Despite the fact that it is the only FDA-approved drug to treat ischemic stroke, Activase, also known as tissue plasminogen activator (tPA), a product from Genentech (South San Francisco, California) is not used in the majority of cases for which it is approved.
Only about 20% of eligible patients receive the drug. Its common use is reduced as the result of two circumstances: tPA can cause dangerous bleeding in the brain, and its brain-saving power fades fast after the third hour of a stroke.
Now, research published in the June 23 online edition of Nature Medicine suggests possibilities for increased use of the drug.
The risk of bleeding for patients who receive it rises over time, which means that tPA treatment is recommended only if the drug can be administered within three hours of a stroke. That three-hour time window "is a little bit controversial," Daniel Lawrence told Cardiovascular Devices & Drugs's sister publication, BioWorld Today. "But the dominant view is that after three hours, the risks outweigh the benefits."
In their paper, Lawrence and his colleagues from the University of Michigan (Ann Arbor) and the Karolinska Institute (Stockholm, Sweden) report on the likely reason for why tPA increases the risk of bleeding, and show that it may be mitigated by using another drug along with it: imatinib (Gleevec), developed by Novartis (Basel, Switzerland).
The new paper details a series of molecular and cellular experiments conducted by the two teams, which began collaborating after hearing of each other's work.
Naturally occurring tPA exists in two places: the blood and the brain. In the blood, where its main target is plasminogen, its role is to help break up clots. "In the brain, we don't believe tPA serves that function," Lawrence said.
Instead, in the brain tPA appears to cut one type of platelet-derived growth factor, which leads to the activation of the platelet-derived growth factor receptor-alpha. Its role here is to ensure the blood-brain-barrier's permeability to energy and nutrients when it is active.
But during a stroke, tPA produced naturally in the brain can act synergistically, and to the patient's detriment, with tPA given therapeutically in the blood. During a stroke, Lawrence said, tPA is naturally upregulated because the brain experiences a lack of oxygen and nutrients due to a lack of blood flow. But if the blood-brain barrier becomes too permeable, high doses of therapeutic tPA can enter from the bloodstream and make the barrier more permeable still in a vicious feedback cycle.
The most extreme consequence can be uncontrolled bleeding. Even in less extreme cases, such leaky vessels release fluids into the brain and contribute to edema or brain swelling.
Lawrence and his colleagues also took advantage of the fact that the platelet-derived growth factor receptor is blocked by Gleevec. They tested whether Gleevec, either alone or in combination with tPA, could reduce the leakiness of the blood brain barrier.
First, they treated mice with Gleevec one hour after induction of an ischemic stroke. Mice that received the drug had one third less leakage than controls, and as a consequence three days after the stroke mice that received the drug also had brain lesions that were on the average one-third smaller than those suffered by controls.
Finally, the researchers tested the effect of Gleevec in combination with tPA. When they administered Gleevec to mice one hour after an induced stroke, and tPA four hours after the Gleevec, mice receiving Gleevec and tPA had significantly reduced bleeding compared to untreated animals.
Karolinska Institute said that in 3Q08 will launch is starting a clinical trial investigating Gleevec as a stroke treatment.
The researchers hope that Gleevec will reduce cerebral swelling and "may permit tPA to be used with a lower incidence of hemorrhagic complications, and possibly also during a longer time window," Lawrence said. "This could be a very big breakthrough for stroke patients."
Redox reaction controls HDAC location, cardiac hypertrophy
"In the cardiology field, many people believe that oxidative stress is very important for both injury and growth," Junichi Sadoshima said. "But not many targets of oxidative stress have been found."
In a paper in the June 13 issue of Cell, Sadoshima, professor and vice chair in the department of cell biology and molecular medicine at the University of Medicine & Denistry-New Jersey Medical School (MMDNJ; Newark) and associate director of its Cardiovascular Research Institute, along with his colleagues at UMDNJ and the University of Cincinnati, identified the target of oxidative stress in one form of injury, cardiac hypertrophy (CH), the thickening of the heart wall. In a nutshell, Sadoshima said, scientists found that "oxidative stress targets histone deacetylases, and thioredoxin can protect the heart."
CH initially is an adaptive response most commonly due to high blood pressure or heart valve stenosis but turns problematic; such growth ultimately increases cell death, and heart tissue does not regenerate. Ultimately, CH is one of the most common causes of heart failure in the U.S.
The scientists first performed a microarray analysis to search for genes activated by the antioxidant protein thioredoxin-1 and found that among those genes is one DnaJb5 that is up-regulated by thioredoxin and goes on to form a complex with thioredoxin and a third protein. That complex suppressed the activity of transcription factors that are active under conditions that normally lead to hypertrophy, and it prevented heart muscle cells from growing.
The thioredoxin-DnaJb5 complex appeared to work by reducing several amino acids on HDAC4, a histone deacetylase expressed in heart muscle cells. That prevented HDAC4 from being transported from the nucleus into the cytoplasm. Since histone deacetylases and their counterpoints, histone acetyltransferases, control gene expression by modifying chromosomal structure to make genes either more or less accessible to the cell's transcription machinery, they need to be located in the nucleus to interact with the chromosomes.
When HDAC4 is reduced, it can remain in the nucleus and inhibit transcription factors that usually respond to hypertrophic stimuli.
Somewhat surprisingly, oxidation appeared to trump phosphorylation the best-known form of HDAC control when it came to determining the location of HDAC4. Mutant HDAC4s that were both phosphorylated which should be a ticket to the nucleus and reduced rather than oxidated which would favor their staying put tended to remain in the nucleus. The authors noted in their paper that oxidation occurs "more rapidly than phosphorylation after hypertrophic stimulation. These findings suggest that nuclear export of HDAC4 may be biphasic, with redox regulation mediating the early phase of nuclear export."
The mechanism appears to be specific to problematic forms of hypertrophy as Sadoshima pointed out, athletes also have enlarged hearts, but in the case of an athlete, when the heart muscle enlarges, its function increases. In hypertension or ischemia patients, however, function decreases as the muscle enlarges.
Sadoshima concluded that targeting thioredoxin "might be a novel way" of approaching cardiac hypertrophy.
However, as a first step, he and his colleagues need to figure out a way to deliver thioredoxin directly to heart cells. Bloodstream delivery is not feasible ironically, because thioredoxin is oxidized too rapidly in the blood to do any good.
GTC, Ovation in deal for development of ATryn
GTC Biotherapeutics (Framingham, Massachusetts) and Ovation Pharmaceuticals (Deerfield, Illinois) have entered a $257 million agreement to develop and market ATryn in the U.S., a deal that includes $3 million upfront, and an additional $2 million expected this year. GTC's ATryn has completed Phase III clinical trials in the U.S. for patients with a rare disorder called hereditary antithrombin deficiency (HAD), by those undergoing high-risk surgical procedures or childbirth. The company recently initiated a biologics license application filing on a rolling basis.
Following approval of ATryn in the U.S., anticipated in early 2009, Ovation would be responsible for the sales and marketing of the product; GTC would continue to be responsible for manufacturing. GTC would be responsible for production of ATryn and will receive a transfer price on commercial product, a royalty on net sales, and a payment for product used in clinical trials.
ATryn is approved in Europe for HAD patients but not in the U.S. for HAD in people who do not have sufficient antithrombin in their bloodstream. In the U.S. about one in 2,000 to one in 5,000 people are diagnosed with HAD each year, and half of all people diagnosed suffer a thrombosis before 25 years of age.
ATryn also is being developed as a potential treatment for acquired antithrombin deficiencies such as heparin resistance (HR) during coronary artery bypass graft and related surgeries and as a potential treatment for disseminated intravascular coagulation associated with severe sepsis (DIC-sepsis). DIC is the widespread formation of clots within blood vessels, which can lead to organ failure, according to Ovation.
LEO Pharma (Bellerup, Denmark) has developed and is commercializing ATryn in Europe. It is already conducting a Phase II dose ranging study of ATryn as a potential treatment for DIC associated with severe sepsis. GTC will have access to LEO's European Phase II study results for use in clinical and regulatory development in the U.S., which is estimated to be a $2 billion to $3 billion market, GTC said.
An international Phase III program is anticipated, in which LEO Pharma and Ovation will share clinical development costs required for approval for this indication in the U.S. and Europe.
Use of ATryn for severe sepsis is a larger indication than the one being sought for preventing deep vein thrombosis in HD patients undergoing high risk surgical procedures and in childbirth surgical procedures, Newberry said.
Ovation and GTC said they expect to develop ATryn as a supplement to restore heparin responsiveness in heparin resistant patients. Coronary artery bypass graft and related surgeries where a cardiopulmonary bypass machine (CPB) is used, requiring that patients are anti-coagulated prior to going on bypass, in order to avoid clot formation.
Over 20% of patients in CPB-related surgeries exhibit heparin resistance. GTC reports that it has conducted studies related to this indication and one or more additional clinical trials may be required to obtain FDA approval.
GTC has submitted the first part of its rolling BLA for the use of ATryn in preventing deep vein thrombosis in HAD patients undergoing high risk surgical procedures and in childbirth. Filing of the second and final part of the BLA submission is planned for the third quarter. ATryn already has been granted both orphan drug and fast track status for HAD by the FDA.
Geoffrey Cox, CEO and chairman of GTC, said Ovation is "a strong match to maximize ATryn's potential as the market's only recombinant antithrombin."
GTC reports having several recombinant forms of plasma proteins in its pipeline, monoclonal antibodies as well as follow-on biologics. Ovation has a number of products focused on hematology/oncology, the central nervous system, and drugs for hospital use.
Encore developing product to treat stroke and TBI
Encore Therapeutics (ETI; Carlsbad, California) reported that it has created a proprietary nano-emulsion intravenous formulation of progesterone suitable for the treatment of stroke and traumatic brain Injury (TBI).
The protective effect of progesterone in treating brain injury has been firmly established, but the inability to develop a product that can be used in the field by first responders and the absence of intellectual property covering a composition of progesterone have prohibited commercialization. To address these deficiencies, ETI has developed ETI-411, a novel lyophilized, easy-to-reconstitute and administer IV progesterone formulation. The company is now seeking a development and commercialization partner to bring ETI-411 to market.
Dr. Paul Marangos, CEO and chairman of ETI, said, "Treatments for stroke and TBI and have eluded the best efforts of drug development, largely due to drug toxicity and lack of efficacy. Progesterone is safe and has been documented by many investigators to have broad neuroprotective efficacy in both pre-clinical and clinical studies but its commercialization has not been feasible till now. We are excited about finding a partner to commercialize ETI-411."
ETI-411 is based on a proprietary phospholipid nano-emulsion formulation that is composed entirely of natural or generally regarded as safe (GRAS) components. This formulation platform has been utilized successfully for a variety of other IV drugs currently in human clinical trials.
Dr. Andrew Chen, chief scientific officer and inventor of the formulation, termed ETI-411 "a substantial improvement over the current means of delivering IV progesterone. It is supplied in a stable, lyophilized format that can be easily reconstituted and administered, making it ideal for first responders and ER personnel treating stroke and TBI victims."
ETI was founded by Marangos and Chen in 2006 to extend and enhance the action of existing drugs through novel formulation strategies. The company has devised multiple applications of its phospholipid-based formulation technologies and is seeking development and marketing partnerships.
United, Lung RX seek approval for inhaleable drug for PAH
United Therapeutics (Silver Spring, Maryland) and its subsidiary, Lung Rx, in late June submitted a New Drug Application to the FDA for an inhaled formulation of treprostinil (ITRE) for the treatment of pulmonary arterial hypertension (PAH), a chronic, life-threatening disease.
United based its application on data from its TReprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH-1) trial, a randomized, double-blind, placebo-controlled trial of patients with PAH. ITRE, prepared once per day, is administered in four daily inhalation sessions using the NEBU-TEC Optineb ultrasonic nebulizer, the sessions one to two minutes long,
The company said that TRIUMPH-1 is one of the first pivotal trials to assess the incremental benefit of an add-on therapy in PAH patients already receiving an approved background therapy. The study population consisted of 235 patients on an approved oral therapy for PAH, either bosentan (Tracleer), an endothelin receptor antagonist, or sildenafil (Revatio), a phosphodiesterase-5 inhibitor. The majority of patients were NYHA Class III (~98%) of varied etiologies, including idiopathic or familial PAH.
TRIUMPH-1's primary endpoint is the change in six-minute walk (6MW) distance at 12 weeks measured at peak exposure, defined by the trial protocol as 10 to 60 minutes after administration of ITRE relative to baseline. TRIUMPH-1 data confirmed improvement in median 6MW distance of about 20 meters (p<0.0005 at peak exposure.
In addition, the 6MW distance at week 12 relative to baseline at trough exposure was significantly improved, with estimated treatment effect of about 14 meters (p<0.007). Side effects were mostly mild or moderate in severity and were not dose-limiting in the majority of patients treated with ITRE, according to the company.
"We believe that an inhaled formulation of treprostinil will be a very desirable option for PAH patients," said Martine Rothblatt, PhD, CEO and chairman of United.
Protherics launches IIa trial of vaccine for hypertension
Protherics (Yorkshire, UK) reported that the first patient has been enrolled in a Phase IIa study of its Angiotensin Therapeutic Vaccine (ATV) for the treatment of hypertension in the UK. The majority of existing hypertension therapies are tablets which need to be taken on daily, usually for the rest of a patient's life. B ut many patients with high blood pressure fail to take their medicines as prescribed, and it is estimated that about 70% of patients with hypertension do not have their blood pressure adequately controlled.
Therefore, according to the company, a vaccine approach, which may require only three injections and a booster after six months rather than daily medication, should improve patient compliance with treatment.
In the Phase IIa, double-blind, placebo-controlled study of patients with mild to moderate hypertension has been initiated in the UK, 124 patients will be given a course of injections over six weeks. The study will assess the safety and tolerability of the vaccine, incorporating Protherics' vaccine adjuvant, CoVaccine HT. In addition both antibody response and effect on blood pressure will be assessed. The blood pressure results are expected in the first half of 2009.
Protherics said that it showed in a previous Phasse IIa study that a formulation of ATV, incorporating the vaccine adjuvant Alhydrogel, modulated key hormones involved in regulating blood pressure. A new formulation of ATV has now been developed, incorporating the CoVaccine HT adjuvant, which has demonstrated stronger immune response in pre-clinical models, the company said.
Andrew Heath, chief executive of Protherics, said, "A vaccine approach to the treatment of high blood pressure promises to address the issue of poor patient compliance with daily medication and thus reduce the incidence of stroke and heart attacks."
• Actelion (Allschwil, Switzerland) reported data showing that, in mildly symptomatic pulmonary arterial hypertension patients with World Health Organization functional Class II PAH, bosentan (Tracleer) prevented clinical deterioration by significantly delaying time to clinical worsening, and it reduced the number of patients worsening to WHO functional Class III/IV disease. A significant reduction in pulmonary vascular resistance and a positive trend in increasing the 6MWD also were observed. The data were published in The Lancet.
• Action Pharma A/S (Copenhagen, Denmark) reported the start of a Phase II trial of AP214, aimed at treating organ failure associated with severe cardiovascular diseases, specifically for patients undergoing cardiac or vascular surgery who are at risk for renal failure. AP214 is designed to act through melano-cortin receptors to prevent both ischemia and reperfusion injuries. The study is expected to enroll about 75 patients.
• BSP (Tel Aviv, Israel) reported raising $2.6 million in a private funding round that included existing shareholders in the company and new investors. The firm, which develops and markets systems for noninvasive diagnosis and monitoring of ischemic heart disease, said the funds will enable it to step up its marketing and business development efforts in the U.S.
• CV Therapeutics (Palo Alto, California) reported earning a milestone payment of $10 million from TPG-Axon Capital in connection with the commercial launch of Lexiscan by Astellas Pharma US (Deerfield, Illinois). CV Therapeutics said it will recognize the milestone as revenue earned in 2Q08. CV Therapeutics received $175 million at the closing of a non-dilutive financing transaction with TPG-Axon in which TPG-Axon agreed to pay up to $185 million in exchange for rights to 50% of its royalty on North American sales of Lexiscan.
• Metabasis Therapeutics (La Jolla, California) reported that results of its 14-day Phase Ib trial in subjects with mild hypercholesterolemia showed that MB07811 was safe and well tolerated across the seven doses tested, ranging from 0.25 mg to 40 mg. No differences in heart rate, heart rhythm or blood pressure were observed between the MB07811 and placebo arms. Mild increases in liver enzymes were observed at the higher doses of MB07811, along with dose-related mean shifts in thyroid hormone levels.
• Resverlogix (Calgary, Alberta) reported completing an exploratory efficacy analysis of the data from Phase I, seven-day RVX-208 treatment subjects. Analysis from two independent and external laboratories of blinded serum samples showed consistent improvements of key biomarkers for the reverse cholesterol transport (RCT) pathway. RCT is a pathway by which accumulated cholesterol is transported from the arterial wall to the liver for excretion, thus preventing atherosclerosis.