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Tom3
0
seekingalpha.com/article/4061135-biom...

Targeting amyloid

With numerous high-profile setbacks in Alzheimer’s disease attention now turns to Probiodrug and its attempt to inhibit glutaminyl cyclase or QC, an enzyme it says is instrumental in catalysing the conversion of beta amyloid into pyroglutamate beta amyloid (pGlu-Abeta). The German company says this form of amlyloid is linked to the formation of soluble, toxic “pre-plaques” that lie behind Alzheimer’s progression.

The double-blind phase IIa Saphir study tests PQ912 against placebo in 120 treatment-naive patients with early Alzheimer’s, dosing 800mg orally twice a day for 12 weeks. The primary endpoint looks at adverse events, while secondary outcomes include mini-mental state examination, changes in Alzheimer’s-related biomarkers in the cerebrospinal fluid, and change in brain function measured by MRI and electroencephalography. Data are due by early June.

A phase I trial in 205 healthy volunteers showed that PQ912 was safe and well tolerated, with the most frequently reported adverse events being gastrointestinal disorders and headache.

Lilly is noteable for looking at a similar approach, but using an antibody to target pGlu-Abeta. Its MAb is coded LY3002813, and phase I data were reported on it at last year's Alzheimer's Association International Conference, showing 10mg/kg to reduce amyloid plaque load by 40%, although there were just six patients in this trial; still, analysts at Rx Securities said the results validated Probiodrug’s strategy. A second phase I trial of LY3002813 is ongoing.

Probiodrug completed its IPO on the Amsterdam Euronext back in 2014, and its shares are down 24% over the past year. The company has €21.9m ($23.4m) in cash, but a licensing deal could be on the cards if data impress. However, Alzheimer’s has eluded big pharma thus far, and PQ912 could prove to be just another nail in the coffin for the amyloid hypothesis.

Tom3
0
OVERVIEW
Name: LY3002813
Synonyms: N3pG-Aß Monoclonal Antibody
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Eli Lilly & Co.
BACKGROUND
LY3002813 is a monoclonal antibody developed from mouse mE8-IgG2a. This antibody recognizes Aß(p3-42), a pyroglutamate form of Aß that is aggregated in amyloid plaques. Most Aß antibodies in therapeutic development bind various soluble or insoluble species but have low affinity to deposited amyloid plaques. The rationale behind LY3002813 is that targeting deposited plaque itself is necessary to clear existing amyloid burden from the brain, rather than merely prevent deposition of new plaques or growth of existing plaques. Some previous plaque-binding antibodies have been abandoned because they caused microhemorrhages in the brain. The mE8 antibody was reported to clear plaques in mice without causing microhemorrhages (deMattos et al., 2012).

At the 2014 AAIC conference, Lilly reported that a randomized preclinical study of combination therapy with LY3002813 and the BACE inhibitor LY2811376 cleared more than 80 percent of amyloid from the brains of PDAPP-transgenic mice, compared to about 50 percent clearance each for the respective monotherapies. Neuropathology studies showed that LY3002813 removed both cored and diffuse plaques (see Jul 2014 conference news).

FINDINGS
In May 2013, Lilly started a Phase 1 study in 100 people with mild cognitive impairment due to Alzheimer's disease, or mild Alzheimer's disease, in the United States and Japan. Participants had to have a positive amyloid PET scan. This seven-arm study evaluates five intravenous doses, from 0.1 mg/kg to 10 mg/kg, infused monthly up to four times, and a single subcutaneous injection against placebo for safety, pharmacokinetics, and pharmacodynamics. It was originally listed to run until 2015 but has been extended to January 2017. At the 2016 AAIC conference in Toronto, Lilly scientists presented results from 49 patients, average age 74, who had completed the trial. Thirty-seven volunteers received a single initial dose, 12 placebo. After adverse event monitoring, they received up to four additional monthly infusions of the same dose; people in the 0.1mg/kg cohort subsequently received 0.3mg/kg. The highest dose was reported to reduce plaque load in the brain, though that group had but six participants. Overall, their mean florbetapir SUVR fell from 1.65 at baseline by 0.26 over seven months, corresponding to a 40 percent reduction. No cases of ARIA were seen in this small trial, but there were two asymptomatic cases of ARIA-H. The antibody was reported to be strongly immunogenic. In the multiple-dose phase, six of the 37 patients had an infusion reaction with chills, flushing, dizziness, rash, and fever, and anti-drug antibodies in plasma (see Aug 2016 conference news).

In December 2015, Lilly started a second Phase 1 study in 150 people with the same diagnosis, again in the United States and Japan. This trial also starts with a single dose and safety monitoring, but it then proceeds to repeated dosing for up to 18 months. The study measures primarily LY3002813's effect on brain amyloid load with florbetapir PET; secondary outcomes include blood pharmacokinetics of LY3002813 and auto-antibodies directed against this biologic drug. The trial is expected to run until 2019.
Tom3
0
OVERVIEW
Name: Solanezumab
Synonyms: LY2062430

Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Eli Lilly & Co.
Approved for: None

BACKGROUND
Solanezumab is a humanized monoclonal IgG1 antibody directed against the mid-domain of the Aß peptide. It recognizes soluble monomeric, not fibrillar, Aß. The therapeutic rationale is that it may exert benefit by sequestering Aß, shifting equilibria between different species of Aß, and removing small soluble species of Aß that are directly toxic to synaptic function. In preclinical research, a single injection of m266, the mouse version of solanezumab, reversed memory deficits in APP-transgenic mouse models while leaving amyloid plaques in place, raising the prospect of targeting the soluble pool of Aß (see Apr 2002 news story).

FINDINGS
In Phase 1, single doses of 0.5, 1.5, 4.0, or 10.0?mg/kg of solanezumab were well-tolerated in healthy volunteers and 19 patients with mild to moderate AD. MRI showed no evidence of inflammation, vasogenic edema, or microhemorrhage. A multiple-dose study in Japan delivered a 400 mg dose to 33 patients with mild to moderate AD intravenously every one, four, or eight weeks, also without serious adverse events related to solanezumab. Pharmacodynamic biomarker studies found changes in plasma and CSFAß40, Aß42, plasma pyro-Glu Aß, and plasma and CSF N-terminally truncated Aß, but not CSF total tau and phosphorylated tau.

In Phase 2, trials administering 100 to 1,600 mg per month of solanezumab for 12 weeks, and monitoring for safety and biomarker effects for one year, confirmed the antibody's safety and tolerability. Phase 2 showed dose-dependent increases of various Aß species in plasma and CSF but no effects on the ADAS-Cog, i.e., no indication of clinical benefit.

In Phase 3, two trials, EXPEDITION-1 and -2, randomized 2,052 people with mild to moderate AD to receive infusions of 400 mg of solanezumab or placebo once a month for 80 weeks. Data analysis was conducted by the study sponsor and independently by the Alzheimer Disease Study Group. Solanezumab continued to be safe, but EXPEDITION overall showed no improvement on the primary outcome measures of ADAS-Cog11 and ADCS-ADL. However, a prespecified subgroup analysis of the EXPEDITION-1 trial showed that solanezumab reduced cognitive decline in mild AD when measured by ADAS-Cog 14, prompting the FDA to approve revision of the primary endpoint of EXPEDITION-2 to a single endpoint of cognition in patients with mild AD before the trial database was locked. That analysis saw a trend to improved cognition with solanezumab in people with mild AD, but it missed statistical significance. Statistically significant benefit was seen in a pooled analysis of patients with mild AD in both trials. Benefit for instrumental activities of daily living was seen also in the mild subpopulation. The benefit appeared late, grew over time, and is thus thought to be consistent with a disease-modifying effect. The effect size of the benefit is small, generally thought to be smaller than that of cholinesterase-inhibitor drugs.

In July 2013, Lilly started EXPEDITION-3, a 39-center Phase 3 trial in 2,100 patients with mild AD and demonstrated brain amyloid burden. The last patient visit is scheduled for October 2016, and topline results are expected to be announded in fall 2016. In March 2016, Lilly announced that it would change the primary outcome for this trial. The original plan registered with regulatory agencies was to use a cognitive (ADAS-Cog 14) and a functional (ADCS-iADL) battery as co-primary outcomes; however, the new plan is to use ADAS-cog as a single primary and ADCS-iADL as a secondary outcome. According to the company, this will change the trial's data analysis but not the conduct of the trial itself, see company release. On November 23, 2016, Lilly announced, based on topline results, that solanezumab had missed primary endpoint in this trial. Primary and secondary outcome results were trending in the direction of a treatment benefit but effects were small and fell short of statistical significance. Lilly will not pursue FDA approval for solanezumab in mild AD (see company release).

Solanezumab's safety record and indication of a small benefit in mild AD has prompted its selection for two secondary prevention studies. The Dominantly Inherited Alzheimer's Network (DIAN) is conducting a five-year Phase 2/3 trial to test solanezumab and Roche's passive immunotherapy gantenerumab in 210 asymptomatic and very mildly symptomatic carriers of autosomal-dominant mutations in the Alzheimer's genes APP, presenilin-1, and presenilin-2. This trial reads out biomarker effects at two years (Phase 2). Subsequently, it will advance promising drugs to a three-year (Phase 3) testing phase whose primary endpoint is a composite battery of cognitive tests shown to be sensitive at the earliest symptomatic stages.

In February 2014, the Alzheimer's Disease Cooperative Study began a three-year trial testing solanezumab in 1,150 asymptomatic or very mildly symptomatic people 65 and older who have biomarker evidence of brain amyloid deposition, i.e., who meet a diagnosis of Phases 2 or 3 of preclinical AD as proposed by the 2011 NIA-AA diagnostic research criteria (see Sperling et al., 2011). Called A4, this secondary prevention trial uses the cognitive battery ADCS-PACC, which was developed to be sensitive at earlier clinical stages (Donohue et al., 2014). Amid a controversial leadership change, oversight of this trial has moved from ADCS to the new Alzheimer's Therapy Research Institute at the University of Southern California (August 4, 2015 press release). In June 2017, the study directors announced a quadrupling of the dose from 400 to 1,600 mg solanezumab or placebo given by IV every four weeks, based on results of the EXPEDITION program. Moreover, A4s study length also increased to four and a half years. The trial will run until early 2022.

In December 2015, Lilly began evaluating a subcutaneous formulation of solanezumab in a phase 1 trial of 130 people.

In June 2016, Lilly began a Phase 3 study in prodromal AD. Called ExpeditionPRO, this trial was to enroll 2,450 people with a clinical diagnosis of prodromal AD per IWG criteria, or of MCI due to AD per NAI-AA criteria. Participants were to have a positive amyloid PET scan and score within a defined range on the MoCA and FCSRT tests. The trial started comparing a two-year course of a monthly infusion of solanezumab to placebo for change on the ADAS-Cog14 scale; 16 listed secondary outcomes ran the gamut from clinical, cognitive, functional, psychiatric, and global measures as well as biomarkers in blood, CSF, and PET scans for both amyloid and tau pathology. This trial had started enrolling in up to 223 locations worldwide; however, in January 2017, word spread at scientific meetings that Lilly was terminating this study.

Tom3
0
Het is wel oorverdovend stil op dit forum zeg. Is iedereen helemaal suf door de koersverliezen? Ik vond nog een paar leuke artikelen op Labiotech.eu over oa de komende 2b trial:
labiotech.eu/probiodrug-alzheimer-pha...

labiotech.eu/probiodrug-alzheimers-di...
effegenoeg
0
quote:

Tom3 schreef op 28 dec 2017 om 23:57:


Het is wel oorverdovend stil op dit forum zeg. Is iedereen helemaal suf door de koersverliezen? Ik vond nog een paar leuke artikelen op Labiotech.eu over oa de komende 2b trial:
labiotech.eu/probiodrug-alzheimer-pha...

labiotech.eu/probiodrug-alzheimers-di...


Meeste beleggers hierin houden zich nu afzijdig voor een bijkoop op een zo laag mogelijke prijs.
Tom3
0
Koersverloop lijkt verdacht veel op dat van Kiadis. Kennelijk wil een grootaandeelhouder eruit en vindt de rest het wel goed zo. Het enige verschil is dat de zittende grootaandeelhouders allemaal ingestapt zijn op 15 en hoger (als je kijkt naar de gefinancierde verliezen per IPO datum) , de IPO prijs en de daarop gerealiseerde emissie tegen euro 20 per aandeel. Bij Kiadis zaten de grootaandeelhouders op een kostprijs van de ca de helft van de IPO prijs. De huidige koers van Probiodrug doet dus wel pijn bij alle zittende aandeelhouders. Enfin als er weer een emissie aankomt zal de beurskoers wel weer naar de 15 of hoger worden gedirigeerd. Eerst echter moet de grote verkoper eruit (bij Kiadis was dit Quest for Growth). Wil JPM er helemaal uit? Heb nog geen melding van de overschrijding van de 3% grens gezien.
Tom3
0
Eindejaarsopruiming van brekebeentjes? Koersverloop is vrij eentonig. Het is niet het hit and run aandeel geworden wat velen gedacht hadden. Op de plank dus.
Tom3
0
AC Immune/Genentech/Roche geven ook niet op:

labiotech.eu/ac-immune-genentech-cren...

globenewswire.com/news-release/2016/1...

Probiodrug mag dan in 2017 de lantaarndrager op de smallcap beurs in Amsterdam geworden zijn maar dat houdt toch niet in dat er geen weg terug is. Beste wensen voor 2018.
Tom3
0
About AC Immune:
AC Immune is a clinical stage Swiss-based biopharmaceutical company focused on neurodegenerative diseases with four product candidates in clinical trials. The Company designs, discovers and develops therapeutic and diagnostic products intended to prevent and modify diseases caused by misfolding proteins. AC Immune's two proprietary technology platforms create antibodies, small molecules and vaccines designed to address a broad spectrum of neurodegenerative indications, such as Alzheimer's disease. The Company's pipeline features seven therapeutic and three diagnostic product candidates. The most advanced of these is crenezumab, an anti-Abeta antibody in Phase 3 clinical studies that is being advanced by the collaboration partner Genentech, Inc., a member of the Roche Group. Other business partners include Biogen, Janssen Pharmaceuticals, Nestlé Institute of Health Sciences and Piramal Imaging.
Tom3
0
AC Immune is een Zwitserse onderneminghelemaal gefocussed op Alzheimer bestrijding met een Nasdaq notering. Beurswaarde is ongeveer het 7-voudige van Probiodrug. Men hecht ook veel waarde aan tau (een enzym) als target voor AD bestrijding. Dit is eigenlijk het enige verschil (qua aanpak dan met Probidrug.
www.bloomberg.com/quote/ACIU:US
www.acimmune.com/
Tom3
0
Vakgenoten (helaas maar 3) op alzforum vinden de uitkomst van het fase 2a onderzoek van Probiodrug interessant en veel belovend. Ook de wetenschappelijke wereld is zwaar verdeeld en heeft zich waarschijnlijk diep ingegraven.

www.alzforum.org/news/research-news/n...
Tom3
0
In 2010 was het theoretische denkwerk al achter de rug. Waarom moet het dan nog 7 jaar duren voordat het een begin van bewijs geleverd wordt?:

www.alzforum.org/news/conference-cove...
MrTrumpHimself
0
Tom3 bedankt voor alle links! Ik ga me straks verdiepen in Probiodrug.

"During the first eight weeks of the study, 27 people in the treatment arm either temporarily or prematurely stopped taking the medication due to side effects, compared with six people in the placebo group." (http://www.alzforum.org/news/research-news/new-alzheimers-drug-shows-safety-hints-efficacy-phase-2)
Nou heb ik in een ander artikel gelezen dat er 60 het medicijn kregen en 60 een placebo. Ze willen het in een vervolgonderzoek dus de dosering stapsgewijs gaan opvoeren.
Zijn de bijeffecten gevaarlijk voor het succes van het medicijn? Of omdat alzheimer zo levensgevaarlijk is dat ze het maar al te graag als bijwerking accepteren?
Dit omdat ik op het galapagos forum ooit gelezen heb dat nieuwe medicijnen eigenlijk ook geen bijwerkingen meer zouden moeten hebben, willen ze überhaupt goedgekeurd worden. Maar ja..., dit lijkt mij wat anders voor iets alzheimer.
MrTrumpHimself
0
ACImmune (concurrent met Crenezumab):
ABBY: ABBY was a Phase 2 trial evaluating up to 15 mg/kg per month of subcutaneous crenezumab injections, conducted at more than 90 sites in North America and Europe in 450 people with mild to moderate AD.

BLAZE: a 91-patient biomarker study called BLAZE were completed in spring 2014; The BLAZE study reported no separation between treatment and placebo groups on the primary endpoint of PET amyloid imaging, but did report a separation on the secondary endpoint of CSF Aß

ABBY: ABBY missed its primary endpoints of change on ADAS-cog and CDR-SOB. Further analysis suggested a possible efficacy signal in mild AD, similarly to solanezumab's EXPEDITION 1 and 2 results.

Crenezumab (voor treatment) zit nu in phase 3, met een verhoogde dosis omdat wetenschappers van het bedrijf claimen dat die wel werkt.

Crenezumab phase 2 ABBY: "Rates of decline on ADASCog-12 over the 18-month double-blind treatment period were lower at all time points in people treated with intravenous (IV) crenezumab compared to the placebo in the overall group. Although the differences did not reach statistical significance in the overall group there was a trend towards slowing cognitive decline in progressively milder patient subsets relative to placebo. In an exploratory analysis, people with milder disease (MMSE 22-26 points) exhibited a statistically significant 35.4 percent reduction in cognitive decline (p=0.036) and a 19.6 percent reduction in global functional decline (p=0.42) (p-values for exploratory analyses were not adjusted for multiplicity)."

Crenezumab BLAZE: Also associated with a trend towards slowing cognitive decline in those with mild disease (not the primary endpoint of the study). 52% reduction in cognitive decline (p=0.29) and a 41.5 percent reduction in functional decline (p=0.44).

Ook: "In terms of its binding specificity, crenezumab is similar to solanezumab, see May 2015 news." (http://www.alzforum.org/therapeutics/crenezumab)
Solanezumab: 25-11-2016: "Alzheimermiddel solanezumab blijkt niet effectief" (https://www.nytimes.com/2016/11/23/health/eli-lillys-experimental-alzheimers-drug-failed-in-large-trial.html?_r=0)


Nu PQ912:
"In terms of effectiveness, the results showed that PQ912 significantly reduced glutaminylcyclase enzyme levels."
"Another effectiveness finding was that it greatly reduced biomarkers of inflammation and damage in patients’ nerve cell connections. In contrast, these levels rose in the placebo group."
"Patients treated with PQ912 also had better scores than the control group on two of the neuropsychological test battery exams. One was the One Card Back Test, which assesses working memory. The other was the Detection Test, which measures attention." (van de hoeveel tests, 7?)
"The treatment group also had a trend toward improvement on a test of attention, but no difference from placebo on five other measures."
"A first-in-class Alzheimer’s therapeutic met its primary endpoint in a Phase 2a trial, according to topline results released by the drug’s sponsor, Probiodrug in Halle, Germany.

“Although I am a bit concerned about the adverse events, the results obtained after such a short treatment period show that the target, the treatment strategy, and the compound are very promising,”

"On the exploratory measures, the researchers saw a highly significant (p=0.002) effect on brainwave activity, as measured by EEG."

"The CSF also provided signals that PQ912 was hitting its target. QC was inhibited by 92 percent in patients on drug, in agreement with Phase 1 data for this dose." "but Lues noted that this data should be interpreted cautiously, since levels in the CSF are so low that they are at the limit of detection for the assay"


Crenezumab lijkt mij ook weer een medicijn dat het niet gaat redden in phase 3. En al helemaal omdat het medicijn volgens mij nogal wat gelijkenissen vertoont met Solanezumab (van lili & co.).
De reden dat PQ912 nog niet effectief bleek op 5 andere waarden, was volgens de onderzoekers zelf omdat de test nog niet lang genoeg duurde.
Een verschil met Crenezumab is wel dat PQ912 zijn primary endpoints wel haalt (voor zover ik weet), maar die zijn dan ook meer gericht op de veiligheid en niet op de effectiviteit.
Daarnaast willen ze de dosering volgens mij geleidelijker opvoeren zodat de bijwerkingen minder worden.

Over het algemeen denk ik dat Crenezumab het ook niet gaat redden, en dat PQ912 een grotere kans heeft, maar eigenlijk is er nog te weinig bekend om daar wat over te zeggen.
Aldus mijn mening.

Alzheimer markt is 15 miljard, laat PQ912 het redden dan: met een netto winst van laten we zeggen 3 miljard per jaar, dit 5 jaar lang = 15 miljard waarde.
15 miljard / 80 miljoen = 187.5 keer.
Dus het is zeker een interessante gok om te wagen.

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