Silicon Investor - Incyte (INCY)

[scaram(o)uche] "Pfizer drops 10 mg dose of best-selling Xeljanz...." endpts.com

scaram(o)uche — 2/20/2019 7:41:47 AM

[Miljenko Zuanic] INCY calls very active on GS upgrade. Where were they when INCY was at ~$55?

Miljenko Zuanic — 1/15/2019 10:55:36 AM

[Miljenko Zuanic] INCY is bit better than MGNX in dealing with China, still far from "brilliant": ...

Miljenko Zuanic — 12/17/2018 11:42:41 AM

INCY is bit better than MGNX in dealing with China, still far from "brilliant":

finance.yahoo.com

[Miljenko Zuanic] With ongoing carnage in bio-sector, INCY is not spared. 3Q results ( finance.yah...

Miljenko Zuanic — 10/30/2018 1:21:25 PM

With ongoing carnage in bio-sector, INCY is not spared. 3Q results ( finance.yahoo.com ) are in line from expected, and that is not enough this days.

[Miljenko Zuanic] Dose levels, 13.5 mg for Pem v 300 mg for 087,...is whole story. To be active ca...

Miljenko Zuanic — 10/21/2018 9:12:59 PM

Dose levels, 13.5 mg for Pem v 300 mg for 087,...is whole story. To be active cancer drug, one need to be "overall toxic' at low concentration, IMO.

[software salesperson] here you go, tuck. 1) Primary bile duct cancer is uncommon in the United States...

software salesperson — 10/21/2018 12:13:50 PM

here you go, tuck.

1) Primary bile duct cancer is uncommon in the United States. Each year, an estimated 8,000 people in the United States are diagnosed with bile duct cancer. The average age people are diagnosed with intrahepatic bile duct cancer is 70. For extrahepatic bile duct cancer, the average age at diagnosis is 72.The number of new cases of bile duct cancer is increasing, mostly due to rising rates of intrahepatic bile duct cancer. The reason for this increase is not known. It may be due to the use of more accurate tests to diagnose this type of cancer. Previously, intrahepatic bile duct cancer may have been thought to be a different type of cancer.

In some parts of the world, a parasite called a liver fluke can infect the bile duct and cause cancer. Liver flukes are very common in Asia, and bile duct cancer is more common in this part of the world. Also, gallstones and inflammatory conditions of the digestive tract, such as ulcerative colitis or an associated condition called Primary Sclerosing Cholangitis (PSC), increase the risk of bile duct cancer. PSC is an autoimmune disease in which the body's immune system attacks the bile ducts and causes scarring. See the Risk Factors section for more information.

The 5-year survival rate tells you what percent of people live at least 5 years after the cancer is found. Percent means how many out of 100. The 5-year survival rate for people with early-stage extrahepatic bile duct cancer is 30%. If the cancer has spread to the regional lymph nodes, the 5-year survival rate is 24%. If the cancer has spread to a distant part of the body, the 5-year survival rate is 2%.

For people with early-stage intrahepatic bile duct cancer, the 5-year survival rate is 15%. If the cancer has spread to the regional lymph nodes, the 5-year survival rate is 6%. If the cancer has spread to a distant part of the body, the 5-year survival rate is 2%.

It is important to remember that statistics on the survival rates for people with bile duct cancer are an estimate. The estimate comes from annual data based on the number of people with this cancer in the United States. Also, experts measure the survival statistics every 5 years. So the estimate may not show the results of better diagnosis or treatment available for less than 5 years. People should talk with their doctor if they have any questions about this information. Learn more about understanding statistics.

Source: American Cancer Society website.

2) clinicaltrials.gov

Brief Summary:
The purpose of this study is evaluate the efficacy of INCB054828 in subjects with advanced/metastatic or surgically unresectable cholangiocarcinoma with FGFR2 translocation who have failed at least 1 previous treatment.

Inclusion Criteria:

Histologically or cytologically confirmed cholangiocarcinoma.Radiographically measurable or evaluable disease per RECIST v1.1.Tumor assessment for FGF/FGFR gene alteration status.Documented disease progression after at least 1 line of prior systemic therapy.Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.Life expectancy = 12 weeks.

Exclusion Criteria:

Prior receipt of a selective FGFR inhibitor.History of and/or current evidence of ectopic mineralization/calcification, including but not limited to soft tissue, kidneys, intestine, myocardia, or lung, excepting calcified lymph nodes and asymptomatic arterial or cartilage/tendon calcifications.Current evidence of clinically significant corneal or retinal disorder confirmed by ophthalmologic examination.Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half-lives, whichever is shorter, before the first dose of study drug. Topical ketoconazole will be allowed.

3) clinicaltrials.gov

Brief Summary:
This pivotal, open-label, single-arm study will evaluate the anti-cancer activity of ARQ 087 by Objective Response Rate (ORR) by central radiology review as per RECIST v1.1 in subjects with inoperable or advanced intrahepatic cholangiocarcinoma (iCCA) whose tumors harbor FGFR2 gene fusions (by FISH performed by the central laboratory) and who received at least one prior regimen of systemic therapy. Subjects will be dosed orally once per day at 300 mg of ARQ 087 capsule

Inclusion Criteria:

Signed written informed consent granted prior to initiation of any study-specific procedures18 years of age or olderHistologically or cytologically confirmed locally advanced, inoperable (where surgery is not indicated due to disease extension, co-morbidities, or other technical reasons), or metastatic iCCA or mixed histology tumors (combined hepatocellular-cholangiocarcinoma [cHCC-CCA])FGFR2 gene fusion status confirmed by NGS or FISH testing

Test positive by FISH by the central laboratory designated by the SponsorHave FGFR2 gene fusion documented by a local or central laboratory using standard protocols and approved by local IRB/EC, by CLIA or other similar agency. If the FGFR2 gene fusion is identified by a laboratory other than the Sponsor's central laboratory, then archival and/or recent tissue biopsy samples or a tissue block suitable for genetic testing must be available for confirmatory testing by FISH by the Sponsor's central laboratory. If a subject has documentation from the central laboratory indicating that they test negative for FGFR2 gene fusion, that subject may not be enrolled in the study.Received at least one regimen of prior systemic therapy and then experienced documented radiographic progression or was not able to tolerate prior systemic therapy.

If the subject received at least 4 cycles of systemic therapy and no measurable tumor reduction compared to the previous scan is observed, such subject can be enrolledIf the subject received immunotherapy, the documented radiographic disease progression is requiredMeasurable disease by RECIST version 1.1ECOG performance status = 1Adequate organ functions as indicated by the following laboratory values (based on screening visit values from the central laboratory).

Hematological

Hemoglobin (Hgb) = 9.0 g/dLAbsolute neutrophil count (ANC) = 1.5 x 109/LPlatelet count = 75 x 109/LInternational normalized ratio (INR) 0.8 to upper limit of normal (ULN) or = 3 for subjects receiving anticoagulant therapy such as Coumadin or heparinHepatic

Total bilirubin = 2 x ULNAST and ALT = 3 ULN (= 5 x ULN for subjects with liver metastases)Albumin = 2.8 g/dLRenal

Serum creatinine = 1.5 x ULNCreatinine clearance of = 60 mL/min as estimated by the Cockcroft-Gault equationMale or female subjects of child-producing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after the last dose of ARQ 087

Exclusion Criteria:

Systemic anti-cancer therapy, such as chemotherapy, immunotherapy, hormonal, targeted therapy, or investigational agents within four weeks of the first dose of ARQ 087Major surgery, locoregional therapy, or radiation therapy within four weeks of the first dose of ARQ 087Previous treatment with any FGFR inhibitor (e.g., ponatinib, dovitinib, nintedanib, AZD4547, NVP-BGJ398, LY2784455, BAY1163877)

- Subjects who received less than four weeks of therapy and were unable to continue therapy due to toxicity will be allowed to participate

Unable or unwilling to swallow the complete daily dose of ARQ 087 capsulesClinically unstable central nervous system (CNS) metastases (to be eligible, subjects must have stable disease = 3 months, confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) scan, and/or have CNS metastases well controlled by low-dose steroids, anti-epileptics, or other symptom-relieving medications)Current evidence of corneal or retinal disorder, including but not limited to bullous/band keratopathy, keratoconjunctivitis, corneal abrasion, inflammation/ulceration, confirmed by ophthalmologic examinationConcurrent uncontrolled or active hepatobiliary disorders, untreated or ongoing complications after laparoscopic procedures or stent placement, including but not limited to active cholangitis, biloma or abscess (to be eligible, the subjects have to be treated and disorders/complications should be resolved within 2 weeks prior to the first dose of ARQ 087)History of significant cardiac disorders:

Myocardial infarction (MI) or congestive heart failure defined as Class II to IV per the New York Heart Association (NYHA) classification within 6 months of the first dose of ARQ 087 (MI that occurred > 6 months prior to the first dose of ARQ 087 will be permitted)QTcF >500 msec (males or females)Significant gastrointestinal disorder(s) that could, in the opinion of the Investigator, interfere with the absorption, metabolism, or excretion of ARQ 087 (e.g., Crohn's disease, ulcerative colitis, extensive gastric resection)Previous malignancy within 2 years of the first dose of ARQ 087, except curatively treated or low grade malignancies such as non-melanoma skin cancer, carcinoma in-situ of the breast, cervix, and superficial bladder tumorsConcurrent uncontrolled illness not related to cancer, including but not limited to:

Psychiatric illness/substance abuse/social situation that would limit compliance with study requirementsKnown uncontrolled human immunodeficiency virus (HIV) infectionBlood or albumin transfusion within 5 days of the blood draw being used to confirm eligibilityPregnant or breast feeding

[tuck] No chatter here on the FGFR inhibitor. Data that superficially looks better tha...

tuck — 10/21/2018 10:58:58 AM

No chatter here on the FGFR inhibitor. Data that superficially looks better than ARQL's competing drug at ESMO, including an ORR twice that of ARQL's:

Positive Interim Data from Phase 2 Trial of Pemigatinib, Its Selective FGFR Inhibitor, in Patients with Cholangiocarcinoma

But, one biotweeter says the baseline patient population is different, with the INCY cohorts having better ECOG status, and exclusion of patient with prior systemic treatment for unresectable or metastatic disease. That information might be confirmable just by looking at clinical trials.gov, but I'm not going to do that just now. If someone else doesn't, I might do it later.

Dunno what the market is for cholangiocarcinoma (incidence/prevalence, etc.)

Cheers, Tuck

[Miljenko Zuanic] 10% discontinuation rate is not that bad, ....but it is not "good" as well.

Miljenko Zuanic — 10/19/2018 12:03:31 PM

[tuck] INC280 Capmanitib at ESMO: INC280 ESMO Some slides regarding SAEs. INC280 E...

tuck — 10/19/2018 11:24:09 AM

INC280 Capmanitib at ESMO:

INC280 ESMO

Some slides regarding SAEs.

INC280 ESMO response and side effects slides

Decent efficacy, but 50% grade 3-4 SAEs, which are apparently pretty diverse.

Cheers, Tuck

[Miljenko Zuanic] There was leak of this news 3 days ago, spike in INCY price from "nowhere"??!!

Miljenko Zuanic — 9/27/2018 11:33:27 AM

[scaram(o)uche] Andy Biotech? @AndyBiotech8m8 minutes ago More $GERN Imetelstat data metamorph...

scaram(o)uche — 9/27/2018 9:17:35 AM

Andy Biotech? @AndyBiotech 8m8 minutes ago

More

$GERN Imetelstat data metamorphosis in Myelofibrosis: Mayo Tefferi ASH13 abstract: 28% ORR, 22% CR $JNJ IMbark data today: 1.7% ORR, 0% CR

[Miljenko Zuanic] bloodjournal.org < In an age- and sex-matched control group with none or conven...

Miljenko Zuanic — 6/15/2018 4:19:21 PM

bloodjournal.org

< In an age- and sex-matched control group with none or conventional therapy (N=44), 7 patients (15.9%) tested positive for IgR (Figure 1E). This indicates the presence of clonal B-cells in the bone marrow of approximately 15% of PMF patients regardless of treatment.>

So, IF statics hold (for JAK1/2 involvement in progression to cancer), 1/3 of those clone identified may develop aB-cL on treatment? That is bad!

RE: REGN This is somehow positive for REGN, because all those a-topic allergic conditions that may be targeted with selective JAK1 may be "At risk" for B-CL!

[scaram(o)uche] hematology.org >> They also speculate that screening for a preexisting B-cell c...

scaram(o)uche — 6/15/2018 3:05:29 PM

hematology.org

>> They also speculate that screening for a preexisting B-cell clone before starting therapy may help prevent this side effect..... <<

[Miljenko Zuanic] Tuck, I was bit sarcastic. That is all! Herve is well aware that Epa is "most l...

Miljenko Zuanic — 5/11/2018 1:22:36 AM

Tuck, I was bit sarcastic. That is all!

Herve is well aware that Epa is "most likely dead", still he invested $+900K, without blinking the eyes. Yes, he profited early by options conversion and stock sale (9-18-2017, so he is playing with house money), but it was signal to SH that he did not lost fate in company.
Should we thrust him (without excessive dinging into pipeline), I guess so. Actually, I do not know...but...let see how will street act post-ASCO period?

Cheers, Miljenko

[tuck] What do you mean? He bought near $60 like you (and me, via sold puts as usual)....

tuck — 5/11/2018 12:42:14 AM

What do you mean? He bought near $60 like you (and me, via sold puts as usual). On a different subject, wondering if there is anything of use at ASCO for INCY. If you (or Rick or PGS or whoever) don't have thoughts off the top of your head, I'll do a little digging and thinking in the next few days . . . for what that's worth.

Initial effort => check the press release, duh. So outside of epacadostat, they highlight: "Data at ASCO 2018 include oral presentations from a Phase 1 study of ruxolitinib (Jakafi®), lenalidomide and methylprednisolone in patients with relapsed and refractory multiple myeloma, the DeCidE1 trial assessing the combination of DPX-Survivac, cyclophosphamide and epacadostat in patients with recurrent epithelial ovarian cancer . . ."

Which are of definite clinical interest, but probably wouldn't move the stock price much.

So, based on that, once my my sold May 60 puts presumably expire worthless, I will likely stay on the sidelines, unless the stock price retreats noticeably shortly after that. Say, back to the level at which Herve bought. Then I'd try another small put sale. But given what happens to biotechs after ASCO, I think I'd take any profits immediately after news, rather than hold the position through expiration.

OT: thinking JNCE is an interesting ASCO play at these levels. They expect more mature data than has been presented to date at ASCO ( but the trial is ongoing for a while longer). It's an early P2. In general, they are looking for continued good safety, some signal, and some useful biomarker data related to ICOS expression and mutational burden. The main show are the TNBC and gastric cancer cohorts. But there are others, and we'll also get updated enrollment numbers for those (H&N, melanoma, NSCLC). Gastric cancer results could be a little muddy. They started with PD-1 naive patients, but then Keytruda got approved in 3rd line last fall, and they started enrolling patients that weren't naive. Thus numbers for specific subsets there could be too small to infer much (possible reason for the recent weakness?). I have a small position again, and may add on further post earnings weakness.

Abstracts off embargo next week (5/16, 2PM PST), so we need to think fast.

Back on topic: Come to think of it, maybe that's a rationale for taking my profits in the May INCY puts . . .

Cheers, Tuck

[Miljenko Zuanic] Is Herve damn?? secfilings.nasdaq.com

Miljenko Zuanic — 5/10/2018 11:21:27 PM

[Miljenko Zuanic] Thnx. Overall, street view/see Ruxo success in acute/chronic GVHD. They need som...

Miljenko Zuanic — 5/5/2018 12:06:28 PM

Thnx. Overall, street view/see Ruxo success in acute/chronic GVHD.
They need something else/additional to change sentiments.
Next week will be interesting, in view what everyone expect from government efforts to control US HC spending (Rx price)?

[scaram(o)uche] cool..... bloodjournal.org >> Topical ruxolitinib, unlike corticosteroids, ...

scaram(o)uche — 5/4/2018 11:22:37 AM

cool..... bloodjournal.org

>> Topical ruxolitinib, unlike corticosteroids, protects Lgr5+ skin stem cells and maintains skin homeostasis in skin GVHD <<

(pointer from Oscar Lahoud)

[scaram(o)uche] OT, again >> Look at the daily chart for qure and once versus that for sgmo << ...

scaram(o)uche — 4/24/2018 4:45:02 PM

OT, again

>> Look at the daily chart for qure and once versus that for sgmo <<

And sgmo goes for $200m offering of common. Guess that could explain why it's come back so hard, BAML, J.P. Morgan and Cowen lubed. Strange time to get greedy. In the last month..... qure up 20%, once up 12%, sgmo down 21%.

There HAS to be perspective out there that I don't have. Anybody????? TIA.

[scaram(o)uche] >> now playing with gains << Cool. House money, nothing feels better. My port...

scaram(o)uche — 4/24/2018 3:14:03 PM

>> now playing with gains <<

Cool. House money, nothing feels better.

My portfolio has been hit HARD, post-epa. Could imagine a few shareholders bumping into margin issues. Loaded up at 3.90, praying seller is finished.

[Miljenko Zuanic] RE:VKTX "force selling"---> it may be!? Secondary @5 was OK, nothing change,...s...

Miljenko Zuanic — 4/24/2018 3:06:54 PM

RE:VKTX
"force selling"---> it may be!? Secondary @5 was OK, nothing change,...so, I have no idea what is going on?

Data in p2 may be bit late (many sites opt to discontinue), the Qs are would it perform? I hope. As I mentioned early, I recover initial investment, now playing with gains.

[scaram(o)uche] So you bought after the disaster, and believe Epa still lives? Interesting, hop...

scaram(o)uche — 4/24/2018 2:45:27 PM

So you bought after the disaster, and believe Epa still lives? Interesting, hope it works for you.

I haven't owned shares for ages. I had no interest in a "universal lever on the immune response", believing that a non-specific lean on Tregs and dendritic cells wouldn't deliver. There are many agents that just gently nudge the balance between effectors and Tregs, still don't understand why IDO became the realm to bet on.

Disaster in I/O space doesn't hold water, my view. Why IDO's issues float into TLR9, sting or GITR (etc.) space escapes me. Wishing you luck, as any success would lead to rather pronounced profit.

off topic.... forced selling in VKTX?

[Miljenko Zuanic] Because of the good safety, I would bump dose to 300mg/day and continue to combi...

Miljenko Zuanic — 4/24/2018 1:52:41 PM

Because of the good safety, I would bump dose to 300mg/day and continue to combine with anti-PD1 (overall IO), and add selected chemo (selected to cancer type). Head & Neck, maybe CRC and Ovarian, Nivo still may be good choice!??

Combination with vaccines, but delivered intra-tumoral.
ASCO may bring some more p2-chombo data from ECHO-204!

[tuck] believe that Epa is not dead Which remaining combos(s) are of interest? Edit: T...

tuck — 4/24/2018 1:11:12 PM

believe that Epa is not dead

Which remaining combos(s) are of interest?

Edit: This P1 with a surviving vaccine looks interesting, and reads out in the next few months.

Study of DPX-Survivac Vaccine Therapy and Epacadostat in Patients With Recurrent Ovarian Cancer

Partial rationale: Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients

TIA & Cheers, Tuck

[Miljenko Zuanic] They (reviewers) had...

Miljenko Zuanic — 4/24/2018 12:30:53 PM

<How could any FDA be more liberal than the Gottlieb FDA?>

They (reviewers) had a chance to change how they should review revised application, but they did not. They kept old (from CRL) format focusing on 4 mg safety, not overall modality of approval, that LLY asked. 2 mg for overall population, refractory/failed methox, and bumping to 4mg for those who need MORE. FDA had a chance to dictate scope of discussion, but they did not!

That is my problem with FDA. I do not favor/disfavor with their decision, but how they come to conclusion is "problematic"!

I own INCY (after 301 fiasko, believe that Epa is not dead), and Bidi does not make thing any easy.

[scaram(o)uche] >> Hope NEW FDA will be more open for suggestions!!? << How could any FDA be mo...

scaram(o)uche — 4/24/2018 12:02:24 PM

>> Hope NEW FDA will be more open for suggestions!!? <<

How could any FDA be more liberal than the Gottlieb FDA?

You'd like 4 mg. approved, with black box? OK, my view.

[Miljenko Zuanic] Not clear is it JAK2 related, not related to platelets count (which actually dec...

Miljenko Zuanic — 4/24/2018 11:56:50 AM

Not clear is it JAK2 related, not related to platelets count (which actually decrease, not increase), so search for an answer not condemn drug in start. No trial can be executed to CONFIRM safety signal (not ETHICAL). So, THE ONLY WAY is REAL LIFE EXPERIENCE (controlled with BOX warning and proper management). Hope NEW FDA will be more open for suggestions!!??

Approval without option to increase dose, IF needed, is worthless.
Some panel members had open mind, but they were in minority.

[scaram(o)uche] Therapeutic window!! Large enough that a panel of FDA-deemed experts said yes! ...

scaram(o)uche — 4/24/2018 11:18:53 AM

Therapeutic window!! Large enough that a panel of FDA-deemed experts said yes!

;-(

[Miljenko Zuanic] Never hear so much (and so many) incompetent panels of RA "experts"! They do no...

Miljenko Zuanic — 4/23/2018 5:50:35 PM

Never hear so much (and so many) incompetent panels of RA "experts"!

They do not know what they voted and for what they voted?

[tuck] Now the FDA AdCom vote. Two doses. 10-5 in favor of 2mg, and 10-5 against the ...

tuck — 4/23/2018 5:03:16 PM

Now the FDA AdCom vote. Two doses. 10-5 in favor of 2mg, and 10-5 against the 4mg on the risk-benefit metric. If approved, can the 2 mg dose make commercial inroads on competing products from PFE and ABBV?

Cheers, Tuck

[Miljenko Zuanic] OT: ONCE benefited the most! EOM

Miljenko Zuanic — 4/10/2018 2:12:31 PM

[scaram(o)uche] Ah, OK. Thought the big move was all avxs sentiment. Thanks!

scaram(o)uche — 4/10/2018 2:02:14 PM

[Miljenko Zuanic] Seems that AAV5 ( AMT-061) has lower pre-existing mAbs titar! They are going str...

Miljenko Zuanic — 4/9/2018 8:31:22 PM

Seems that AAV5 ( AMT-061) has lower pre-existing mAbs titar! They are going strait with dose of 2 x 10^13 gc/kg: clinicaltrials.gov

[scaram(o)uche] OT >> OT: Nice move in QURE, too! << Look at the daily chart for qure and once...

scaram(o)uche — 4/9/2018 3:32:04 PM

OT

>> OT: Nice move in QURE, too! <<

Look at the daily chart for qure and once versus that for sgmo. Edit et al. having trouble due to fear over pre-existing antibody?

[scaram(o)uche] RA.... I still do not understand the fast turnaround from the baricitinib CRL...

scaram(o)uche — 4/9/2018 2:09:26 PM

RA.... I still do not understand the fast turnaround from the baricitinib CRL. Guess all will be clear on the 23rd.

[Miljenko Zuanic] Indeed, strong data for JAK1 Upadacitinib. Competition for GLPG/GILD too. Two ...

Miljenko Zuanic — 4/9/2018 10:55:00 AM

Indeed, strong data for JAK1 Upadacitinib. Competition for GLPG/GILD too. Two Qs, are Humira response numbers bit on low side and why MACE/Death is pronounced in Humira/placebo? Bit biased in randomization, baseline unbalance?

OT: Nice move in QURE, too!

[tuck] AbbVie scores a clinical win with its JAK1 inhibitor in RA. Not good news for I...

tuck — 4/9/2018 9:54:52 AM

AbbVie scores a clinical win with its JAK1 inhibitor in RA. Not good news for INCY, competition is stiffening:

Upadacitinib beats Humira in P3

Cheers, Tuck

[scaram(o)uche] >> How big is this limb we're on?? << Twig.

scaram(o)uche — 4/6/2018 1:14:24 PM

[Miljenko Zuanic] Well, regards the in-house combination, ...they are main sponsor and they let Ke...

Miljenko Zuanic — 1/23/2018 8:45:57 PM

Well, regards the in-house combination, ...they are main sponsor and they let Keytruda be in up-front position:

clinicaltrials.gov

Sometimes, I think what is wrong with them????

[scaram(o)uche] downstream = wrong word

scaram(o)uche — 1/9/2018 5:07:04 PM

[DewDiligence_on_SI] You're not the only one who's talking about a PFE-BMY hookup :- )

DewDiligence_on_SI — 1/9/2018 3:46:26 PM

[Miljenko Zuanic] Indeed, P2 Epa-PD1 chombo data v PD1 mono (multiple indications) are very stron...

Miljenko Zuanic — 1/9/2018 3:42:07 PM

Indeed, P2 Epa-PD1 chombo data v PD1 mono (multiple indications) are very strong, still Mr. Market expect much translating P2 data to P3. That was INCY position. If they do not believe in chombo they will never license MGA012 (let MRK and BMY promote "marginal" IDO1 data), or for any other in-house combination. They know that they can not depend on partners if they want full and fair benefit from their own drugs, Epa included.

[scaram(o)uche] These findings are important translationally, because they suggest broader clini...

scaram(o)uche — 1/9/2018 3:29:40 PM

These findings are important translationally, because they suggest broader clinical uses for D-1MT against cancers that overexpress any tryptophan catabolic enzyme (IDO1, IDO2 or TDO).

ncbi.nlm.nih.gov

>> does suggest one would make a mistake by extrapolating heavily based on the indoximod data <<

Yeah, but a mistake in which direction?? Isn't downstream inhibition of IDO1, IDO2 and TDO better than IDO1 alone??

The Incyte rationale for IOD1 selective agents is given here, third paragraph.....

ncbi.nlm.nih.gov

So they would say "no".

[scaram(o)uche] >> At JPM, INCY was cautious on IDO1 << With all of the commentary about durati...

scaram(o)uche — 1/9/2018 2:47:15 PM

>> At JPM, INCY was cautious on IDO1 <<

With all of the commentary about duration and deepening of the response, and with the slide showing data vs. historical for PD-1 alone? Emphasizing that nivo/epa results were as strong as pembro/epa? I got the opposite feel, that they were very strong re. IDO1.

[Miljenko Zuanic] At JPM, INCY was cautious on IDO1, so...PFE exiting IDO-target may (after hearin...

Miljenko Zuanic — 1/9/2018 1:59:18 PM

At JPM, INCY was cautious on IDO1, so...PFE exiting IDO-target may (after hearing their and BMY presentation) sound as diversification from BMY-overlapping programs. IF PFE can afford (at least) 40% premium to current BMY MC, they would go after it.

Sorry to pollute INCY tread with PFE/BMY thoughts!

[scaram(o)uche] Celgene buying fedratinib for what????? PGS and friends discussing it at twitte...

scaram(o)uche — 1/7/2018 7:32:20 PM

Celgene buying fedratinib for what?????

PGS and friends discussing it at twitter, no need to digest here. "Incremental" has become CELG-important, a shame.

[Miljenko Zuanic] Thanks, we agree Indo is not an INDO-1 inhibitor.
Miljenko Zuanic — 1/4/2018 7:13:53 PM
Thanks, we agree Indo is not an INDO-1 inhibitor.

<Thus, indoximod acts as a high-potency tryptophan mimetic in reversing mTORC1 inhibition and the accompanying autophagy that is induced by tryptophan depletion in cells.>

Can this explain synergy with IO path and added activity, seen for other INDO-1 inhibitor? Should re-activation of the mTORC1 bring "survival" benefit to cancer cells?

[former_pgs] I don't really understand the PFE decision. Based on IDO's role, it's not expect...

former_pgs — 1/4/2018 2:39:23 PM

I don't really understand the PFE decision. Based on IDO's role, it's not expected to have single agent activity, so it's bizarre to see them drop this drug after <20 patients and without even trying a combo. Regardless of whether or not IDO is a good target, I don't think this trial is an indictment as it seems strangely limited in scope. PFE clearly got spooked by something. My suspicion is given their trailing status, they had a very high internal bar for what this drug had to do to make it seem worthwhile.

>I was sceptical about Inoximod MOA early and still am<

A couple of excerpts below from a recent review paper. I'm relatively convinced that indoximod is not an IDO inhibitor. This doesn't validate the IDO inhibitors out there, but does suggest one would make a mistake by extrapolating heavily based on the indoximod data.

"By far, the IDO probe most employed in the preclinical liter- ature is the simple racemic compound 1-methyl-D,L-tryptophan (1MT) with a reported Ki for IDO1 of 34 mmol/L (65, 66). The L isomer acts as a weak substrate for IDO1 and is ascribed the weak inhibitory activity observed with the racemate, as the D isomer neither binds nor inhibits the purified IDO1 enzyme (4)." - note, indoximod is the D isomer of 1MT

"A number of studies have addressed the mechanism of action of indoximod. However, in considering an evaluation of human pharmacokinetics where clinical responses have been noted (69), only one study has provided an explanative mechanism consis- tent with blood serum levels achieved in clinical trials (70). Specifically, this study revealed that indoximod can resuscitate cellular mTORC1 activity inhibited by tryptophan depletion with an IC50 of approximately 70 nmol/L (70). Thus, indoximod acts as a high-potency tryptophan mimetic in reversing mTORC1 inhibition and the accompanying autophagy that is induced by tryptophan depletion in cells."

[Miljenko Zuanic] I do not think that it is kynurenine level (as biomarker) that describe path for...

Miljenko Zuanic — 1/4/2018 1:08:22 PM

I do not think that it is kynurenine level (as biomarker) that describe path for cancer IDO-1 activity, it was biopsy of resected brain tumors. So, my guess is that regardless long t1/2 and high dose (in addition to preclinical model), PFE candidate did not penetrate tymor mass...results was inactivity.
In general, this guy from SA favorise NLNK Inoximod:

seekingalpha.com

but, I was sceptical about Inoximod MOA early and still am. Wish, PGS can stop by and drop few words on topic (I do not like conversation @ twitter).

PS: IF INCY drop further (due to luck of data at JPM), I am considering position.

[tuck] The main differentiating characteristic of the iTeos compound was its penetratio...

tuck — 1/4/2018 12:30:27 PM

The main differentiating characteristic of the iTeos compound was its penetration into the brain. Unfortunately, IDO apparently isn't really a good target for brain tumors per this guy:

TDO better target

iTeos talks of a TDO2 program, but nothing shows in their pipeline about it.

Cheers, Tuck