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SELB KOL call today on Slightshot Insights at 11:30am PST, join project, ask questions, should be informative!
https://slingshotinsights.com/projects/486
I'm back in $KURA with large position.
Diligence deck here with thesis: "Successfully Targeting RAS: Kura Oncology" http://bit.ly/2ogK4NH
$KURA Call with CEO Troy Wilson Thursday, let me know if you have questions!
KURA Cancer Type of 3 Other Patients?
Anyone ask IR what the cancer type of the other 3 evaluable patients is? I got no response, I'm guessing some bladder?
MCRB p2 failure analysis
Wow this one I was thinking >50% success with p1 data=97% (29/30) prevention of CDI recurrence and read through from OpenBiome's FMT success.
I was previously invested neat $1B but at $1.4B mc I thought limited upside with large downside and closed my position. Seems like I got the large downside correct.
Data: "CDI recurrence occurred in 44% of subjects (26 of 59) who received SER-109, compared to 53% of subjects (16 of 30) who received placebo."
The placebo group looks about right, for patents with 3 or more recent recurrences I had ~60% recurrent rate, they got 53%, which gave them an even better chance at showing a difference.
The treatment arm of recurrence 44% (26/59) is super bad (56% prevention of recurrence), especially compared to the p1 data of 97%. I think trial designs were similar enough, what went wrong? Some would say open label p1 with n=30 pts could also have something to do with it, although OpenBiome's success is around 90%. My guess would be since they were sourcing their product from a few donors, maybe something changed with those donors microbiome.
Drug appears safe.
Their treatment was similar in groups of <65 and >65, but older patient reoccur more on placebo, 90% vs. 27%.
It is good they are working on making their own microbe mix so they don't have to deal with donor variability, but making the mix has been difficult. Good one to keep an eye on trading near cash but not jumping in yet.
ADRO Pancreatic Phase 2b Analysis GVAX+CRS-207
Check out my diligence, feedback appreciated!
Accessing Aduro's Imminent Phase 2b Pancreatic Cancer Data
http://seekingalpha.com/article/3958255-accessing-aduros-imminent-phase-2b-pancreatic-cancer-data
But webcast is Dec 8th, poster isn't until Dec 11th. The data will be released at the webcast and not the conference. This order isn't odd to you?
$ONTY data webcast BEFORE #SABCS15
Is it common for good data to be presented before a conference? Does it mean anything? Could it mean they need to "explain" the data? Or such a technical reason?
#ASH15 What does "Program: Oral and Poster Abstracts" mean?
$BLCM time looks like poster, but do they have oral too?
https://ash.confex.com/ash/2015/webprogram/Paper85451.html
Thanks!
CF-301 Ideal Human Target Dose is 0.2mg/kg
Does this seem right?
No observable effect level (“NOEL”) = 2.5mg/kg in mouse
Phase 1 starting dose 10-fold below NOEL, so 0.25mg/kg
Based on preclinical mouse data
0.25mg/kg = Minimal efficacy
0.5 mg/kg = Good efficacy
2.5 mg/kg = Maximal efficacy
Convert mouse dose to human dose using FDA guidelines: multiply mouse dose by 0.08
Starting Dose: Should be safe, may have some efficacy: 0.25 mg/kg mouse = 0.02mg/kg human
CF-301 Ideal Human Target Dose: 2.5 mg/kg mouse (Maximal efficacy) = 0.2mg/kg human
TKAI rPFA from p2 with AR-V7?
TKAI Does anyone know when they will release rPFS from p2 with AR-V7 patients? I want to believe but...
XNCR R&D Day Notes
Welcome and Introductory Remarks
Bassil I. Dahiyat, Ph.D.
President and Chief Executive Officer, Director
XmAb5871 (CD19xCD3 ,FcgRIIb-B-cell inhibitory, >400 interaction with Fc)
--Complete Phase 1b/2a rheumatoid arthritis data from EULAR 2015
--Additional details on planned pilot study in IgG4-Related Disease
--Dr. Stone’s presentation on the history, emerging understanding of the pathogenesis and potential for treatment of IgG4-RD
XmAb7195 (IgExCD3)
--Interim Phase 1a data from healthy subjects
--Commenced multi-dose (2 infusions) part of Phase 1a trial of examining IgE reduction and safety profile, prime with small dose, then dose escalation
--Study with subcutaneous formulation of XmAb7195 to begin in 2016, slower antibody delivery, might improve AE profile
XmAb13676 (CD20xCD3)
--Bispecific clinical candidate for development in B-cell malignancies
--Phase 1 2016, could partner more quickly, broad indications
Bispecifics
--Future include Tregs
--Others
2015 data announcements
--XmAb5871 Phase 2a in rheumatoid arthritis
--XmAb7195 Phase 1a topline IgE reduction and initial safety in healthy volunteers cohorts
Follow-on financing
--Net proceeds $115M @ $14.25/share
--Cash at 3/31/2015 $166.9 million, runway expected through 2019
Staff additions to enable growing development pipeline, speed research
--48 employees as of June 1
--VP in Regulatory Affairs and VP in Oncology recently added
XmAb5871 Overview
Mechanism
John R. Desjarlais, Ph.D.
Senior Vice President, Research and Chief Scientific Officer
Mechanism: XmAb5871 (CD19xCD3 ,FcgRIIb-B-cell inhibitory, >400 interaction with Fc)
--Good understanding
Development Program
Paul Foster, M.D.
Chief Medical Officer
--RA single ascending dose, Start Oct. 2011, complete Dec. 2012 0.03-10mg/kg, safety, PK, 48p 3:1, no SAEs, well tolerated at 10mg/kg, 22% IB infusion related GI symptoms, resolved after vomiting, all continued after 15-52min interruption, no symptoms after
--Circulating B-cells saturated. reduced in CD20+ B-cells nadir 40-50% at doses >0.1mg/kg, recovery after 10 days
-- [2b/2a RA, Start Jan 2013, complete Sept. 2014, every 14 days, 6 doses, p1b 0.3, 1, 3, 10, p2a 10mg/kg, 56p, 3 withdrew due to AEs at 10mg/kg, 2 SAEs, infusion reaction hypotension/venous thrombosis, other AEs moderate
-- DAS28-CRP Score: Remission 20% vs 0%, Low 13.3% vs 0%, ACR hybrid score, also effective, over time
--Encouraging data, refocus on autoimmune diseases, more unmet medical need, IgG4-Related Diseases, no approved therapy (corticosteriods used), subq p1 start 2016
--IG4-Related Disease, Dr. Stone IgG4-RD Responder Index, 10-20k patients, p2, multiple dose, 15p, 5mg/kg every 14 days for 12 doses
IgG4-Related Disease: Autoimmunity and Unmet Need
John H. Stone, M.D., Ph.D.
Professor of Medicine, Harvard Medical School
Director, Clinical Rheumatology, Massachusetts General Hospital
--Jon Stone #1 KOL, published papers/lead trials with rituximab in IgG4-Related Disease, it’s great they got him on their side, knows how to do trials, is he running XmAb5871 trials?
--Hard to diagnosis, “sclerosing pancreatitis” high serum IgG4 concentration, “crow flying through the dark night”, can affect every organ system in the body, but pathology is the same, don’t fully understand, submandibular gland looks like lymphoma,
--During B-cell maturation, somatic mutation, IgG4 plasma cells, 200 patients now, explains many different patients, pathology, “sclerosing cholangitis”, IgG4 IHC
--Glucocorticoid treatment (prednisone), 15% don’t respond, ~82% remission then flare off, only 3% stable
--Patients treated with rituximab (anti-CD20), remission, serum IgG4 1,560mg/dL 2 months treatment 390, another patient IgG4 1140 to 31, another women with skin disease also responded, elevation/decline is IgG4 specific, not others
--Short “lived-plasmablasts” power IgG4-RD, increase, CD19loCD20-CD38+CD27+, circulating plasmablast have undergone extensive somatic hypermutation
--Rituximab inhibits CD20+ B-cell precursor, created IgG4-RD responder index, rituximab trial, responses very good but only 8/19 normalized completely even though, T-cells also depleted
--Rapidly emerging disease, underdiagnosed, IgG4 important in clinical assessment, not central player, plasmablasts useful biomarker, XmAb5871 should disrupt plasmablast
Q&A
--No read through from RA trial for information on depleting plasmablasts
--Broad in inclusion criteria, not organ based
--Biopsy best way to diagnose, exclude malignancy (cancer), plasmablast biomarker from blood also future
--Multiorgan disease, higher IgG4 in serum, they need more B-cell depletion, patients can respond and still have elevated serum IgG4, those patients are likely to flare again, 3 major determinant, elevated serum IgG4, IgE, peripheral eosinophilia,
--No current p3 trial with Rituximab, Genentech isn’t going to develop further, Rituximab off patent, Dr. Love’s p1 trial: Rituximab in IgG4-related Disease: A Phase 1-2 Trial
XmAb7195 (anti-CD19, FycRIIb) Overview
Mechanism
John R. Desjarlais, Ph.D.
Senior Vice President, Research and Chief Scientific Officer
--1. Binds IgE and blocks IgE binding to mast cells 2. Enhanced Fc domain inhibits B-cell differentiation to IgE producing plasma cells 3. Send IgE to liver for destruction (liver sinusoidal endothelial cells, express FcyRIIb as scavenger receptor (good preclinical data for all)
--Measure both total (is IgE being produced?) and free IgE (gE not bound)
--Chimps high IgE, total IgE goes up with Xolair, bind IgE, binds and extend half-life of IgE, XmAb7195 drops IgE, below 0.2ug/ml LLQ, Xolar drops to 50ng/ml not efficacious, XmAb7195 <4ng/ml (single digit needed), single 5mg/kg dose
Development Program
Paul Foster, M.D.
Chief Medical Officer
--p1 started May 2014, 2 parts, part 1 single dose, 0.3-10mg/kg, part 1 elevated IgE, 40p 3:1
--Transient asymptomatic thrombocytopenia at 3mg/kg, reduced to 0.75mg/kg, urticaria 23% (7/30), start, treated with oral antihistamines, infusions continued, platelets express FcRIIa, could be activated
--Reduced 90% (26/29) serum IgE below limit of detection 10ng/mL, reduced 87% (26/30) total IgE <2.0IU/mL below limit of detection, dose dependent, 2 had igh IgE high, both reduced below limit, part 2 ongoing, blinded (should be positive), amended protocol for 2nd dose in healthy cohorts, priming dose, and ascending 2nd dose 1wk later, small priming dose might reduce AEs,data 1H16, further development on subq formulation in 2016, might also have safety advantages (why continue testing IV Part 3 if going into subq anyway?)
XmAb Bispecific Platform and Oncology Pipeline Overview
John R. Desjarlais, Ph.D.
Senior Vice President, Research and Chief Scientific Officer
--BiTe/DART short half-life, simple and efficient manufacturing, major challenges, their manufacturing like normal antibody 1-3 g/L, stable, pure
--Reuse anti-CD3 arm, optimized, plug in new Fab domain, CD123, CD20, CD38, robust killing and half-life ~1wk, rapid production and testing preclinically, CD123 and CD20 advancing
--CD123 expressed on leukemic blast cells and stem cells, more CD123 = poor prognosis, single dose effect ~1wk, 100L volume, 2.7g/L, standard 3-step purification process
--Expand CD3 platform with potency tuning, cytokine release syndrome (CRS) (IL-6), tested CD20 affinity antibodies, choose lower affinity, dose 10x higher without CRS, also antigen sink, also modulate CD3 affinity, different thresholds for cytotoxicity and T cell activation
--Checkpoint targeting, checkpoint bispecifics, anti-PD1 + TIM-3, CTLA4, LAG-3, etc. T-cells often express multiple, more specific, Pricing and convenience over dosing two drugs together
--Treg targeting, no specific Treg marker, target multiple surface receptors to enhance specificity
--They think CD-20 is still more important, tone potency, CD20 therapies clinical successful (reason for not going after CD19)
--Reneron also anti-CD3xCD20
Reprogramming T Cells for Cancer Therapy
Guest Speaker Tyler Curiel, M.D., M.P.H.
Skinner Chair in Cancer Immunotherapy, Professor of Medicine,
University of Texas Health Sciences Center San Antonio Cancer Therapy and Research Center
Team Leader, Phase 1 Clinical Trials
--Cancer patients develop cancer specific T-cells, but can’t function, tumor microenvironment, dysfunction APCs, suppress anti-tumor immune response, CD25+ (Treg), high affinity IL-2 receptor, preclinical deplete improves immunity, more Treg in ovarian cancer, the faster you die, true across most cancers, Tregs in humans inhibiting existing immune response
--Phase 1 trial, high affinity IL-2 with denileukin diftitox, kill Tregs, stage IV metastatic ovarian cancer patient depleted Tregs, IFN-y increases ~2.5x increase in CD8+IFN-y+, cancer went away except for 1 cancer, immune escape single agent, allows for mutations, more trials ovarian, renal, melanoma, clinical results but not cures across all
--Phase 2 ovarian, denileukin diftitox (DT) alone failed, alone is building block, not going to cure
--IL-2 with DT should also kill IL-2 receptor CTLs, “just doesn't”, but give drug too often can kill CTLs, designed careful phase 2 dosing
--Anti-CD25 antibody should also work to deplete Tregs, different off target effects, different against Treg subtypes, anti-CD15 antibody better, DT not optimal
--Ant-CTLA-4, combos with others expensive ($85k, $250k for both), AEs
--CAR-T don’t work well in solid tumors, rapid depletion, don’t traffic into solid tumors wel, exhaustion
--Interferon-A improves DT response in some patients, Treg depletion + checkpoint blockade works in mice
--Attributes of effective cancer immunotherapy: #3 Adequate tumor penetration as needed, Generate/augment tumor-specific immunity, #1 Generate antigen-specific immune memory, #2 Mitigate local immune dysfunction (exhaustion), Improve tumor immune
Thanks! I should use Nasdaq more.
Thanks, Link?
C. diff Microbiome Treatment Seres Health (MCRB) IPOing Friday, oral, validated by FMT, BTD, management from Merck, clinical cure rate 97% 29/30 in phase 1b/2, phase 2 data mid-2016, ~$700M mc, anyone following?
LOXO RXDX NTKR Risks/Discussion
Risks
1. NTRK not driver oncogene, inhibiting NTRK won’t have efficacy (low)
Preclinical NTRK models, mutually exclusive with other oncogenes
Entrectinib Sept. 2014, 1/1 PR in CRC, ESMO Poster
Entrectinib June 2015, 3/3 PRs in Acinic Cell, CRC, and NSCLC
LOXO-101 sarcoma NTRK patient, response TBA
2. LOXO-101 not safe, not efficacious (low)
April 2015 100mg BID safe, great PK
3. LOXO will have trouble recruiting NTRK patients (~1%) with other ongoing NTRK trials (Ignyta’s Entrectinib) (high)
LOXO-101 p2 expected to start 2H15
Entrectinib p2 expected to start 2H15
4. LOXO-101 will not be superior with AEs and/or responses compared to Entrectinib (medium)
LOXO-101 is more specific, but PRs with Entrectinib, so may not matter
Thoughts?
Great ONTY-380 analysis iwfal!
I think every agrees it is far from a slam dunk, but valuation matters and phase 1 data provides enough rational for phase 2.
Grade 3/4 across all doses:
Table heading says "Patients with treatment-emergent AEs" then "Any grade 3/4, 25/37 = 67.6%".
Are these just not very severe and nothing to worry about?
Ok, safety then:
At 10mg/kg:
Any grade 3/4 AE: 66%
Any AE leading discontinuation: 66%
Isn't that bad?
Low ORR, ~50% had disease progression, disagree?
JQ:
"As of no ORR, what can I say? Do people read carefully before they write? The study included mostly patients who had experienced CR/PR by previous treatments!"
Poster
"Eighteen patients (49%) discontinued the study prematurely including 13 because of disease progression, 3 for AE’s and 2 for other reasons. This trial was not designed to detect antitumor as many patients were still responding to prior therapy at study entry"
My CNAT ACLF Phase 2b Takeaways
My Takeaways from emricasan acute-on-chronic liver failure (ACLF) p2b data Jan. 8, 2015
1. ACLF was the wrong lead indication and will not be advanced
- Patients very sick, difficult to follow up (expected 60 patients, only got 21, by day 14 only 12 patient left on study)
- In these highly cirrhotic patients emricasan bypasses liver and goes to blood (BAD)
- 25mg BID did NOT sustain decreased biomarkers (cCK18), 50mg DID
- 25mg BID: Day 2/4/7 = 44%/30%/6%
- 50mg BID: Day 2/4/7 = 54%/56%/50% (Sustained? Why not follow to day 14?)
- 25mg BID expected to be sufficient in other trials where patients have less cirrhosis
- Clinical benefit is unclear because small patient numbers and some recover on their own
- Placebo: 2/4 (50%)
- Emricasan 50mg: BID: 3/5 (60%)
2. Additional biomarker data supports mechanism of action of emricasan for other indications
- >30% reduction in cCK18 at 8 hour post called “responders” and most patients who achieved clinical benefit (including placebo) were “responders” (don’t show actual data?)
- Dose dependent decrease in cCK18 and flCK18 at day 2/4/7 for 25mg and 50mg (no statistics?)
- Other patient populations which could still benefit from emricasan
- Nonalcoholic fatty liver disease/Nonalcoholic steatohepatitis( NAFLS/NASH): p2 1Q15
- Post Liver Transplant HCV Clearance with Unresolved Fibrosis (POLT-HCV-SVR): p2b 1H15
- Portal Hypertension (PH): p2 3Q15
- Liver Cirrhosis (LC): p2 2H15
Are NDRM bulls worried about IPLX Rytary?
Oral L-DOPA which reduces off-time, FDA NDA decision Jan. 9, 2015
It was just published today on BioPortfolio today for some reason, guess they are about 5 years slow.
http://www.bioportfolio.com/resources/pmarticle/74561/Anti-CD47-Antibody-Synergizes-with-Rituximab-to-Promote-Phagocytosis-and-Eradicate-Non.html
$ACAD Negative Adcom?
How likely do you think a negative Adcom is? Not all doctors think pima's development is done, Dr. Susan H Fox, http://bit.ly/1xyvZHU
"Further studies will be needed to determine relative efficacy of pimavanserin and clozapine or quetiapine. The ability of a drug to show significance in all endpoints in a Parkinson’s disease trial is unusual, and might reflect the relatively short period of the study (6 weeks) and the fluctuating nature of psychosis."
Thanks for the info! Abiraterone has about the same fatigue though right?
Enza Fatigue
All grades 36% (placebo 26%)
Grade 3/4, 2% (placebo 2%)
Abi Fatigue
All grades 40% (prednisone 35%)
Grade 3/4, 2% (predmosone 2%)
Enzalutamide in Metastatic Prostate Cancer before Chemotherapy (PREVAIL June 2014)
Updated Interim Efficacy Analysis and Long-term Safety of Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Without Prior Chemotherapy (COU-AA-302) March 2014
Thanks a lot!
Is it possible that the data is just so-so because if it was outstanding they would be in the official press program and/or have an oral slot?
When is MDVN ezna TNBC data available?
Day conference starts (12/9) or day poster is presented (12/12)?
CBR >30% would be nice
Dew, $ILMN threat to $FMI?
Potential threat? Why or why not?
Reflecting on ARWR Developments
Listened to the call, looked over the data again, and re-read the letter to shareholders. Here is the main issues and a summary of important information.
1. Do we believe the "steepness" of the dose response curve? They really stressed this point on the call, but then data shows 1mg/kg = 31% peak KD and 2mg/kg = 51% peak KD. Double the dose and do not double the KD, as they suggest during the call. But if they are really only in the middle of the curve with 2mg/kg then 3mg/kg should be much better, they think it will be good, but of course they do, they are management. Will they get 50%, 60%, 70%, 80%, 90% KD? <70% would probably be bad, >70% would probably be good?
COO
"We think that we are right around the middle of the ascending part of dose response curve at the 2 mg per kg dose."
"I mean, the one thing that we can say is that with all of our RNAi programs across mice, rats, primates, the one thing that we have consistently seen is the various deep dose response curve."
"In all of our animal species studied so far, the dose response curve for DPC assisted RNAi triggers has been steep. Assuming this holds for humans, and we think it will, the 3 mg/kg dose is likely to give deep knockdown. "
"Frankly, having been in the industry a long time, these are the steepest dose response curve I’ve ever seen. And I think it just has to do with the catalytic nature of risk and how the process works. But from my perspective, if in human, it is similarly steep then I think we’re going to be in good shape at 3mgs/kg"
"But if we are as steep as we’ve seen in primates and other species, the chances are pretty good that 3mgs/kg gives us what we have been looking for."
CEO
"We see substantial opportunity to demonstrate deep knockdown because of the steep dose response curve observed in non-human primates." (Is this true!!??)
"We now have unblinded Phase 1 safety data in healthy volunteers through 4 mg/kg and we continue to see a favorable safety profile: no dose-limiting toxicities or adverse events rated serious or severe."
"(3mg/kg) We believe we’ll have it during AASLD. Now we are hopeful that we will able to apply for a late breaker presentation and present it at AASLD. And so if that should work out then we hope to present it at AASLD. If not, at least, we feel pretty good that the data will come out around that time."
A. Promotional language/blinded data speculation
Not a fan of the promotional language, also related to management speculating about blinded data, obviously feeling the pressure from Wall Street. Easier to see how a huge miscommunication could occur and drop the stock 50% when data was actually decent. They learned the hard way to manage investor expectations, hopefully they learned.
"Our interim results have been extremely exciting". "The fiscal third quarter and recent period have been exciting and productive times for Arrowhead. We continue to push forward rapidly with our product development and pipeline expansion goals". We have generated impressive data sets in animal models and are moving quickly toward the clinic.Overall, we continue to demonstrate rapid and effective execution of our product development programs and we have clearly made great strides in the recent period. Our clinical data are tracking our field-leading non-clinical data, and I believe we are increasing our first mover advantage in HBV. Similarly, we are well positioned as leaders in liver disease associated with AATD and I expect that advantage to continue. We have begun a very exciting phase, characterized by the transition from a science-based company that is full of promise to a drug company providing real benefits to patients. Until now, we have demonstrated exciting data in animal models – some of the most dramatic in the field.
This speculation of blinding data is kind of reckless, although it looks like they were right. Don't support his type of behavior.
"While the trial is still blinded, we have been able to review anonymized profiles for individual surface antigen levels. The 1mg/kg dose showed clear activity at a modest level."
B. Safety
Since everyone is freaking out over dose, safety is really what matters, and it looks good. 3mg/kg has already started and they might need to go to 4mg/kg.
"That study was designed to assess doses up to 2 mg/kg and was reported at the end of last year to show no premature discontinuations, no serious adverse events, similar rate and severity of mild or moderate adverse events for placebo and ARC-520 subjects and no laboratory or other safety parameters looking to us or the investigator like end-organ toxicity. We did note a flushing reaction at 0.6 mg/kg and an urticarial rash at 2 mg/kg, both in ARC-520 treated patients. Those seemed like histamine related events to us so we repeated the 2mg/kg dose, but with pre-treatment with an over the counter oral anti-histamine.This dose cohort also went smoothly and no skin-related AEs were observed."
"As in the normal volunteers, the treatment has been well tolerated. There have been no dropouts, and no serious adverse events. The overall rate of AEs has been even lower than in the normal volunteers and nothing out of the ordinary has occurred. Safety labs continue to lack indication of end organ toxicity. These patients also received oral over the counter anti-histamine and no skin reactions have occurred."
"This dose also performed well, without detected differences from safety and tolerability results at the other doses. Overall AEs do not appear to be increasing in frequency or severity with dose."
C. Future Combo Trials
Seems like they are preparing well for the future, 4Q14 combo treatments with current SoC. Think the entecavir /tenofovir doses will be 3 and 4? Then immune simulatory combos, thinking ahead, good.
"We think these data bode well for our upcoming Phase 2b studies, which I want to talk about briefly. Our current plan is to initiate a study in the fourth quarter that
will test two dose levels in e-antigen negative and e-antigen positive patients on entecavir or tenofovir. It will be multi-dose, placebo controlled study conducted in
the United States, Western Europe, and Asia with a long-term extension. Our primary endpoint in the extension will be achieving a functional cure in patients,
characterized by s-antigen clearance with or without seroconversion. We consider these our core or anchor Phase 2b studies. We also plan to initiate a number of
smaller exploratory studies in 2015 including various dosing regimens and studies of ARC-520 in combination with immune stimulatory agents. The core Phase 2b
and additional exploratory studies aim to provide us with a comprehensive understanding of ARC-520’s activity in a broad range of settings, and we believe will allow us to expand our leadership position in HBV."
"the Phase 2b core studies are designed to last 12 weeks and then patients will roll into an extension. And that extension will take patients out to somewhere around a year of therapy. We don’t know if the theory is correct that you need to derepress these patients by reducing surface energy. We don’t know how long -- how long therapy needs to be for that to work."
D. Duration
Unexpected and "good" news
"Given what we’ve already seen at 1 and 2 mg/kg, we would expect that knockdown to be prolonged well beyond 30 days and likely even longer than predicted by non-human primate models. This suggests that we will be able to explore dosing less frequent than once per month in the phase 2b."
E. Summary of Events
Some of our upcoming goals include the following:
• We will present additional clinical data on the Phase 2a study of ARC-520 around AASLD and additional nonclinical data on ARC-AAT through press release and at key scientific and medical meetings in the fourth quarter
• File in the fourth quarter to initiate first-in-man studies for ARC-AAT
• Also in the fourth quarter we plan to initiate the core Phase 2b studies of ARC-520
• Throughout 2015 we plan to initiate multiple pilot or exploratory clinical studies of ARC-520 to look at dosing schedules and combinations that may improve cure rates
• Also in 2015 we intend to nominate one or more additional clinical candidates, which we will talk more about in the future
"Our interim results have been extremely exciting. We completed dosing of 1 and 2 mg/kg in June and though the study is still blinded, several exciting conclusions may already be drawn. We are seeing clear knockdown in both groups and duration of that knockdown has been substantially longer than we expected. We currently have data from the 2mg/kg cohort as far out as 2 months after dosing, and in the patients we perceive as having received ARC-520 we still see substantial knockdown at this timepoint. Interestingly, some of those patients may have santigen levels that are still declining. Safety profiles in both groups were also at least as good as those seen in the Phase 1 study. Because of the favorable safety profiles in volunteers and patients and because we thought we could demonstrate even deeper knockdown, we decided to explore 3mg/kg in patients. We have begun dosing that cohort. We see substantial opportunity to demonstrate deep knockdown because of the steep dose-response curve observed in non-human primates. We also see limited downside risk at this dose because we completed 3mg/kg in healthy volunteers and that safety profile was quite positive, consistent with all other groups tested."
F. Importance of 1 log (90%) KD
"Let us begin with our goal. We have said for some time that our goal was to identify a dose of ARC-520 capable of achieving HBsAg reduction of around 1 log (corresponding with 90% knockdown) after a single administration. This was a somewhat arbitrary goal since it is unknown what level of HBsAg reduction is necessary to de-repress the immune system and potentially enable a functional cure. Indeed, the entire concept of enabling a functional cure by suppressing HBsAg release remains an untested theory, but that is one of the challenges of being a pioneer in the field. We chose 1 log as a goal because, according to the scientific literature, the small number of patients who achieve functional cure from Interferon therapy demonstrate ½ log reduction in HBsAg (approximately 70% knockdown) after 12 weeks and 1 log (90% knockdown) after 24 weeks. We expected that if ARC-520 is active it should lead to more rapid reduction, particularly on repeat dosing, so a full log might not be needed after a single administration. Even so, we believed that a 1 log goal is intellectually honest and we wanted to share our thinking publicly rather than establish an artificially low goal just so we could beat it."
"Sure, I’ll take a crack and I’ll hand it over to Bruce as well. Regarding our confidence level in achieving the log knockdown with 3 mgs/kg, we feel pretty good about that. What we saw in one 2 mgs/kg is that the depths of knockdown seems to track reasonably well with non-human primate models. But of course the durability of the fact is, it’s substantially longer. And so that that gives us -- that gives us good confidence that 3 mgs/kg will give us good deep knockdown.
But until we just don't know until we’re in-humans and the fact of the matter, this is the dose-binding study. And so from my perspective, I really don't care what the dose level is that gets us that that goal as long as we get there safely. And it looks like we have plenty of room in terms of safety. We haven't seen anything that that has been concerning any of the groups.
So if we need to go to 4mgs/kg, for instance, we think we have got plenty of room to do that. In fact, to ensure that we’ve got -- that we can do that in a timely fashion, we decided to go ahead and initiate a 4 mgs/kg group in healthy volunteers, which we may or may not use to move into 4mgs/kg in patients but it’s a good thing how we figured.
Regarding our confidence in achieving the functional cure that is the fill in the blank number of dollars question. We are for good or for bad pioneers in this field and we are doing something now. In fact, we have already done something now the world has never seen which has deep and sustained knockdown and consistent knockdown of s-antigen in humans. So that’s the first hurdle that we appear to be getting over right now.
And now we will be the testing the theory that are KOLs and frankly the vast majority of KOLs that we speak with believe to be true, which is, if you knockdown s-antigen, you can enable immune system to come back and clear the virus. We’ll see that. I suspect that we’ll start to, if in fact, this drug work as we all hope and expect it does, I expect that we could start to see some functional cures in 2015.
Sure. It’s good question. Thanks very much Alethia. We think that that is an aggressive bogie and it is not clear to what we actually need to reach that level of knockdown. Having said that we think that we can certainly get there so we’re more comfortable if we have it. The reason that we have, we have stuck to that bogie, is that the only thing that gives any kind of (indiscernible) semi reliable functional cures is interferon. After a year of interferon, about 10% of patients will reach a functional sure and all those patients who do get to that functional cure will see about half a log reduction in s-antigen in around 12 weeks and around one log after 24 weeks.
So it’s not clear that that we need to reach that full log, but we do know that if at least under interferon therapy, if patient does not see that, sort of, s- reduction then there is no chance they will get a functional cure. So that's why that feels like a safe zone for us.
Now we will be seeing reductions in s- that there are far more rapid that you see in the handful of time we see it within interferon. And so those difference in kinetics may suggest that that we don't need to get a full log. But again, because we can do it safely, we felt most comfortable making that our goal.
Having a -- half a log dose could do just as well as full log dose could do. And of course, it could always turnout that the s-antigen hypothesis is too simple and there’s something else needed as well.
But both of those groups are serious group, so those are both serious levels of knockdown. And keep n mind also that that’s based on what we see it as single dose. Under multiple-dose scenario, it’s entirely possible that there will be continuous step down on the surface antigen level as well."
G. Did management mislead?
ARWR DID NOT mislead with "similar"
"However, depth of knockdown appears to be similar in magnitude with what we see in non-human primates at the same doses, including the HBV infected chimpanzee presented at AASLD last year."
They got 51% KD (at lowest point-nadir) in human with single 2mg/kg dose (followed for 85 days). Chimp data with SINGLE 2mg/kg KD was 50% (only after 14 days though because 3mg/kg dose was given). 51% is SIMILAR to 50% people. The chimp data with 2mg/kg dose AND 3mg/kg dose had a >80% KD, which is closer to where expectations were for some reason, wrong comparison, do your diligence.
Thomas Wei's first question is perfect, expected 0.3 log KD or 0.7 log KD, management messes it up BAD. WHY WEREN'T THEY JUST CLEAR? Like they decide to be after the fact in the letter to shareholders below.
Thomas Wei - Jefferies
Thanks. Just wanted to clarify a couple of things that you've said. First, the language in the press release and what you've reiterated on the call about the magnitude of the knockdown being similar to the non-human primate studies. So I guess what I'm a little bit confused by is that in the non-human primate studies, you actually gave two doses, 2 mgs/kg and 3 mgs/kg on day 1 and Day 15.
So when you're talking about it being similar for the six patients at 2 mgs/kg, who you think are on drug, are you seeing something that’s around a 0.7 log reduction? Like what the chimp got after two doses or are you talking about what the chimp experienced after the single 2mgs/kg dose, before she got her second 3mgs/kg dose?
Dr. Christopher Anzalone - President and CEO
Well, so Thomas, first of all we’re not just talking about chimp. We’re also talking generally about what we’ve seen in non-human primates across number of siRNA. And generally what yield is that that 2 mg/kg dose, if you look across our full experience, it tends not to be the maximal dose, tends to be sort of your somewhere in that broad middle range of the ascending part of the dose response curve.
When you get up to 3 mg/kg and higher, that’s when we tend to be up more at the top of the dose response curve and you start to get into the log and even multi-log levels, if that makes sense.
No. What we’re seeing is that we are at a part of the dose response curve that's quite easy to differentiate from no knockdown but that not yet [Technical Difficulty] that's really what we’re seeing.
We can't be a lot more specific in that because it’s still a blinded study and we don't know what certainty which two patients in each cohort have received placebo. We think we know who they are but we don't know the certainty.
Dr. Bruce Given - Chief Operating Officer and Head, R&D
And we also -- it also appears that some patients are still declining in terms of s-antigen, particularly in s-antigen. So right now even if it was unblinded it will be premature to talk about peak knockdown because it not clearly speaks that.
Thomas Wei - Jefferies
Okay. But so the data that we have, maybe, I don’t have a full complete set of data, but we all have seen the data that you presented at AASLD in the one chimp. And then you're saying there are other non-human primate studies? Do we have the data for those other studies or has that not been presented before?
Dr. Christopher Anzalone - President and CEO
I’m not sure how much is actually they published, I think most of it in one way or another has probably been presented in places like tied. Not talking about things like Factor 7 and AAT, where we did show data at the Analyst Meeting that we had in middle of this year and so there is other data out there. Recall that for new world monkey HBV does not actually affect new world monkey.
So the only primary data we have for HBV happens to be the one chimpanzee and as you likely pointed out, we only have two week data for that chimpanzee at the 2 mg per kg dose.
So they were mostly talking about sort of the qualitative sense of the knockdown that was achieved there since we didn't follow it long enough probably even get to the nadir for a 2 mg per kg dose.
Thomas Wei - Jefferies
Right. I am still doing down and so you’re talking about kind of what would have been predicted if you have been able to follow that chimp out at 2 mg per kg for longer that 14 days. What you’re seeing is better than that? You’re seeing kind of what the natural extension of that curve would be, if that had been point out?
Dr. Christopher Anzalone - President and CEO
I think it’s fair to say that yes.
Thomas Wei - Jefferies
Okay. Sorry that, I have got confused about that. I also just wanted to ask about your commentary around the steepness? So when you keep talking about the steepness of the dose response curve, it sounds like you have a minimal amount of activity of 1 mg per kg and then you actually have much more robust activity at 2 mg per kg. So two is much more than twice as effective as 1 mg per kg?
Dr. Christopher Anzalone - President and CEO
We don’t want to get into a numbers gain. I think again that’s dangerous for us in those small parts because the data is still blinded. But what we’re talking about is that the nature of what we've seen across all of these different RNAs that we’ve studied and all these different species, is just always struck us that the dose response curve, at least for us, because of -- probably because of that fact that we have endosomal escape tends to be very steep. From the onset of knockdown to getting very high levels of knockdown tends to just be your couple 3 mg per kg. It’s not a factor of across 10 mg per kg. It’s something like we are seen in some. So it’s really very steep and we’ve just always been struck by that.
Dr. Bruce Given - Chief Operating Officer and Head, R&D
And qualitatively, you're exactly right, when you’re on that your response curve. If you double the dose, you substantially more than double the response.
Thomas Wei - Jefferies
And that -- so you need that curve to continue along better than linear trajectory to meet your target, that what I should, I think you had mentioned that earlier during the Q&A that it need to continue along that very kind of super linear steep dose response to get your log?
Dr. Christopher Anzalone - President and CEO
Well, I think, we’d say the other way around. We would just say that, if it behaves the same way as we've seen in other species. We feel that the 3 mg per kg dose should give us very deep knockdown. That’s what we’re saying. But everyone wants to put nothing or have us put throw a dart at the dart board and say exactly what that knockdowns going to be. That’s a little hard for us.
But it feels like extrapolating for what we see with another animal model. The 3 mg per kg should be -- if it’s not a goal, it should be very near goal, would be our expectation, but now we get very forward looking. When we’re going to have the data in our hands and ready to show people around AASLD.
Thomas Wei - Jefferies
Okay. Great. Thanks. I’ll jump back in the queue
Letter to Share Holders
Ohhhhhhh, so now you want to answer clearly! Very clear and detailed, opposite of answering Thomas Wei's questions during cc before the data release.
"We also said on the August conference call that we believed the knockdown we were seeing in humans was similar in magnitude to that which we have seen in previous studies with non-human primates at similar doses. More specifically, the chimpanzee with chronic HBV that we treated received two doses of ARC-520: 2 mg/kg on day 1 and then 3 mg/kg on day 15. Prior to receiving the second dose, HBsAg was reduced about 50% from baseline. To repeat, we reported mean peak HBsAg knockdown of 51% in patients receiving 2 mg/kg in the Phase 2a while the chimpanzee knockdown at that dose was approximately 50%. The chimpanzee ultimately experienced 80-85% reduction in HBsAg, but only after receiving the 3 mg/kg dose. That was not the only study with non-human primates that can be referenced. In a paper we published in the scientific journal Molecular Therapy in May 2013, we showed that doses around 2 mg/kg (using siRNAs targeting a different liver-expressed gene) inhibit Factor 7 activity between 30-60%. As with the chimpanzee study, this certainly feels similar in magnitude to the 51% HBsAg knockdown we saw in patients receiving 2 mg/kg ARC-520."
"On our August 12th quarterly conference call, we disclosed that the first 2 dose levels tested in patients with chronic HBV would not meet our goal."
"So where are we? We have only completed the first two dose levels in an ongoing dose finding study and have not yet identified a dose in humans that will meet our knockdown goal… but we are not yet finished. We now have unblinded Phase 1 safety data in healthy volunteers through 4 mg/kg and we continue to see a favorable safety profile: no dose-limiting toxicities or adverse events rated serious or severe. We have just finished dosing all 8 patients in the 3 mg/kg cohort and as data come in, we will decide whether to escalate to 4 mg/kg. We do not expect timing of the program to be impacted. We plan to submit regulatory filings by the end of the year in support of the multi-dose Phase 2b study whether or not we escalate to 4mg/kg in the Phase 2a study."
"We continue to be excited about ARC-520 and the potential to enable a functional cure for patients with chronic HBV infection. There is still much we do not know about ARC-520 and how effective a therapy it may be one day, but there are some important things that we do know. It appears to be well tolerated at all doses tested in our prior Phase 1 study: 1 mg/kg - 4 mg/kg. The drug appears to do what it is designed to do. We have seen clear knockdown in the first 2 doses tested in patients and the favorable safety profile enables us to increase the dose to see if we can induce deeper knockdown. Interestingly, we have seen unexpectedly durable knockdown in patients, even though the low doses provided relatively shallow depth of HBsAg reductions. At the final time points studied, nearly 3 months after a single injection, we continue to see knockdown. We believe that this is important and quite unique. We expect that it will provide significant advantages, particularly as we increase dose and initiate planned multi-dose studies."
ARWR DID NOT mislead with "similar"
"However, depth of knockdown appears to be similar in magnitude with what we see in non-human primates at the same doses, including the HBV infected chimpanzee presented at AASLD last year."
They got 51% KD in human with single 2mg/kg dose. Chimp data with SINGLE 2mg/kg KD was 50%. 51% is SIMILAR to 50% people. The chimp data with 2mg/kg dose AND 3mg/kg dose had a >80% KD, which is closer to where expectations were for some reason, wrong comparison, do your diligence.
Dew, could you share all the other companies you know of with glutaminase inhibitors? Thanks!
MDVN What would be a good Clinical Benefit Rate for AR+ TNBC p2 data in Dec 2014?
EXEL Does COMET data even matter? How will Cabozantinib sell vs. Xofigo?
Which AR-509 trial is biggest threat to Xtandi and and MDVN? SPARTAN? http://1.usa.gov/1oaku1g
MDVN: Why is control arm placebo and not chemo in PROSPER?
EU Pima PDP filling, $2B today, what do you think it trades at if EU does or doesn't say file pima for PDP? Should know in the next ~5 months.
Favorite SHORT?
Anti-CD47 IP
Yeah agree, "should" be ok, completely different mechanism, CD47 binding, SIRPa, not anti-CD47 antibody.
Agree, do you know anything about the IP in the anti-CD47 space?
XNCR is probably my favorite company right now, data from all 3 lead compounds in 2H14 1. p1a XmAb7195 (asthma) 2. p2a XmAb5871 (RA) 3. p2 MOR208 (B-ALL). Is this on anyone else's radar?