The next news is the FDA briefing docs, and given the selective disclosures to-date from the company, one may not want to hold through the full reveal.

Speaking of placebo, I was pretty dissatisfied by CEO's response to Michael Yee's question about why we can't see the placebo arm data for NDD...basically this is a post hoc analysis anyway.

Still haven't seen a MACE number for NDD and we've been waiting for an entire year for publication of the full dataset. Just enough question marks remain on this to keep it trading in it's range.

Agree, an ADCOM would seem very unlikely at this point. I'm not as confident about the read through to a black box warning at this point. Seems like CEO has been thinking about potential of a black-box around NDD and not one for DD, based on the last interview I listened to. This has traded sideways for so long it's hard to imagine it ever trading up again, even with a clean label, LOL.

Lots of applications getting held up by inspections, and idea if FGEN needs one? Seems like in this case it should be pretty straightforward if they do.

re:FGEN AdCom

I'm not sure what the shortest amount of time is to convene an AdCom, but the FDA dropped one on AMRN about a week closer to the PDUFA than FGEN is now, and then pushed the PDUFA date out. At this point if they call for an Adcom I suspect it's going to require a PDUFA extension. I agree the closer this gets the less likely they are to get an Adcom, but calling one this late is still within recent historical precedent.

There might be some tradable positions here, but I think the market still has room on the downside. I hear too many people still writing this off as overblown and don't understand the scope of the disease or the level of social distancing that is going to have to happen.

I'm holding off.

Correct. There was only a single voting question that asked if they had demonstrated both efficacy and safety in preventing adverse CV outcomes.

It did not specify a population, age, comorbidities etc etc. Hence the 16-0 vote. Then each voting member elaborated on their vote and their views of primary vs secondary prevention. I was surprised a bit by having only one vote, but it gives the FDA a nominal unanimous 'approval' to do what they want I guess.

Re: AMRN AdCom

Beyond the 16-0 vote in favor of efficacy and safety, there was considerable discussion about whether the voters would support a broader primary prevention label or just secondary prevention. Group seemed split roughly in half on that point.

As a refresher, the study was powered about 70/30 secondary/primary. When you broke out the subgroups, the secondary prevention group was the only group that had a stat sig result, trend only for primary.

The "secondary only" group seemed to think it had a good chance of working in primary, but that the sponsor hadn't demonstrated it and needed to in a properly powered trial.

The "primary" group kind of argued that this was one trial that should be evaluated as a whole that covered both groups, and it wasn't right to split out and exclude subgroups that were underpowered.

I don't know this section well enough to know what the FDA will do, although I'd lean gently towards a primary label based on cost and safety. Pazdur would limit it to secondary only if it came to him back in the day I would guess. Curious what others may think.

$Fgen

Just to summarize a bit, ZIP said he's being told the exclusion of PYRENEES was "directed by the FDA". Awaiting where he got this information from, but others have cited a screenshot from Bloomberg referencing Astra responding to this. Just to clarify, that screenshot says the pooling was "agreed" with the FDA.

Maybe I'm splitting hairs, but by the time this gets to AdCom/Review there could be a material difference between "agreed with FDA" and "directed by FDA".

Agree w/ dewohpile, it wouldn't be hard to say come out with a PR stating WHY it was excluded and that it was directed by, or agreed to with, the FDA.

Rhetorical question: is all this a canary in the coal mine or is it a buying opp afforded by corporate incompetence?

Re: $FGEN PYRENEES not in the pooled analysis.

This is a great question. Not being individually powered for (pick any outcome) is not a reason to exclude from the pool.

AZN disclosed this in a PR from Friday Nov. 8th, so it's not new today on the 12th:
"PYRENEES was not included in the pooled CV safety analyses."
https://www.astrazeneca.com/media-centre/press-releases/2019/roxadustat-phase-iii-programme-pooled-analyses-showed-positive-efficacy-and-no-increased-cv-risk-in-patients-with-anaemia-from-chronic-kidney-disease.html


However, the program abstract at ASN that reported efficacy for PYRENEES says:
"Roxadustat safety data will be integrated across all trials", which is counter to excluding PYRENEES from the pooled analysis.
https://www.asn-online.org/education/kidneyweek/2019/program-abstract.aspx?controlId=3234790



A PR from AZN on May 10th 2019 is titled:Pooled analyses of the roxadustat global Phase III programme confirmed cardiovascular safety. The only reference to PYRENEES would imply that it was part of the pooled analyses at that time:

"The global Phase III programme consists of more than 9,000 patients and was conducted by AstraZeneca, FibroGen and Astellas.

The OLYMPUS, ALPS and ANDES trials evaluated roxadustat vs. placebo in NDD patients; HIMALAYAS evaluated roxadustat vs. epoetin alfa in ID patients; and ROCKIES, SIERRAS and PYRENEES evaluated roxadustat vs. epoetin alfa in DD patients.
https://www.astrazeneca.com/media-centre/press-releases/2019/pooled-analyses-of-the-roxadustat-global-phase-3-programme-confirmed-cardiovascular-safety.html

Has anyone seen an explanation for this?

ARWR R&D Day slides (2019):

http://ir.arrowheadpharma.com/static-files/26bc6a27-874e-4524-87e2-2134b56d00e4


Link to webcast (3+ hours)
http://lifesci.rampard.com/20191018/reg.jsp

I haven't gone over the whole thing, but the HBV work isn't mentioned much in the slide deck. They will have late breakers on both APOC3 and ANG3 and AHA November 18th.

Amgen seems to have dropped one of their collaborations on an undisclosed CV target.

FGEN

Remind me if you think the worse results in the population is because

A) FGEN created this subgroup post-hoc and therefore selected a line that made the >15 look better

B) This sicker group had differential and higher dropouts in the placebo arm, specifically bc they weren't on treatment (ie if you analyzed the endpoint as a combination of (MACE or dropout) the worse results would disappear

C) Some underlying real biological effect

D) Other


Agree re: The Big Three questions. Whenever they talk about the "totality of data", I worry they won't answer those questions with direct answers until the FDA formally weighs in. Feels like they trust the FDA to accurately/fairly incorporate the totality of data, but not the street, so the B) scenario above.

re: $FGEN Pooled data

Does this term "pooled" worry anybody in light sadly ambiguous presentation of the safety datato date? Are they signaling here they are going to not actually provide a HR for MACE NDD for the trials being used for the NDA?

I hope we don't need to wait for the Adcom get get a look at that...

re:MRKR

Agree with this, but would add that this data will be fairly preliminary, correct? I think they finished recruiting earlier this year right? MRKR website says the study is active but not recruiting, but clinicaltrials.gov says it's still recruiting.

Re; Failures

You seem a little bitter...

I'm pretty sure all of us playing biotech have failures

Without getting into the back and forth, I will say that RVNC has yet to play out commercially, although clinically it seems to have played out in the trials just like he thought it would. That story isn't entirely told yet (no position).

ENTA was another of his spectacular failures... oh wait.

re: EDIT

My gut agrees with your gut, that it's the latter, at least with respect to the current iteration of CRISPR/Cas9 companies. Just to be clear, this is in respect to human in vivo genome editing. It works great in the lab and biological experimentation.

Re: EDIT

I listened to some of Katrine Bosley's presentation at JPM, and it seemed vacuous/amorphous to me. I went into it wondering about taking a small speculative stake in a gene editing company and came away from it wondering if she really believed in the technology.

In her tweet she says she believes in the mission, their accomplishments and most of all the team… she sure doesn't say much about a technology that if it works in humans (big if) could be transformative to humanity if you go down the rabbit hole far enough. I wouldn’t be a comfortable shareholder today…

Dear friends & colleagues,
Five years ago at Editas, we asked the (rather daunting) question, “What if you could repair broken genes?” The journey since then has been intense, exciting, and important. (1/4)

We’ve made great progress towards answering that question, with a lot of changes and transitions along the way. Today, I have news to share of another transition: this time, my own. I’ll soon be stepping down from my role as CEO. (2/4)

As many of you will understand, this was a tough decision. I believe in the mission; in our many unprecedented accomplishments; and, most of all, in the team of Editors we built. I wish them great success – it’s a really important mission. (3/4)

I’m proud of everything we achieved and built together, and I’ll always be cheering them on – now as Editas Emeritas, as we say.
In genome Editas,
Katrine
(4/4)

RE: SGMO

Selloff seems to be related to this line from the PR:

"At baseline and for the first 16 weeks post-dosing of SB-913, plasma IDS activity (measurements obtained at trough of weekly ERT dosing) was below the level of quantification of the current assay."

However, they showed a dose response decrease in glycosaminoglycans, dermatan sulfate and heparan sulfate (% change at 16 weeks of +9%, +4%, -23% respectively for first dose cohort vs. -50%, -42%, -51% for second dose cohort). Hard to say with just two doses and two patients per dose, but suggests there is enzymatic activity even though the enzyme itself is below level of detection. Second cohort was 2x the first cohort dose, and third cohort is 5x the second cohort dose. Third cohort has already been dosed.

Seems like 20% sell off could be overdone here, although being able to measure the enzyme directly would have given one more confidence. Third cohort dosing will be interesting.

"This again points to mistake TRIL made by declaring MTD with 1st sign of DLT, rushing to expansion cohorts before adequate dosing work by exploring alternative dosing schedules of priming, frequency etc to increase dose. "

Exactly my thought when I saw the FTSV dosing. This mistake has potentially cost TRIL dearly in time and resources. Nothing like a small company on a tight budget squander their clinical lead chasing indications with the wrong dose. They've tried to back into trying higher doses after a loading dose in some more recent work, but I'm still not convinced they've adequately explored the optimal dosing regime.

Any hints as to why the CEO resigned so abruptly? I didn't see any explanation.

He came to SYNX I think from Pfizer and seems to be well connected in the industry.

https://www.fiercebiotech.com/biotech/pfizer-taps-new-r-d-leaders-as-guti%C3%A9rrez-ramos-heads-back-into-biotech

re: Pair trade

What about IRWD/SGYP?

Not super up to speed on this, but was under some impression that Trulance update was impaired by rebates on Linzess

Re:HPV and cervical cancer.

That women in their 30s wouldn't have discussed the vaccine with their providers (or know about it's role in preventing cervical cancer) is partly explained by the fact that it it only recommended for women up through age 26, and I think (but might be wrong) that the original vaccine had and even narrower recommended age range.

Some of them might never have been in the age range recommended to get the vaccine. Hopefully those would be different numbers for women in their 20s.

Re: MGNX - INCY collaboration

In addition to the upfront $150M, MGNX also eligible for $750 in biobucks, and tiered royalties on sales from 15-24%. INCY will handle the development.


"Per the terms of the collaboration, MacroGenics will also be eligible to receive up to $420 million in potential development and regulatory milestones, and up to $330 million in potential commercial milestones. If MGA012 is approved and commercialized, MacroGenics would be eligible to receive royalties, tiered from 15 percent to 24 percent, on future sales of MGA012 by Incyte."

https://finance.yahoo.com/news/incyte-macrogenics-announce-global-collaboration-104500627.html

TRIL, Any events causing the recent hike?

Nothing from their most recent conference call was worth moving the price at all. The only recent news I see is the addition of Dr. Helen Tayton-Martin to the BOD announced yesterday.

She's the CBO and co-founder of Adaptimmune. I don't know anything about her. Personally I think upward moves based on BOD additions are unwarranted.

Not sure if anything else caused the move.

TORONTO, Oct. 11, 2017 – Trillium Therapeutics Inc. (NASDAQ/TSX: TRIL), a clinical stage immuno-oncology company developing innovative therapies for the treatment of cancer, announced today that Dr. Helen Tayton-Martin has been appointed to its board of directors.

Dr. Tayton-Martin, Chief Business Officer at Adaptimmune, has over 25 years of experience working within the pharma, biotech and consulting environment in disciplines across preclinical and clinical development, outsourcing, strategic planning, due diligence and business development. She co-founded Adaptimmune from the former company, Avidex Limited, where she had been responsible for commercial development of the soluble TCR program in cancer and HIV therapy from 2005 to 2008. Dr. Tayton-Martin transitioned to become Adaptimmune's Chief Business Officer in March 2017, having served as its Chief Operating Officer since 2008, a role in which she oversaw the transition of all operations in the company from 5 to 300 staff, through transatlantic growth, multiple clinical, academic and commercial collaborations and private and public financing through to its NASDAQ IPO.

Today, Dr. Tayton-Martin is responsible for optimizing the strategic and commercial opportunity for Adaptimmune’s assets, leading business development and commercial activities. Her role encompasses all aspects of pipeline and technology assessment, strategic portfolio analysis, integrated program management and commercial planning and partnerships, including the company’s strategic partnership with GSK. Dr. Tayton-Martin holds a Ph.D. in molecular immunology from the University of Bristol, U.K. and an MBA from London Business School.

“We welcome Dr. Tayton-Martin to the Board of Trillium Therapeutics,” said Dr. Calvin Stiller, Trillium’s Chair. “Helen’s experience and involvement with a wide variety of operational and strategic activities in a rapidly growing life sciences company makes her addition to our board very opportune.”

http://trilliumtherapeutics.com/investors/news/Press-Release-Details/2017/Trillium-Therapeutics-Welcomes-Dr-Helen-Tayton-martin-to-Its-Board-of-Directors/default.aspx

I resemble this comment in every aspect. My more costly investing mistakes have been selling too early rather than not taking profits, although I have a few instances of each. I'm willing to wait for the full value of the company to manifest, even if it takes a few years. Still like the risk/reward here relative to other places I could put the money to work.

Roxa China seems underappreciated, and the anti-fibrotic potential might be just unfolding. Still some good potential catalysts to come this year.

I didn't read this as a single investor willing to take the whole offering, just that an existing one would participate and it could take them over 10%, at which point they would get a seat on the board.

I pursued the filings, but couldn't see that this happened or the existing shareholder was identified. Anybody know whether it happened and if so, who it was?

re:Tril

Eh, I don't think they have really resolved the issues. They've given some explanations, but a lot of open questions remain. They are still sitting on a dose of .2 mg/kg, which may or may not be high enough to drive efficacy. They say it is, but their PI trial was designed to go up to 10mg/kg, so this still seems low. They have some platelet issues that they didn't see preclinically that seem to resolve with longer duration of dosing, but need more info here. I still have some questions about dosing and efficacy, based on the design to give IT injection at much much higher doses than the systemic study. If .2 was enough, why plan to "flood the tumor with as much drug as possible" in their other PI study?

There is a thought that they might be able to do a loading dose (like Stanford for RBC sink) and go higher, but they haven't rolled out any plans for that.

There was minor efficacy signal, but it was pretty minor. So the market is still rightfully skeptical whether this will work as a monotherapy well enough to move along. Probably not, and that means they have to design/launch combo studies, for which they haven't presented much preclinical data. They are moving their less potent Ig4 compound along now too under the assumption that it is more suited for combo studies. This just pushes the timeline back quite a ways potentially.

Also, although the story is still promising, there haven't been any good human data coming out of any of the other competitors and their trials, which is some cause for questioning the entire MOA in humans.

My summary is that it's still a big gamble. I'm holding some shares bc I think the risk/reward is reasonable here at $60M MC, but I think failure is more likely than success.

Irv Wasserman has a fairly aggressive critique of that "replication" paper in the comment section.

His summary: "In summary, the studies published in the replication report in eLife do not pertain to the title or the major findings of our PNAS paper."

I'm not a cancer biologist so I might be oversimplifying this, but among the issues Wasserman points out are that the Stanford group used primary human cancer samples with minimal xenograft passage, and the replicators used a mouse breast cancer line. The replicators also failed to get a robust transplantation of their own cancer lines in the mice, and therefore didn't have a viable experimental platform in which to test the hypotesis re:CD47. The peer reviewers agreed with this, and some said the replication wasn't publishable without further experiments, but it was published anyway.

Wasserman notes: The beginning of replication is to show experience and competence in the transplantability of the cancer.

After noting several possible reasons why the replicators failed to do this, he says "When the replication study lab interacted with us early on, we offered to do the experiments side by side with them to facilitate technology transfer. Horrigan et al declined. The offer still stands."

Not sure whether CD47 blockade works clincally, but it doesn't seem like this replication paper is of high value or gives much read through to the original Wasserman study.

They've said they are doing this in the lab, IO, radiation etc etc. It's not the wrong approach, but it's also why I'm afraid this is going to take longer to play out than one might have hoped based on the preclinical data from Wasserman/TRIL etc. We'll know more by the time it starts trading again.

So how would you reconcile that with the Ladenburg call where the CEO said of the 1b they "wanted to make sure that we flood the solid tumor with as much TTI-621 as we can and get as much of a blockage as we can", and were therefore going IT injection? He mentioned twice that this choice was based partly on their preclinical data.

Re: Bios trading below cash.

Most of the bios that trade below cash seem to have platform problems, a dying one-trick pony, or a long history of serial failures. If these companies ever just ceased operations and paid out shareholders I might be inclined towards taking a chance on them. Maybe I'm jaded, but it seems that this group almost always finds a way to keep their salaries/bonuses flowing until there is no cash left (zebra's law).

It's almost become a red-flag to be trading at or below cash. Not that there might not be a few that had some spectacular upside, but mostly my impression is they go much lower as their cash pile dwindles.

TRIL>>

Worth noting here that on the last cc CEO said one driving reason behind the IT solid tumor dosing was to flood the tumor with as much drug as possible. So it does seem that they think getting a higher dose matters.

I sat down with one of the "DMD experts" to talk about another subject, but we ended up drifting to this topic and hashed it out. He ultimately agreed with the conclusion that the company had completely mismanaged the development of the drug (unfortunately) and that efficacy wasn't well enough established to meet the rigor the FDA requires for approval, and that it would be bad precedent for the FDA to approve the drug based on the current information. He seemed hopeful that the drug would work eventually but had a healthy amount of skepticism.

At the very conclusion of our conversation I gathered that he (or his institution) has had at least one patient enrolled in one of the Etep studies, but there was specific discussion about this.

When I went back and checked the open letter to the FDA from DMD experts calling for approval, I found his name on the list. I was somewhat surprised to find his name there given our conversation. I lean to the conclusion that there is such a strong advocacy from the patient groups that it was just easier to sign than to become a target. Or maybe he's just as conflicted as the rest of everybody between hope and well-designed trials.

Anyway, my point is that I don't think "listening to the DMD experts" is as straightforward as you might think.

My disclosure is that I have no position in SRPT or any related companies, although I am a former SRPT long and got out when it became apparent that they were going to try and lobby their way to approval rather than properly develop the drug.

Re: TRIL and Lymphoma.

I like this news.

I'd heard (not from tril) that CD47 was perhaps too effective at killing leukemia cells, which release cytokines into the bloodstream in the process of being killed by the macrophage. The fear is of a fatal immune response to the high load of cytokines dumped in the rapid killing. This group is pursuing solid tumors instead as a first line, and thinks some more delicate work needs to be done before circling back to leukemia. Not sure why this isn't simply a dosing issue, but take it for what it's worth.

I had been worried that TRIL might see SAEs if they in fact when into leukemia first. Perhaps this switch is after some IND discussion with the FDA, I wouldn't be surprised.

$PPHM

"Positive Trends in Time to Progression, Disease Control Rates and 4-Month Progression-Free Survival Endpoints"

...

in yet another single arm, single center trial with no controls.

$SRPT

So I used to own them, rode them up and then part way back down before selling.

I'm having a hard time re-buying because the way management exhausted every means possible to avoid running a well-controlled adequately powered trial. Makes you wonder what they are afraid of? Feels too much like PPHM although I'm trying to get over that association.

Flo-

How do you know these are new positions and not replacement positions for people abandoning ship?

Whole Genome Mapping Technology

Definitely out of my area, but anybody have an opinion on private company offering whole genome mapping technology? It's called OpGen http://www.opgen.com.

That's pretty nimble for a stock that's up 100% for the week, 185% for three months and hit a 52 week high today.

I'm currently underwater on a short in the mid 12s and then doubled down on around 14.80.

The January 15 calls are being bid at 1.10. Amazing euphoria for the space.

"The first two" was in reference to the first two items on my list, before I'd seen the 8K and just read the PR. Those were included in the 8K and are the total potential royalties and the terms for profit share/development costs.

I agree we don't expect to hear about which the compounds are, and don't consider that a negative, although it is something i'd like to know.