Despite setbacks, Alzheimer’s tx pipeline is full

More than 60 drugs remain in the developmental pipeline for Alzheimer’s disease, although the past several years have seen numerous once-promising agents bite the dust.

‘It’s discouraging. A number of medications have gone out of research development in the last 2 to 3 years, and they were the ones that had great hope for.”

“A lot of hope and money and work time has been put into Alzheimer’s disease, and it doesn’t always come up positive. It’s kind of sad how many of these things go belly up after looking very promising in phase I and early phase II that they go boom,” observed a professor of neurology, psychology, and psychiatry, and director of the behavioral neuroscience and Alzheimer’s clinic at the University of Arizona, Tucson.

Among the notable failures was tarenflurbil. This drug is a modulator of gamma-secretase, a protease that cleaves amyloid precursor protein to produce the amyloid-beta peptide that consists of amyloid plaques, a defining feature of Alzheimer’s disease. The phase III trial for tarenflurbil was negative. Similarly, phase II/III clinical trials of hydroxylvaleryl mono-benzoca-prolactam, a gammasecretase inhibitor, have been halted.

An alternative approach to the treatment of Alzheimer’s disease relies upon inhibiting aggregation of amyloid fibrils with the goal of reducing levels of soluble amyloid-beta peptide. One such agent, tramiprosate, showed evidence of disease stabilization in phase II studies, but North America phase II trials proved either negative or inconclusive, and the phase III European study has been stopped. Tramiprosate’s manufacturer, Neurochem, plans to market it as nutraceutical rather than pursuing further development of tramiprosate as a drug.

Development of neotrofin, a drug that mimics the effects of nerve growth factor and other neuroptrophins, which generate or support the growth of brain cells, has been discontinued because of disappointing phase II results.

So what still looks promising for Alzheimer’s disease?

Amyloid fibril antiaggregation therapy is not dead, despite the setback with tramiprosate. A research is now ongoing phase II/III clinical trials of Elan’s amyloid fibril antiaggregation agent known for now as D005, is based upon a sugar found in coconut, oak bark, and dogwood flowers.

Nor is treatment with neurotrophic agents a closed avenue, despite the failure of neotrofin. Proof of principle has been provided by evidence of efficacy for intrathecal infusion of nerve growth factor in patients with Alzheimer’s disease, although this is a therapy that’s clinically impractical as it entails aggressing the basal forebrain via stereotactic brain surgery. Interest is now focused on Cerebrolysin, an intramuscularly administered agent which phase II trials led to improvements in memory and concentration in about twothirds of treated patients. Cerebrolysin is approved in Austria and several dozen other countries, and US clinical trials are ongoing.

Immunotherapy, both active and passive, continues to be a highly active areas of investigation in Alzheimer’s disease. Active immunization was nearly detailed for a time with the early halt of a phase IIa study of AN-1792, the highly publicized first so-called Alzheimer’s vaccine, after 18 of 360 subjects developed florid encephalitis, paralysis, or death. Intriguingly, however, 5-year follow-up of titer-positive patients showed a significant reduction in placement in longterm care facilities.

AN-1792’s downfall is thought to have been that it was a synthetic form of the full 42 amino acid amyloidbeta peptide. Pfizer, Wyeth, and Novartis are now developing vaccines that use smaller amyloid fragments as immunogens. The Pfizer vaccine, for example, uses just 6 of the 42 amino acids from amyloid-beta peptide. These new vaccines seem to have far fewer side effects.

But the first immunotherapy to gain an indication for Alzheimer’s disease may well be Baxter’s polyclonal intravenous immunoglobulin, a doctor at University of Arizona predicted. This passive immunotherapy is already familiar to neurologists, who have long used it for patients with multiple sclerosis, Guillain-Barre syndrome, and other disorders. It’s well tolerated. Data from phase II studies showed evidence of benefit in patients with mild to moderate Alzheimer’s disease, and phase III trials are ongoing.

Another approach to passive immunization using exogenous antibodies is bapineuzumab, a monoclonal antibody against amyloid-beta protein, being develop by Wyeth and now in phase III testing. A monoclonal antibody is a more specific form of therapy than IV immunoglobulin, which could be advantageous. of a title to a landmass or a maritime area of the earth and its use and exploitation. Noted international law scholar L. Oppenheim emphasizes the importance of effective control or possession of a territory when he noted:

The territory must really be taken into possession by the occupying state. For this purpose it is necessary that it should take the territory under its sway (corpus) with the intention of acquiring sovereignty over it (animus). This can be done by acquiring sovereignty over its animus. This can be done by a settlement on the territory accompanied by some formal act, which announces both that the territory has been taken possession of and that the possessor intends to keep it under his sovereignty.

A more contemporary scholar on territorial acquisition, Surya Sharma, supported this opinion when he wrote:

“Discovery and symbolic annexation, taken separately or together, were not regarded by states as sufficient to constitute an independent mode of exclusive territorial acquisition. These modalities were frequently equated with the intent to occupy. The most extreme legal title which the general community concedes in favor of these modes [of territorial acquisition] was the creation of an “inchoate title,” which had to be perfected within a reasonable time by effective occupation, or else the inchoate title would lapse. In short, nothing less than effective occupation was regarded as sufficient to establish title to territory and temporary titles created by discovery and symbolic annexation have to be perfected within a reasonable time by effective control. This view, has the support of the majority of influential writers and a vast body of state practice, in addition to judicial backing.”

The importance of effective control over discovery has been clearly imputed by famous legal cases such as the Island of Palmas Case ( 1928), the Clipperton Arbitration Case (1931) and the Minquiers and Ecrehos Case (1953).

The island of Palmas Case involved a dispute between the United States and the Netherlands over the island of Palmas, which is located between the Celebes Island and the Philippines. The United States, as a successor to the rights of Spain over the Philippines, at beast it creates an inchoate title which must be perfected within a reasonable time by effective occupation or it will lapse.”

“Another case that provides an important precedent on the importance of effective occupation over discovery is the Clipperton Case Island Arbitration Award.”

Rene mentioned a third case to demonstrate his point — the Minguiers and Ecrehos Case.

He wrote: “The three cases raise valid questions on the legal validity of China’s claim of sovereignty to the Spratlys in three ways. First, they weakened China’s claim over those islands on the basis of discovery. The three cases uphold an argument that discovery, in itself, is an insufficient basis for the acquisition of a territory.”

Rene’s article provided more insights but we opted to use only this portion that drives home the point — historic claims, such as the one we have with Sabah, are the weakest cases when international courts decide territorial dispute. Favoring the historical claims would have opened a Pandora’s box worldwide.

The problem with our charlatans and self-appointed Sabah experts is that they choked on reference materials and failed to see the big picture. They should first make sure that their brains were engaged before putting their mouths into gear. They didn’t bother to check if we have a say in something that’s strictly a row between the Kiram family and Malaysia.

Never mind the President Benigno S. Aquino III (P-Noy) haters who rode on this Sabah issue to try to bring down the president’s political stock. They’re best left to wallowing in their venom. What’s deplorable is how otherwise right thinking Filipinos had been taken for an emotional ride. Many bit into the Sultanate of Sulu’s deception and were ready to castigate one of the best presidents that we ever had.

Alas, we’re indeed our biggest enemies.

Shakespeare: “Madness in great ones must not unwatched go.”

E-mail: macesposo@yahoo.com Website: www.chairwrecker.com