Replies to post #209104 on Biotech Values

[DewDiligence]

Other companies with BACE inhibitors (scan to bottom):

http://www.epvantage.com/Universal/View.aspx?type=Story&id=688512&isEPVantage=yes

[mcbio]

I feel like $biib aducanumab has a decent shot, but im not in love with their trial design. the biomarker entry criteria is an important step, moving up into the early and prodromal stage is an important step, but I feel that the duration of treatment may not be long enough. I would have preferred to see a 30 or 36 month tx duration as opposed to 18 months. The pathology of the disease has been progressing, even in these early patients, for 20 yrs. Longer wouldve have given the trial a higher probability of success. I dont see a lot of differentiation from aducanumab and bapineuzumab, apart from $biib heavily benefited by Elan/JnJ being 1st, maybe studying disease too late, being too early for good biomarkers, and paving the way regarding ARIA/vasogenic edma as a marker for efficacy.

Thanks for the detailed response. I really appreciate it. I think that is a really interesting point from BIIB about CDR being a secondary endpoint in the LLY sola trial and actually being positive with p-value <.05 even in mild patients in that P3 trial. Obviously, no guarantee at all that carries over to aduca P3 primary endpoint readout even with it being in earlier stage prodromal/early mild. Still an interesting point I think.

There are 2 other antibodies to keep eyes on. Ganterumab from ROche, which is somewhat similar to aducanumab and bapineuzumab, as well as crenezumab from Genentech.

Doesn't it concern you that gantenerumab already failed its P3 trial in prodromal patients (http://www.roche.com/media/store/releases/med-cor-2014-12-19b.htm )? You don't think any read-through to aduca P3 here? More a trial design issue?

[DFRAI]

Why not Anavex - AVXL in AD

Patient interview

Link and slide deck CTAD 2016
http://www.anavex.com/9-months-and-12-months-safety-and-exploratory-efficacy-data-of-anavex-2-73-in-a-phase-2a-study-in-mild-to-moderate-alzheimers-disease-patients/

[DFRAI]

Masterlongevity - Anavex (AVXL) primer

Allways wondered why Anavex is not being discussed on this board since so many other compounds for AD are being highlighted. I do understand that Anavex may have had a checkered past and while still low on finances - they are able to connect with Rhetts foundation and Fox foundation in AD.

Their lead compound 273 has completed a 1 year trial in Australia and has been extended for another year at the request of patients.

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=128842430
Compliments of Mycroft from Anavex board

RE: 273 distinctions

Apologies for the length of my reply. It seemed good to leave this as one complete response.

I recommend that one read the very complete Nobel Analysis before delving into any academic papers.
nobleresearch.com/reports/AVXL_20170206_9669.pdf

I tend to break down the research into 2 categories:
1) What is the problem we are trying to solve?
2) Is A2-73 promising amongst sigma receptors to solve these problems?

1) What is the problem we are trying to solve?
One can look at the causes of neurodegeneration mentioned in the excellent paper you cited
(touroscholar.touro.edu/cgi/viewcontent.cgi?article=1004&context=tuccop_pubs )

Common mechanisms of neurodegeneration
- Excitotoxicity and calcium overload
- Oxidative and nitrosative stress
- Endoplasmic reticulum (ER) stress
- Mitochondrial dysfunction
- Reactive gliosis

2) Is A2-73 promising amongst SR1 active molecules to solve these problems?

Neuroprotective actions by sigma ligands
- Modulation of calcium homeostasis and glutamate activity
- Attenuation of reactive species production
- Modulation of ER and mitochondrial function
- Modulation of glial activity


General A2-73 Facts
A2-73 acts as an agonist at M1 and S1 receptors, acts as an antagonist to M2, M3, NMDA receptors, and at high enough doses as an antagonist to sodium and calcium channels. The compound appears to have influence on IRE1 and Bcl-2 which seems to impede apoptosis signaling thereby prolonging cell life and modifies ion channels at Mitochondria to assist in homeostasis. In general, the compound seems to lower oxidative stress, reduce mitochondrial dysfunction, prolong apoptosis and thus cell life, and reboot the cellular machinery to clear mis-folded proteins via the usual cell process.

When reading the science, I tend to keep this cheat sheet handy

A2-73 molecules are:
Sigma-1 receptor agonists;
Muscarinic M1 receptor agonists;
Muscarinic M2 receptor antagonists;
Muscarinic M3 receptor antagonists;
NMDA receptor antagonists;

Calcium channel antagonists;
Chloride channel modulators;
Sodium channel antagonists;
Sodium channel modulators


A2-73 has duration
Both the compound and its metabolite are active.

A2-73 is well tolerated/selective
The compound's is more selective to SR1 than other compounds which suggests a more targeted SR1 effect with reduced side-effects. Unlike other SR1 compounds (cocaine) A2-73 is reportedly only active in cells under stress. The exact mechanism here is unknown to me but I assume has to do with Ca+ ion imbalance.
Quote:
While preclinical evidence suggests that sigma-1 receptor agonists may be useful in treating Alzheimer's disease, no selective sigma-1 agonist is currently available for clinical use. Two currently approved drugs, donepezil and memantine, both act on sigma-1 receptors in addition to their other primary pharmacological targets, but whether any of their therapeutic effects are mediated by sigma-1 receptor activity has not been determined.
http://touroscholar.touro.edu/cgi/viewcontent.cgi?article=1004&context=tuccop_pubs

A2-73 impacts modulation of calcium homeostasis and glutamate activity, Attenuation of reactive species production, Modulation of ER and mitochondrial function
Through a cascade of activity, SR1 agonists influence Ca+, ROS, and Apotosis signals both at the ER-Mitochondira MAM and at other parts of the cell. A2-73 also acts directly as a NMDA antagonist which is thought to further increase this SR1 effect; An important added punch.
Quote:
Upon ER Ca2+ depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca2+ signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis.
http://www.cell.com/cell/abstract/S0092-8674(07)01099-9?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867407010999%3Fshowall%3Dtrue&cc=y=

Quote:
Recent studies now suggest the possibility that s-1Rs could exert neuroprotective effects via targeted disruption of protein-protein interactions between NMDARs and their associated intracellular signaling machinery, specifically the neuronal nitric oxide synthase (nNOS). This targeted disruption of protein-protein interactions between NMDARs and nNOS results in lower levels of nitric oxide generation, thus having a neuroprotective effect.
http://www.karger.com/Article/Abstract/376549

A2-73 Postpones cell death and provokes Unfolded Protein Response
As proper SR1 agonist, it sets off a chain reaction to help the cell 'reboot' and recover its function.

A2-73 mixed s1/muscarinic ligand shows evidence of being neuroprotective in Alzheimer’s disease
As the original question had to do with what makes A2-73 'different' it is instructive to note that A2-73 outperformed PRE-084 another highly selective SR1 agonist.
Quote:
The main objective of the present study was to establish whether the mixed s1/muscarinic ligand ANAVEX2-73, shown to be neuroprotective in Alzheimer’s disease (AD) models in vivo and currently in clinical phase I/IIa, could have the ability to reduce the appearance of hyperphosphorylated Tau and amyloid-ß1–42 (Aß1–42) in the Aß25–35 mouse model of AD. We therefore first confirmed that Aß25–35 injection induced hyperphosphorylation of Tau protein, by showing that it rapidly decreased Akt activity and activated glycogen synthase kinase-3ß (GSK-3ß) in the mouse hippocampus. Second, we showed that the kinase activation, and resulting Tau alteration, directly contributed to the amyloid toxicity, as co-administration of the selective GSK-3ß inhibitor 2-thio(3-iodobenzyl)-5-(1-pyridyl)-[1,3,4]-oxidiazole blocked both Tau phosphorylation and Aß25–35-induced memory impairments. Third, we analyzed the ANAVEX2-73 effect on Tau phosphorylation and activation of the related kinase pathways (Akt and GSK-3ß). And fourth, we also addressed the impact of the drug on Aß25–35-induced Aß1–42 seeding and observed that the compound significantly blocked the increase in Aß1–42 and C99 levels in the hippocampus, suggesting that it may alleviate amyloid load in AD models. The comparison with PRE-084, a selective and reference s1 receptor agonist, and xanomeline, a muscarinic ligand presenting similar profile as ANAVEX2-73 on M1 and M2 subtypes, confirmed that both muscarinic and s1 targets are involved in the ANAVEX2-73 effects. The drug, acting synergistically on both targets, but with moderate affinity, presents a promising pharmacological profile.
http://www.nature.com/npp/journal/v38/n9/full/npp201370a.html

[mcbio]

Eisai/(BIIB) - Exercises Option to Co-Promote Aducanumab

http://www.eisai.com/news/enews201760pdf.pdf

FOR IMMEDIATE RELEASE
October 23, 2017
BIOGEN AND EISAI EXPAND EXISTING COLLABORATION AGREEMENT TO DEVELOP AND COMMERCIALIZE INVESTIGATIONAL ALZHEIMER’S DISEASE TREATMENTS INCLUDING PHASE 3 ADUCANUMAB

? Eisai has exercised its option to jointly develop and commercialize aducanumab, with Biogen continuing as development lead
? The expanded collaboration agreement leverages each company’s respective geographic strengths for commercialization and adjusts the respective share of potential profits from potential sales of aducanumab
? Biogen and Eisai will now co-promote Biogen’s multiple sclerosis (MS) treatments, AVONEX ® (interferon beta 1a), TYSABRI ® (natalizumab), and TECFIDERA ® (dimethyl fumarate) in Japan to accounts that Biogen currently does not call upon

Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Biogen Inc. (NASDAQ: BIIB) (Headquarters: Cambridge, Massachusetts, United States, CEO: Michel Vounatsos, “Biogen”) announced today that the companies have expanded their existing agreement to jointly develop and commercialize investigational Alzheimer’s disease treatments.

Under the terms of the agreement Eisai has exercised its option to co-develop and co- promote aducanumab, Biogen’s investigational anti-amyloid beta (Aß) antibody for patients with Alzheimer’s disease (“AD”).

The expanded agreement leverages each company’s respective geographic strengths for commercialization and adjusts the respective share of profits from potential sales of aducanumab. Biogen will receive 55 percent of the potential profits in the United States and 68.5 percent of the potential profits in Europe. Eisai will receive 80 percent of the potential profits in Japan and Asia (excluding China and South Korea). The companies will have a 50:50 co-promotion split of potential profits in the rest of the world. Further, Biogen will book sales in the United States, Europe, and rest of world markets while Eisai will book sales in Japan and Asia (excluding China, South Korea).
Biogen will continue to lead the ongoing Phase 3 development of aducanumab and will remain solely responsible for all development costs for aducanumab until April 2018. Eisai will then reimburse Biogen for 15 percent of expenses from April 2018 through December 2018, and 45 percent from January 2019 onwards.

Neither party is making any upfront payments associated with the exercise of the aducanumab option. Furthermore, Eisai’s and Biogen’s respective milestone payments under the original agreement for aducanumab and BAN2401, an anti-Aß protofibril antibody, have been eliminated.

The companies will continue to jointly develop elenbecestat* (E2609), a beta amyloid cleaving enzyme (BACE) inhibitor, and BAN2401. The financial terms for elenbecestat and BAN2401 remain unchanged, other than the eliminated BAN2401 milestone payments.

Additionally, Eisai and Biogen have agreed to co-promote Biogen’s multiple sclerosis (MS) treatments, AVONEX (interferon beta-1a), TYSABRI (natalizumab) and TECFIDERA (dimethyl fumarate) in Japan to those accounts that Biogen currently does not call upon.

Eisai will also distribute and book sales for AVONEX, TYSABRI, TECFIDERA and PLEGRIDY® (peginterferon beta-1a) in India and other Asia-Pacific markets (excluding China).
“Through this new agreement, we believe we have improved our ability to maximize the value of aducanumab and expand the potential reach of our industry-leading multiple sclerosis portfolio,” said Michel Vounatsos, Chief Executive Officer of Biogen. “The ongoing collaboration between Biogen and Eisai leverages our respective expertise and strengths in our efforts to bring new treatments to patients and families affected by Alzheimer’s disease.”

Eisai CEO Haruo Naito commented, “Genetic epidemiological studies such as the Icelandic genetic research as well as the knowledge recently gained from various clinical studies such as the aducanumab Phase 1b trial have deepened our conviction in the amyloid hypothesis. We hope to establish a new treatment paradigm for fighting dementia by expanding the strategic collaboration between Biogen, a company that leverages its cutting-edge bio- technology to develop innovative therapies for people living with serious neurological and neurodegenerative diseases, and Eisai, a company which possesses a rich pipeline based on holistic approaches. In accordance with this new paradigm, we plan to further co-develop the collaboration products and hope to advance the world’s potentially first new treatment for Alzheimer’s disease based on the amyloid hypothesis. Through the collaboration and by leveraging each company’s respective strengths in each region, we hope to maximize the benefits for patients and their families.”

[mcbio]

ACIU/(other AD antibody players) - EP Vantage Interview

[So, obvious question to me is why isn't BAN2401 showing ARIA-E if they're blaming the issue of ARIA-E on IgG1 Mabs and BAN2401 is itself an IgG1 antibody? Does this weaken ACIU's arguments?]

http://epvantage.com/Universal/View.aspx?type=Story&id=748937&isEPVantage=yes

Interview – How AC Immune could finally (dis)prove the amyloid hypothesis

Date November 27, 2017
The failure of just about everything thrown at Alzheimer’s disease so far has not deterred the industry. And last year’s Nasdaq float of AC Immune – which claims to have the broadest Alzheimer’s pipeline in the business – shows that investors, too, remain enthusiastic.

AC’s chief executive, Andrea Pfeifer, insists that the Swiss group really is doing things differently. The keys to success? Accurate diagnosis and the ability to dose patients at high enough levels, she tells EP Vantage. What is more, she reckons she could have foreseen the failures of at least three competing Alzheimer’s projects.

Still, Ms Pfeifer remains an ardent believer in the amyloid hypothesis, and says the problem here is not the target but the lack of a therapeutic window. “[Elan’s] bapineuzumab was highly toxic,” she states, pointing to a high incidence of vasogenic oedema (ARIA-E), which was confirmed as a class effect in an early trial of Biogen’s aducanumab.

Meanwhile, recent setbacks with Merck & Co’s Bace inhibitor verubecestat could have been foreseen given that Bace is involved in amyloid-beta accumulation, so once the protein has formed inhibiting it is useless, Ms Pfeifer says.

“We are not in Bace – this was a very conscious decision,” she says, adding that Bace also suffers from a lack of specificity, hitting 80 proteins in addition to amyloid precursor.

The failure of Lilly’s solanezumab, however, was more mysterious. “I’m convinced that if [Lilly] had given double or triple the dose – which they could have done, because the side effects were pretty minor – I think they would have seen something,” says Ms Pfeifer. “Why they didn’t do it I don’t know.”

Crenezumab and the therapeutic window

AC is perhaps most famous for being the licensor of crenezumab, which along with the Morphosys-originated gantenerumab represents Roche’s two-shot bet on the amyloid-beta hypothesis.

Perhaps less well known is that AC also licensed to Roche the anti-tau MAb RG7345, while its anti-tau vaccine ACI-35 is partnered with Johnson & Johnson. One of its imaging agents, for detecting alpha-synuclein in Parkinson’s disease, is licensed to Biogen.

Diagnostics are a major part of AC’s clinical, if not commercial, strategy, as evidenced by the fact that crenezumab’s pivotal trials require evidence of amyloid-beta in the cerebrospinal fluid to be confirmed by immunoassay or PET scanning.

This points to another failure of competing amyloid-beta-targeting studies, which Ms Pfeifer insists used the wrong population, possibly too broad and definitely too late in the course of Alzheimer’s progression, she reckons: “You couldn’t start early enough because you didn’t have a diagnostic.”

But as well as imaging-assisted early dosing, Ms Pfeifer says you need to have a compound with a decent therapeutic window, which according to her calculations aducanumab, gantenerumab and bapineuzumab might not have.

Why not? Largely because they are IgG1 MAbs, whereas crenezumab is IgG4-based, meaning that it “clears the brain without inflammation. With a mechanism of action on oligomers... it does not attack vascular amyloid-beta. ARIA-E is linked to vascular amyloid-beta perforation.”

Characteristics of selected Abeta-targeting MAbs
Compound Company Isotype Dose* ARIA-E incidence
Crenezumab AC Immune/Roche IgG4 60mg/kg <0.2%
Aducanumab Eisai/Biogen IgG1 3-10mg/kg 35-41%
Gantenerumab Morphosys/Roche IgG1 1.5-17.1mg/kg 10.0-22.9%
Solanezumab Lilly IgG1 5.7mg/kg 1%
BAN2401 Eisai/Biogen IgG1 2.5-10mg/kg 0%
Bapineuzumab Elan/J&J IgG1 0.5-1mg/kg ~10%
Source: AC Immune, scientific papers; *calculated from Clinicaltrials.gov.

To underline her point Ms Pfeifer says AC has dosed crenezumab at 60mg/kg – severalfold higher than competing agents – with no relevant side effects. She says almost all the new competing anti-Alzheimer’s antibodies, though none targeting amyloid-beta, are IgG4s: “I think that’s what our contribution was to the field.”

It is an open question why Eisai/Biogen’s IgG1 MAb BAN2401 has not been associated with ARIA-E, as is the groups’ apparent reluctance to dose higher.

And another intriguing though now hypothetical question is whether bapineuzumab in an IgG4 form would have had a cleaner profile, and could at a high enough dose have shown efficacy (Axovant scraps Alzheimer’s bid – now back to the amyloid hypothesis, September 26, 2017).

Multiple shots

In addition to amyloid-beta AC is targeting tau, with a MAb, small molecule, vaccine and diagnostic. The imaging agent “allows us to discriminate between the different forms of tau”, Ms Pfeifer says, stressing that it is still unclear how many prodromal patients have this protein, or when it develops in the course of disease.

And she thinks only Lilly has tracers to pinpoint amyloid-beta and tau, which if true is surprising given the complexity of Alzheimer’s. “Do we think that with one shot we are going to cure Alzheimer’s?” she asks. “No, it doesn’t work like that.”

While it will be some time before AC’s theories will be proved or disproved – crenezumab’s pivotal trials start reading out in 2020 – Ms Pfeifer is convinced that patient profiling, not genetically but at a protein expression level, is set to grow in importance in Alzheimer’s.

“We are not precise enough,” she says. “You should look at our company as [being in] a situation where oncology was 30 years ago.”

To contact the writer of this story email Jacob Plieth in London at [e-mail] or follow @JacobPlieth on Twitter

[DewDiligence]

MRK—BACE-inhibitor prodromal phase-3 stopped for futility:

https://www.businesswire.com/news/home/20180213006582/en

This trial had been scheduled to read out in 2019 (#msg-128708268).

The drug in question, Verubecestat, has now failed phase-3 AD trials in both the both mild-to-moderate and prodromol populations.

[DewDiligence]

BIIB -7% on bearish Aducanumab blurb from Leerink webcast:

$BIIB adding ~255 pts/arm (510 total) for a-mab study, from LR conf

citing 'increased variability'

— zach (@zbiotech) February 14, 2018