Are you surprised by this? Would figure the VXRT oral vaccine assets are more important than AVIR's cash but VXRT did indicate in the CC that they needed the cash infusion.

VXRT/AVIR -

I listened to the related CC and the first caller during Q&A asked if there are concerns in using an adenovirus vector for baseline neutralizing antibody titers. VXRT said this is a phenomenon seen in using vectors by injection. And wIth their vector given orally in non-replicating form, VXRT believes they circumvent any pre-existing anti-vector issues.

But, isn't H1N1 going to be the key strain to cover most years? Seems unlikely to expect most years to be like this year going forward though I guess you can never know. Also, people still get the flu shot each year even when it seems obvious it's not covering the key strain that year. Would certainly seem to be a role for a pill if it's deemed at least as safe and effective.

WIth the caveat of the difficulty of making cross-trial comparisons, the data does at least seem encouraging, doesn't it? I also assume, all-things-being-equal, that there would be a market for a pill vs. shot.

EPIX @ Noble

http://noble.mediasite.com/mediasite/Play/771606a950c14c9da74e5bf0bb3a06271d

[Good to see they finally raised a big chunk of cash (even though at very dilutive levels). Also good to see they are presenting at conferences and webcasting now.]

1. IND filing of next-gen Aniten compound (2nd gen version of EPI-506) expected by 1Q19.
2. Estimate of 60% of mCRPC tumors post-Xtandi or Zytiga failure may still be androgen receptor driven.
3. Claimed safety issues arose from the exceedingly high levels of the prior drug, EPI-506, because the drug was in a castor oil excipient.
4. Prior drug did not shut down androgen biology a full 24 hours (at best, effect seemed to be out to 12 hours for highest dose). The problem was not absorption of the prior drug but metabolism. Believe they now understand where the metabolic vulnerabilities were with EPI-506 (in the liver).
5. Next-gen drugs are 10x more potent and less susceptible to metabolism.
6. In next trial, EPIX will characterize patients' circulating tumor DNA and look at gene expression driven by androgen receptor (assays newly available for this) and allow them to select the patients that progress on Xtandi that still have an activated androgen receptor and whose tumors are still driven by androgens.
7. For these next-gen Anitens, EPIX started with 150 compounds that they have now narrowed down to three. Will select the most optimal molecule in the next few months.
8. Made comment that continue to work on the side to see if it's possible to get even greater potency but CEO stated wasn't sure if this was necessary (still makes you wonder if this foreshadows a possible concern with the initial 2nd gen drug).
9. All of the competitive drugs, including JNJ's apalutamide, work through the C-terminal domain, which is where mechanisms of resistance arise, whereas EPIX drugs work through N-terminal domain so a point of differentiation.
10. After recent financing, EPIX has 159M shares outstanding.

Do you have any thoughts on this one? I like that they are going after a fairly novel target and there is already some clinical PoC from both MNLO and a few private competitors in these indications. That said, I'll probably just watch for now as fully-diluted market cap looks to be around $700M. I listened to their Retail Roadshow presentation (thanks ghmm) and thought it was well done.

Thanks Peter. I'm largely in agreement. Been holding for several years now and haven't sold a single share and have enjoyed the nice run to date.

I'm still nervous about violating one of my principle rules of never holding through Phase 3 data. While we have the initial positive China Phase 3 data for roxa, the Phase 3 U.S. data is obviously the much higher bar. But, also having pamrevlumab being more advanced with positive clinical data as well, gives me some comfort to continue to gamble on FGEN for the P3 U.S. roxa data.

SMMT - P2 ezutromid 24-week data

[So, the biggest takeaway from me from this PR is that ezutromid is trending in the wrong direction at week 24 to meet the primary endpoint at week 48. This is buried in the PR. See the bolded text below.]

http://otp.investis.com/clients/uk/summit_corporation_plc/rns/regulatory-story.aspx?cid=1575&newsid=970514

Released : 25 Jan 2018 12:05

Summit Therapeutics plc
('Summit', or 'the Company')

EZUTROMID SIGNIFICANTLY REDUCED MUSCLE DAMAGE IN DMD PATIENTS IN 24-WEEK INTERIM DATA FROM SUMMIT'S PhaseOut DMD CLINICAL TRIAL

Increase in Utrophin Protein Expression Observed
Summit Accelerating Preparations for Pivotal Clinical Trial
Ezutromid is a Potential Disease-Modifying Treatment for the Entire DMD Patient Population
Conference Call Scheduled for 1:00pm GMT / 8:00am EST

Oxford, UK, 25 January 2018 - Summit Therapeutics plc (NASDAQ:SMMT, AIM:SUMM), the drug discovery and development company advancing therapies for rare diseases and infectious diseases, today announces positive 24-week interim results from the open-label Phase 2 proof of concept clinical trial, PhaseOut DMD. PhaseOut DMD is evaluating the utrophin modulator ezutromid in patients with Duchenne muscular dystrophy ('DMD'). The focus of the planned interim analysis was on biopsy measures that show:

Treatment with ezutromid resulted in a statistically significant and meaningful reduction in muscle damage as measured by a 23% decrease in mean developmental myosin in muscle biopsies at 24 weeks compared to baseline (11.37% to 8.76%, 95% CI, -4.33, -0.90). Developmental myosin is a biomarker of muscle damage and is found in repairing fibres.

A total of 14 of 22 patients showed a decrease in developmental myosin, with five of those showing a greater than 40% reduction.

Increase in mean utrophin protein intensity levels of 7% in biopsies at 24 weeks compared to baseline (0.370 to 0.396, 95% CI, -0.005, 0.058).

The combination of reduced muscle fibre damage and increased levels of utrophin provides the first evidence of ezutromid target engagement and proof of mechanism.

"The significant reduction in muscle damage coupled with the increase in utrophin expression seen in PhaseOut DMD trial patients at 24 weeks is very encouraging as it suggests ezutromid may slow the relentless cycle of muscle fibre degeneration and regeneration that is a hallmark of DMD," said Professor Francesco Muntoni, Director of the Dubowitz Neuromuscular Centre, at the UCL Institute of Child Health and Great Ormond Street Hospital for Children, London, UK, and Principal Investigator in PhaseOut DMD. "These favourable interim results are certainly a step forward in the development of utrophin modulation as a treatment approach for this fatal disease in all patients with DMD."

"The benefits of continual production of utrophin protein to protect against the progression of DMD have been well established in preclinical studies," added Professor Dame Kay E. Davies FRS, Dr Lee's Professor of Anatomy of the University of Oxford and Co-Founder of Summit. "These data provide the first evidence of utrophin modulation working in patients. If further findings build on this evidence they could establish ezutromid as a universal, disease-modifying treatment and bring hope to all patients and families living with DMD."

DMD is caused by genetic faults that prevent muscle cells from making dystrophin, a protein that maintains the structure and healthy functioning of muscles. The absence of dystrophin, as seen in patients with DMD, leads to a catastrophic cycle of muscle damage and repair. Utrophin protein performs a similar role to dystrophin in developing and repairing muscle fibres. As a muscle fibre matures, utrophin is switched off and replaced by dystrophin in the case of healthy individuals. During the early stages of natural muscle repair, utrophin and developmental myosin are expressed concurrently, and are then slowly switched off. Ezutromid aims to maintain utrophin expression in patients with DMD so it can substitute for the lack of dystrophin and break this cycle.

"Achieving this significant reduction in muscle damage after only 24 weeks of ezutromid treatment is a landmark moment for our utrophin modulation programme," commented Mr Glyn Edwards, Chief Executive Officer of Summit. "These promising interim data enhance our belief that longer-term treatment with ezutromid could achieve meaningful functional benefits for patients living with DMD. We now look forward to announcing the top-line data from the full 48-week trial in the third quarter of this year and in parallel accelerating preparations for the advancement of ezutromid into a pivotal clinical trial in patients."

Additional findings from the PhaseOut DMD 24-week interim results:

All patients achieved plasma levels of ezutromid sufficient to modulate utrophin.
Pharmacological responses were observed in patients treated with either the F3 or F6 formulations. There were no observed relationships between drug exposure and responses in pharmacology or safety measures at this stage.

In an additional biopsy measure, average muscle fibre diameter decreased from 42.1µm at baseline to 40.3µm at 24-weeks.

Changes in muscle pathology can be monitored using magnetic resonance spectroscopy ('MRS') to evaluate the amount of fat in muscles, which increases over time in DMD. The mean fat fraction in the vastus lateralis (thigh) was 14.7% at baseline and 18.5% at 24 weeks (n=37). Longer term dosing of patients is expected to be required to detect changes in MRS parameters, which is the 48-week primary endpoint.

Functional tests, which naturally decline over time in DMD, were included as exploratory measures. The mean six-minute walk distance was 404m at baseline and 395m at 24 weeks (n=39). Mean North Star Ambulatory Assessment score was 25.0 at baseline and 24.4 at 24 weeks (n=39). The North Star Ambulatory Assessment is a multi-point test of motor function with a maximum score of 34.

All patients retained ambulation after 24 weeks of treatment.

Ezutromid has been well tolerated to date.

The muscle biopsies were analysed using fully automated techniques that can assess whole cross-sections of biopsies containing several thousand individual fibres. These techniques were developed by Summit in collaboration with Flagship Biosciences Inc. Following strict handling and processing protocols, all biopsies contributed to the overall dataset with 22 matched pairs of baseline/week 24 biopsies assessed in the developmental myosin and fibre diameter assay and 18 matched pairs of baseline/week 24 biopsies assessed in the utrophin assay.

PhaseOut DMD is ongoing. Top-line results are expected to be reported in the third quarter of 2018. After 48 weeks of treatment, all patients have the option of enrolling into an extension phase, which is gathering long-term MRS, functional and safety data on ezutromid; to date 18 of 19 eligible patients have enrolled into the extension phase. Summit plans to conduct a randomised, placebo controlled trial that could potentially support the accelerated and conditional approval of ezutromid in the US and EU respectively.

Additional details of the 24-week interim data are expected to be presented at medical and scientific conferences.

FPRX - $25M cabiralizumab milestone from BMY

http://investor.fiveprime.com/releasedetail.cfm?ReleaseID=1055356

January 25, 2018
Five Prime Therapeutics Announces $25 Million Payment by Bristol-Myers Squibb for Cabiralizumab Development Milestone
Initiation of Phase 2 study of Cabiralizumab plus Opdivo in advanced pancreatic cancer
SOUTH SAN FRANCISCO, Calif., Jan. 25, 2018 (GLOBE NEWSWIRE) -- Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a biotechnology company discovering and developing innovative immuno-oncology protein therapeutics, today announced that a development milestone for cabiralizumab has been achieved, triggering a $25 million payment from Bristol-Myers Squibb Company (BMS) (NYSE:BMY) under the license and collaboration agreement between the companies established in 2015. The milestone was triggered by initiation of a multi-arm Phase 2 clinical trial (NCT03336216), sponsored by Bristol-Myers Squibb Company, evaluating cabiralizumab and Opdivo® (nivolumab) with and without chemotherapy in patients with advanced pancreatic cancer.

"Effective treatment for patients with pancreatic cancer remains a significant unmet need and is a cancer for which existing immunotherapies have not been successful to date," said Helen Collins, M.D., Senior Vice President and Chief Medical Officer of Five Prime. "We are encouraged by the preliminary data presented at SITC 2017 and are pleased to see this trial underway."

The Phase 2 trial is expected to enroll approximately 160 patients with locally advanced or metastatic pancreatic cancer that has progressed during or after one line of chemotherapy.

About Cabiralizumab (FPA008)
Cabiralizumab is an investigational antibody that inhibits the CSF-1 receptor and has been shown in preclinical models to block the activation and survival of monocytes and macrophages. Inhibition of CSF1R in preclinical models of several cancers reduces the number of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment, thereby facilitating an immune response against tumors. Cabiralizumab is currently in clinical trials in oncology indications and in pigmented villonodular synovitis (PVNS). Cabiralizumab is being developed under an exclusive worldwide license and collaboration agreement entered into with Bristol-Myers Squibb (BMS) in October 2015.

BPMC -

Peter, any thoughts on any upside from a potential buyout at this level? Market cap is already close to $4B. To be fair, I've been asking about the valuation from about the $1B or so level (joke's on me there).

As Peter has pointed out, roxa is a HIF stabilizer, not inhibitor. Hopefully the individual dosage amount, coupled with the fact FGEN (and others) are doing intermittent dosing, will get around any relevant safety concerns here.

Re: NBRV/other antibiotic plays

I currently don't hold any antibiotic plays though it's something I've considered off and on as the sub-sector does seem generally depressed. That said, I'm wondering if the true catalyst in this space will be when companies start to run superiority trials, rather than just non-inferiority trials, particularly in resistant settings. Is it going to take positive data from these types of trials to ignite more interest in the antibiotic players?

I no longer hold a position in SMMT but I at least give them credit for being bold and attempting to run a superiority trial against vancomycin in P3 in c difficile setting.

GTHX -

Speaking of CDK4/6 more generally, did you see this on the potential for CDK4/6 inhibitors in enzalutamide-resistant and abiraterone-resistant CRPC: http://ascopubs.org/doi/full/10.1200/PO.17.00140 ? Any thoughts on the potential of CDK4/6 inhibitors here?

Also, will what EPIX is trying to do here in targeting the N-terminal domain potentially work on this front as well?

Very annoying. I never understand companies that won't webcast their presentation. My rule of thumb in most instances (particularly with a company like this that has ~$1B market cap) is if you're not going to let me hear your investment thesis, I'm not going to bother investing.

Companies that routinely don't webcast presentations send a bit of a red flag to me. But, doesn't always mean something. I think it may have been the former VRUS that rarely webcasted their presentations or just didn't participate at all. Obviously that one turned out well.

EPIX - 9/17 slide deck

http://www.essapharma.com/wp-content/uploads/2017/09/ESSA_Rodman-Slide-Deck_090917_FINAL.pdf

Here's the aforementioned slide deck. Big question for me is whether or not the limitations of the first-gen NTD inhibitor (EPI-506) for mCRPC were truly due to lack of potency, bioavailability, etc. or is it simply due to the target itself?

EPIX - raises $21M initially

[Obviously one could say the company should have done this much earlier but hindsight is always 20/20. Although very dilutive, this should at least allow them to get to the point where they can bring their next gen NTD inhibitor to the clinic (based on separate investor slide deck I saw, it looks like they are aiming to be in clinic by 1Q19).]

http://www.essapharma.com/wp-content/uploads/2018/01/BRND_CDN_VANCOUVER-51068865-v4-ESSA_-_Press_Release_Announcing_Initial_Closing_09JAN2018.pdf

ESSA COMPLETES US$21 MILLION EQUITY OFFERING
NOT FOR DISTRIBUTION TO U.S. NEWSWIRE SERVICES OR FOR DISSEMINATION IN THE UNITED STATES

Houston and Vancouver, Canada, January 9, 2018 – ESSA Pharma Inc. (TSXV: EPI; NASDAQ: EPIX) (“ESSA” or the “Company”) announced today that, further to its previously announced offering of equity securities, it has closed an initial US$20,325,000 brokered equity offering (the “Offering”) and a concurrent US$675,000 non-brokered private placement (the “Private Placement”) for aggregate gross proceeds of US$21 million.

Pursuant to the Offering, ESSA issued 68,545,000 common shares of the Company (“Common Shares”) and 33,080,000 pre-funded common share purchase warrants of the Company (“Warrants”, and together with the Common Shares, the “Securities”) each at a price of US$0.20 per Security (the “Offering Price”) for aggregate gross proceeds of US$20,325,000. Each Warrant entitles the holder thereof to acquire, for a nominal exercise price, one common share in the capital of the Company (each, a “Warrant Share”) until 4:30 p.m. (Toronto time) on the date that is 60 months following its date of issuance.

Pursuant to the Concurrent Private Placement, the Company issued 3,375,000 Common Shares at the Offering Price to certain directors of the Company for additional aggregate gross proceeds of US$675,000. All securities issued in connection with the Concurrent Private Placement are subject to a prescribed four month plus one day hold period from the date of issuance, and no finders’ fee or commission was paid in respect of the Common Shares issued under the Concurrent Private Placement.
The Company expects to close an additional US$4 million worth of Securities under the Offering on or about January 16, 2018, for total gross proceeds of US$25 million under the Offering and Concurrent Private Placement.

The Securities were issued pursuant to the terms and conditions of a second amended and restated agency agreement dated January 5, 2018 between the Company and Bloom Burton Securities Inc. as the Company’s sole agent for the Offering in Canada, with an exclusive U.S. placement agent being part of the selling group. H.C. Wainwright & Co., LLC acted as exclusive U.S. placement agent. The selling group was: (a) paid a cash commission equal to 7.0% of the gross proceeds of the Offering (except in respect of Common Shares and Warrants issued in certain circumstances to specified purchasers, in which case the cash commission was reduced to 3.5%); and (b) issued broker warrants (the “Broker Warrants”) representing 5.0% of the aggregate number of Common Shares and Warrants issued and sold under the Offering. No Broker Warrants were issuable with respect to any Common Shares or Warrants purchased under the Offering in certain circumstances to specified purchasers. Each Broker Warrant entitles the holder thereof to acquire one common share of the Company (a “Broker Warrant Share”) at the Offering Price for a period of 60 months following its date of issuance.

The Company intends to use the net proceeds of the Offering and Concurrent Private Placement primarily to continue the ongoing preclinical development of the Company’s next- generation Aniten compounds. The net proceeds will also be used for the interest and principal payments on the Company’s outstanding debt and for working capital and general corporate purposes.

The Offering was completed in each of the provinces of British Columbia, Alberta and Ontario by way of a second amended and restated prospectus supplement dated January 5, 2018 to ESSA’s base shelf prospectus dated December 22, 2015 and elsewhere on a private placement basis.

The issuance of the Common Shares under the Concurrent Private Placement constitutes a related-party transaction under Multilateral Instrument 61-101 - Protection of Minority Security Holders in Special Transactions (“MI 61-101”). These transactions are exempt from the formal valuation and minority shareholder approval requirements of MI 61-101 pursuant to sections 5.5(a) and 5.7(1)(a) of MI 61-101 as neither the fair market value of any securities issued to nor the consideration paid by such persons would exceed 25.0% of the Company’s market capitalization.

The securities described herein have not been registered under the United States Securities Act of 1933, as amended (the “U.S. Securities Act”), or any state securities laws, and accordingly, may not be offered or sold to, or for the account or benefit of, persons in the United States or “U.S. persons,” as such term is defined in Regulation S promulgated under the U.S. Securities Act (“U.S. Persons”), except in compliance with the registration requirements of the U.S. Securities Act and applicable state securities requirements or pursuant to exemptions therefrom. This press release does not constitute an offer to sell or a solicitation of an offer to buy any of the Company’s securities to, or for the account of benefit of, persons in the United States or U.S. Persons.

ACIU - 1/8/18 CEO interview

https://labiotech.eu/alzheimers-disease-acimmune-andrea-pfeifer/?utm_source=twitter&utm_medium=social&utm_campaign=meetedgar

Meet the Swiss CEO Pulling Out All the Stops Against Alzheimer’s Disease

Evelyn Warner Evelyn Warner on 08/01/2018

Efforts to treat Alzheimer’s Disease have been hit with failure after failure in the last year or so. Andrea Pfeifer, co-founder and CEO of AC Immune, told me about how her company hopes to pull off a win.

Andrea Pfeifer started out as toxicologist in oncology before she moved into entrepreneurship. She left Germany after her PhD at the University of Würzburg for a postdoc at the NIH, but moved back for personal reasons. : “It was by pure chance that I ended up in Nestlé for two years, which turned into sixteen years,” she told me.

At Nestlé, she headed Global Research in Switzerland, managed more than 600 people and raised €100M to co-found the company’s venture capital fund for life sciences. Pfeifer described the role as “internal entrepreneurship,” such that it didn’t seem like a huge change to move into a biotech startup. Pfeifer left Nestlé because she saw the opportunity to help people even more than through Nestlé when she met the founders of AC Immune, where she found her place as a co-founding CEO.

Since the company was founded in 2003, the field of neurodegenerative disease has taken off, though Alzheimer’s Disease, on which AC Immune focuses, has taken some notable hits in the past year: Both Eli Lilly and Merck suffered late-stage efficacy failures, and Merck’s candidate presented some serious side effects, as seems to be the case for drugs inhibiting ß-secretase. Most recently, Axovant’s abject efficacy failure became the latest blowout despite high hopes and confidence in its founder, the famed Vivek Ramaswamy.

Efforts to treat Alzheimer’s Disease are grounded in one of two theories, that the pathology is driven by plaques of amyloid-beta (Aß) proteins or bundles of their tau counterparts. Until now, the majority of treatments to enter the clinic have targeted Aß plaques, but the case for aiming for tau in addition to or instead of these is increasingly gaining traction.

AC Immune is one of the few companies with a drug targeting tau bundles, and not to mention one of the few with programs in both tau and Aß. Its lead candidate is crenezumab, which has made it as far as Phase III for Alzheimer’s treatment and Phase II for prevention in partnership with Genentech/Roche. The company has other antibodies and vaccines for Alzheimer’s, in addition to various other diseases.

I sat down with co-founder and CEO Andrea Pfeifer to talk about drug development for Alzheimer’s Disease and what has made it a graveyard for biotechs.

You really dove into the deep end by taking on Alzheimer’s Disease right away. Why did you go for it?
When I met the scientific founders, they were interested in working on prions — at that time it was a very big topic — and they were looking for people with my experience. My contribution was to focus the company towards Alzheimer’s.

I was under the impression — wrongly so, in retrospect — that there had been so much progress in cancer that I wasn’t needed. I was always thinking, “they don’t need me.” Because of that, I thought that I would dedicate my scientific and entrepreneurial knowledge to help in Alzheimer’s. This is still my motivation.

What excited you about joining the company? What was it about the technology that drew you in?
The SupraAntigen and Morphomer platforms produce highly specific antibodies, vaccines and small molecules that bind to misfolded proteins. These proteins are difficult to target because they are still recognized as the body’s own proteins, even though they are harmful. The line between harmful and benign comes down to a conformational change in protein structure that adds another level of complexity to the challenge of hitting a target.

Also, our scientific founders were very established, and they were all very successful in initiating products — they were scientists, but they also had a lot of entrepreneurial spirit.

What do you think makes Alzheimer’s so challenging?
One of the three pillars of our R&D strategy is biomarker development, because this allows you to select patients and follow their treatments. I think that in areas where we don’t yet have a treatment, it’s exactly because of a lack of diagnostic.

When we entered the field, it was clear to us that we needed a safe and pathological protein-specific antibody for efficacious treatment. Aß plaques and tau bundles occur normally in the body, and it’s by a still unknown mechanism that these proteins change their structure and conformation to become pathological.

At this point, they can aggregate to form the fibers that are hallmarks of Alzheimer’s. We were extremely lucky that crenezumab is particularly sensitive to structures called oligomers, the most toxic subunits of the pathological proteins. These are what really kill neurons when you put them together, and crenezumab has a really high affinity for them.

At the time we started developing crenezumab, oligomers hadn’t reproducibly been isolated, but with a little bit of luck, we got things right. For tau, it’s much more complicated because there are many subtypes, and we have to make sure that we’re binding them all. We did a long selection process for this.

When we started the company in 2003, there were about 23 antibodies against Aß in development, so we were definitely late; but now there are only two left in late stage Phase III clinical development, aducanumab from Biogen and crenezumab from us. The really challenging thing is that we don’t know how much we actually need in the brain in order to really have an effect.

Today, between 1 and 5% of what you find in the plasma goes into the brain. It’s a low concentration, but people showed that this concentration is actually enough to actually have the antibody act. You need to have this concentration to be effective, and it’s probably related to equilibrium so that the microglia absorb it and activate the complex.

The reason why crenezumab is given in such a high amount – 60 milligrams per kilogram – is of course linked to this. The studies showed that even 15 mg has an effect, but the higher the better the percentage that goes into the brain. In a way, we’ve solved the problem, but the biggest challenge in developing an Alzheimer’s drug is perhaps delivering drugs in a high enough quantity to the brain.

How do you select patients and design a clinical trial for such a long-term disease?
We pre-select the patients for Aß positivity using Aß imaging; more and more we use tau imaging as well, using a PET imaging agent we developed. Studies are increasingly done in patients who have Aß plaques and cognitive impairment, but not yet any clinical symptoms. We want to go as early as possible, and it’s very important. It’s even more essential to find the right population with biomarkers before you start.

How would you characterize the roles of A-beta and tau proteins?
Tau in Alzheimer’s is often described as an Aß-mediated tauopathy, meaning it works well as a predictor. AC Immune started its first program in 2007, and in 2012 we made the first deal. It wasn’t really known how an antibody could treat tau until a year or so before that, and now it’s known with certainty that tau can infect cells in a prion-like way. Companies now choose their assets based on whether or not they can inhibit that spreading.

Aß came first because genetically it’s very strongly linked to Alzheimer’s, so it’s probably the starter while tau is the spreader.

Last question, have you been frustrated with respect to gender diversity in biotech?
In my generation it was difficult. I think I was the first female head of research at Nestle; I was effectively the exception, and it is still is that way. Even today, when I go to award events I’m sometimes really shocked when no women are even nominated. On the other hand, I’m very proud that at AC Immune over 60% of our staff are women.

I think there are two important factors to increase their presence. First, when you’re looking for the right profile and looking for the absolute best fit, you have to look very carefully at female applications. The second is natural: Women look up to me and see that they can do what I’ve done, and it really motivates them to have the same goals. I’m now coaching some of them a little bit to make it a bit easier than it was for me.

The women at our company have big careers ahead of them, and we support them with for example sometimes working at home to make childcare easier. Gender diversity is definitely an issue in Switzerland, a bit more than in America, but when I go to CEO workshops I can assure you that I’m very often not the only woman.

So can we change it? Yes, I think we can and by giving a good example, which is what I’m trying to do. This issue is very close to my heart.

ACIU -

Do you have any idea when the Colombian trial is set to report any data? Based on ACIU slides, it was started in 4Q13 but there appears to be no mention of when data is due. I suppose this simply has to be a very long-term study. Even if positive, it's only a Phase 2 trial so not sure how that timeline is going to work given how long this trial is taking and how long another trial (Phase 3) of this design would presumably take.

I take it you probably don't think the other crenezumab P3 trials set to report out in 2020 and 2021 have a great shot to succeed. Both P2 trials tested out to 18 months and the ongoing P3 trials are testing out to two years. So, at least a little bit longer. Based on the slides, at 60 mg/kg every four weeks, they are also dosing four times higher in the P3 trials than in the two P2 trials. So, higher dosing and for longer duration though that still doesn't guarantee anything of course (I know you said before you'd prefer to see a P3 trial going out to 3 years or so).

Also, primary endpoint for P3 is CDR-SB at two-year mark with ADAS-cog at two-year mark a key secondary endpoint. CDR is the primary endpoint BIIB/Eisai also using in aducanumab P3 trial and for which BIIB indicated before that solanezumab was positive for in its prior P3 trial in mild patients but it was only a secondary endpoint. Also similar to aducanumab P3, crenezumab being tested in prodromal to mild AD patients and not just mild as was case with solanezumab.

All this said, I looked at the P2 data and they only discuss the trends for the ADAS-cog endpoint and it appears a complete fail on the CDR endpoint without any trend so I don't know how that bodes well for P3 with CDR now as the primary endpoint (presumably hoping the 4-fold dose increase will make up for it I guess). Edit: Genentech apparently did a subsequent P1b dose escalation trial to better define the P3 dose and this is where they predicted the P3 dose would have a shot according to their modeling: http://cws.huginonline.com/A/171580/PR/201612/2063662_5.html .

ACIU -

Just FYI I was looking at ACIU's slides from their prior Jefferies presentation and one slide notes that solanezumab apparently only targets monomers (as opposed to oligomers). It also notes that crenezumab targets all of oligomers, monomers, and fibrils whereas aducanumab solely targets oligomers and fibrils.

Curious if you take any issue with that. Also, assuming the slide is correct, do you think by also targeting monomers that could confer an advantage for crenezumab over aducanumab? Actually, based on the binding profile from the slide compared to other AD drugs, the binding profile of crenezumab looks like it most closely resembles bapineuzumab as it shows that bapi hit all of monomers, oligomers, and fibrils as well (as you said). But, it shows bapi only being dosed as high as 1 mg/kg in Phase 3 whereas crenezumab is being tested at 60 mg/kg due to better safety.

EDIT CEO - 1/8/18 CNBC interview

https://www.cnbc.com/video/2018/01/08/editas-lower-on-questions-about-crispr-efficacy.html

1. I thought this was a nice confident (even if brief) retort by EDIT's CEO. Full disclosure: I now have a position in EDIT.

2. Even though not covered in that brief interview, I would point out that paper is specific to Cas9. Even if this turns out to be a clinical issue, I would note that EDIT is the only public CRISPR play I am aware of that is working beyond Cas9 as well given that the company is also focused on CRISPR treatments that involve Cpf1.

3. Note that paper was not peer reviewed.

ASMB -

Sounds like a plan. Here's their recent slide deck: https://investor.assemblybio.com/static-files/0049af77-02fa-4796-8141-ca47e9cdfe78 .

Beyond those prior questions, slide 12 shows clinical data from other capsid inhibitors, including JNJ-379. Someone mentioned that JNJ recently dropped 379 but I have yet to see confirmation of that. If that is true, would be worth knowing if it was just due to not enough potency in their eye (did have 2.89 log drop at 28 days) or some type of safety concern (if safety, presumably a possible read-through to ASMB drugs).

Re: ASMB

What's the story on ASMB? Have you followed this one closely? Stock has had a heck of a run past few years and now sports close to a $1B market cap with limited clinical data for their lead HBV drug (in Phase 1B now). That doesn't necessarily mean the stock is expensive because if they truly have something in HBV, the stock could still be worth a look. A few questions:

1. Looks like they are developing capsid inhibitors against the HBV core protein which I believe others are doing as well. What differentiates ASMB approach from others like ABUS and big pharma?

2. Why are they running the Phase 1B trial solely in New Zealand? Just seems odd doesn't it? Why not in U.S.?

3. Is it a concern that they are developing multiple follow-on generations of capsid inhibitors beyond the lead drug? Concern with lead drug? I read the latest 10-Q and the second drug is at least apparently more potent than the lead. Is the lead a non-starter?

4. On top of this recent raise, ASMB filed a $250M mixed shelf on 12/29/17. They are expecting Phase 1B data from lead drug this quarter.

I get MDGL is already in decent financial shape. Still, in the face of a sharp move up and key binary events still to come, it's not unusual at all to see a biotech even in good financial shape to take advantage of a sharp rise in price in such a scenario.

I'm waiting until the new year to take profits in a name to delay my tax bill but MDGL is on my short list of names to consider early next year.

MDGL -

I have to say that it's interesting to me they haven't done any kind of raise yet after the sharp run-up. The longer they go without doing any kind of raise, the more interesting it seems to me.

Or you could simply short those names you don't believe in. ; )

Thanks, I'll give the CC a listen. Just seems hard to trust given the dubious track record so far of cancer vaccines.

I saw this PR. Given that the trial is not controlled, how do we know that most, if not all, of the response isn't due to epacadostat and/or low-dose cyclophosphamide?

SRPT -

Still assuming the biggest thing for SRPT is if their next gen platform (PPMO) gets around, or at least improves upon, any safety concerns for Etep.

Separately, there's still the GT programs as well. FWIW, I threw in the towel on SMMT's ezutromid as SRPT barely even mentions that drug on CCs and SMMT CEO has made remarks as well in CCs to the effect of potential concerns about whether the diagnostic they are using in the ongoing P2B will be adequate. Didn't really inspire confidence for me in the ongoing trial set to read out next year (they also significantly pushed back the readout of this trial which may well be another red flag).

VKTX/MDGL -

I think this is the PR from VKTX regarding the P1 trial of VK2809 you're referring to: http://ir.vikingtherapeutics.com/2016-11-15-Viking-Therapeutics-Presents-New-Clinical-Data-on-VK2809-in-Subjects-with-Elevated-Cholesterol-at-American-Heart-Association-Scientific-Sessions-2016 .

In particular, I found the following quote interesting: "Consistent with liver-targeted thyroid receptor activation, mild, asymptomatic elevations in liver enzymes and decreased thyroid hormone levels were observed at higher doses."

So, if a class effect, why is it that the MDGL drug did not raise liver enzymes in the P2 trial and, in fact, led to statistically significant reductions at higher doses? It would seem to me that the MDGL drug may be differentiated from the VKTX drug on this front. Note: the class effect reference seems to imply the indication (whether NASH or HeFH trial) or length of the trial (I get this was just 14-day VKTX trial vs. 12 week trial in NASH for MDGL) might not matter.

DNLI -

I do love the novelty of the targets they are pursuing and management has good pedigree but agree with the valuation comments. As I said before, my gut is to at least wait until they have some early safety data in man to ensure there won't be tox concerns with the LRRK2 and RIPK1 drugs (given some of the concerns noted in pre-clinical work). Hopefully valuation will have come down some at that point as well. If those two things occur, then I might still be willing to take some type of gamble on there being at least some sort of efficacy signal in the clinic at some point from one of those two drugs (it's still a big gamble to be sure).

And to be clear, I'm not knocking VKTX. I get that it trades at a huge discount to MDGL so may well still be worth the gamble here. But, it would be more interesting if someone could show why that is a reasonable tweet. Perhaps it might be helpful to directly compare the animal data between the two drugs. I do have VKTX at least on my watchlist now to think about.

I wonder if the best time to take a gamble on VKTX might be to wait to see the additional MDGL data just to confirm they hit the NASH resolution endpoint and further boost the outlook for this class of drug. Even if you have to pay up even more then, I wonder if that might be an ideal time to consider VKTX.

MDGL/VKTX -

That is based on animal data for the VKTX drug, right? Assuming so, how can you extrapolate animal data to what the Phase 2 data will show?

Based on the amended S-1 (https://www.sec.gov/Archives/edgar/data/1714899/000119312517363254/d445892ds1a.htm), looks like there will be about 90M shares outstanding after this offering. It looks like the fully-diluted share count will be approximately 104M shares outstanding. So, about a fully-diluted market cap of about $1.9 billion at that offering price. For better or worse, I'm still inclined to wait for some safety data in man at least. ; ) Still, seems like a very innovative company and I will be following them.

As an aside, it's completely meaningless in the grand scheme of things, but they have one of the coolest home pages IMHO: https://www.denalitherapeutics.com/#home

MDGL -

We just don't know for certain that kind of reduction in MRI-PDFF will result in resolution of NASH, do we? Isn't the ultimate key endpoint a resolution of NASH and not just an improvement?

Idorsia (IDIA.SW) - Janssen deal for aprocitentan ($230M up-front)

[Idorsia shares have done quite well since the IPO in June as they're up over 60%.]

https://www.idorsia.com/media/news-details?newsId=2153595

Idorsia announces collaboration with Janssen Biotech on aprocitentan (ACT-132577)
Idorsia to receive milestone payment of USD 230 million
Idorsia and Janssen Biotech to share costs of Phase 3 development equally
Idorsia entitled to royalty payments on potential future net sales

Allschwil, Switzerland - 4 December 2017 - Idorsia Ltd (SIX:IDIA) announced today that Janssen Biotech, Inc. (Janssen), one of the Janssen Pharmaceutical Companies of Johnson & Johnson, has exercised its option to enter into a collaboration agreement with Idorsia to jointly develop and commercialize aprocitentan and any of its derivative compounds or products. Headline results from the phase 2 study were released on 22 May 2017.

Jean-Paul Clozel, CEO of Idorsia, commented: "I am delighted by Janssen's decision to collaborate on the development of aprocitentan, which is a strong endorsement for our product. Together we can accelerate the next steps of development and bring this compound to patients in need of new treatment options as quickly as possible."

Milestone: Following Janssen's opt-in decision, Idorsia will receive a one-time milestone payment of USD 230 million that will be reflected in its fourth quarter 2017 financial results.

André Muller, Chief Financial Officer of Idorsia, explained: "The one-time milestone payment will be recognized in two parts: about 160 million US dollars are expected to be recognized immediately as contract revenue in the fourth quarter 2017, while the remainder of the milestone payment is expected to be recognized as contract revenue over the next three and a half years. Hence, combining this revenue with our unchanged financial guidance on non-GAAP operating expenses between 160 and 170 million Swiss francs, Idorsia expects to report a net loss close to breakeven, barring unforeseen events."

Development: Both parties have joint development rights over aprocitentan. Idorsia will oversee the Phase 3 development and regulatory submission for the treatment of patients with hypertension that is not controlled by at least three therapies (called resistant hypertension in the medical community). The costs will be shared equally between both partners. Janssen will oversee the Phase 3 development and submission for any additional indications.

Commercialization: Janssen will have the sole worldwide commercialization rights. Idorsia is entitled to royalty payments on any future net sales generated. Royalty payments will amount to 20% of annual net sales up to USD 500 million, 30% of annual net sales between USD 500 million and USD 2 billion, 35% of annual net sales above USD 2 billion.

Martine Clozel, Chief Scientific Officer of Idorsia, said: "With this decision, Janssen has recognized the potential of aprocitentan, the latest product from a research effort that was initiated nearly 30 years ago and resulted in a broad understanding of the endothelin system and two endothelin receptor antagonists on the market. Aprocitentan can be envisioned to have many other potential applications, in addition to hypertension. This makes the collaboration with Janssen even more meaningful for us."

About aprocitentan in development for resistant hypertension management (RHM)

Aprocitentan is an orally active dual endothelin receptor antagonist that is being investigated for patients whose hypertension is uncontrolled despite the use of at least three anti-hypertensive drugs (called resistant hypertension in the medical community). Resistant hypertension is defined as persisting high systemic blood pressure (i.e., failure to lower blood pressure to a pre-defined threshold) despite concurrent administration of at least three antihypertensive therapies of different pharmacological classes at maximal or optimal doses, including a diuretic. Resistant hypertension is associated with a higher risk of cardiovascular disease. Patients with resistant hypertension are also more likely to have a medical history of chronic kidney disease and diabetes mellitus, amplifying their vulnerability and the complexity of treatment.

A Phase 2 study that evaluated the efficacy, safety and tolerability of aprocitentan in patients with essential hypertension to identify the optimal dose for further studies was completed in May 2017. Based on the positive dose-finding results and the feedback from health authorities, Idorsia is currently finalizing the design of a Phase 3 study. It will consist of a specifically designed study evaluating the initial and long-term effect of aprocitentan on systolic and diastolic blood pressure in patients requiring resistant hypertension management (RHM). The study is expected to start in 2018. If successful, the study will provide the basis for registration of the product.
***
Notes to the editor
About the dose-finding study with aprocitentan
In May 2017, the clinical development team completed a multi-center, double-blind, double-dummy, randomized, placebo-controlled with an active-reference arm, parallel group, dose-finding study with aprocitentan, an orally active dual endothelin receptor antagonist, in patients with essential hypertension. The study evaluated the efficacy, safety and tolerability of a once-a-day oral regimen of 4 dose levels of aprocitentan (5, 10, 25, and 50mg) to identify the optimal doses for further studies.
In this study 490 patients were randomized to receive either aprocitentan 5, 10, 25, 50 mg, placebo, or lisinopril 20 mg once daily. After 8 weeks of treatment the mean reduction from baseline in diastolic blood pressure - as measured at trough with a novel automated office blood pressure device - ranged between 6.3 and 12.0 mmHg in a statistically significant dose-dependent manner for the aprocitentan groups versus a decrease of 4.9 mmHg in the placebo group and a decrease of 8.4 mmHg in the lisinopril group (in the per-protocol population comprised of 410 patients).

Systolic blood pressure reductions ranged from 10.3 to 18.5 mmHg in a statistically significant dose-dependent manner in the aprocitentan groups and were 7.7 and 12.8 mmHg in the placebo and lisinopril groups, respectively.

These findings were confirmed in all randomized patients (Intent-to-Treat principle) and by 24 hours Ambulatory Blood Pressure Monitoring.

The safety population included 327 patients in the aprocitentan groups, 82 patients in the placebo group and 81 in the lisinopril group. Aprocitentan was well tolerated across all four doses in this patient population. Discontinuation from study treatment due to an adverse event ranged between 1.2% and 3.7% for the aprocitentan groups versus 6.1% in the placebo group and 3.7% in the lisinopril group. The overall frequency of adverse events was similar to those observed in the placebo group. In this study, there were two cases of increased liver enzymes above three times the upper limit of the normal range, one in the placebo and one in the aprocitentan 5 mg group. Four cases of peripheral edema were observed, two in the aprocitentan 25 mg group and two in the aprocitentan 50 mg group. Mean body weight remained unchanged from baseline in the aprocitentan 5, and 10 mg groups, increased by 0.4 kg in the aprocitentan 25 and 50 mg groups, and by 0.3 kg in the placebo group and decreased by 0.3 kg on lisinopril. There was an expected dose related decrease from baseline in the hemoglobin concentration in the aprocitentan groups (ranging from 1.3 to 6.7 g/L) versus increases of 2.2 and 0.1 g/L in the placebo and lisinopril groups, respectively.

About Idorsia
Idorsia Ltd is reaching out for more - We have more ideas, we see more opportunities and we want to help more patients.
In order to achieve this we intend to develop Idorsia into Europe's leading biopharmaceutical company, with a strong scientific core.
Headquartered in Switzerland - a European biotech hub - Idorsia is specialized in the discovery and development of small molecules, to transform the horizon of therapeutic options. Idorsia has a broad portfolio of innovative drugs in the pipeline, an experienced team, a fully-functional research center, and a strong balance sheet - the ideal constellation to bringing R&D efforts to business success.
Idorsia was listed on SIX Swiss Exchange (ticker symbol: IDIA) in June 2017 and has over 600 highly qualified specialists dedicated to realizing our ambitious targets.
For further information please contact:
Andrew C. Weiss
Senior Vice President, Head of Investor Relations & Corporate Communications
Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil
+41 58 844 10 10
www.idorsia.com

I'm still following this space but haven't taken the plunge in any names. Kind of lost interest in RARX as there have been these warts in the data. Any next-gen Soliris is obviously going to have to stack up well to ALXN's next-gen Soliris. I think APLS might be one of the more interesting names to watch in this space but shares already have some expectations baked in at what I think is close to a ~$1B fully-diluted market cap.

So they hit the primary endpoint but missed on secondaries. Presumably still get enough to get the "drug"/device approved under the 510(k) pathway? Also, given the novelty and fact it's more a device than drug, wonder how quickly this would catch on in the market if approved?

DNLI -

Don't think we really discussed the clinical hold with lead drug and also some of the pre-clinical issues with the RIPK1 drug based on what's disclosed in the S-1. For LRRK2 drug, that was placed on a partial clinical hold to impose a Phase 1 exposure cap on the drug based on pre-clinical tox findings. DNLI says that based on current allowed exposures, they think the drug can inhibit LRRK2 50% on average over the dosing period and should effectively normalize LRRK2 kinase activity. I guess the question remains for now, if not ultimately allowed to dose higher, if they will actually hit that 50% mark in the clinic and whether or not that will be truly meaningful.

For the RIPK1 drug, pg. 21 of the S-1 also notes that they observed tox at high doses in cynomolgus monkeys in the 28-day GLP safety study and DNLI is in the process of completing that analysis. There is a reference to a possible exposure cap for that drug as well once it hits Phase 1 so there will presumably be questions about whether they will be able to dose high enough for that drug as well.

Given the valuation, I think I'm inclined to wait a while on this one and see some of the early safety data in man.

Ok, thanks for clarifying. But, then there's the issue of whether ARIA-E is itself a good or bad thing. If it's indeed a good thing as a sign of efficacy, then you would want to see it, right? This AD is too complicated. ; )

Thanks, I remember you making this point before. Seems hard to have a lot of confidence in ACIU if CEO doesn't get that point but who knows for sure?

But, how does that explain why BAN2401 isn't showing ARIA-E if they're blaming the issue of ARIA-E on IG1 and BAN2401 is itself an IG1 antibody?

Note she had a different take than you on solanezumab FWIW.