UDARNA SNAGA ISTINE - Novi lekovi protiv hemofilije
 
Friday
2016-12-09
7:44 AM
Welcome Guest
RSS
 
My site
Main Registration Login
Novi lekovi protiv hemofilije »
Site menu

Our poll
Rate my site
Total of answers: 33

Statistics

Total online: 1
Guests: 1
Users: 0

Login form

Treatment Breakthroughs

More new drugs are in the pipeline now than in past decades

By Sarah Aldridge | 02.09.2012
Originally Published February 2012
OJO Images/Glow Images

The marketing terms "new and improved” and "longer lasting” are not limited to the latest brand of chewing gum. They also apply to a long list of therapies now in clinical trials for people with bleeding disorders. Some people have waited years for a new recombinant product; others a lifetime for any factor product to treat their rare condition. For many, their patience is about to pay off.

There are more drugs in the pipeline now than in the past few decades. "The companies’ commitment to continue to work on behalf of patients with bleeding disorders is what’s driving it,” says Val D. Bias, CEO of the National Hemophilia Foundation (NHF). The dilemma facing many patients in the future won’t be a lack of medications, but a plethora of products that act in a variety of ways. (See table "Bleeding Disorders Drugs in Human Clinical Trials.”)

For drugs to be approved and licensed by the US Food and Drug Administration (FDA), they have to go through a series of clinical trials. First they are tested on animals, such as mice; then they are tested on humans. Each phase of a clinical trial helps determine the drug’s safety, efficacy, optimal dosage and side effects. (See sidebar, "Clinical Trial Phases.”) The National Institutes of Health clinical trials registry at clinicaltrials.gov lists more than 250 trials on hemophilia and more than 60 on von Willebrand disease (VWD). (See "Clinical Trials 101.").)

Tried and True vs. Something New

Prophylactic medications to treat hemophilia have given patients a new degree of freedom. They can self-infuse whenever and wherever it’s convenient.

"In terms of hemophilia A and B, I feel that the products we have right now are really good,” says Marion Koerper, MD, NHF medical advisor. She is also director emerita of the hemophilia treatment center at the University of California, San Francisco, where she practices pediatric hematology and oncology. "The factors do work to stop bleeding or, in the case of prophylaxis, prevent bleeding.”

However, prophylaxis is not perfect. "It’s only efficacious if the patient takes it the prescribed way,” Koerper says. The best time to give factor is in the morning before school or work, often the most hectic time of day. For busy families who delay treatment until bedtime, there are consequences. "That is not optimal because the child’s highest levels are while he’s asleep, rather than when he’s running around with his pals on the playground,” says Koerper.

Further, taking a product two or three times a week means that clotting strength can plummet on the off days. "When we give prophylaxis right now for a hemophilia A patient, we’re resolved to the fact that before their next prophy dose, their level in plasma could be as low as about 1% to 2%,” says Steven W. Pipe, MD, medical director, Pediatric Hemophilia and Coagulation Disorders Program, University of Michigan, Ann Arbor. That puts patients at risk for bleeding, especially if there is trauma. "Clearly, that’s not correction of their hemostasis.”

[Steps for Living: Treat Responsibly Today for a Healthy Tomorrow]

Products With Staying Power

To remedy that risk, pharmaceutical companies are creating new products that last longer in the bloodstream. The amount of factor VIII (FVIII) or factor FIX (FIX) in the blood is measured by its half-life, the time it takes for the amount of factor to be reduced by half. There are many variables involved, including blood type, but FVIII’s half-life is about 8–12 hours; FIX’s is about 18–24 hours. One option is to increase the interval between prophylactic doses, ideally to once a week for FIX products and twice a week for FVIII products. 

Another option is to retain the current prophylactic regimen, but avoid the precipitous drop in clotting factor as the next dosing time approaches. "We may be able to maintain much higher plasma levels than we’ve been able to previously with the same intervals that we’re currently using,” says Pipe.

One way to prevent factor products from degrading too quickly is to attach them to the chemical compound polyethylene glycol (PEG). This process, called PEGylation, increases the size of the factor protein molecule so that it circulates in the blood longer and is not cleared by the kidneys prematurely.

"Another strategy is to fuse the recombinant factor protein molecule to a partner protein that already has a long half-life,” says Pipe. Two naturally occurring partner proteins being fused to the FVIII or FIX molecule are albumin, which moves small molecules through the bloodstream, and Fc, a protein fragment that facilitates binding and recycling of immunoglobulin G (IgG).

Data from early clinical trials on Biogen Idec’s recombinant FVIII and FIX Fc fusion products, rFVIIIFc and rFIXFc, look promising. The A-LONG study on patients with severe hemophilia A showed a 1.7-fold increase in half-life during phase 1/2a clinical trials. B-LONG studies on patients with severe hemophilia B showed a nearly threefold increase in half-life during phase 1/2 trials. (See "Long Strides,” HemAware Summer 2011, p. 14.)

Adjunctive therapies, or drugs that are added to the primary factor product, are also being tested in clinical trials. Some use molecules that bind to tissue factor pathway inhibitor (TFPI), preventing it from hindering the action of FXa and thrombin, necessary for clot initiation and formation. Baxter’s BAX513 uses fucoidan, a seaweed extract being tested on healthy volunteers without hemophilia.

"If you block the proteins that are slowing down coagulation, you can actually restore normal clotting in hemophilic plasma without replacing the missing clotting factor,” says Pipe. For some patients, the adjunctive therapy may become the primary therapy, reducing the number of infusions needed, he says. A bonus is that some TFPI antagonists could be taken orally, such as the capsule form that delivered fucoidan to trial subjects.

"Compliance with bleeding disorders’ treatment is always an issue,” says Bias. "A drug that works better, faster and that you have to take less often can only improve that.”

Innovations for Inhibitors

An estimated 25% of patients with severe hemophilia A develop antibodies, called inhibitors, to the infused factor. Currently, patients undergo immune tolerance therapy to desensitize their immune systems or take a bypassing agent, such as FVIIa. The main drawbacks of the recombinant FVIIa product are that its half-life is only two hours and it is very expensive.

Inspiration Biopharmaceuticals is developing a recombinant porcine (pig) FVIII product for patients with inhibitors. "You can give a dose and get the measurable level of FVIII. That’s a distinct advantage when there’s a life-threatening­ bleed, like a head bleed (intracranial hemorrhage), or a limb-threatening bleed in someone with a compartment syndrome (increased pressure in a muscle in an enclosed space),” Koerper says. But because 80% of patients developed antibodies to plasma-derived pig factor within five days or after five doses, it is possible that a similar scenario might occur with the recombinant product. Results of the clinical trials will provide more data, but its use will probably be restricted.

The longer-lasting products may have an added benefit for inhibitor patients. "Some forms of PEGylation strategy and possibly even some of the fusion proteins may result in reduced risk for inhibitors,” says Pipe. Another product now being tested, Octapharma’s recombinant human-cl rhFVIII, may reduce the rate of inhibitor development because it uses proteins from human cells, not the typical hamster cells.

Recombinant VWD Product at Last

Recombinant products to treat FVIII and FIX were approved in 1992 and 1998, respectively; not so for von Willebrand factor (VWF). "It has bothered me for almost 20 years that I couldn’t offer a recombinant VWF product to my VWD patients,” says Koerper. That need will be fulfilled once Baxter’s recombinant VWF product goes through FDA approval and licensure. It will be targeted to patients with type 3 VWD, the most severe form, and those unresponsive to DDAVP, a synthetic hormone used to prevent or stop bleeds.

Gene Therapy Revisited

Researchers can now create precision drugs that treat diseases caused by specific genetic mutations. One such drug in phase 2 trials is Ataluren (PTC 124®), manufactured by PTC Therapeutics Inc. It will be used for the approximately 10%–15% of patients with hemophilia A and B with a nonsense mutation, which halts factor production early. Ataluren introduces a molecule that allows the cell to read through the stop signal, making more clotting factor. It comes in a powder that is mixed in water. "Something that you can swallow is going to be a huge advantage because there are no needles involved,” Koerper says. (See sidebar "The Allure of Ataluren” in "What’s Your Genotype?” HemAware Spring 2010, p. 29.)

Rare Bleeding Disorders on the Radar

Patients with rare factor deficiencies know that being one in a million is hardly a cause for celebration. "People forget that there are other clotting factor deficiencies that, in some cases, have no treatment,” says Bias.

But hope is on the horizon. Companies that fractionate, or separate, plasma are interested in getting as many products out of it as they can, says Pipe. "Developing new markets for new plasma derivatives, such as the new FXIII product Corifact™ (approved by the FDA in March 2011), and RiaSTAP®, a fibrinogen concentrate to treat FI deficiency (indicated for patients with congenital fibrinogen deficiency including afibrinogenemia and hypofibrinogenemia only), increases the sustainability and viability of the plasma fractionation industry.” Both products are manufactured by CSL Behring. Currently, Novo Nordisk has applied for a license for its recombinant FXIII product. British Plasma Laboratories has a plasma-derived FX product in phase 3 clinical trials.

"NHF is most supportive of new products for rare disorders or categories where products don’t currently exist, like the recombinant VWD product,” Bias says. "It’s important that people have access to a product that’s made for them.”

Time Frame for Trials

For drugs now in clinical trials, that access may take a few years. "From initiation of clinical trials to approval, it’s about a five-year window,” says Pipe. Drugs nearing the finish line—those in phase 3 or moving to FDA licensing—still have between 18 and 30 months, he says.

New Era of Optimism

Patients awaiting better, more effective or first-time products to treat their bleeding disorders have many reasons to be optimistic. "For the first time we’re now going to be offering agents that clearly behave differently. We’re not going to be faced with just a single-breed entity to choose from,” Pipe says.

The idea of having more distinct options may be foreign to some, but should be very welcome. New products with different mechanisms mean that treatments may soon be given in a more targeted, personalized manner. "When you have multiple choices it’s going to take some time for the clinicians and families to figure out what’s best for individual patients,” Pipe says.

When recombinant FVIII and FIX drugs came out two decades ago, Koerper thought they were the "ultimate products.” But with all of these recent innovations, she’s changed her thinking. "Now I realize there is so much more that can be done.”

Clinical Trial Phases

A drug must go through several stages of testing, called "phases” in clinical trials, before it can seek approval review by the Food and Drug Administration (FDA) for use in the US. Depending on how well things go in each phase, the drug progresses from one phase to the next. However, some drug trials are halted voluntarily or by the FDA at certain stages because of concerns about safety or efficacy, for instance. It can take up to five years or more for a new drug to pass muster and make it to the marketplace.

Phase 1

An experimental drug is given to a small number of people (20–100*) to test its safety, tolerability, pharmacokinetics (absorption, distribution, metabolism and excretion) and pharmacodynamics (biochemistry and physiology). Dose-escalating studies are done during this phase to find the optimal dosage.

Phase 2

The drug is given to a larger number of people (100–300*) to evaluate its effectiveness and safety.

Phase 3

The drug is tested in an even larger group of people (1,000–3,000*) at multiple centers across the country to confirm its effectiveness and safety compared with current treatments. During this phase, side effects are also monitored. The studies are randomized and controlled, meaning some patients receive the drug and others get a placebo. Once this "pivotal phase” is successfully completed, the manufacturer can apply for licensing review by the FDA.

Phase 4

Once a drug is licensed for sale, post-marketing surveillance trials are required by the FDA. These trials provide important information on risks, including less common side effects, benefits and optimal use.

*Note: these figures are for standard clinical trials. For bleeding disorders products, the number of trial subjects is often much smaller.

Information partially adapted from clinicaltrials.gov.

Bleeding Disorders Drugs in Human Clinical Trials*

Bleeding Disorder Drug Name Company Clinical Trial
Hemophilia A Recombinant FVIII-Fc Fusion Biogen Idec Phase 3
  NN7088 Recombinant FVIII, third generation Novo Nordisk Phase 3
  Human-cl rhFVIII (recomb FVIII, human cell line) Octapharma Phase 3
  OBI-1 Recombinant Porcine FVIII Inspiration Phase 2/3
  ARC 19499 PEG-conjugated aptamer Archemix Phase 1/2
  BAX499 FVIII, subcutaneous Baxter Phase 1
  CSL627 Recombinant FVIII-single chain CSL Behring Phase 1
Hemophilia B BAX326 Recombinant FIX Baxter Phase 3
  Recombinant FIX-Fc Fusion Biogen Idec Phase 3
  OB1001 Recombinant FIX Inspiration Phase 2/3
  NN7999 Glyco-PEGylated Recombinant FIX Novo Nordisk Phase 3
  ARC 19499 PEG-conjugated aptamer Archemix Phase 1/2
  BAX499 FIX, subcutaneous Baxter Phase 1
  CSL654 Recombinant FIX-Albumin Fusion CSL Behring Phase 1/2
Hemophilia A & B
Nonsense mutation
PTC 124 Ataluren PTC Phase 2
Inhibitors rFVII analog Novo Nordisk Phase 3
  CSL689 Recombinant FVII-Albumin Fusion CSL Behring Phase 2
  GlycoPEG-rFVIIa Novo Nordisk Phase 2
  SQ GlycoPEG-rFVIIa Novo Nordisk Phase 1
Von Willebrand Disease BAX 111, rVWF Baxter Phase 3
Rare Factor Deficiencies Recombinant FXIII Novo Nordisk License applied for
  Plasma-derived FX BPL Phase 3

*This table provides a sampling of drugs now in clinical trials to treat various bleeding disorders. It is by no means comprehensive. NHF does not endorse or recommend any of the products or manufacturers listed. To check the status of drugs now in clinical trials, visit clinicaltrials.gov.

Learn More

  • Visit clinicaltrials.gov.
  • Read "Clinical Trials 101,” March 2010, at hemaware.org/story/clinical-trials-101.
  • Read "New Hemophilia Therapies,” June 2010: ­hemaware.org/story/new-hemophilia-therapies.
  • Steps for Living: Treat Responsibly Today for a Healthy Tomorrow




    ========================



     

    ALN-AT3: Hemophilia and Rare Bleeding Disorders

    ALN-AT3 is an RNAi therapeutic for the treatment of hemophilia and rare bleeding disorders (RBD). Utilizing our proprietary GalNAc-siRNA conjugate delivery formulation, ALN-AT3 is a subcutaneous novel therapeutic approach aimed at re-balancing the coagulation cascade and normalizing hemostasis in severe hemophilia A and B patients, including patients with "inhibitors" against their replacement factor, by silencing antithrombin (AT). AT is an endogenous inhibitor of thrombin generation, an optimal anticoagulant target.

    AT, also known as "antithrombin III" and "SERPINC1", is a liver-expressed plasma protein that acts as an important endogenous anticoagulant by inactivating factor Xa and thrombin. AT plays a key role in normal hemostasis, which has evolved to balance the need to control blood loss through clotting with the need to prevent pathologic thrombosis through anticoagulation. In hemophilia, the loss of certain procoagulant factors (factor VIII and factor IX, in the case of hemophilia A and B, respectively) results in an imbalance of the hemostatic system toward a bleeding phenotype. In contrast, in thrombophilia (e.g., factor V Leiden, protein C deficiency, antithrombin deficiency, amongst others), certain mutations result in an imbalance in the hemostatic system toward a thrombotic phenotype. Since co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, inhibition of AT defines a novel strategy for improving hemostasis.

    In addition to hemophilia A and B, ALN-AT3 has the potential to treat RBD that are defined by deficiencies in Factors II, V, VII, X, and XI. There exists a significant need for novel therapeutics to treat severe hemophilia patients and patients with RBD.

    Pre-clinical data ppresented at the Congress of the International Society on Thrombosis and Haemostasis (ISTH) in July 2013, showed that ALN-AT3 demonstrated normalization of thrombin generation and improvement of hemostasis in hemophilia models, including showing that ALN-AT3 can fully correct thrombin generation in large animal models. Additionally, by administering highly exaggerated doses of ALN-AT3 to wild type and hemophilia animals, we've demonstrated that our RNAi therapeutic has a very wide therapeutic index in the hemophilia setting.

    In October 2013, we filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase I clinical trial with ALN-AT3. The Phase I trial of ALN-AT3 will be conducted in the U.K. as a single- and multi-dose, dose-escalation study consisting of two parts. The first part will be a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, enrolling up to 24 healthy volunteer subjects. The primary objective of the first part of the study is to evaluate the safety and tolerability of a single dose of subcutaneously administered ALN-AT3. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels. The second part of the study will be an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate to severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in ex vivo thrombin generation. We plan to start this Phase I trial in early 2014 with data from hemophilia subjects expected by end of 2014.

    We intend to directly commercialize ALN-AT3 in North and South America, Europe, and other parts of the world, and will seek a partner for this program in Japan and other Asian territories.

    ALN-AT3 Clinical timeline

    ALN-AT3 Phase I trial
    The Phase I trial of ALN-AT3 will be conducted in the U.K. as a single- and multi-dose, dose-escalation study consisting of two parts. The first part will be a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, enrolling up to 24 healthy volunteer subjects. The primary objective of the first part of the study is to evaluate the safety and tolerability of a single dose of subcutaneously administered ALN-AT3. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels. The second part of the study will be an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate to severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in ex vivo thrombin generation.

    ---------------------------------------
     

    6.6. Blood Homeostasis

    It is beyond the scope of this review to consider the entire recent research on fucoidan fractions and blood homeostasis. In brief, fucoidan compounds have a retarding effect on coagulation in part due to interference with antithrombin III and heparin cofactor II [87]. The in vivo effects of intravenous delivery of most types of fucoidan are to extend global clotting time, an effect which is reversible [36]. Kwak recently investigated Fucus vesiculosis fucoidans inhibitory effect in a ferric chloride induced thrombosis model in mice [88]. Fucoidan showed a stronger antithrombotic effect than heparin. The anti-thrombin and anti-factor Xa activities of fucoidan in vitro were less than those of heparin, which implies that the antithrombotic activities are due to binding with heparin cofactor II rather than with antithrombin.

    Pomin addresses the issues of strong anticoagulant activity of fucoidans by desulfation, producing fractions with desirable bioactivity unfettered by anticoagulant behaviors [89]. A linear sulfated fucoidan from sea urchin egg jelly required significantly longer chains than mammalian glycosaminoglycans to achieve the same anticoagulant activity. A slight decrease in the molecular size of the sulfated fucan dramatically reduced its effect on thrombin inactivation mediated by heparin cofactor II. A sulfated fucoidan with 45 tetrasaccharide repeating units was able to bind to heparin cofactor II but was unable to link efficiently the plasma inhibitor and thrombin, which required fucoidan with 100 or more tetrasaccharide repeating units.

    A recent clinical study examined the effects of orally ingested fucoidan on clotting times. 3 g of Undaria pinnatifida fucoidan were ingested daily for 12 days by healthy subjects [29]. A significant prolongation of global clotting time was noted but this was within normal clinical parameters. Toxicological studies on Undaria pinnatifida fucoidan in rats showed no effect on clotting times, even at very high doses [25]. A toxicology study on Laminaria japonica fucoidan did show some pertubations in clotting at 900 mg/kg [26], far above the dose used in the clinical study.

    More recent research into activity illustrates the somewhat counter-intuitive "procoagulant” effect of fucoidan in hemophilia model [31]. In hemophilia A dogs, orally delivered Laminaria japonica fucoidan fraction improved clotting times, perhaps by creating a bypass in the normally blocked clotting pathway.
    -----------------------------------
     

    Anticoagulant, blood thinner

    Sulfated alpha-L-fucans from brown algae (also known as fucoidan) have complex and heterogeneous structures but recent studies revealed the occurrence of ordered repeat units in the sulfated fucans from several species. Another source of sulfated alpha-L-fucans (and their parental compounds sulfated alpha-L-galactans and fucosylated chondroitin sulfate) is marine invertebrates. The invertebrate polysaccharides have simple, ordered structures, which differ in the specific patterns of sulfation and/or position of the glycosidic linkages within their repeating units. The algal and invertebrate sulfated fucans have potent anticoagulant activity, mediated by antithrombin and/or heparin cofactor II.
    --------------------------

     

    Thromb Haemost. 2006 Jan;95(1):68-76.

    Improved coagulation in bleeding disorders by Non-Anticoagulant Sulfated Polysaccharides (NASP).

    Abstract

    Additional therapeutic options are needed for patients with bleeding disorders such as hemophilia A, hemophilia B, severe von Willebrand disease, and other rare factor deficiencies. A novel approach to improve coagulation in such clotting disorders has been identified that, parodoxically, involves heparinlike sulfated polysaccharides. Select molecules of this broad class are largely devoid of anticoagulant activity and are here denoted Non-Anticoagulant Sulfated Polysaccharides (NASPs). A mechanism involving blockade of the extrinsic pathway downregulator, Tissue Factor Pathway Inhibitor (TFPI) by NASPs, was conceived as an approach for improving procoagulant behavior in hemophilic settings. A subset of NASPs, including pentosan polysulfate (PPS) and fucoidan inhibited both full-length and Kunitz 1 and 2 (K1K2) TFPI and, at concentrations from 4-500 nM, improved (i.e. accelerated) the clotting time of human hemophilia A and hemophilia B plasmas or plasma with reduced factor VII levels when tested in dilute prothrombin time (dPT) assays. Fucoidan did not reduce normal plasma APTT times implying specificity for extrinsic pathway control. Improved hemostasis in vivo was observed in mice with hemophilias A or B following low dose subcutaneous administration of PPS or fucoidan, or a combination of NASP plus factor supplement. Increased survival of factor deficient mice following a bleeding challenge was observed. Accordingly, administration of select NASP(s), via mechanism(s) not fully understood, represents a unique means of improving coagulation in bleeding disorders.

    PMID:
    16543964
    [PubMed - indexed for MEDLINE]
    --------------------------------------------

    MARINE NUTRACEUTICALS
    Prospect and Perspectives

    On the other hand, a fucoidan fraction isolated from L. japonica and F. vesiculosus, designated AV513, exhibited potent non-anticoagulant (i.e.,hemostatic) activity in canine and murine models of hemophilia A (Prasad et.al.,2008)
                                                                                                                             Fucoidan from marine Brown Macroalgae
    -----------------------

    The present invention relates generally to the production of fucoidan (also termed AV513 herein). More particularly, the invention relates to methods of purifying fucoidan extract to remove heavy metal ions, bacterial and endotoxin contaminants, and other impurities without affecting the desired biological activity.

    In constrast to heparin, another sulfated polysaccharide, fucoidan, a sulfated polysaccharide isolated from sea algae, has been shown to regulate (i.e., promote) coagulation ( U.S. Patent Publication No. 2005/0282771 ). Specifically, fucoidans, when administered at low concentrations in vitro, or low subcutaneous doses in vivo, provide improved (accelerated) clotting in hemophilic settings through extrinsic pathway activation (Liu, T., et al., and Johnson, K.W., Thrombosis and Haemostasis, 95:68-76, 2006), demonstrating a pro-coagulant activity. At higher doses fucoidan can have an anti-coagulant effect similar to heparin. In light of the problems associated with current anticoagulants like heparin or warfarin, there clearly remains a need for agents, such as fucoidan, that can overcome one or more of the problems associated with currently available anticoagulant therapy.

    In one embodiment, the fucoidan possesses from 5 to 25 percent by weight sulfur. In another embodiment, the fucoidan is of algal origin. In a preferred embodiment, the fucoidan is derived from the genus Fucus or Laminaria. Exemplary fucoidans are those derived from Fucus vesiculosis or from Laminaria japonica or other sources including, but not limited to Undaria pinnitifada and Ascophyllum nodosum.

    In another aspect, the invention provides a composition comprising fucoidan produced by any of the methods described herein. In one embodiment, the fucoidan possesses from 5 to 25 percent by weight sulfur. In another embodiment, the fucoidan is of algal origin. In a preferred embodiment, the fucoidan is derived from the genus Fucus or Laminaria. Exemplary fucoidans are those derived from Fucus vesiculosis or from Laminaria japonica or from Chorda filum, Cladosiphon okamuranus, Undaria pinnatifida, Leathesia difformis, Ascophyllum nodosum, Ecklonia kurome, Pelvetia fastigiata, Saundersella simplex, Chordaria flagelliformis, or any other species of sea plant or animal containing fucoidan. In a preferred embodiment, the fucoidan is biologically active, for example, having pro-coagulant activity. In certain embodiments, the composition may further comprise a pharmaceutically acceptable excipient.

    In another aspect, the invention provides a method for treating a subject in need of enhanced blood coagulation comprising administering a therapeutically effective amount of a composition comprising fucoidan, produced by any of the methods described herein, to said subject. In certain embodiments, the subject has a bleeding disorder selected from the group consisting of a chronic or acute bleeding disorder, a congenital coagulation disorder caused by a blood factor deficiency, and an acquired coagulation disorder. In other embodiments, the cause of the need for enhanced blood coagulation is prior administration of an anticoagulant, surgery, or other invasive procedure. In certain embodiments, the fucoidan is administered at a dosage of about 0.01 mg/kg to about 100 mg/kg.

    The term "fucoidan," as used herein, refers to a sulfated alpha-L-fucan found in many sea plants and animals. Fucoidan is particularly abundant in the cell walls of brown algae and includes fucoidans derived from the genus Fucus (e.g., Fucus vesiculosis, Fucus evanescens, Fucus distichus, and Fucus serratus) or Laminaria (e.g., Laminaria japonica, Laminaria religiosa, and Laminaria abyssalis). Fucoidan also includes fucoidans derived from Chorda filum, Cladosiphon okamuranus, Undaria pinnatifada, Leathesia difformis, Ascophyllum nodosum, Ecklonia kurome, Pelvetia fastigiata, Soundersella simplex, Chordaria flagelliformis, or any other species of sea plant or animal containing fucoidan. In addition, the term fucoidan includes biologically active fragments, derivatives, or analogues thereof. Fucoidan may include fragments of fucoidan generated by degradation (e.g., hydrolysis) of larger fucoidan molecules. Degradation can be achieved by any of a variety of means known to those skilled in the art including treatment of fucoidan with acid, base, heat, or enzymes to yield degraded fucoidan. Fucoidans may also be chemically altered and may have modifications, including but not limited to, sulfation, polysulfation, acetylation, esterification, and methylation.

    An "anticoagulant" as used herein refers to any agent capable of preventing or slowing clot formation.
    A "procoagulant" as used herein refers to any agent capable accelerating clot formation.

    Any source of fucoidan extract can be used in the purification. Fucoidans are found in many sea plants and animals and are particularly abundant in the cell walls of brown algae (Phaeaphyceae). For example, fucoidan derived from brown algae of the genus Fucus (e.g., Fucus vesiculosis, Fucus evanescens, Fucus distichus, and Fucus serratus) or Laminaria (e.g., Laminaria japonica, Laminaria religiosa, and Laminaria abyssalis) can be used in the purification. Alternatively, fucoidan from other sources, including but not limited to, Chorda filum, Cladosiphon okamuranus, Undaria pinnatifida, Leathesia difformis, Ascophyllum nodosum, Ecklonia kurome, Pelvetia fastigiata, Saundersella simplex, Chordaria flargelliformis, or any other species of sea plant or animal containing fucoidan can also be used in the practice of the invention.

    In certain embodiments, multiple therapeutically effective doses of compositions comprising fucoidan and/or one or more other therapeutic agents, such as hemostatic agents, blood factors, or other medications will be administered. The compositions of the present invention are typically, although not necessarily, administered orally, via injection (subcutaneously, intravenously or intramuscularly), by infusion, or locally. The pharmaceutical preparation can be in the form of a liquid solution or suspension immediately prior to administration, but may also take another form such as a syrup, cream, ointment, tablet, capsule, powder, gel, matrix, suppository, or the like. Additional modes of administration are also contemplated, such as pulmonary, rectal, transdermal, transmucosal, intrathecal, pericardial, intra-arterial, intracerebral, intraocular, intraperitoneal, and so forth. The pharmaceutical compositions comprising fucoidan and other agents may be administered using the same or different routes of administration in accordance with any medically acceptable method known in the art.

    Generally, a therapeutically effective amount will range from about 0.01 mg/kg to 200 mg/kg of a fucoidan daily, more preferably from about 0.01 mg/kg to 20 mg/kg daily, even more preferably from about 0.02 mg/kg to 2 mg/kg daily. Preferably, such doses are in the range of 0.01-50 mg/kg four times a day (QID), 0.01-10 mg/kg QID, 0.01-2 mg/kg QID, 0.01-0.2 mg/kg QID, 0.01-50 mg/kg three times a day (TID), 0.01-10 mg/kg TID, 0.01-2 mg/kg TID, 0.01-0.2 mg/kg TID, 0.01-100 mg/kg twice daily (BID), 0.01-10 mg/kg BID, 0.01-2 mg/kg BID, or 0.01-0.2 mg/kg BID and 0.1 to 10% for topical single and multiple applications a day. The amount of compound administered will depend on the potency of the specific fucoidan and the magnitude or procoagulant effect desired and the route of administration.
    --------------------------------

    AV513 – Bleeding disorders, including hemophilia

         AV513 is being developed as an oral therapy for the treatment of bleeding disorders. AV513 is a botanical drug based on a carbohydrate molecule which is extracted from sea algae and has a good human safety profile as documented by others. While outside our strategic focus on neurological and neuromuscular disorders, AV513 leverages our previous experience with hemophilia. Based on our research, we believe that AV513 has the potential to become the first approved non-gene therapy and non-Factor approach to treating hemophilia A and B, and other bleeding disorders such as Factor VII deficiency and severe von Willebrand’s disease. Currently approved treatments involve frequent intravenous administration of recombinant clotting factor.

         We have observed efficacy of AV513 in preclinical bleeding models for hemophilia and are preparing to file an IND with the FDA later in the 2008.

Calendar
«  December 2016  »
SuMoTuWeThFrSa
    123
45678910
11121314151617
18192021222324
25262728293031

Site friends
  • Create your own site


  • Copyright MyCorp © 2016
    Free website builderuCoz