Replies to post #106544 on Biotech Values

[RockRat]

I see what you mean. Check out this earlier effort from TransTech Pharma:

>>J Thromb Haemost. 2008 Mar;6(3):457-63. Epub 2007 Dec 12.
Partial factor IXa inhibition with TTP889 for prevention of venous thromboembolism: an exploratory study.

Eriksson BI, Dahl OE, Lassen MR, Ward DP, Rothlein R, Davis G, Turpie AG; Fixit Study Group.

Sahlgrenska University Hospital/Ostra, Göteborg, Sweden. [e-mail]
Abstract

BACKGROUND: Inhibitors of factor (F) IXa show potent antithrombotic activity with a low risk of bleeding in preclinical models. We investigated the anticoagulant potential of oral TTP889, a small molecule that inhibits up to 90% of FIXa activity at therapeutic doses, using a clinical model of extended prophylaxis in hip fracture surgery (HFS).

METHODS: In this multicenter, randomized, double-blind study, 261 patients received oral TTP889 (300 mg once daily) or placebo starting 6-10 days after HFS, and standard thromboprophylaxis for 5-9 days. Treatment was continued for 3 weeks and all patients then underwent mandatory bilateral venography. The primary efficacy outcome was venous thromboembolism (VTE; venographic or symptomatic deep vein thrombosis or pulmonary embolism) during treatment, and it was evaluated centrally by an independent adjudication panel. The main safety outcome was bleeding (major, clinically relevant non-major, and minor events).

RESULTS: Two hundred and twelve patients with an evaluable venogram were included in the efficacy analysis. The primary efficacy outcome occurred in 32.1% (35/109) of patients who had been allocated TTP889, and 28.2% (29/103) of patients on placebo (P = 0.58). There were no major bleeding events, and only two clinically relevant non-major bleeding events with TTP889.

CONCLUSION: Partial FIXa inhibition with TTP889 300 mg daily was not effective for extended prevention of VTE after standard prophylaxis for up to 9 days. Coupled with the low incidence of bleeding episodes, this suggests a lack of antithrombotic potential. Further investigation of TTP889 in different clinical settings is needed. (Clinical trial registration information URL: http://www.clinicaltrials.gov. Unique identifier: NCT00119457).<<

And guess what?

>>Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):382-7. Epub 2010 Feb 5.
Coagulation factor IXa as a target for treatment and prophylaxis of venous thromboembolism.

Eikelboom JW, Zelenkofske SL, Rusconi CP.

Regado Biosciences, Inc., 318 Blackwell St, STE 130, Durham, NC 27701, USA.
Abstract

Venous thromboembolism remains a frequent cause of vascular death. Despite advances in anticoagulant drug development, unmet needs remain, including limited treatment options for patients with severe renal impairment and the inability to fully reverse the effects of anticoagulants approved or in late-stage development. Because coagulation factor IXa plays a pivotal role in tissue factor-mediated thrombin generation, it represents an attractive target for anticoagulant development. This article discusses the rationale for factor IXa as an anticoagulant target and the potential role in venous thromboembolism prevention or management of the 2 factor IXa inhibitors that have undergone testing in phase 1 or 2 trials: TTP889, an oral, small-molecule compound, and RB006, an aptamer-based compound, the intravenous and subcutaneous formulations of which are the anticoagulant components of the REG1 and REG2 anticoagulation systems, respectively.<<

So Regado apparently licensed this and is trying again with a non-oral approach to administration. Wonder how likely that is to fix the lack of antithrombotic activity? Are they hoping said activity merely got lost in the gut in the oral version, so that given IV or sub q, it'll work? VC are still funding this?! Analysts (I think it's DB, in particular) consider this a threat?! Incidentally, you won't find that history at either company's website.

Not sure if this one is on your radar:

>>Thromb Res. 2010 Oct;126(4):e286-93.
Comparison of a direct Factor Xa inhibitor, edoxaban, with dalteparin and ximelagatran: a randomised controlled trial in healthy elderly adults.

Samama MM, Kunitada S, Oursin A, Depasse F, Heptinstall S.

Biomnis, 78 Avenue de Verdun, 94208 Ivry-sur-Seine Cedex, France. [e-mail]
Abstract

INTRODUCTION: Edoxaban (the free base of DU-176b) is a new, oral direct Factor Xa inhibitor. This is the first study to compare the hemostatic response to edoxaban, ximelagatran, and dalteparin in healthy, elderly adults.

MATERIALS AND METHODS: In this open-label, active-controlled clinical trial, 40 adults (65-75 years), were randomised to: oral edoxaban (60 mg, twice-daily, 7 doses), subcutaneous dalteparin (5000 IU, once-daily, 4 doses), oral ximelagatran (24 mg, twice-daily, 7 doses) or no drug. Blood samples were taken before, and 1.5, 4, 12, 24, 72, 84, 96, 108, 120, and 144 hours after, the first dose. The primary outcomes were changes in thrombin-antithrombin complex, prothrombin fragment 1+2 and D-dimer, and adverse events. Additional biomarkers of coagulation, and endothelial cell and platelet activation were compared (ANOVA).

RESULTS: All subjects completed the study. Inhibition of thrombin generation lag time, peak, and constant velocity index were significantly greater, and extended for a longer period of time, following edoxaban administration, compared with dalteparin. We found that the traditional assay for anti-FXa activity was not appropriate for the new anticoagulants. Biomarker changes following edoxaban administration (including prolongation of prothrombin time) reflected inhibition of Factor Xa; there was no effect on platelet, tissue factor or endothelial activation. There were no clinically significant changes in primary outcomes. No serious adverse events were reported.

CONCLUSION: Oral administration of edoxaban resulted in effective Factor Xa and TG inhibition, and was well-tolerated. Studies are needed to confirm edoxaban (60 mg daily) use in clinical practice.

SPONSORSHIP: Daiichi Sankyo Pharma Development.<<

I've seen that remark about assays before, in Momenta's patent regarding M118. " . . . the standard tests for UFH activity, activated partial thromboplastin time (aPTT) or activated clotting time (ACT), are not useful as they rely primarily on anti-IIa activity for a readout."

Regards, RockRat

[DewDiligence]

RGDO—which IPO’d just one month ago—is already laying off workers:

http://www.sec.gov/Archives/edgar/data/1311596/000119312513380270/d606114d8k.htm

On September 26, 2013, Regado Biosciences, Inc. (the “Company”) committed to a reduction in the Company’s workforce.

If that’s not a record for shortest time from IPO to layoff, it must be damn close!

I’ve long been skeptical of RGDO and it’s oddball anticoagulant program (e.g. #msg-55677135).