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SRPT:
I do think there is a lot of emotional pressure being applied to all respects of this decision. That pressure has people glossing over many germane items that you've pointed out: conflicts of interest, adequacy of trial design, etc...
I do think FDA officials like Woodcock and Temple have a sober and reasoned view of the drug approval process. As difficult as the subject matter is in this case, I'm rather confident the FDA will not undermine many basic principles in order to get this drug on the market.
I completely agree that this is political noisemaking. Investors who fear patents being invalidated are out to lunch.
On top of it, the lawmakers generally pick poor targets. GILD and MDVN's drugs are exactly what the US healthcare system needs: efficacious (one a game changer) small molecule drugs that will eventually be available as cheap generics.
PPHM:
Did we ever figure out why that highly decorated academic guy took a job at a company that has a crappy drug? I can't be the first one to think that it would be easy for big pharma to torpedo the bavi threat from the inside, right?
TRIL / Fluorinov:
Interesting to see a modest capitalization company buy someone else out.
Have to admit though that they're in tough with many of these projects. BET has plenty of competition, granted none are approved. The oral proteasome inhibitor is competition with at least one approved (ixazomib) and one investigational (oprozomib) competitor.
Do you think they're going to finance and spend money on these or is it a measured bet that they can out-license these for a cumulative up-front that outpaces the purchase price?
SRPT:
It's been interesting watching this stock dispassionately from the outside. Did the company use the parents to forward their agenda, or did the parents use the company? And if the latter, why does there appear to be so much more emotion towards the etep effort than the drisa effort?
INCY / MRK:
This MRK purchase is interesting and I have to admit that it is not what I would have expected, unless it's a relatively cheap deal for the IP and expertise. I wasn't all that successful at finding a valuation ballpark for IOmet. Anyone familiar with a valuation range?
Part of the problem for very "smart" people is that they still need the occasional service of other, not-so-"smart" people.
For example, when reading the indictment, i had a good chuckle at the transfer agreement that was fraudulently backdated by co-conspirator #1 simply using redacting tape.
All in all, this reads of the actions of a person who just knew he was smarter than everyone and would eventually strike it big, but in the meantime he just had to delay/defer a few niggling annoyances. Looks like he just kept rolling indiscretions from one to another in order to buy time for his greatness to surface.
I'm waiting for media inquiries as to how I coaxed him to post on iHub...
Dew's board is becoming infamous.
:D
TRVN:
I'm not trying to be controversial or anything. The totality of the preclinical and clinical data to date show that it works primarily in ways very similar to AT1R antagonists. In fact, much of the unique effects of TRV027 may actually end up being due to effects on renal function rather than on the heart. I just think the synopsis you copied did not accurately reflect the totality and likely cause of benefit. But that's just me.
I like the science here and am interested to see if it translates to the clinic.
TRVN:
The long story of THLD may finally be over. I hope Wallstarb is doing ok in this time of difficulty.
Threshold Pharmaceuticals Announces Its Two Phase 3 Studies Evaluating Evofosfamide Did Not Meet Primary Endpoints
Studies of Evofosfamide Combined With Chemotherapy in Advanced Pancreatic Cancer (MAESTRO) and Advanced Soft Tissue Sarcoma (TH-CR-406/SARC021) Did Not Meet Primary Endpoints of Improving Overall Survival With Statistical Significance
????
SOUTH SAN FRANCISCO, CA--(Marketwired - Dec 7, 2015) - Threshold Pharmaceuticals, Inc. (NASDAQ: THLD) today announced the outcomes of two Phase 3 cancer studies (MAESTRO and TH-CR-406/SARC021) of evofosfamide (previously known as TH-302), an investigational hypoxia-activated prodrug, which is being evaluated for first-line treatment of advanced pancreatic adenocarcinoma and advanced soft tissue sarcoma, in combination with chemotherapy. The Phase 3 studies are being conducted under Threshold's collaboration with Merck KGaA, Darmstadt, Germany.
In the Phase 3 MAESTRO study, patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with evofosfamide in combination with gemcitabine did not demonstrate a statistically significant improvement in overall survival (OS) compared with gemcitabine plus placebo (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.71 - 1.01; p=0.0589).
In the Phase 3 TH-CR-406/SARC021 study being conducted in collaboration with the Sarcoma Alliance for Research through Collaboration (SARC), patients with locally advanced unresectable or metastatic soft tissue sarcoma treated with evofosfamide in combination with doxorubicin did not demonstrate a statistically significant improvement in OS compared with doxorubicin alone (HR: 1.06; 95% CI: 0.88 - 1.29).
PFE / AGN:
Any idea on how we can get an idea of the magnitude of "taxable" in this case? Since AGN is receiving PFE shares, I'm not sure how I as a PFE shareholder can model the tax implications.
BMRN / SRPT:
I'm generally drawing a blank, but when was the last time that we can reasonably say the FDA backed down due to pressure from outside groups?
It's talked about a lot whenever an iffy data package is about to head to the FDA, but to my recollection it rarely (if ever) happens. Almost makes it irresponsible to write the next "the FDA is under pressure to approve just so they have *something*" article.
SEC Filing Question:
Was reading the ZSPH Initial Solicitation filing regarding the AZN transaction. The filing explicitly had a section entitled "Information Regarding Golden Parachute Compensation."
Anyone know how long actual SEC filings have formalized the lovely Golden Parachute euphemism? I thought it was always a sneering / deservedly mocking term used by investors to express their disdain at management compensation. But when did Wall Street begin to just embrace their greed and start using the term in actual filings?
BLCM:
LOXO:
They should be careful reporting 100% response rates. You can only go down from there, and then the market will be greatly disappointed!
Nice results though. I still think LOXO and RXDX can be part of a basket as I'm not clear which approach is better. Both seem to be producing numerically high response rates.
INCY:
INCY:
INCY:
I think people are misreading the NSCLC data and that is the major reason for the fall.
The results are fine for a dose-ranging trial. Caveats for small numbers and all that, but the melanoma results show an incremental uptick above pembro alone.
In NSCLC, pembro alone has an ORR of ~20%. However, when PD-L1 expression is measured and those patients with a proportional score of >49% are analyzed, then the ORR goes up to ~40%. I think people look at that 40% number for pembro and the 38% number for this trials pembro + IDO and write it off.
This combo trial provided data for all PD-L1 expression levels. For the 10 NSCLC patients, only 2 had scores >49% while 3 had results pending. So at most, 5 of these 10 will meet that >49% threshold. If you treat these combo data as an all-comers trial wrt to PD-L1 expression, then the more appropriate comparison is the 20% pembro ORR versus the 38% ORR in this combo trial.
This obviously has caveats with respect to the skepticism surrounding the overall reliability of PD-L1 expression and its clinical significance, and the small numbers in this combo trial. But a small effort at making a more comparable comparison gives a more nuanced view of the data.
ESPR:
I don't really follow it. I've always been bored with the whole lipid area.
Cardioxyl:
This is yet another attempt to promote vasodilation and relieve stress on the heart. One of the founders, Kass, has long been beating the drum that the viagra target PDE5 is present in the heart and through its inhibition could mediate beneficial effects. As brief background, NO donors work to increase intracellular cGMP (via guanylate cyclase activation) and this is a primary mechanism of blood vessel relaxation. Viagra (sildenafil) induces relaxation by inhibiting PDE5, the enzyme responsible for breaking down cGMP.
Most people accept that the NO effect is directed at the vasculature; Kass insists that the heart is also major direct target. He has published multiple papers showing that "PDE5" inhibition in the heart is beneficial in animal models*.
This HNO approach seems to come at it from another way: to increase guanylate cyclase activity via HNO in order to increase cGMP production rather than decrease its breakdown via PDE5 inhibition. I don't see why this would be anything meaningful. They make a fuss that HNO is not just simply NO, but then show that the HNO effect in relaxing the vasculature is dependent on guanylate cyclase activity just like NO. So really, the only thing left is the magic that they claim for this compound once it enters the heart. They note that it may also react with some redox sensitive amino acids (like cysteine) to impact intracellular signaling. Not exactly a targeted approach, and definitely ill-defined. All in all, it's a compound that, despite their protests, seems to act a lot like NO; I'm unconvinced that there is any special sauce here.
They also claim that:
INCY:
The abstracts for RA-BEGIN and RA-BEAM from ACR 2015. Pleasantly surprised by baricitinib competing much better with adalimumab than I would have expected, although the AE profile merits attention. If you follow the links, there are tables with the efficacy and AE data.
RA-BEAM :
Baricitinib Versus Placebo or Adalimumab in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to Background Methotrexate Therapy: Results of a Phase 3 Study
Background/Purpose: In phase 3 studies, baricitinib (bari) improved disease activity in patients (pts) with active RA and an inadequate response (IR) to conventional synthetic DMARDs1 or biologic DMARDs2. This abstract reports the 24-wk results from a 52-wk, global, phase 3, double-blind, placebo (PBO) and active-controlled study of bari in MTX-IR RA pts.
Methods: Pts with active RA (TJC≥6 & SJC≥6 & hsCRP≥6 mg/L) despite stable background MTX were randomized 3:3:2 to PBO, bari 4 mg once daily (QD), or adalimumab (ADA) 40 mg biweekly (Q2W), stratified by region and baseline joint erosion status. Non-responders were rescued from Wk 16. At Wk 24, pts on PBO switched to bari 4 mg QD. The primary endpoint was ACR20 response at Wk 12 for bari vs. PBO. Major secondary endpoints included comparisons of bari vs. ADA for ACR20 and change in DAS28-CRP at Wk 12.
Results: Of 1305 randomized pts, 89%, 94% and 93% completed Wk 24 in PBO, bari and ADA groups, respectively. Rescue rates were 26%, 7% and 12% for PBO, bari and ADA, respectively. ACR20 response at Wk 12 was higher for bari vs. PBO (70% vs. 40%, p≤.001 – Table 1). At Wks 12 and 24, statistically significant improvements in ACR 20/50/70 & HAQ-DI response rates, and DAS28, CDAI, and SDAI low disease activity and remission rates were seen for bari vs. PBO, many as early as Wk 1. Compared to ADA, bari was superior with respect to measures including ACR20 response and improvement in DAS28-CRP at Wk 12. Compared to PBO, daily diary measures of morning joint stiffness (MJS) duration and severity, worst tiredness, and worst joint pain were significantly improved in pts receiving bari, from as early as Wk 1. Rates of treatment-emergent adverse events (TEAEs), including infections, were higher for bari and ADA compared to PBO (Table 2). Compared to PBO, serious adverse events (SAE) rates were similar for bari and lower for ADA; serious infection rates were similar across groups. Two deaths occurred (bari), 1 pneumonia and 1 duodenal ulcer haemorrhage. Five malignancies were reported, 2 bari and 3 PBO. Three potential opportunistic infections occurred, 2 bari and 1 PBO; none were SAEs. One case of tuberculosis occurred (ADA). There were no GI perforations. Lab abnormalities were consistent with other phase 3 studies1,2; few led to discontinuation.
Conclusion: In pts with active RA despite background MTX, once-daily oral bari was associated with significant clinical improvements compared to PBO and to ADA, with an acceptable safety and tolerability profile.
RA-BEGIN:
Background/Purpose:
In 2 completed phase 3 studies, baricitinib (bari) improved disease activity with a satisfactory safety profile in patients (pts) with moderately-to-severely active RA who were inadequate responders to either conventional synthetic1 or biologic2DMARDs. This abstract reports results from a phase 3 study of bari administered as monotherapy or in combination with methotrexate (MTX) to pts with early active RA who had limited or no prior treatment with DMARDs. MTX monotherapy was the active comparator.
Methods: Pts with active RA (TJC & SJC ≥6, hsCRP ≥3.6 mg/L) and no previous DMARD treatment other than ≤3 doses of MTX were randomized 4:3:4 to MTX, bari 4 mg once daily (QD; bari monotherapy), or bari 4 mg QD + MTX for up to 52 wks. MTX dose, with or without bari, was up-titrated from 10 to 20 mg once weekly over 8 weeks (wks). Rescue was not allowed prior to Wk 24, the time point for primary and all major secondary efficacy endpoints. The primary objective evaluated non-inferiority of bari 4 mg monotherapy to MTX on ACR20 at Wk 24 (using a 12% margin).
Results: Of 584 randomized pts, 87%, 91%, and 89% of pts completed Wk 24 in the MTX, bari 4 mg monotherapy, and bari 4 mg + MTX groups, respectively. ACR20 response at Wk 24 was higher with bari 4 mg monotherapy vs. MTX (77% vs. 62%, p≤.01). Compared to MTX, bari 4 mg monotherapy produced significantly greater improvements in multiple secondary measures of disease activity (Table 1), many as early as Wk 1. MTX in combination with bari 4 mg did not appear to increase the benefit observed with bari 4 mg monotherapy. Clinical remission was seen in a significantly higher proportions of pts treated with bari 4 mg alone or in combination with MTX compared to MTX alone (Table 1). Rates of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) were similar across groups (Table 2). Through 24 wks, 2 (1.0%), 6 (3.8%) and 14 (6.5%) pts discontinued the study because of an adverse event in the MTX, bari 4 mg monotherapy, and bari 4 mg + MTX groups, respectively. No GI perforations occurred during the study. Laboratory abnormalities were generally less frequent in the bari 4 mg group compared to either the MTX or bari 4 mg + MTX groups (Table 2).
Conclusion:
In pts with early RA, all treatment groups experienced improvements in disease activity with bari 4 mg monotherapy producing significantly larger and more rapid improvements and higher rates of clinical remission compared to MTX monotherapy, with a satisfactory safety profile. MTX addition to bari 4 mg did not increase the benefit observed with bari monotherapy, while it appeared to increase the frequency of laboratory abnormalities.
INCY:
Here is the RA-BEAM PR. As usual, these PRs are as important for what they do say as what they don't say. It looks to me that baricitinib competes with, but still lags, humira. An outright beat of humira was unlikely, so in that respect the data are reasonable. Not a homerun, but likely a good set of data to compete with Pfizer's tofacitinib. Before the PR, I've copied the endpoints that were prospectively disclosed to clinicaltrials.gov:
Primary Outcome Measures:
• Proportion of Participants Achieving American College of Rheumatology 20% Improvement (ACR20) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
• Change from Baseline in the Modified Total Sharp Score (mTSS) [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
• Change from Baseline in the Disease Activity Score based on a 28-Joint Count (DAS-28) [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
• Proportion of Participants Achieving American College of Rheumatology 50% (ACR50) and 70% (ACR70) Response [ Time Frame: Week 12, Week 24, Week 52 ] [ Designated as safety issue: No ]
• Change from Baseline in Measures of Clinical Disease Activity and Severity [ Time Frame: Baseline, up to Week 52 ] [ Designated as safety issue: No ]
• Change from Baseline in Patient Reported Outcomes [ Time Frame: Baseline, up to Week 52 ] [ Designated as safety issue: No ]
• Change from Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) Score [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
The PR:
Eli Lilly and Company Print E-mail PDF Add to Briefcase « Previous Release | Next Release »
Baricitinib Demonstrates Superiority to Adalimumab in Improving Signs and Symptoms of Rheumatoid Arthritis in Pivotal Phase 3 Study
INDIANAPOLIS, Oct. 14, 2015 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) and Incyte Corporation (NASDAQ: INCY) today announced positive topline results of RA-BEAM, the fourth successful Phase 3 study of baricitinib, an investigational medicine for patients with moderately-to-severely active rheumatoid arthritis.
The study met its primary objective of demonstrating superiority compared to placebo after 12 weeks of treatment based on ACR20 response - a standard clinical measure that represents at least a 20 percent improvement in RA disease activity. Baricitinib was also superior to adalimumab on key secondary objectives of ACR20 response and improvement in DAS28-hsCRP score after 12 weeks of treatment. Following 24 weeks of treatment, baricitinib was superior to placebo in preventing progressive radiographic structural joint damage. These treatment benefits with baricitinib observed at 12 and 24 weeks were maintained through 52 weeks of therapy.
"RA-BEAM is the first study to demonstrate that a once-daily oral treatment was superior in improving signs and symptoms of rheumatoid arthritis compared to the current injectable standard of care," said David Ricks, Lilly senior vice president, and president, Lilly Bio-Medicines. "If approved, baricitinib could help change expectations for people living with this debilitating disease."
"Combined results of these four Phase 3 studies give us confidence that, if approved, baricitinib could represent a valuable new treatment option for patients with RA," said Rich Levy, M.D., chief drug development officer, Incyte Corporation.
RA-BEAM evaluated the safety and efficacy of baricitinib in patients with active disease despite treatment with methotrexate, compared to placebo for 24 weeks or adalimumab (Humira®)* for 52 weeks. Part of a larger Phase 3 program of more than 3,000 RA patients at various points in the RA treatment continuum, RA-BEAM enrolled more than 1,300 patients who were randomized to one of three treatment groups:
4 mg oral once-daily baricitinib on background methotrexate
40 mg injectable every-other-week adalimumab on background methotrexate
placebo on background methotrexate
Compared to placebo, serious adverse events rates were similar for baricitinib and lower for adalimumab; serious infection rates were similar across groups. There were no cases of gastrointestinal perforations. One event of tuberculosis was reported in each of the baricitinib and adalimumab groups. Rates of treatment-emergent adverse events, including infections, were higher for baricitinib and adalimumab compared to placebo. The most common adverse events observed with baricitinib were nasopharyngitis and bronchitis. Discontinuations due to adverse events occurred with similar frequency across treatment groups. A large majority of patients completing this trial opted to participate in a long-term extension study.
Lilly and Incyte announced top-line results in December 2014 for the first Phase 3 trial of baricitinib, RA-BEACON, and in February 2015 for the second, RA-BUILD. Data from these studies were presented at the EULAR annual scientific congress in June 2015. Topline results of the third Phase 3 trial, RA-BEGIN, were announced in September 2015 and will be presented at the American College of Rheumatology annual scientific congress in November. The companies plan to submit detailed data from RA-BEAM and other Phase 3 studies for presentation at scientific meetings and publication in peer-reviewed journals in 2015 and 2016.
About Baricitinib
Baricitinib is a once-daily, oral, selective JAK1 and JAK2 inhibitor. There are four known JAK enzymes: JAK1, JAK2, JAK3 and TYK2. JAK-dependent cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases, suggesting that JAK inhibitors may be useful for the treatment of a broad range of inflammatory conditions. Baricitinib demonstrates approximately 100-fold greater potency of inhibition against JAK1 and JAK2 than JAK 3 in kinase assays.
In December 2009, Lilly and Incyte announced an exclusive worldwide license and collaboration agreement for the development and commercialization of baricitinib and certain follow-on compounds for patients with inflammatory and autoimmune diseases. Baricitinib is currently in Phase 3 clinical development for rheumatoid arthritis and Phase 2 development for psoriasis and diabetic nephropathy.
About Rheumatoid Arthritis
Rheumatoid arthritis is an autoimmune diseasei characterized by inflammation and progressive destruction of joints.ii More than 23 million people worldwide suffer from RA.iii Approximately three times as many women as men have the disease. Patients and physicians indicate there remains an important opportunity to improve patient care. Current treatment of RA includes the use of non-steroidal anti-inflammatory drugs, oral disease-modifying anti-rheumatic drugs such as methotrexate, and injectable biological response modifiers that target selected mediators implicated in the pathogenesis of RA.iv
About Baricitinib Phase 3 Trials
Lilly and Incyte have conducted four pivotal Phase 3 clinical trials of baricitinib in patients with moderately-to-severely active rheumatoid arthritis to support regulatory submission in most countries. An additional Phase 3 study was initiated to support clinical development in China and remains ongoing. The clinical trial program includes a wide range of patients including those who are methotrexate naïve, inadequate responders to methotrexate, inadequate responders to conventional disease-modifying anti-rheumatic drugs, or inadequate responders to TNF inhibitors. Patients completing any of the five Phase 3 studies can enroll in a long-term extension study. For additional information on this clinical trial program, please visit www.clinicaltrials.gov.
INCY IDOs:
Drug Pricing:
The strange irony is, despite the current upheaval, I thought the system was largely working the way I'd like it to. I've posted here before that I'm supportive of pricing power for efficacious drugs because, in the long term, society pays an upfront price for a long term benefits. I consider the eventual availability of generics as the commensurate benefit in exchange for the run of relatively higher priced branded drugs.
Case in point, I think the "outrage" over Gilead's pricing of HCV drugs is just shortsighted folly. In the long run, this is a small price to pay for the societal benefit.
Sadly, Shkreli's intention of abusing the system (yeah I said it) now has people focused with the aim of reacting rather than properly assessing. I hope we can get over this bump without adversely impacting the sector in the long run.
SRPT:
That post is a perfect example of losing objectivity.
SRPT:
I appreciate this write-up. Thank you.
INCY:
I guess INCY holders have another shot at holding or selling at 130 :D
SRPT:
Admittedly I've enjoyed watching this story and honestly have no idea how to handicap approval prospects. I don't know where the FDA will place their emphasis.
SRPT:
Sarepta:
I really feel for these families. But I wish they had a better steward of this drug.
Myokardia:
I'm very meh. I spoke to them about a job a couple of years ago and it sure seemed like they were going to walk in the footsteps of Cytokinetics. The section head I spoke to was even a former CYTK guy. The founding story is also similar, with James Spudich having a role in starting both CYTK and MYOK.
They were interested in some cardiomyopathy targets that aren't very exciting at all, and got relatively hand-wavey about how they were going to target them and what it was supposed to achieve. It didn't fill me with confidence that they were indeed looking at a new way to attack and treat this disease.
I'd wait for some data before investing hard-earned money.
INCY:
BLPH:
Seems to be a big jump. Pulmonary hypertension in COPD is a big deal, but I don't think there is any great proof for NO. Don't see why this 6 patient trial without a control arm would change anything.
INCY:
INCY:
R&D Spend / Drug Prices:
I'm happy to let the facts accumulate.
But at this point, that level of industry is not where I, as an admitted defender of the pharma / bio industry, am willing to stick my neck out. I've followed a good number of companies over the last 20 years, and many have been able to research and develop without resorting to such a "strategy."
Turing etc...
Turing: