By Mandy Jackson
April 20, 2012
The tiny company whose technology underpins the development of the experimental anti-beta-amyloid antibodies being developed as an Alzheimer's prophylactic by Janssen, Elan, and Pfizer is looking to leapfrog that approach and develop a second line of attack for Alzheimer's disease therapeutics.
While the patent for its Antisenilin technology underlying two amyloid therapeutics under development by Pfizer have been challenged at the European Patent Office (EPO), New York-based Intellect Neurosciences has engaged researchers at the University of California, Irvine (UCI) to study RV03, the company’s preclinical immunotherapy created with its Recall-Vax technology to target the delta tau protein as well as beta-amyloid, which could be the first prophylactic Alzheimer’s vaccine.
Intellect's passive immunotherapy Antisenilin technology was licensed for the development of bapineuzumab, the anti-beta-amyloid monoclonal antibody that the Janssen/Elan/Pfizer partnership is currently testing in multiple Phase III safety and efficacy studies. Pfizer also has a Phase II antibody ponezumab that was developed using Antisenilin.
Meanwhile, Intellect sees RV03, which does not rely on the company’s Antisenilin platform, as a best-in-class follow-on to those more advanced passive immunotherapies that seek to slow or stop progression of Alzheimer’s disease. RV03 is an active immunotherapy based on Intellect’s Recall-Vax platform in which a "flu shot-like" injection is used to provoke an immune response, and RV03 is directed at two rather than one of the plaque-forming targets seen in Alzheimer’s disease.
"Until now, all Alzheimer's immunotherapy, whether active or passive, have been to target just one toxic protein, usually amyloid beta. RV03 targets both amyloid beta and delta tau, two proteins that act in concert early in the disease and have synergistic effects that together cause irreversible damage and death of nerve cells." Intellect CEO and Chairman Dr Daniel Chain told Scrip. He believes that dual targeting meant that RV03 was expected to be "more efficacious that other vaccines."
Intellect is the exclusive owner of the intellectual property underlying RV03 and it will fund the preclinical research at UCI led by Dr Frank LaFerla, director of the university's Institute for Memory Impairments and Neurological Disorders.
Although neither UCI nor its scientists has a commercial interest in RV03, Dr Chain said Dr LaFerla's lab "has unique resources and abilities" needed to steer RV03 towards clinical trials and regulatory submissions. According to Dr LaFerla, his laboratory was the first to demonstrate that amyloid-beta facilitates the accumulation of tau through a variety of mechanisms, including by interfering with proteasome function and by reducing a key chaperone protein called Chip.
The studies at UCI will focus on demonstrating decreased pathology and improved cognition in preclinical Alzheimer's models.
"We previously tested similar candidates across species and demonstrated the ability of these vaccines to provoke a robust and highly specific immune response," Dr Chain said.
While Intellect reported $3.9 million in research and administrative expenses for the three months of 2011 and just $1.1 million in cash and investments as of 31 December 2011, Dr Chain said the company has multiple ways to monetize its technology and licensing portfolio.
"The company anticipates funding the development of RV03 through a combination of new equity investments, strategic partnerships and other sources of non-dilutive funding, including government grants," he said.
Intellect had $14 million in net income during the last three months of 2011, because of $18.3 million in revenue based on changes in the value of derivative instruments and preferred stock liability. The company is traded on the Pink Sheets and its stock traded at $.05 per share as of 19 April. Its market cap was $3.91 million.
Intellect has built a considerable patent estate –31 patents in the US, EU and Japan – around the Antisenilin technology, but the company is still caught up in a patent dispute initiated in 2009 by Elan and Wyeth, now part of Pfizer.
The European Patent Office in a preliminary action suggested that it would revoke the Antisenilin patents for passive immunotherapy for Alzheimer's disease based, Intellect claims, on formalistic objections rather than concerns about inventiveness or novelty. Intellect responded to that action in February by appealing against that decision.
Dr Chain believes that the large pharmaceutical companies are flexing their muscles in an attempt to swim against Intellect's established intellectual property tide. "Intellect was quite surprised and disappointed by the action of these companies, which it believes are using bullying tactics meant to intimidate a company the small size of Intellect," Dr Chain said.
He noting that Intellect expects to be granted additional patents in Europe by the time therapies that use Antisenilin technology are approved in the EU. In addition, the company received notice in March from the US Patent and Trademark Office that patent claims on therapeutic antibodies generated by Antisenilin for the treatment of Alzheimer's disease would be allowed. The granting of the patent involved should trigger a $2 million milestone payment from one of Intellect's licensees.
The broader Alzheimer's disease landscape
Until more clinical data is available, the promise of beta amyloid-targeting immunotherapy – passive or active – will remain unrealized. Dr Howard Fillit, a practicing geriatrician, neurologist and executive director of the Alzheimer's Drug Discovery Foundation (ADDF), told Scrip that antibodies have been shown during the past five to seven years to be effective in removing amyloid-beta from the brain, but they haven't shown that they can significantly prevent the progression of dementia. "We need proof-of-concept," he said.
Antibodies against tau are relatively new, with work still in the preclinical stage. Dr Fillit noted that animals treated with monoclonal antibodies that target tau showed improvement in Alzheimer's symptoms.
Other tau-based technology focuses on preventing the breakdown of tau protein. Tau stabilizes microtubules, which can tangle and cause Alzheimer's and other neurodegenerative diseases when tau breaks down. ADDF has funded research in this area by Vancouver, British Columbia-based Allon Therapeutics Inc., which has a therapeutic in Phase II development.
"We started out 10 years ago or more funding research on amyloid therapies, but we were also the first to fund tau therapies," Dr Fillit said. "We're sort of a seed capital foundation to fund innovative therapeutics. We're glad the pharmaceutical industry is investing billions of dollars in clinical trials."
Now, ADDF is moving on to other approaches, such as mitochondrial agents to reduce energy deficits in the brain, because it most likely will take a combination of treatments to slow or prevent the progression of Alzheimer's disease.
Dr Fillit said that demonstrating efficacy was the most important issue now, because both regulators and patients were willing to accept some safety risks for a therapy that proves effective at slowing or stopping progression of dementia. He said amyloid-beta vaccines generally have proven to be pretty safe, except for some small haemorrhages, but efficacy was still a hurdle.
The 9 April FDA approval of Amyvid, a radioactive diagnostic agent for imaging amyloid-beta plaques in patients, was a key step forward in the field, said Dr Fillit. "It was a landmark event in the history of Alzheimer's disease. It's important for early diagnosis and it's already being used to accelerate clinical trials," Dr Fillit said.
Use of Amyvid and similar agents should allow better and earlier assessments of the impact of immunotherapies and other Alzheimer’s treatment in patients' brains.
ADDF provided early funding for research conducted at the University of Pennsylvania, which led to the development of Amyvid before the technology was spun out in a company called Avid Radiopharmaceuticals, now a subsidiary of Lilly.