Well, I do as I'm still long. ; ) I have to admit I don't know what to make of all the high-level executive departures of late. The CEO, CMO, and CSO have all recently left or announced intentions to leave. I normally take it as a bearish sign when the high-level execs start to leave. I guess the counter-point hopeful thought would be it could be a sign they are trying to sell the company. That is the only positive spin I can put on this. All told, when multiple high-level execs leave, I think it's either a very bearish or very bullish sign but I probably lean more to the former. For now, I've decided to still hold as I have always liked their broad pipeline, nice INCY partnership, PoC with lead drug in NRG1+ cancers last year, decent cash position, and what I thought was a reasonable valuation.

That said, the numerous high-level executive departures substantially increases the risk I think. I know I have seen examples in the past where multiple high-level executive departures have preceded a buyout. But, there are also recent examples in SYBX and EDIT where this was not (at least to date) the case.

ASMB - ASBM +29% on HBV presentations for AASLD

Am I reading it wrong or is the decline in HBsAg (along with other biomarkers) still relatively small for the combo? PR says: "...observed mean log changes of ≥0.6 for HBeAg (11 patients ≥0.5, 4 patients ≥1.0), >0.8 log for HBcrAg (7 patients ≥1.0, 3 patients ≥2.0) and ≥0.4 log for HBsAg (7 patients ≥0.5, 3 patients ≥1.0)."

How strong is the evidence that the combo will ultimately lead to a functional cure?

XENE - 2Q19 CC note

Based on the CC today, the CEO mentioned that he expects XENE will need to show about a 30-40% delta for XEN496 response vs. placebo in the P3 for KCNQ2-EE.

Writing seemed to be on the wall that CELG would be returning at least some rights to JNCE. See item 3 of: #msg-147379183 .

ALEC @ BAML 5/15/19

I listened to the ALEC presentation here and they noted that they eventually plan to test a combo of AL002 (targeting TREM2) and AL003 (targeting Siglec3) in the clinic given that the former drug effectively pushes the gas pedal on microglia while the latter releases the brakes.

FTSV - updated P1B 5F9 AML/MDS data

https://ir.fortyseveninc.com/news-releases/news-release-details/forty-seven-inc-announces-updated-initial-data-phase-1b-clinical

Forty Seven, Inc. Announces Updated Initial Data from Phase 1b Clinical Trial of 5F9 in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia
-- 5F9 Well Tolerated with Clinical Activity as Monotherapy and in Combination with Azacitidine --
-- CR Rate of 55% and ORR of 100% Observed in Patients with Higher-Risk MDS --
-- CR/CRi Rate of 50% and ORR of 64% Observed in Patients with Untreated AML Who Are Ineligible for Induction Chemotherapy --
-- Received FDA Feedback Suggesting Single Arm Pivotal Trial May Support Registration of 5F9 in Combination with Azacitidine in Higher-Risk MDS --
-- Forty Seven to Host Investor Event and Webcast at 6:30 p.m. CT --

MENLO PARK, Calif., June 03, 2019 (GLOBE NEWSWIRE) -- Forty Seven, Inc., a clinical-stage, immuno-oncology company focused on developing therapies to activate macrophages in the fight against cancer, today announced updated initial data from its Phase 1b clinical trial evaluating 5F9 as a monotherapy and in combination with azacitidine for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The data, which have matured since the abstract submission and now include additional patients and longer-term follow-up, will be presented in a poster discussion session at the 2019 ASCO Annual Meeting in Chicago, Illinois.

“These new data for 5F9 show encouraging clinical activity in a broad population of patients with MDS and AML, who may be unfit for existing therapeutic options or at higher risk for developing rapidly-advancing disease,” said David Sallman, M.D., H. Lee Moffit Cancer Center and Research Institute, an investigator for the clinical trial. “Despite an evolving treatment landscape, physicians continue to seek new therapies for MDS and AML that can be used safely to help patients more rapidly achieve durable responses. I am excited to see meaningful clinical activity in a majority of patients treated with 5F9 in combination with azacitidine, with a median time to response of under two months. These results confirm our preclinical data demonstrating synergy between 5F9 and azacitidine, and warrant the further exploration of this combination in patients with MDS and AML.”

“We are extremely pleased by the tolerability and clinical activity observed for 5F9 in combination with azacitidine to date, which validates the approach of combining 5F9 with other therapeutic agents that induce prophagocytic ‘eat me’ signals on tumor cells. This supports our belief in the potential of 5F9 as an immune checkpoint inhibitor,” said Chris Takimoto, M.D., Ph.D., F.A.C.P., Chief Medical Officer of Forty Seven, Inc. “In particular, we are encouraged to see activity in patients with MDS, a disease characterized by significant morbidity, such as the need for frequent blood transfusions, and which can progress to AML. Despite advances in the treatment of hematologic cancers, the standard of care for MDS has not changed in over a decade, and existing agents demonstrate objective activity in only a limited fraction of treated patients. As a result, many MDS patients receive only supportive care, and there is a clear and compelling need for new, disease-modifying options. Following recent engagement with the U.S. Food and Drug Administration (FDA), we believe a single arm pivotal trial may serve as the basis for a biologics license application for 5F9 in combination with azacitidine in higher-risk MDS, and we are working hard to finalize the design of our potentially registration-enabling study, while continuing to enroll expansion cohorts in our ongoing study in MDS and AML.”

Data from the Ongoing Phase 1b Clinical Trial

Forty Seven’s Phase 1b trial, which is being funded in part by the California Institute for Regenerative Medicine (CIRM), is designed to evaluate 5F9 as a monotherapy in patients with relapsed or refractory (r/r) MDS or AML, and 5F9 in combination with azacitidine in higher-risk MDS patients and untreated, induction chemotherapy-ineligible AML patients. All patients received a 1 mg/kg priming dose of 5F9, coupled with intrapatient dose escalation, to mitigate on-target anemia. Patients in the combination cohort were then treated with full doses of azacitidine and a 5F9 maintenance dose of 30 mg/kg once weekly.

As of the data cutoff of May 10, 2019, 46 patients had been treated in the Phase 1b portion of the trial, including 10 r/r MDS or AML patients who received monotherapy 5F9, and 36 untreated higher-risk MDS patients or untreated AML patients ineligible for induction chemotherapy, who received 5F9 in combination with azacitidine.

Preliminary Safety Data

As of the data cutoff, 5F9 was well-tolerated both as a monotherapy and in combination with azacitidine, with no evidence of increased toxicities compared to azacitidine alone. Adverse events (AEs) were consistent with what has been previously seen with 5F9, and no significant cytopenias or autoimmune-related AEs were observed in patients treated with monotherapy 5F9. Overall, the most commonly reported treatment-related AEs were expected CD47-mechanism-based effects on red blood cells, which led to a temporary and reversible anemia, and many patients in the combination cohort experienced a hemoglobin improvement over the course of their treatment with a decrease in transfusions. Importantly, no treatment-related infections were observed, and only one patient out of 36 treated with the combination experienced neutropenic fever (3%). No deaths were observed in the first 60 days on combination treatment. Only one patient out of 46 (2%) discontinued treatment due to a treatment-related AE.

Preliminary Clinical Activity Data

As of the data cutoff, 35 patients were evaluable for response assessment, including 25 patients with untreated higher-risk MDS or AML who were treated with 5F9 and azacitidine (11 patients with higher-risk MDS and 14 patients with untreated AML) and 10 patients with r/r MDS or AML who were treated with monotherapy 5F9.

In higher-risk MDS, the overall response rate (ORR) for the combination was 100%, with six patients (55%) achieving a complete response (CR), four patients (36%) achieving a marrow CR and one patient (9%) achieving hematologic improvement.
In untreated AML, the ORR for the combination was 64%, with five patients (36%) achieving a CR, two patients (14%) achieving a complete response with incomplete blood count recovery (CRi), and two patients (14%) achieving a morphologic leukemia-free state (MLFS). Additionally, five patients (36%) achieved stable disease (SD).
In r/r MDS or AML treated with monotherapy 5F9, the ORR was 10%, consisting of one patient who achieved a MLFS. Additionally, seven patients (70%) achieved SD.
The median time to response among MDS and AML patients treated with the combination was 1.9 months.
Six patients (30% of responders) receiving the combination who had an objective response have experienced deepening responses over time resulting in complete remissions. Five patients (25% of responders) have also successfully received allogeneic stem cell transplants.
Historical response rates for single-agent azacitidine, show CR rates of approximately 15-20% in higher-risk MDS and untreated AML patients, with initial responses generally occurring after 4-6 months in most patients who respond.1
_______________
1 Azacitidine US package insert, Al-Ali et al., 2012; Dombretet al., 2015; Fenauxet al., 2010; Silverman et al., 2002

Clinical Development Plans for 5F9 in MDS and AML

Based on the favorable safety profile and encouraging clinical activity observed in this Phase 1b clinical trial to-date, expansion cohorts have been initiated in patients with both higher-risk MDS and untreated AML with 5F9 in combination with azacitidine.

Additionally, based on feedback from a Type B meeting with the FDA in May 2019, Forty Seven believes that data from a single arm pivotal study evaluating durability, CRs and partial responses may be sufficient to support the registration of 5F9 in combination with azacitidine in patients with untreated, higher-risk MDS. The Company is currently finalizing the operational components of the proposed registrational study, including details on trial design and chemistry, manufacturing and controls (CMC), and will provide a detailed update in the second half of 2019.

In August 2015, the FDA granted orphan drug designation to 5F9 for the treatment of AML.

Investor Event and Webcast Information

Forty Seven will host an investor event on Monday, June 3, 2019 beginning at 6:30 p.m. CT (7:30 p.m. ET) in Chicago to review the initial clinical data presented at ASCO. The event will be webcast live and can be accessed under “Events & Presentations” in the Investors section of the Forty Seven website at www.fortyseveninc.com. A replay of the webcast will be available approximately two hours after the event and will be available for 30 days following the event.

FPRX - 5/8/19 Q1'19 CC

Did anyone listen to this FPRX CC? I found it to be one of the more confusing CCs I've ever listened to. This had to do with discussion of enrollment of patients in the ongoing P3 trial of bemarituzumab in gastric cancer patients. Essentially, it sounds like FPRX is seeing a different patient population being enrolled into their P3 trial than what they expected. As a result, they decided to introduce a futility analysis early on into this trial (sounds like this will occur early next year). There was some discussion on whether or not the tests being used to select patients for FGFR2b amplification and also over expression were accurate (company seems to think so). Ultimately, it sounds like they are mostly seeing patients that just have over expression of FGFR2b and not also amplification and sounds like their prior positive data that informed this P3 trial was based on patients that had both FGFR2b amplification and over expression.

All told, given the comments in the CC, including references to being "fiscally responsible" about the trial, it sure seems like management is a lot less optimistic about a positive outcome for the trial. Seems like this likely accounts for the recent sell-off in shares.

PRPO -

Something you don't hear every day: At the end of their most recent CC, the CEO was pitching company sweater vests available on their web site. LOL

Been disappointing action in the short-term on FGEN based on that CC, but I am still hoping shares can recover in time and with more details provided. Rightly or wrongly, I still take some solace in that disclosure in Q&A about MACE+ HR for Roxadustat in dialysis being <1 and incident dialysis being much lower than 1. I am hopeful they have a good shot broadly with the EMA given MACE+ is the key endpoint there.

For U.S., I certainly get the questions on how they handled the MACE reporting. Hopefully good still on at least incident dialysis as well in U.S. with more clarity being needed on the other settings.

Judging by ASMB's own actions via the development of much more potent follow-on versions, I'd say they likely agree. ; )

ASMB/(ENTA) -

I was going to ask you what read-through you see from the disappointing ASMB HBsAg declines to the ENTA drug. What gives you more confidence in the ENTA CpAM? Is it much greater potency for their drug pre-clinical? I still wonder if potency is the issue given that ASMB keeps developing all those follow-on versions (despite the 2nd one being 10x as potent as the lead).

Also, not sure if you saw this tweet from @JohnTuckerPhd : https://twitter.com/JohnTuckerPhD/status/1117493685057400837 . He seems to be questioning the whole HBsAg theory.

Yep, have to agree with Julia that seems likely that ASMB shares probably won't open nicely on Monday. Would be surprised if they don't end up down on the day given the disappointment with the HBsAg declines. Certainly seemed pretty obvious that the announcement of the 4th and 5th CpAMs to come foreshadowed this disappointing data with the lead drug. One other thing I didn't mention on my prior notes beyond the additional CpAM candidates was that the CEO pretty clearly hinted that this would be early data and stressed the need for more mature data. That was another pretty clear hint that this data would be disappointing.

Guess remains to be seen if 48-week data will look any better for the lead on HBsAg declines but, given all these follow-on drugs, I'm just going to continue to remain skeptical.

POXEL.PA - positive P3 imeglimin T2D data

https://www.poxelpharma.com/en_us/news-media/press-releases/detail/117/poxel-and-sumitomo-dainippon-pharma-announce-positive

Poxel and Sumitomo Dainippon Pharma Announce Positive Top-Line Results for Imeglimin Phase 3 Trial (TIMES 1) in Japan for the Treatment of Type 2 Diabetes

DOWNLOAD AS PDF APRIL 09, 2019
Imeglimin Phase 3 trial (TIMES 1) met its primary and main secondary endpoints
Imeglimin Phase 3 TIMES 3 16-week, double-blind, placebo controlled, randomized part of the trial is expected to report data mid-year and TIMES 2 and full results from the TIMES 3 trials are anticipated to report top-line results around the end of 2019
Imeglimin Japanese New Drug Application (JNDA) targeted for 2020
The Japanese diabetes market is fast-growing and anticipated to reach approximately $6B by 2020

LYON, France & OSAKA, Japan--(BUSINESS WIRE)-- POXEL SA (Euronext – POXEL - FR0012432516), a biopharmaceutical company focused on the development of innovative treatments for metabolic disorders, including type 2 diabetes and non-alcoholic steatohepatitis (NASH) and Sumitomo Dainippon Pharma Co., Ltd (Head Office: Osaka, Japan; Representative Director, President and CEO: Hiroshi Nomura; Securities Code: 4506, First Section of TSE), announced today positive top-line Phase 3 data results for the Imeglimin TIMES 1 trial for the treatment of type 2 diabetes in Japan. Referred to as TIMES (Trials of IMeglimin for Efficacy and Safety), the Imeglimin Phase 3 program in Japan includes three pivotal trials to evaluate Imeglimin’s efficacy and safety in over 1,100 patients.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20190408005788/en/

“I am very excited to contribute to the development of a new and innovative potential treatment option for Japanese patients with type 2 diabetes,” said Professor Kohjiro Ueki, MD, PhD, Director, Diabetes Research Center, the National Center for Global Health and Medicine, Tokyo, Japan. “Imeglimin’s safety profile combined with its unique mechanism of action that targets very important deficiencies occurring in diabetes, namely beta-cell function, as well as insulin resistance, could be helpful for Japanese patients to manage their disease.”

The TIMES 1 randomized, double-blind, placebo-controlled monotherapy trial orally administered 1,000 mg of Imeglimin twice-daily versus placebo for 24 weeks in 213 Japanese patients. The TIMES 1 trial demonstrated robust efficacy and achieved statistical significance (p<0.0001) for its primary endpoint, defined as a change of glycated hemoglobin A1c (HbA1c) versus placebo at week 24, with an HbA1c placebo-corrected mean change from baseline of -0.87%.

For the trial’s main secondary endpoint of a decrease from baseline in fasting plasma glucose (FPG), Imeglimin achieved statistical significance (p<0.0001) versus placebo at week 24, with a FPG placebo-corrected mean change from baseline of -19 mg/dL. Analyses of data for the additional secondary endpoints are ongoing. In this trial, the overall safety and tolerability of Imeglimin was similar to placebo and the adverse event profile was consistent with what was observed in the Phase 2b trial in Japan and the U.S. and European Phase 1 and 2 programs.

"This is a significant milestone for Poxel and for the development of our most advanced drug candidate. The TIMES 1 results confirm the robust efficacy combined with favorable safety observed in the Phase 2b trial in Japan and the potential benefits that Imeglimin can bring to type 2 diabetes patients globally,” said Thomas Kuhn, CEO of Poxel. “The TIMES 1 data is the first major step towards filing the Japanese New Drug Application in 2020. Japan represents the second largest single market for type 2 diabetes and, Asia, in broader terms, is considered the most important geographic location with regards to treating the diabetes pandemic in the future."

The TIMES program is a joint development effort between Poxel and Sumitomo Dainippon Pharma. The companies entered into a strategic partnership in October 2017 for the development and commercialization of Imeglimin in Japan, China, South Korea, Taiwan and nine other Southeast and East Asian countries.2

“Our commitment to diabetes patients is to continue to innovate and provide new therapeutic options to help them manage their disease. We are very pleased with the TIMES 1 data results and to be working closely with Poxel on the TIMES clinical trials,” said Nobuhiko Tamura, Senior Executive Officer; Drug Development Division of Sumitomo Dainippon Pharma. “Diabetes is a significant area for our company in Japan, and we believe that Imeglimin will be a very important addition to our existing diabetes franchise.”

Poxel anticipates presenting data results from the Phase 3 (TIMES 1) trial at an upcoming scientific meeting.

Poxel will host a conference call to discuss the results later today. To access the information please click this link or refer to Poxel’s website.

About the TIMES Program
TIMES (Trials of Imeglimin for Efficacy and Safety), the Phase 3 program for Imeglimin for the treatment of type 2 diabetes in Japan, consists of three pivotal trials involving over 1,100 patients. The TIMES program includes the following three trials that will be performed using the dose of 1,000 mg twice daily:

TIMES 1: A Phase 3, 24-week, double-blind placebo-controlled, randomized, monotherapy trial to assess the efficacy, safety and tolerability of Imeglimin in Japanese patients with type 2 diabetes, using the change in HbA1c as the primary endpoint. Secondary endpoints of the trial include fasting plasma glucose, other standard glycemic and non-glycemic parameters.

TIMES 2: A Phase 3, 52-week, open-label, parallel-group trial to assess the long-term safety and efficacy of Imeglimin in Japanese patients with type 2 diabetes. In this trial, Imeglimin will be administrated orally as a monotherapy or combination therapy with existing hypoglycemic agents, including a DPP4 inhibitor, SGLT2 inhibitor, biguanide, sulphonylurea and GLP1 receptor agonist.

TIMES 3: A Phase 3, 16-week, double-blind, placebo-controlled, randomized trial with a 36-week open-label extension period to evaluate the efficacy and safety of Imeglimin in combination with insulin in Japanese patients with type 2 diabetes and inadequate glycemic control on insulin therapy.

About Imeglimin
Imeglimin is the first clinical candidate in a new chemical class of oral agents called Glimins by the World Health Organization. Imeglimin has a unique mechanism of action (“MOA”) that targets mitochondrial bioenergetics. Imeglimin acts on all three key organs which play an important role in the treatment of type 2 diabetes: the liver, muscles and the pancreas, and it has demonstrated glucose lowering benefits by increasing insulin secretion in response to glucose, improving insulin sensitivity and suppressing gluconeogenesis. This MOA has the potential to prevent endothelial and diastolic dysfunction, which can provide protective effects on micro- and macro-vascular defects induced by diabetes. It also has the potential for protective effect on beta-cell survival and function. This unique MOA offers the potential opportunity for Imeglimin to be a candidate for the treatment of type 2 diabetes in almost all stages of the current anti-diabetic treatment paradigm, including monotherapy or as an add-on to other glucose-lowering therapies.

About Poxel SA
Poxel uses its development expertise in metabolism to advance a pipeline of drug candidates focused on the treatment of metabolic disorders, including type 2 diabetes and non-alcoholic steatohepatitis (NASH). We have successfully completed the Phase 2 clinical program for our first-in-class lead product, Imeglimin, which targets mitochondrial dysfunction, in the U.S., Europe and Japan. Together, with our partner Sumitomo Dainippon Pharma, we are conducting the Phase 3 Trials of IMeglimin for Efficacy and Safety (TIMES) program for the treatment of type 2 diabetes in Japan. Our partner Roivant Sciences is responsible for Imeglimin’s development and commercialization in countries outside of Poxel’s partnership with Sumitomo Dainippon Pharma, including the U.S. and Europe. PXL770, a first in class direct adenosine monophosphate-activated protein kinase (AMPK) activator, is in a Phase 2a proof-of-concept program for the treatment of NASH. PXL770 could also have the potential to treat additional metabolic diseases. PXL065 (deuterium-stabilized R-pioglitazone), a mitochondrial pyruvate carrier (MPC) inhibitor, is in Phase 1 and being developed for the treatment of NASH. Poxel also has additional earlier-stage programs, including deuterated drug candidates for metabolic, specialty and rare diseases. We intend to generate further growth through strategic partnerships and pipeline development. (Euronext: POXEL, www.poxelpharma.com)

About Sumitomo Dainippon Pharma
Sumitomo Dainippon Pharma defines its corporate mission as "to broadly contribute to society through value creation based on innovative research and development activities for the betterment of healthcare and fuller lives of people worldwide". By pouring all our efforts into the research and development of new drugs, we aim to provide innovative and effective pharmaceutical solutions to people not only in Japan but also around the world in order to realize our corporate mission. Sumitomo Dainippon Pharma aims to create innovative pharmaceutical products in the Psychiatry & Neurology area, the Oncology area and Regenerative Medicine & Cell Therapy, which have been designated as the focus research areas. Sumitomo Dainippon Pharma has also positioned Psychiatry & Neurology, Diabetes and Specialty as our focus marketing areas in Japan. For more detail, please visit our website. (URL: https://www.ds-pharma.com)

Just looking more into CDTX, what do you see as the biggest questions from this prior P2 data? I'm assuming it's the fact that the 400mg once on first week/200mg once each subsequent week out performed the 400mg/400mg arm so much. I guess the obvious question is why a much less potent dose on subsequent weeks would have much greater efficacy than the much higher dose. Is that your biggest concern? FWIW, it looks like the data in the 400mg/200mg looks good compared to the comparator arm.

I wonder if it has anything to do with patient selection in each arm. Anyways, the ongoing P3 trial appears to mirror that 400mg/200mg design so assuming they can replicate those results in P3, they should be in good shape I assume. Also, just as it relates to competitor drugs, I'm assuming a once weekly formulation would have advantages over a drug that needs to be taken daily.

ARVN -

Thanks for posting this as there's a lot of good detail there. It certainly seems to point to a lot of risk for the lead drug to me. I will certainly keep watching these guys as I like the novel work they are doing. Not sure I'm willing to take a gamble on the lead drug panning out though.

BPMC -

What impact, if any, do you see this having on the prospects for ultimate approval for BLU-667?

It's not to same extreme degree as ASMB (with potentially 4 follow-on drugs behind the lead), but bugs me that ARVN has one direct "next generation" version of their lead drug ARV-110 in what looks like much earlier development. Why do they feel they need a next gen version of the lead drug?

ASMB @ Jefferies HBV summit (3/18/19)

I just listened to the ASMB presentation at this conference and the CEO stated that they will soon have a 4th and possibly even 5th CpAM drug in development for HBV. With P2 data due for their lead CpAM next quarter, I can't say this exactly inspires a lot of confidence. What is wrong with the first 3 CpAMs for HBV? I can honestly say I've never seen a lead drug already being developed over so many times so early in its development.

JNCE/(BMY/CELG) -

Actually, I'm not even sure there is true overlap between BMY's existing pipeline and JNCE's drugs. Does BMY have an ICOS agonist already in development (or drug targeting LILRB2 for that matter)? I don't believe so.

Also, I looked at the BMY slides tied to the 2/19 investor presentation (https://www.bms.com/investors/events-and-presentations.html ) and they don't even list either of the JNCE drugs on slide 30 among the "high potential agents and pipeline assets to watch." Note they do identify several other CELG drugs there in similar early stage of development.

NITE/(AGTC) -

Presumably another red flag for AGTC in that BIIB would move so quickly from their former partnership with AGTC to outright acquiring a direct competitor in the eye GT space.

SEEL/(PRTA) -

Well, SEEL is WAY behind PRTA (and others) in targeting alpha-synuclein for PD. And no obvious description of how they may be differentiated.

JNCE 4Q18/YE CC notes

1. Said posters at upcoming AACR will show "important validation" of their ICOS hi CD4 t-cell biomarker demonstrating improved PFS and OS in patients with the biomarker. [During Q&A, it was noted that "improved" was in reference to ICOS hi CD4 vs ICOS low CD4 and overall study population. I'm not sure if actual PFS and OS in ICOS hi CD4 subset has already been presented to some degree before (SITC last year?) and if it has then this may not be much of a meaningful update but if never presented then it could be more meaningful.]

2. Called LIILRB2, the target of JTX-8064, a "macrophage checkpoint."

3. During planned remarks, specifically called out the risks of the BMY/CELG deal going through and the possibility of rights to their drugs in the CELG partnership being returned to them in light of some overlap with BMY's pipeline. Makes me wonder if they think this may happen to bring it up during planned remarks and not in response to a question during Q&A. Of course, they brought up the potential good angle of regaining all rights but I'd take it as a bad sign myself if BMY were to ultimately pass on their drugs.

4. Will not need to select patients with their predictive biomarker (presumably will be revealed at AACR?) to help identify patients with pre-existing ICOS hi CD4 t-cells when combining vopratelimab with ipilimumab as ipilimumab itself can generate ICOS hi CD4 t-cells and has been shown to do that in the first or second cycle of tx. JNCE will have to use their specific biomarker to select patients for vopratelimab when not combining with ipilimumab.

5. GSK will have an update on their ICOS drug at ESMO later this year. JNCE doesn't see a difference yet between their drug and GSK's but noted that GSK hasn't presented a lot of data yet.

Re: AGTC (insider ownership)

I will say one thing that really is a turn off for me is the lack of insider ownership. The CEO and CMO each barely own over 20K shares. And the CSO owns no shares. You'd think they would own a lot more shares if they believed the story.

AGTC -

That's a good question and I don't know the answer. Just assuming the answer is probably after. FWIW, here is the latest slide deck where they go through some of the differences: http://ir.agtc.com/static-files/836dcb4c-0374-4873-a7e2-3c5e750458fb . In particular, slide 17 notes pre-clinical XLRS data was in mouse model whereas pre-clinical XLRP data is in dog model. They also note that the only similarity between the XLRP and XLRS programs are the capsid (obviously if capsid was the issue in XLRS then that's a problem!).

Re: AGTC

I hadn't looked at AGTC for a long time until just now. Stock is languishing below its EV and they have several data read-outs later this year on both the XLRP and achromatopsia programs. I know the company and stock have been a disaster to date but just wondering if any value here. NITE has at least had some PoC in XLRP and wondering if this could bode well for AGTC. I listened to their latest CC and they said what distinguishes their XLRP program from the XLRS that failed is that XLRP apparently has a good pre-clinical model where they have shown success vs. XLRS that had no good model. Also, they claim they are dosing sub-retinal with XLRP whereas XLRS indication was intravitreal (assuming that means chance for better delivery and, ultimately, efficacy).

Given the foregoing, you think they have a decent chance to show efficacy in the XLRP program?

Re: ASMB

Thanks. I'm still holding a smaller position in this one (actually my smallest holding). I still don't trust how the stock will react to the P2 data for the lead drug next Q. I'm typically a bit wary when companies have multiple next-gen versions of a lead drug right behind in development as it just makes me wonder if the lead drug won't be sufficient. Keeping a bit of dry powder to potentially add big if there is any significant sell-off.

INCY/MRUS (4-1BBxPD-L1) -

Thanks much. Completely different target but still under the general IO umbrella, I listened to INCY at JPM and, among their early programs, INCY seemed to single out the 4-1BBxPD-L1 bispecific partnered with MRUS (MRUS got great terms on this deal, keeping full U.S. rights).

Alector (ALEC) - TREM2

FYI this upcoming IPO Alector (ALEC) is also targeting TREM2 and they are actually already in the clinic (well ahead of DNLI for this target). See: https://www.businesswire.com/news/home/20181115005291/en/Alector-Initiates-Phase-1-Trial-AL002-Treatment .

ALEC reminds me a lot of DNLI with all the novel neurodegenerative targets they are pursuing (TREM2/progranulin/sieglec3). And, like DNLI, this one will be pricey out of the gate with about 75M fully-diluted shares O/S it looks like so at least a $1.5B market cap to start. ALEC is partnered with ABBV on the TREM2 and sieglec3 programs but they at least got good terms as they can split profits on each program. In a webcast I listened to, they described the sieglec3 program as effectively releasing the brake on microglia.

VRCA - positive P3 data (molluscum contagiosum)

[You see any obvious issues in the data? Certainly looks like the drug works. Is there a reason to believe this drug won't be approved or will otherwise have trouble gaining traction commercially? I'm assuming the AEs are the big question but looks like the efficacy is there to me.]

https://investors.verrica.com/news-releases/news-release-details/verrica-achieves-positive-topline-results-two-pivotal-phase-3

Verrica Achieves Positive Topline Results from Two Pivotal Phase 3 Clinical Trials of VP-102 in Patients with Molluscum Contagiosum

January 3, 2019 at 6:30 AM EST
Download PDF
CAMP-1 and CAMP-2 Phase 3 pivotal trials for molluscum contagiosum both achieve statistical significance for the primary endpoint with p-values less than 0.0001

No serious adverse events in VP-102 treated subjects

Verrica to submit a Section 505(b)(1) New Drug Application (NDA) in 2H 2019

No FDA approved treatments are currently available for molluscum contagiosum, a highly contagious, primarily pediatric, common skin diseaseaffecting an estimated 6 million people in the United States

Management to host webcast and conference call today at 8 a.m. ET

WEST CHESTER, Pa., Jan. 03, 2019 (GLOBE NEWSWIRE) -- Verrica Pharmaceuticals Inc. (Verrica) (Nasdaq: VRCA), a pharmaceutical company focused on identifying, developing and commercializing innovative pharmaceutical products for the treatment of skin diseases with significant unmet needs, today announced positive topline results from its Phase 3 CAMP-1 and CAMP-2 pivotal trials with VP-102 for the treatment of molluscum contagiosum (molluscum). Molluscum is a highly contagious skin disease affecting primarily children, with no current FDA approved treatment. Both clinical trials evaluated the safety and efficacy of VP-102, a proprietary drug-device combination containing a novel topical solution of 0.7% cantharidin, compared to placebo. In each trial, VP-102 exhibited a clinically and statistically significant proportion of subjects demonstrating complete clearance of all treatable molluscum lesions versus placebo. VP-102 was well-tolerated in both trials, with no serious adverse events reported in VP-102 treated subjects.

“The topline results from CAMP-1 and CAMP-2 validate our platform and bring us one step closer to our goal of providing patients with the first FDA approved treatment for molluscum contagiosum, a significantly undertreated skin disease affecting an estimated 6 million people in the United States,” commented Ted White, President and Chief Executive Officer of Verrica. “We believe the efficacy and safety profiles of VP-102 observed in these two trials provide a strong foundation for our U.S. NDA which we intend to submit in the second half of this year.”

The Phase 3 program for molluscum consisted of two clinical trials, CAMP-1 (study VP-102-101) and CAMP-2 (study VP-102-102). The two trials, identical in design, were randomized, double-blind, multicenter, placebo-controlled trials of VP-102 for the treatment of molluscum. CAMP-1 was conducted under an FDA Special Protocol Assessment (SPA). The primary objective of the trials was to evaluate the efficacy of dermal application of VP-102 relative to placebo, when treated once every 21 days for up to four applications, by assessing the proportion of subjects achieving complete clearance of all treatable molluscum lesions at Day 84 (Week 12/End of Study visit). Secondary endpoints included the proportion of subjects with complete clearance at study visits on Days 21 (Week 3), 42 (Week 6) and 63 (Week 9).

CAMP-1 and CAMP-2 enrolled 528 subjects in total and were conducted at 31 centers in the United States. The trials evaluated the safety and efficacy of VP-102 compared to placebo in subjects 2 years of age and older with molluscum contagiosum. Complete clearance was evaluated through assessment of lesion number at study visits over 12 weeks. Results from CAMP-1 and CAMP-2 showed 46% and 54% of subjects treated with VP-102, respectively, achieved complete clearance of all treatable molluscum lesions at day 84 versus 18% and 13% of subjects in the placebo groups (p<0.0001). By the end of the trials (Day 84), VP-102 treated subjects had a 69% and 83% mean reduction in the number of molluscum lesions, a pre-specified endpoint, in CAMP-1 and CAMP-2, respectively, compared to 20% and 19% for subjects on placebo.

“Molluscum contagiosum can often have a negative impact on the quality of life of affected children, exacerbated by the skin irritation and inflammation that can result as complications of the disease. The high lesion clearance rate demonstrated at Day 84 for VP-102 compared to placebo in the Phase 3 trials is clinically significant and could potentially position VP-102 to become the standard of care for treating molluscum,” stated Lawrence Eichenfield, M.D., Chief of Pediatric and Adolescent Dermatology at Rady Children’s Hospital-San Diego and lead investigator for the VP-102 Phase 3 molluscum program.

Additional CAMP-1 Results

The proportion of subjects achieving complete clearance at Week 9 (Day 63), a secondary endpoint, was 32% of subjects compared to 17% of placebo treated subjects (p=0.007).
The proportion of subjects achieving complete clearance at Week 6 (Day 42), a secondary endpoint, was 21% of subjects compared to 9% of placebo treated subjects (p=0.015).
The proportion of subjects achieving complete clearance at Week 3 (Day 21), a secondary endpoint, was 11% of subjects compared to 4% of placebo treated subjects (p=0.030). VP-102 demonstrated superiority over placebo with only one application of study drug.
In this trial, 160 subjects were randomized to receive VP-102 and 106 subjects were randomized to receive placebo. Of the subjects enrolled in the trial, 150 (94%) patients who received VP-102 completed the study, compared to 100 (94%) placebo treated subjects.
Additional CAMP-2 Results

The proportion of subjects achieving complete clearance at Week 9 (Day 63), a secondary endpoint, was 28% of subjects compared to 5% of placebo treated subjects (p<0.0001).
The proportion of subjects achieving complete clearance at Week 6 (Day 42), a secondary endpoint, was 13% of subjects compared to 4% of placebo treated subjects (p=0.010).
The proportion of subjects achieving complete clearance at Week 3 (Day 21), a secondary endpoint, was 5% of subjects compared to 2% of placebo treated subjects (p=0.138).
In this trial, 150 subjects were randomized to receive VP-102 and 112 subjects were randomized to receive placebo. Of the subjects enrolled in the trial, 139 (93%) subjects who received VP-102 completed the study, compared to 108 (96%) placebo treated subjects.
Consistent with the results from the Phase 2 clinical trials, VP-102 was also well-tolerated in the Phase 3 trials, with side effects that were primarily mild to moderate. The most frequently reported adverse events were application site reactions that are well-known, reversible side effects related to the mechanism of action of cantharidin, a blistering agent, which is the active ingredient in VP-102. There were no treatment-related serious adverse events reported in CAMP-1 or CAMP-2.

The most frequently reported adverse events in the CAMP-1 trial (>10% in either group) were application site vesicles (81% and 25% for VP-102 and placebo, respectively), application site pain (59% and 14%), application site pruritus (55% and 30%), application site erythema (33% and 18%), application site scab (31% and 17%), application site discoloration (25% and 8%) and application site dryness (13% and 5%). Five subjects (3%) in the VP-102 group and no placebo subjects discontinued due to an adverse event.

The most frequently reported adverse events in the CAMP-2 trial (>10% in either group) were application site vesicles (94% and 30% for VP-102 and placebo, respectively), application site scab (57% and 20%), application site pain (55% and 14%), application site erythema (47%% and 25%), application site pruritus (43% and 33%), application site discoloration (31% and 8%) and application site dryness (26% and 18%). One subject each in the VP-102 and placebo groups (<1% each) discontinued due to an adverse event.

Verrica plans to submit this data for presentation at future medical meetings and for publication in a peer-reviewed medical journal.

Is it time to buy CL and PG? Haha

EDIT -

In addition to the CEO and CFO, the CMO also left last year. Seems really hard to take any positive sign out of all these departures. I had to sell out end of last year for tax reasons but had plans to potentially get back in. I won't be doing so now after this latest departure.

I do wonder if there's any potential positive read-through to the other CRISPR players like CRSP or if this is potentially a negative broad read-through for the entire field (my gut is the latter).

Co-stim IO assets (FPRX/ALPN) -

Completely separate target but still on the co-stim angle, have you looked at what FPRX is attempting to do with their FPT155 asset? It's a soluble CD80 fusion protein designed to directly engage CD28 while blocking CTLA-4 from competing for endogenous CD80: https://www.fiveprime.com/programs/FPT155/ . They are in P1 now and expecting some data 2H of this year. I don't think FPRX gets enough credit for all the novel work they do (first-in-class B7-H4 asset in clinic now as well).

ALPN is taking a similar approach with their ALPN-202 asset, which is a PD-L1/CTLA-4 antagonist and a CD28 agonist, but they are earlier stage as don't enter clinic until 4Q this year (so likely no initial data until mid-2020 or 2H2020). See: https://www.alpineimmunesciences.com/pipeline/oncology/ .

Thanks to you and the others chiming in on this. Very helpful!

GSK/(JNCE) -

Hey thanks so much. Did a quick search of clinicaltrials.gov and found the following for the GSK ICOS agonist: https://clinicaltrials.gov/ct2/results?cond=&term=GSK3359609&cntry=&state=&city=&dist= . So, as you can see, one of the four trials is testing their ICOS agonist in combo with an anti-CTLA-4 (tremelimumab). So, at least adds some support for what JNCE will try next. I'll have to dig and see if there's any meaningful clinical data yet for the GSK ICOS agonist (assuming not). EDIT: I do see RockRat's post now (thanks!). Just looks like that is alone or with pembrolizumab. Guessing no sign yet of how their drug may work in combo with an anti-CTLA-4.

Re: JNCE

Do you give JNCE a shot to show a signal in the next trial combining JTX-2011 with ipilimumab or does the fact that management didn't pick up on this combo before give you overall pause?

Not saying this one will be the winner but, in general, it almost feels to me that the pendulum has swung far too far the other way in terms of IO hype. It feels to me like a lot of the small-cap IO biotechs are being priced as if there is unlikely to be much progress in the coming years. Seems a bit extreme to me so I'm looking for some exposure here again.

DCPH - censored patients in P1 trial

Peter, the latest DCPH presentation gives a bit more detail on the prior P1 data in GIST. See slide 19 as it references a number of censored patients: https://investors.deciphera.com/static-files/49c2191e-b58d-4843-b221-1b8061f155a0 . Is there any chance there is any concern with their presented data to date in light of the censored patients? I normally see "censoring" brought up in a negative context so not sure if a red flag here.

Re: JNCE

Thanks so much for the post and links! Those certainly do at least seem to provide some support for what JNCE is proposing to do next. I'm with you as I'm still assuming it's likely just a long shot. JNCE just caught my eye trading below cash and at least being a very novel IO player. And they're a fairly new company so I don't want to completely discredit them for what is really just one failure to date.

I'd be surprised at this valuation even if they were to have rights returned from the CELG partnership that it would seriously cause shares to tank much as shares are already so depressed. To their credit, JNCE did get great terms on their drugs partnered under the CELG deal. Looks like LILRB2 is the next drug from their partnership set to enter the clinic (targeting macrophages). Not sure if you have any opinions on that target.

I'll probably just continue to watch for now myself even if it is a bit tempting with the valuation, cash, and novel pipe.

JNCE @ JPM19

JNCE has obviously been off to a poor start as a public company with the early initial disappointing data from their lead IO drug JTX-2011 (anti-ICOS). I gave a listen to their JPM presentation just because they are still relatively young and I like to follow novel IO companies and shares are below cash (no position).

They claim they have identified the best setting for JTX-2011 and they think it works best in patients that have ICOS Hi CD4 cells. For the patients that did show good response from their prior data (was a small sub-set), they had these ICOS Hi CD4 cells and they claim they emerged during treatment (either during JTX-2011 mono therapy or in combo with nivolumab). The poorest responders had ICOS Low CD4 cells.

They're moving forward in their next trial testing JTX-2011 in combo with ipilimumab as they claim CTLA-4 inhibitors do generate ICOS Hi CD4 cells. They also think they have identified patients from the prior trial that have certain characteristics where treatment with JTX-2011 (or perhaps some other drug not limited to a CTLA-4 inhibitor) will make them more prone to generate ICOS Hi CD4 cells and thus lead to good outcome.

Anyone see any chance for success here or just a bunch of data mining from their prior (mostly disappointing) trial?

Given the quick max out on the ATM with the key binary data due so soon (later this quarter) and combined with skipping that final interim efficacy analysis, my gut is this all doesn't bode as the best sign for that pending P3 data. But, doesn't mean doomed for failure either. Still, I don't think I'm willing to gamble on that P3 data myself (stock certainly seems really cheap if the P3 data is positive though).

FTSV - 2019 Priorities/Milestones

[Looks like they are increasing the max dose of 5F9 to be administered in combo with Rituxan in R/R NHL from the prior 30 mg/kg max dose to 45 mg/kg now. Be interesting to see if this leads to better efficacy data than what has already been reported in the Phase 1B while still showing manageable safety.]

https://ir.fortyseveninc.com/news-releases/news-release-details/forty-seven-inc-announces-2019-strategic-priorities-and-expected

Forty Seven Inc. Announces 2019 Strategic Priorities and Expected Milestones
-- Updated Data from Phase 1b/2 Trial of 5F9 in Combination with Rituximab for r/r NHL Expected Mid-2019 --
-- Clinical Data from Two Additional Trials of 5F9 Expected in 2019 --
-- Expanding Pipeline of Macrophage-Directed Therapies; Advancing FSI-189 into IND-Enabling Studies and Naming FSI-174, anti-cKIT Antibody, as Third Development Candidate --

MENLO PARK, Calif., Jan. 07, 2019 (GLOBE NEWSWIRE) -- Forty Seven Inc. (NASDAQ:FTSV) a clinical-stage, immuno-oncology company focused on developing therapies to activate macrophages in the fight against cancer, today outlined its strategic plan and expected milestones for 2019.

“We believe 2019 will be a transformational year for Forty Seven, as we apply our scientific insights and nimble execution capabilities to build a leading immuno-oncology company, with a broad pipeline of macrophage-directed therapies,” said Mark McCamish, M.D., Ph.D., President and Chief Executive Officer of Forty Seven, Inc. “In addition to progressing our development program for 5F9 towards three clinical readouts across three treatment modalities, we are excited to expand our research-stage efforts, with plans to move FSI-189, an anti-SIRPa antibody, into IND-enabling studies and advance FSI-174, an anti-cKIT antibody, as our third development program. Together, these expected milestones reflect our commitment to exploiting the full potential of the CD47/SIRPa pathway as a novel oncology target, in hopes of helping patients defeat their cancer.”

5F9: Lead Antibody Against CD47

“We are focused on executing our broad clinical development strategy for 5F9 across multiple treatment modalities and patient populations, and we look forward to reading out data from three ongoing trials in 2019,” said Chris Takimoto, M.D., Ph.D., Chief Medical Officer of Forty Seven, Inc. “Based on our clinical experience to date, we believe 5F9, coupled with our proprietary priming dosing strategy, may offer patients a differentiated treatment option, with the potential to be safely administered at clinically relevant doses to achieve meaningful benefit.”

Also announced today, in mid-2019, Forty Seven expects to report out data from dose optimization cohorts evaluated as part of its Phase 1b/2 trial of 5F9 in combination with rituximab in patients with relapsed/refractory non-Hodgkin lymphoma (r/r NHL). In the dose optimization cohorts, Forty Seven is evaluating 5F9 doses of 30 or 45 mg/kg, administered with or without a loading dose. This follows the observation of a potential positive dose-response correlation in the Phase 1b portion of the trial, suggesting that higher doses or a loading dose may be associated with enhanced efficacy.

Expected 2019 Milestones for 5F9:

Report data from the Phase 1b/2 trial of 5F9 in combination with rituximab in patients with r/r NHL, including initial data from the dose optimization cohorts, mid-year;
Report data from the Phase 1b trial of 5F9 as a monotherapy and in combination with azacitidine in patients with acute myeloid leukemia and myelodysplastic syndrome mid-year;
Report data from the Phase 1b trial of 5F9 in combination with avelumab in patients with ovarian cancer in the fourth quarter.
Research Programs

“We are committed to developing a broad pipeline of novel medicines, which leverages our pioneering understanding of macrophage biology to help patients defeat their disease,” said Jens-Peter Volkmer, M.D., Founder and VP Research and Early Development of Forty Seven, Inc. “Today, we are pleased to unveil our third development candidate, FSI-174, an anti-cKIT antibody that we intend to develop in combination with 5F9 as a non-toxic transplant conditioning regimen, as well as a treatment for targeted hematologic malignancies. Like CD47, cKIT is expressed on various cancers, hematopoietic stem cells and certain tumor stem cells. In binding to these cells, anti-cKIT antibodies could provide an additional ‘eat me’ signal to macrophages, enabling an even more robust therapeutic response. We look forward to sharing initial preclinical data from this program in 2019, as we advance our next wave of programs toward development.”

cKIT, also known as CD117, is a stem cell factor receptor. In preclinical studies, anti-cKIT antibodies, when combined with anti-CD47 antibodies, induced the depletion of endogenous blood-forming stem cells. In addition, anti-cKIT antibodies have shown anti-tumor effects in in vitro and in vivo mouse models. Based on these observations, Forty Seven believes that anti-cKIT antibodies combined with anti-CD47 antibodies could offer a less toxic conditioning regimen for transplantation of blood-forming stem cells, as well as a therapeutic approach for targeted hematologic malignancies.

Expected 2019 Milestones for Research Programs:

Initiate investigational new drug (IND)-application enabling studies for FSI-189, an anti-SIRPa antibody;
Outline initial development strategy for FSI-174 at key opinion leader (KOL) symposium on January 22, 2019 in New York City;
Present preclinical data for FSI-174 in the first half the year and complete IND enabling studies.
Cash Position and Financial Guidance:
As of December 31, 2018, Forty Seven had cash, cash equivalents and short-term investments of $139.0 million. Based on its current operating plans, Forty Seven expects that its cash, cash equivalents and short-term investments will fund operating expenses and capital expenditure requirements through the first half of 2020.