PASI90 (Placebo abermals 1 %) erzielt Die ACR50-Werte in Woche 8 bzw. 20 wurden von 40 % bzw. 57 % der Patienten erreicht.

Man darf gespannt sein, zu welchen Ergebnissen der multispezifische Antikörper UCB0159 führen wird, der außer IL-17A/F noch TNF adressiert und zusätzlich (zwecks Verlängerung der Halbwertszeit) an Albumin bindet.

Ab wann würde Janssen denn hier Konkurrenz bekommen? Wie viel Vorsprung haben sie?
Novartis ARROW trial to assess mechanistic superiority of direct IL-17A inhibition (Cosentyx®) over IL-23 inhibition (Tremfya®*)


ARROW study to assess the mechanistic superiority of direct IL-17A inhibition (Cosentyx) over IL-23 inhibition (Tremfya®*) in clearing of Stelara®*-resistant psoriatic plaques[1]

This is the 100th trial with Cosentyx in the last 10 years, adding to the wealth of data[2]. Cosentyx has been prescribed to more than 150,000 patients to date[3]

Cosentyx has a broad head-to-head study program that includes FIXTURE, CLEAR, CLARITY, SURPASS and EXCEED clinical superiority trials[4]-[8]

Basel, May 15, 2018 - Novartis announced today the plan to initiate ARROW, a head-to-head proof of concept study to assess the mechanistic superiority of the direct inhibition of IL-17A with Cosentyx® (secukinumab) over the inhibition of IL-23 with Tremfya®* (guselkumab) in patients with psoriatic plaques resistant to treatment with Stelara®*[1]. Study results are expected in 2019.

 

"We know there are different immune mechanisms driving the clinical manifestations of psoriasis, including the involvement of joints, scalp, nails, palms and soles psoriasis. Results from the ARROW trial could help us learn more about the differences between the direct targeting of IL-17A and IL-23 in psoriasis," said Kristian Reich, M.D., Ph.D., Georg-August-University Göttingen and Dermatologikum Hamburg, Germany. "It's great to see Novartis leading the science in psoriasis, psoriatic arthritis and ankylosing spondylitis."

 

"Treating all manifestations of psoriasis in the most effective way is crucial for patients and physicians. We are proud to be driving scientific activities to elucidate the biologic pathways in these diseases with the goal of transforming treatment options for patients," said Shreeram Aradhye, Chief Medical Officer and Global Head, Medical Affairs, Novartis Pharmaceuticals.

 

The ARROW study objective is to assess the mechanistic superiority of Cosentyx® over Tremfya®* in controlling clinical activity in psoriatic plaques resistant to treatment with Stelara®*[1]. IL-23 independent pathways of IL-17A release are potentially involved in inflammation of other persistent localizations, including joints, scalp, nails, palms and soles psoriasis[9]. Up to 90% of people with psoriasis may develop nail or palmoplantar psoriasis[10],[11]. Nail psoriasis is an important predictor of psoriatic arthritis (PsA) which affects up to 40% of patients with psoriasis[12].

 

Cosentyx is the first fully-human biologic that specifically inhibitsinterleukin-17A (IL-17A), a cornerstone cytokine involved in the inflammation and development of psoriasis, ankylosing spondylitis (AS), and psoriatic arthritis (PsA)[13]-[16]. IL-17A is produced by both IL-23 dependent and IL-23 independent pathways, by various cells from both the innate immune system (which can be triggered by mechanical stress) and the adaptive immune system[9]. By acting directly on IL-17A, Cosentyx inhibits this cornerstone cytokine irrespective of where the IL-17A comes from[13].

 

This study is now the 100th trial with Cosentyx in the last 10 years, adding to the wealth of data[2]. Cosentyx has a broad head-to-head study program that includes FIXTURE, CLEAR, CLARITY, SURPASS and EXCEED clinical superiority trials[1],[4]-[8]. To date, Cosentyx has been prescribed to more than 150,000 patients with psoriasis, PsA and AS worldwide[3].

 

About ARROW[1]

ARROW (CAIN457A2403) is a global multicenter open label randomized proof of concept Phase 2a study designed to assess the mechanistic superiority of secukinumab 300 mg over guselkumab 100 mg in achieving the clearing of psoriatic skin plaques resistant to treatment with ustekinumab after 16 weeks. 40 patients will be randomized 1:1 to secukinumab or guselkumab and treated for 16 weeks. The primary endpoint of the study is the percentage of patients achieving clear or almost clear status of the ustekinumab-resistant plaques as assessed through the Total Clinical Score (TCS =<2). The mechanistic exploratory endpoints of this study will explore the hypothesis that the direct targeting of IL-17A is able to overcome IL-23 independent mechanisms of resistance, providing a more complete approach to the control of alternative pathways of psoriasis inflammation.
Antwort auf Beitrag Nr.: 55.149.869 von deadflowers am 16.06.17 09:14:36
Zitat von deadflowers: Eine der großen offenen Fragen zu CAR-T ist allerdings, wie das alles finanzierbar sein soll. Das betrifft die Therapie selbst und die sehr teure lebenlange IVIG Gabe. Wenn man das in der Breite einsetzt, läuft das ganzes System aus dem Ruder. M.E. unbezahlbar, und eigentlich nicht vorstellbar, dass es bei Patienten zum Einsatz kommt, wo es noch andere Therapiemöglichkeiten gibt.


Kritischer Artikel im NEJM zu CAR-T-Therapien und deren Kosten und Nutzen für Patienten und Public Health:
https://www.nejm.org/doi/full/10.1056/NEJMp1807382


The two approved CAR-T therapies have boxed warnings regarding serious side effects, and each costs about $400,000. Ancillary costs include initial leukapheresis and inpatient stays that may be necessitated by frequent treatment complications, which may result in administration of tocilizumab (up to four doses at $2,500 per dose). Hernandez and colleagues estimate that these ancillary costs would average around $33,000 per patient; media reports suggest a figure 10 times as high.2


CAR-T therapies have broken new ground on many fronts — they have shown efficacy in patients who previously had few options, but they cost multiple times what any previously approved cancer therapy costs. Their rapid approval based on small, uncontrolled studies reflects their promise. But they are no panacea. Ms. Kearney died a few weeks after receiving her dose of the CAR-T therapy that cost nearly $400,000, and she endured an extended hospital and ICU stay along the way. She told WBUR reporter Richard Knox that she knew death was a possible outcome, and she was grateful for the chance to receive a possibly effective treatment — a reminder of what’s at stake for Medicare patients when CMS considers CAR-T therapy coverage. If Medicare chooses to cover this therapy, it should think carefully about how to do it.
Antwort auf Beitrag Nr.: 58.461.202 von rollingovermilestones am 16.08.18 10:51:11News zu Gantenerumab:

https://www.alzforum.org/news/conference-coverage/four-immun…

…At least four drugs have now demonstrated the ability to clear plaques from the brain: aducanumab, gantenerumab, Lilly’s LY3002813, and BAN2401…

…It clinched the case that these antibodies can mop up brain amyloid, bringing many people with early symptomatic Alzheimer’s disease below the threshold for amyloid positivity. At one to two years, this clearance took a long time. But still: Gregory Klein at Roche claimed that two years of treatment with high-dose gantenerumab essentially resets a person’s trajectory of amyloid accumulation. “We are setting back the clock by 15 years,” Klein told the audience…
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