On April 10, FDA approved Lilly’s Amyvid (florbetapir F 18 injection) as a PET imaging reagent to be used in adults who are being evaluated for Alzheimer disease (AD) and other causes of cognitive decline.
Lilly gained Amyvid through its acquisition of Avid Radiopharmaceuticals in 2010 for an up-front payment of $300 million. Avid stockholders are eligible to receive up to $500 million contingent upon regulatory and commercial milestones.
The test detects and images beta amyloid neuritic plaque density in the brain. A negative Amyvid scan indicates few to no neuritic plaques and reduces the likelihood that any cognitive impairment is due to AD. A positive scan indicates moderate to frequent plaques, or amounts of plaque found in patients with AD, in patients with other types of cognitive impairment, and in older people with normal cognition.
Thus, since beta amyloid accumulates naturally in some people as they age, the FDA did not allow use of the test as a sole diagnostic for the disease. Should beta amyloid accumulations occur along with other disease symptoms such as cognitive decline, the test can help guide a diagnosis.
“It’s estimated that one in five patients clinically diagnosed with probable Alzheimer disease during life do not end up having Alzheimer disease pathology upon autopsy,” commented Daniel Skovronsky, M.D., Ph.D., Avid’s president and CEO and global brand development leader for Amyvid at Lilly. “The approval of Amyvid offers physicians a tool that, in conjunction with other diagnostic evaluations, can provide information to help physicians evaluate their patients.”
The test may also provide a means of assessing the efficacy of other AD and neurodegenerative disease drugs in development aimed at preventing neuritic plaque formation.
While physicians evaluating older patients may have another tool to help make an Alzheimer disease diagnosis, few to no drugs have emerged that impact either the cause or progression of these diseases. Early- and late-stage drug failures, mostly with small molecule drugs and the odd peptide, populate the neurodegenerative disease landscape.
Companies have moved away from these types of drugs toward biologics like mAb therapeutics. Those that can successfully develop novel treatments, despite the formidable obstacles to drug development, have a lot to gain. The global market for neurodegenerative drugs will exceed $43.4 billion by 2015, Global Industry Analysts predict.
Failed Attempts at Treatment
In July 2010, Vernalis and Biogen Idec halted development of their Parkinson disease drug at an early stage of development due to its potential to cause serious adverse side effects. The companies elected to discontinue work on vipadenant, an adenosine A2A receptor antagonist, following a review of preclinical toxicology studies.
It was hoped that the drug candidate might have helped restore motor function in Parkinson patients without side effects such as nausea and uncontrolled movement seen with current treatments.
Among the more spectacular failures of the recent past is Medivation’s dimebon. The firm reported in March that the drug did not produce significant improvements for patients in a 12-month study. Results mirrored two shorter Phase III trials in which dimebon failed to produce results surpassing those of a sugar pill.
Medivation’s shares fell 98% on the news. Shortly thereafter Pfizer then exited its partnership with the company, writing off its $225 million up-front payment; Pfizer had agreed to a $500 million milestone program. Medivation and Pfizer also discontinued development of dimebon for the treatment of Huntington disease (HD) due to its failure to show benefits in the Phase III Horizon trial.
Lilly’s contender for AD was its semagacestat, a peptide intended to inhibit the enzyme γ-secretase, which (along with β-secretase) catalyzes proteolysis of the precursor to β-amyloid. Research on laboratory rats suggested that the soluble form of this peptide is a causative agent in the development of Alzheimer disease.
In August 2010, however, Lilly announced that it had halted development of semagacestat because preliminary results from two ongoing long-term Phase III studies showed that it failed to slow disease progression and was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living.
Biologics with Potential
Companies are increasingly looking toward mAbs to overcome the challenges that small molecules and peptides have had with treating neurodegenerative diseases. The mAb candidates are being directed against components of the plaques characteristic of AD and other neurodegenerative diseases. The plaques are believed to play a fundamental role in their etiology and pathology.
This year may see the emergence of one of these novel mAb-based drugs. Among these are Lilly’s solanezumab, a humanized antibody that binds to soluble β-amyloid resulting in a reduction of amyloid plaque formation. Lilly began enrolling patients in two separate but identical Phase III trials in May 2009. The objective of the 18-month trials, expected to enroll a total of 2,000 patients age 55 and over, was to test whether solanezumab could slow the cognitive and functional decline of mild-to-moderate Alzheimer disease patients compared with placebo.
Analysts predict that even modest success for solanezumab in these trials will bode well for an entirely new class of drugs that can modify the disease itself instead of treating the symptoms. The total Alzheimer disease drug market is expected to nearly triple over the next decade, increasing from $5.4 billion in 2010 to $14.4 billion in 2020 in the U.S., France, Germany, Italy, Spain, the U.K., and Japan.
Lilly is expected to release final data from the trials this summer. This combined with the commercial launch of Amyvid puts Lilly in the completely unique position of owning both a diagnostic aid and a treatment for AD.
Another viable mAb therapeutic candidate for AD is bapineuzumab, being jointly developed by Elan, Johnson & Johnson, and Wyeth (now owned by Pfizer). Preliminary findings from a Phase II study reported in 2008 pointed to the candidate’s efficacy in clinical activity in noncarriers of the apolipoprotein E4 (ApoE4) allele, estimated to exist in 40% to 70% of AD patients. ApoE4 is a known genetic risk factor for development of AD.
A study reported in 2009 concluded that the primary efficacy outcomes in the Phase II trial were not significant and that treatment differences in the exploratory analyses “supported further investigation of bapineuzumab in Phase III with special attention to APOE ε4 carrier status.”
Other analyses of patients in the same studies found that treatment with bapineuzumab decreased levels of total and phosphorylated tau in the cerebrospinal fluid of patients with mild-to-moderate disease. Tau is another protein player thought to participate in plaque formation.
“This study provides support that anti-amyloid immunotherapy may affect the degenerative process in AD,” Kaj Blennow, M.D., Ph.D., of the clinical neurochemistry laboratory, University of Gothenburg, said in an interview with Medscape Medical News.
The study authors wrote that “the CSF level of P-tau thus seems to reflect the phosphorylation state of tau and the formation of tangles in the brain. The reduction in the downstream biomarker CSF P-tau following treatment with bapineuzumab suggests that bapineuzumab reduces brain levels of P-tau, which may also reduce the formation of tangles in the brain.”
But the authors also noted that “an important question remains whether such changes in CSF biomarkers correlate with clinical benefit. This question will be addressed in the ongoing bapineuzumab Phase III trials.”
Biogen Idec, meanwhile, is also pursuing biologics as a means of treating neurodegenerative disorders. In 2010, it acquired a subsidiary of Neurimmune and with it the worldwide rights to three preclinical immunotherapy programs for an initial payment of $32.5 million and up to $395 million in contingency fees. The three programs focus on human antibodies that target the proteins alpha-synuclein, tau, and TDP-43. All three targets are considered relevant for treating and preventing several neurodegenerative diseases including AD, PD, and amyotrophic lateral sclerosis.
Development of a treatment for AD and other neurodegenerative diseases remains a brass ring for the pharmaceutical industry. It is one of the few therapeutic areas, some analysts have said, where a new drug could achieve blockbuster status.
Questions about clinical benefits of preventing plaque formation, either through interfering with plaques themselves or with their potential components, will haunt the development of any biological aimed at them. As data from such antibody studies emerges in the third quarter of this year, clear clinical evidence may establish the value of inhibiting the plaque formation thought to kill brain cells.