Replies to post #52404 on Biotech Values

[DewDiligence]

Idraparinux Causes Excess Bleeding in A-Fib Patients

[This is a big story insofar as biotinylated idraparinux (SSR126517), an injectable FXa inhibitor, was one of the drugs with which SNY had hoped to replace Lovenox revenue when Lovenox generics eventually hit the market. In the phase-3 trial reported here, idraparinux had efficacy similar to warfarin in preventing stroke and embolism, but it caused statsig greater bleeding. This outcome puts the further development of idraparinux very much in doubt, IMO.]

http://www.medpagetoday.com/Cardiology/Arrhythmias/tb/8108

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By Todd Neale
January 25, 2008

AMSTERDAM, Jan. 25 -- Significant excess bleeding (P<0.0001) halted a trial of idraparinux for stroke prevention in patients with atrial fibrillation.

Before the trial was stopped, idraparinux had efficacy similar to that of the vitamin K antagonists, the standard treatment for preventing thromboembolism in these patients (HR 0.71, 95% CI 0.39 to 1.30, P=0.007 for noninferiority), reported Harry Buller, M.D., of Academic Medical Center here, and colleagues in the Jan. 26 issue of The Lancet.

In an accompanying comment, Alan Go, M.D., of Kaiser Permanente in Oakland, Calif., and Daniel Singer, M.D., of Harvard and Massachusetts General Hospital in Boston, wrote that the push to find new medications to prevent thromboembolism in atrial fibrillation patients is fueled by the problems associated with vitamin K antagonists, particularly the need for constant monitoring, despite their effectiveness.

The safety and efficacy of vitamin K antagonists depend on maintaining a narrow range of anticoagulation intensity, they wrote. "This goal is complicated by the fact that the effect of these drugs is altered by underlying genotype, coexisting illnesses, dietary intake, and exposure to other drugs, which necessitates frequent INR testing and dose adjustment."

Idraparinux, which inhibits activated factor X, would require only fixed weekly dosing without constant coagulation monitoring, Dr. Buller and colleagues theorized.

So they initiated the Amadeus trial, a multicenter, randomized, open-label, noninferiority trial with a blinded outcome assessment. The researchers randomized 2,283 participants to 2.5 mg of subcutaneous idraparinux once a week and 2,293 participants to the vitamin K antagonists warfarin or acenocoumarol with INR of 2.0 to 3.0.

For patients with calculated creatinine clearance at baseline of 10 to 30 mL/min, dosing with idraparinux was changed to 1.5 mg from the second dose through the end of the study.

All participants (mean age 70.1) had atrial fibrillation with an indication for long-term anticoagulation.

Primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism and the principal safety outcome was clinically relevant bleeding.

After a mean follow-up of 10.7 months, the trial was stopped because of an excess of clinically relevant bleeding in the idraparinux group compared with the vitamin K antagonist group (346 cases versus 226, HR 1.74, 95% CI 1.47 to 2.06, P<0.0001).

Non-major but clinically relevant bleeding also occurred more frequently in the idraparinux group than in the vitamin K antagonist group (HR 1.60, CI 1.34 to 1.91, P<0.0001).

Intracranial bleeding occurred more in the idraparinux group (21 occurrences versus 9 in the control group, HR 2.58, 95% CI 1.18 to 5.63, P=0.014).

Older patients and those with renal impairment were at increased risk for additional bleeding.

Hazard ratios for clinically relevant bleeding with idraparinux varied by creatinine clearance rates, despite adjustment of idraparinux dose according to renal function. For rates:

• of 80 mL/min or more, the hazard ratio was 1.4 (95% CI 1.0 to 1.9)

• of 30 to 50 mL/min, HR was 3.0 (1.9 to 4.6)

• of less than 30 mL/min, HR was 3.9 (1.3 to 11.7)

The idraparinux to vitamin K antagonist hazard ratio for clinically relevant bleeding also varied by age. It was 1.5 (95% CI 1.2 to 1.8) in patients under 75 years and 2.4 (95% CI 1.8 to 3.1) in those 75 or older.

Despite the excessive bleeding, mortality did not differ between the two groups (62 deaths with idraparinux versus 61 with the vitamin K antagonists, P=0.49).

Taking antiplatelet medications such as aspirin, clopidogrel, or ticlopidine, in addition to either idraparinux or one of the vitamin K antagonists, increased clinically relevant bleeding, prompting the researchers to advise avoiding these combinations.

Irrespective of treatment allocation, clinically relevant bleeding was more frequent in the 971 patients (21%) who took aspirin in combination with the anticoagulant (30.5 per 100 patient-years with idraparinux versus 17.7 per 100 patient-years with vitamin K antagonists) and in the 126 (3%) who took clopidogrel or ticlopidine (42.7 per 100 patient-years with idraparinux and 23.4 per 100 patient-years with vitamin K antagonists) than in those not taking concurrent platelet inhibitor medication (16.4 per 100 patient-years with idraparinux and 9.3 per 100 patient-years with vitamin K antagonists).

Dr. Buller and colleagues were not ready to give up on idraparinux altogether, despite the failure of the Amadeus trial. "An idraparinux dose regimen adjusted to patients' characteristics -- e.g., age and renal clearance -- might preserve efficacy without an increased hemorrhagic risk, and should be addressed by further studies," they said.

Drs. Go and Singer suggested that the search for alternatives to vitamin K antagonists would eventually bear fruit, even though attempts so far have been unsuccessful.

"We believe that on the basis of positive features of recent trial experiences, one or more approaches (e.g., inhibition of factor Xa, thrombin, or other clotting factors) will emerge as an alternative to vitamin K antagonists and facilitate more widespread use of effective and acceptably safe stroke prevention in patients with atrial fibrillation," they wrote.

"Yet, while we wait for the new antithrombotics to emerge, we still need dedicated innovative efforts to improve the delivery of vitamin K antagonists for the growing population with atrial fibrillation," they concluded.
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[DewDiligence]

SNY’s Otamixaban Is Unimpressive in Phase-2 ACS Trial

[The above header reflects my own opinion, which I think is borne out by the PR below. The 27-42% reduction in risk relative to the control arm in the primary endpoint sounds impressive, but: a) the lowest dose was excluded from the calculation; and b) no p-value is given in the PR. Moreover, otamixaban does not have a clean safety profile—as is the case with most anticoagulants, the efficacy comes at a cost in dose-dependent bleeding risk. Investors should want to know the bleeding risk of each individual dose, but these data are not given in the PR; instead, the PR combined the two middle doses of the six doses tested and asserts that the bleeding rate in these two arms was no worse than in the (unfractionated heparin + Integrillin) control arm.

Based on this PR, I cannot tell whether there are any dose(s) of otamixaban that warrant advancing the program into phase-3, but my suspicion is that there aren’t.

Otamixaban is several years behind some members of the class of oral FXa inhibitors: Xarelto from Bayer/JNJ is already approved in the EU for VTE and is in phase-3 for ACS, while Apixaban from BMY/PFE has completed a portion of its phase-3 program (#msg-40912878). SNY suggests in this PR that otamixaban is well suited to use in ACS because it has a short half-life; however, drugs that lack anti-thrombin (anti-FIIa) activity, a feature of all of the oral FXa inhibitors, have a built-in MoA disadvantage in ACS relative to Pradaxa, an oral inhibitor of thrombin that is already on the market in the EU (#msg-40912878). (MNTA’s M118 inhibits both FXa and thrombin, but is not oral.)

All told, I fail to see how SNY can differentiate otamixaban from the oral anticoagulants on the market and in development. If the decision were up to me, I would drop the program.

It’s notable that SNY hardly ever talks about otamixaban. I’ve never heard the drug discussed on SNY’s regular CC’s, and I had to go back almost two years to find a post on this board that mentions it.]

http://finance.yahoo.com/news/Study-Shows-Otamixaban-prnews-2175273349.html/print?x=0

›Study Shows Otamixaban Substantially Reduced Complications of Invasive Management of Acute Coronary Syndromes

Sunday August 30, 2009, 6:12 am EDT

- SEPIA-ACS Multiple-dose Phase II Results Showing 27- 42% Risk Reduction in ACS Complications Presented in Plenary Session of European Society of Cardiology Congress and Published in The Lancet

PARIS, August 30 /PRNewswire-FirstCall/ -- Sanofi-aventis (EURONEXT: SAN and NYSE: SNY) announced today that the investigational anti-Xa intravenous anticoagulant otamixaban reduced by 27 to 42 percent the odds of the composite primary endpoint of death, myocardial infarction, urgent revascularization or rescue GPIIb/IIIa use in 4 out of the 5 otamixaban tested doses [i.e. all doses but the lowest one, which was discontinued], versus standard UFH/eptifibatide combination [unfractionated heparin + Integrilin] in [non-ST] ACS patients suitable for invasive strategy. The results of the SEPIA-ACS1/ TIMI-42 were presented today at the plenary session of the Annual European Society of Cardiology congress in Barcelona and simultaneously published online in The Lancet.

Otamixaban is a first in class, rapid onset antithrombotic compound, acting as a direct selective inhibitor of factor Xa. Otamixaban is originating from Sanofi-aventis world-class thrombosis research portfolio and is currently in phase IIb clinical development phase.

"The data show that intermediate dosages of otamixaban may offer substantial reduction in major coronary complications in patients presenting with acute coronary syndrome, with bleeding rate comparable to current therapy," said Dr Marc Sabatine, MD, MPH, an Investigator in the TIMI Study Group and a cardiologist at Brigham and Women's Hospital, Harvard Medical School. "This research is addressing an important medical need, by potentially significantly improving outcomes of ACS patients undergoing PCI while simplifying the treatment pattern of the acute management phase of the disease." he added.

The double-blind phase II SEPIA-ACS1/ TIMI-42 study randomized 3241 patients from 36 countries in 6 treatment arms. The study assessed the efficacy and safety of five different doses of otamixaban versus the standard unfractionated heparin plus Glycoprotein IIb/IIIa inhibitor (eptifibatide), on background of standard dual antiplatelet therapy, in patients with high-risk non-ST-elevation acute coronary syndromes. SEPIA-ACS1 study showed that otamixaban displayed clinically meaningful activity on the primary endpoint from the threshold dose of 0.070 mg/kg/h, the second tested dose, with a consistent antithrombotic effect up to the 5th highest tested dosage. The lowest studied dosage was prematurely stopped due to insufficient activity, based on recommendation by an independent data monitoring board. Moreover. a combined analysis of the intermediate doses (0.105 and 0.140 mg/kg/h) of otamixaban arms showed that otamixaban reduced by approximately 46 percent (p=0.0198) the risk of the composite of death or a second myocardial infarction, a predefined study secondary efficacy endpoint [However, combining two of the six doses in this post hoc manner does not make for a compelling finding.]

The potent antithrombotic effect of otamixaban was also accompanied with a dose-dependent bleeding profile. Combined intermediate otamixaban dosages showed a safety profile not statistically different with regard to TIMI major or minor bleeding through 7 days, in comparison to UFH and GPIIb/IIIa inhibitor comparator (RR 1.20, 95% CI 0.64-2.27, p=0.5634). [A breakdown of the bleeding data by dose is highly relevant, obviously; that such data are not given in this PR is a red flag.]

"The SEPIA-ACS1 trial is providing very encouraging results for a new and more effective treatment approach," said Marc Cluzel, MD Senior Vice President Research and Development Sanofi-aventis. "We aim, on the basis of these findings to address through our development program remaining patients', practionners' and payers' needs for management of ACS."

Acute Coronary Syndromes is a general term used to regroup clinical symptoms related to acute myocardial ischemia. ACS represents an area of important medical need, as despite use of several antithrombotic therapies, death and myocardial infarction still occur in 5 to 8% of patients in the following week after an initial event.‹

[DewDiligence]

Sanofi’s Shrinking Stable of Anticoagulant Aspirants

A post on this board about two years ago (#msg-22938795) contains a description of SNY’s anticoagulant pipeline as reported by SNY at an investor presentation in the fall of 2007. The four drug candidates mentioned in the 2007 presentation—and the current status of each—are as follows:


1. AVE5026, a daily injected low-molecular-weight heparin that SNY once described as “the successor to Lovenox.”

Status: SNY once had grandiose plans for AVE5026. However, in late 2008, SNY’s new CEO, Chris Viehbacher, downsized the AVE5026 program to include only VTE prevention following orthopedic surgery or chemotherapy usage. As part of this downsizing decision, the most ambitious phase-3 trial—a comparison of AVE5026 vs Lovenox in 12,000 acutely ill patients with restricted mobility—was terminated prematurely (http://clinicaltrials.gov/ct2/show/NCT00714597 ). Several phase-3 trials of AVE5026 vs Lovenox in VTE prevention that were started in 2007-2008 are still in progress; a few others were recently completed, but SNY has not yet reported their results.


2. Idraparinux, a synthesized, Arixtra-like, injected FXa inhibitor given weekly, which came in two flavors: regular and biotinylated. The biotinylated version (a/k/a SSR126517, idrabiotaparinux) supposedly has the advantage of being reversible with a specific antidote. (Unfractionated heparin and MNTA’s M118 are reversible, but Lovenox, Arixtra, and the new oral anticoagulants are not.)

Status: the regular (non-biotinylated) version of idraparinux caused statsig excess bleeding relative to warfarin in the phase-3 AMADEUS trial in atrial fibrillation; this trial was halted for safety reasons in Feb 2008 (#msg-26298260). As a result, the idraparinux program is likely dead; the new CEO, Chris Viehbacher, said a few months ago, “I would be skeptical of the product.” However, for now the program remains on life support: a phase-3 trial of the biotinylated version vs warfarin in AF that was already underway when the AMADEUS trial was halted is expected to have results in Mar 2011 (http://clinicaltrials.gov/ct2/show/NCT00580216 ).


3. SR123781 (a/k/a/ hexadecasaccharide), a synthesized, Arixtra-like, injected FXa inhibitor with rapid onset and clearance, intended for acute-care settings.

Status: The SR123781 program was terminated in Feb 2008 (http://en.sanofi-aventis.com/binaries/080212_PDF_Slides_media_tcm28-15767.pdf [page 86]). No explanation was given by SNY for the termination, but it’s reasonable to infer that the demise of idraparinux in the AMADEUS trial and the failure of Arixtra to gain significant traction in the commercial marketplace were key factors.


4. Otamixaban, an oral FXa inhibitor.

Status: Otamixaban just finished a phase-2 trial in ACS that I would characterize as a day late and a dollar short: #msg-41012818. I’ll be surprised if SNY advances the program into phase-3.

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All told, the set of four anticoagulant projects described in this post consists of one project that’s defunct, one that’s on life support, one that’s been greatly downsized, and one that’s a day late and a dollar short. Not a pretty picture.