Ablynx Reports Phase-1b Results for ALX-0081 in PCI
[The most notable outcome here is that ALX-0081 did not cause any clinical bleeding. The efficacy data is sketchy insofar as it consists merely of inhibition of the vWF biomarker; no studies to date have tried to show a decrease in clinically relevant clots. Moreover, this PR says that additional work on dosing and biomarker analysis is needed before proceeding to phase-2.
ALX-0081 has a sister drug called ALX-0681, which is administered sub-Q (#msg-34108151). Nanobodies are Ablynx’s trademarked name for small, llama-derived antibody fragments; their molecular weight is ~28 kDa, about one-sixth the size of a typical mAb drug. Among the advantages cited by Ablynx for nanobodies relative to mAbs are stability/lack of aggregation, solubility, and low manufacturing cost. Please see #msg-10617249 and #msg-18452920 for background info. Ablynx is publicly traded on the Euronext Brussels exchange; Boehringer-Ingelheim owns an equity stake.]
›GHENT, Belgium, 30 March 2009 - Ablynx [Euronext Brussels: ABLX], a pioneer in the discovery and development of Nanobodies, a novel class of antibody-derived therapeutic proteins, announced today the detailed results from the Phase Ib study of its anti-thrombotic ALX-0081. The primary endpoint, demonstrating the complete inhibition of the target protein as measured by a specific biomarker, was reached in December 2008. These positive detailed data support the progression of ALX-0081 into Phase II testing, expected to commence in Q3 2009.
During the period May to December 2008, the study recruited a total of 25 patients with stable angina undergoing an elective percutaneous coronary intervention (PCI) procedure. Total daily doses of ALX- 0081 ranging from 2 to 18 mg were added to a standard anti-thrombotic regimen including aspirin, heparin and Plavix. The double blind study randomized patients in a 3:1 ratio to either active study drug (ALX-0081) or placebo, resulting in a total of 19 patients receiving ALX-0081 intravenous infusions and six patients receiving placebo.
The biological effect of ALX-0081 was determined via a biomarker, indicating the complete inhibition of von Willebrand Factor (vWF) and its mediated effect on platelet aggregation and clotting in coronary arteries. The study included a single dose and a multiple dose escalation. Single doses were escalated until the required biological effect (complete biomarker inhibition for at least six hours in all ALX-0081 treated patients) was confirmed.
The subsequent multiple dosing was aimed to ensure complete inhibition of the biomarker for at least 24 hours. All patients who received ALX-0081 showed complete inhibition of the biomarker with a duration of 4 to 18 hours in the single dose group and for at least 24 hours in the multiple dose group. In all patients, the pharmacological markers returned to normal 12-36 hours after dosing.
The study treatment was safe and well tolerated. There were no apparent clinical differences in the number of patients with adverse events and in the intensity of these adverse events between the placebo group and the ALX-0081 treatment groups. Importantly, the treatment with ALX-0081 was not associated with any clinical signs of bleeding. Neither the single nor the multiple dose treatment resulted in detectable immunogenicity and no human anti-vWF antibody responses were detected during the 30 day follow up after the last injection, suggesting inherently low immunogenicity of the drug.
The pharmacological profile of ALX-0081 in this Phase Ib study confirmed the findings of the Phase Ia study in healthy volunteers, with a vWF adopted plasma half-life of 27 hours in the single ascending dose. The pharmacodynamic profile of the multiple dosing resulted in effective drug concentrations that correlate with the favorable pharmacodynamic effect (inhibition of biomarker) and did not result in adverse findings in the pharmacodynamic profile, i.e. no signs of drug accumulation were detected.
The resulting pharmacokinetic and pharmacodynamic profiles of the four sequential administrations of ALX- 0081 support the progression into Phase II testing. In order to gain additional information on optimal dosing and scheduling in preparation for a Phase II trial, Ablynx has extended its Phase Ib study to look in more detail at biological markers, optimization of concurrent treatment with the standard anti-thrombotic regimen, tolerance and administration.
Edwin Moses, CEO and Chairman commented: “We are delighted with the rapid progress made to date and these positive Phase Ib results for ALX-0081 mean that we expect to proceed to a multi-centre Phase II study in PCI patients. The positive detailed analysis of our Phase Ib clinical trial is a significant milestone for Ablynx and represents a major step towards the potential development of an improved treatment option for PCI patients. We look forward to a positive outcome from our discussions with the regulatory authorities which should lead to initiation of the Phase II study in the third quarter of this year.”
Ablynx continues to advance its development portfolio. ALX-0681, which also targets vWF but is administered subcutaneously rather than intravenously, entered a healthy volunteer study in December 2008 and Ablynx expects to announce the final results of this Phase I study before the end of the third quarter of this year. By the end of 2009, Ablynx also aims to start a Phase I study for ALX-0141, which targets RANKL, an important target in osteoporosis.
About ALX-0681 and ALX-0081
ALX-0681 and ALX-0081 are novel “first-in-class” therapeutic Nanobodies targeting von Willebrand factor ("vWF"), a protein found in the blood that acts at a very early stage in the coagulation cascade, namely platelet adhesion, in contrast to currently available anti-platelet drugs which act only in the late stage of platelet aggregation. ALX-0081 is administered intravenously while ALX-0681 is administered subcutaneously. ALX-0081 is a bivalent Nanobody with a molecular weight of 28,000 daltons, designed to selectively prevent unwanted thrombus formation in vessels under high shear conditions without interfering with desirable haemostasis and, as such, to minimize bleeding complications.
About the Thrombosis Market
Ablynx believes that ALX-0681 and ALX-0081 target a key opportunity in the anti-thrombotic market as they may provide a solution to the cardiologist’s current dilemma in acute coronary syndrome (ACS) which typically involves achieving a balance between the prevention of unwanted blood clots and potentially life-threatening bleeding complications. ALX-0081 and ALX-0681 could potentially prevent arterial thrombosis following angioplasty, which is a serious clinical problem. Other potential indications for ALX-0081 and ALX-0681 include thrombotic thrombocytopenic purpura (TTP), myocardial infarction (MI) and stroke.
About Acute Coronary Syndrome (ACS)
ACS is expected to afflict approximately 2.9 million people in the Unites States, Japan and certain European countries in 2009 according to Datamonitor’s Pipeline Insight: Antithrombotics, Reaching the untreated prophylaxis market report, DMHC2284 March 2007, and is the leading cause of mortality in the area of cardiovascular disease. Experts believe that the prevalence and incidence of acute infarcts due to arteriosclerosis will increase further, due to the ageing population. Peripheral artery occlusive disease (PAOD) will affect an estimated 22.1 million individuals in the US, Japan and certain European countries in 2009 and is associated with significant morbidity and mortality.
About Percutaneous Coronary Intervention (PCI)
The term percutaneous coronary intervention (sometimes called PTCA, angioplasty or stenting) describes a range of procedures that treat narrowing or blockages in coronary arteries supplying blood to the heart. Many patients undergoing this procedure will have previously had cardiac catheterisation (sometimes called coronary angiography) to examine the condition of the coronary vessels. Alternatively, percutaneous coronary intervention may be undertaken immediately after the diagnostic angiogram. Most patients with angina can be helped substantially by coronary stenting. For some patients with very mild disease stents are not required and medication is sufficient. For a small number of people bypass surgery is necessary. Almost all stent procedures are successful and completed in < 2 hours. Inevitably however there are risks and it is important that patients understand these risks before accepting treatment. Source: http://www.thecardiologist.co.uk/coronary.htm
About Thrombotic Thrombocytopenic Purpura (TTP)
TTP is a disease related to the formation of white clots. The underlying abnormality in TTP is the formation of small platelet clots, which leads to occlusions of small vessels throughout the body particularly within blood vessels supplying the brain and the kidneys. It has been shown that these small platelet clots are caused by the presence of large clusters or strings of activated vWF. Approximately four cases of TTP per million inhabitants are diagnosed per year in Europe and the United States. This incidence estimate suggests that orphan drug designation should be achievable for this indication, which would enable an accelerated development and approval timetable. There is currently no approved drug therapy for TPP and plasma exchange is the only available treatment for these patients today. Plasma exchange involves the removal of the patient’s plasma (the non-cellular component of blood) and its replacement by donor plasma. TTP remains a condition with extremely high morbidity and mortality, even with timely plasma exchange, and so there is still a significant unmet medical need for this disease.
Founded in 2001 in Ghent, Belgium, Ablynx is a biopharmaceutical company focused on the discovery and development of Nanobodies, a novel class of therapeutic proteins based on single-domain antibody fragments, for a range of serious and life-threatening human diseases. The Company currently has over 200 employees. Ablynx completed a successful IPO on Euronext Brussels [ABLX] on 7 November 2007. Ablynx is developing a portfolio of Nanobody-based therapeutic programmes in a number of major disease areas, including inflammation, thrombosis, oncology and Alzheimer’s disease. Nanobodies have been generated against more than 100 different disease targets. Importantly the Nanobodies which naturally exist in llamas have a very high homology with humans. Efficacy data has been obtained in over 25 in vivo models for Nanobodies against a range of different targets. Ablynx has an extensive patent position in the field of Nanobodies for healthcare applications. It has exclusive and worldwide rights to more than 50 families of granted patents and pending patent applications, including the Hamers patents covering the basic structure, composition, preparation and uses of Nanobodies. Ablynx has ongoing research collaborations and significant partnerships with several major pharmaceutical companies, including Boehringer Ingelheim, Merck Serono, Novartis and Wyeth Pharmaceuticals. Ablynx is building a diverse and broad portfolio of therapeutic Nanobodies through these collaborations as well as through its own internal discovery programmes. The Company’s lead programme, ALX-0081, an intravenously administered novel anti-thrombotic has reached its primary endpoint in a multi-dose Phase Ib study in patients undergoing PCI and ALX-0681, also an anti-thrombotic but with a subcutaneous route of administration has started Phase I in healthy volunteers. Ablynx has progressed ALX-0141, an anti-RANKL Nanobody for bone disorders into preclinical development. In addition, Ablynx’s partner Wyeth Pharmaceuticals has initiated a Phase I study in December 2008 for an anti-TNF alpha Nanobody.‹
Ablynx Reports Phase-1 Results for ALX-0681 ‘Nanobody’ Anticoagulant
[‘Nanobody’ is the Ablynx-trademarked name for a drug derived from a fragment of llama antibody; its molecular weight is ~28 kDa, only one-sixth the size of a mAb drug. Among the advantages cited by Ablynx for nanobodies relative to mAbs are enhanced stability, increased solubility, and lower manufacturing cost.
ALX-0681 is the sub-Q version of ALX-0081, the lead nanobody in the program. Ablynx hopes to develop these drugs for thrombotic thrombocytopenic purpura (TTP)—an orphan indication—and eventually for ACS, the big enchilada of CV indications. ALX-0081 (the infused drug) completed a phase-1b trial of 25 patients with PCI/stable angina in Mar 2009 but, by the company’s own admission, it requires additional formulation work before entering phase-2: #msg-29601951 . (PCI/stable angina is the same indication as MNTA’s recently completed phase-2a trial for M118.)
ALX-0681 (the sub-Q drug) is the subject of this PR. The most notable results of the phase-1 trial reported here are that the drug seems to have an acceptable PK/PD profile and it does not cause detectable immunogenicity, which was a worry given the llama derivation. There are not yet any meaningful efficacy data on ALX-0681; inasmuch as the subjects in the phase-1 trial were healthy volunteers, the trial examined the inhibition of coagulation biomarkers (Factor VIII and von Willebrand factor) rather than the ability to treat or prevent clinically relevant clots.
Please see #msg-10617249 and #msg-18452920 for somewhat dated background info on the competitive landscape for “enhanced” antibody drugs. Ablynx is publicly traded on the Euronext Brussels exchange.]
GHENT, BELGIUM--(Marketwire - 08/18/09) - Ablynx [Euronext Brussels: ABLX] today announced the positive results from its double- blind, randomized, placebo-controlled, single and multiple dose Phase I study with ALX-0681, a subcutaneous formulation of its novel anti-thrombotic Nanobody that selectively targets von Willebrand factor (vWF). The positive Phase I data support the progression of ALX-0681 towards Phase II testing in patients with thrombotic thrombocytopenic purpura (TTP), expected to commence in Q2 2010. The anti-vWF Nanobody received orphan drug designation by the EMEA and the FDA for the treatment of TTP in May this year.
The Phase I study was designed to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and repeated subcutaneous administrations of ALX-0681. A total of 36 healthy volunteers were treated with either single subcutaneous doses of ALX-0681 ranging from 2mg to 16mg or daily 10 mg subcutaneous injections for 7 or 14 days.
All administrations of ALX-0681 were well tolerated and did not result in clinically significant adverse events. No signs of local intolerance or clinically significant bleeding events occurred and no evidence of immunogenicity was observed for 45 days after completion of treatment.
The desired biological effect, determined by complete inhibition of a biomarker, was achieved for more than 14 days with daily injections of 10mg of the anti-vWF Nanobody, confirming the biological efficacy of ALX-0681. The PD parameters for coagulation Factor VIII and vWF showed a fast and reversible decrease compared to pre-dose values, with normalisation between 24 and 72 hours after the last administration, depending on dose. The PK profile remained unchanged after multiple administrations, confirming the favourable pharmacological behaviour of ALX-0681.
ALX-0681 is being developed for the treatment of patients with TTP. It is also anticipated that the subcutaneous administration of ALX-0681 will provide access to additional patient populations suffering from unwanted blood-clot formation, such as those with acute coronary syndrome (ACS), which are not currently addressed by the intravenous administration of ALX-0081.‹
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