The approval of Eli Lilly & Co.’s Amyvid (florbetapir F 18) as a diagnostic agent for Alzheimer’s disease is a significant addition to the armamentarium, but the true need in the space is the approval of therapies that can alter the course of the disease.

Amyvid, from Lilly’s Avid Radiopharmaceuticals Inc. unit, cleared FDA April 6 as a radioactive diagnostic agent to be used with Positron Emission Tomography imaging of the brain to estimate beta-amyloid plaque density; the agent works by binding to beta-amyloid plaques so they will show up on a PET scan.

But in the absence of a cure, injecting an imaging agent to measure the extent of Alzheimer’s trademark plaque deposits may be an invasive and expensive exercise not unlike genetic testing for an incurable disease like Huntington’s. Amyvid will be available in June at a price of $1,600 per patient-ready dose, and the cost is not yet reimbursable. Lilly has petitioned the Centers for Medicare and Medicaid Services to revise its Medicare national coverage policy, which forces newly approved PET imaging agents to go through a national coverage analysis by CMS before Medicare will pay for them Also see "Medicare Coverage For Amyvid Complicated By PET Policy; Lilly Seeks Revision" - Pink Sheet, 6 February, 2012..

Amyvid is approved for use in adults with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline Also see "Lilly Gains Amyvid Approval, But Reimbursement Still A Hurdle" - Pink Sheet, 9 April, 2012.. Labeling cautions it is to be used as an adjunct to other diagnostic evaluations and that “a positive Amyvid scan does not establish a diagnosis of AD or other cognitive disorder.” It also cautions that Amyvid-assisted scanning is not to be used to predict dementia or other neurologic conditions.

In March 2011, FDA issued a “complete response” letter on Avid’s marketing application after an advisory committee voted against approval over concerns that physicians wouldn’t know how to interpret the results Also see "Avid Amyvid Could Be Approved If Training Improves, Advisory Committee Says" - Pink Sheet, 20 January, 2011..

While Amyvid may be an imperfect tool, it is a welcome advance against an intractable disease.

The approval a year later came with no Risk Evaluation and Mitigation Strategy requirement for training, though labeling is very clear that a negative scan merely “reduces the likelihood that a patient’s cognitive impairment is due to AD.” If the scan does reveal moderate to frequent amyloid plaques, language cautions that, while this amount of amyloid plaque has been found to be present in patients with AD, it can also be present in patients with other neurologic conditions, as well as in older people with normal cognition.

Still, while Amyvid may be an imperfect tool, it is a welcome advance against an intractable disease.

The Alzheimer’s community is optimistic that readouts from Phase III trials due this year of two different experimental biologics will support at least one regulatory submission for a disease-modifying therapy, but the preceding failures in the space have tempered expectations. Then again, even if Amyvid isn’t pressed into use right away as a precursor to an effective therapy, it is still a boon for clinical investigators designing future trials.

Needed: A Cholesterol Number For The Brain

Though most of the forward movement against Alzheimer’s has been in the area of diagnosis and prediction, a substantial obstacle to progress against the disease remains the lack of biomarkers, a stakeholder panel at the recent annual meeting of the Massachusetts Biotechnology Council agreed.

Both PET scans and spinal taps – to obtain cerebrospinal fluid (CSF) and assess levels of Abeta-42, the protein that clumps to form amyloid plaque – are invasive and expensive procedures that can’t be easily repeated and can’t be done in a primary care physician’s office.

The panelists, who met March 26 to assess the state of drug development in the space, named biomarkers and the closely related regulatory challenge of designing and conducting trials as their top concerns. “We really are desperately in need of the equivalent of the cholesterol number or the blood glucose number or blood pressure number for the brain that can be measured very conveniently,” said Ajay Verma, vice president for translational neurology at Biogen Idec. Inc. “That would be transformative.”

If there were a “really good CSF biomarker,” Verma pointed out, Alzheimer’s is “a serious enough disorder that it would get adopted.”

Actually, North American physicians are far too conservative about using spinal fluid analysis, said Dennis Selkoe, co-director of the center for neurologic diseases at Brigham & Women’s Hospital and Harvard Medical School. Selkoe, a scientific founder of Elan Neurosciences, which evolved into Elan Corp. PLC, asserted that “until we get a good blood test or until the imaging technology becomes inexpensive and widely available, the spinal fluid exam is safe if properly done.”

Alternatively, more sensitive imaging agents may soon follow Amyvid. Radiopharmaceutical company Navidea Biopharmaceuticals Inc., in Dublin, Ohio, has an Alzheimer’s imaging agent it licensed from AstraZeneca PLC headed into late-stage development. The agent, AZD4964, which also binds to beta amyloid deposits, may have superior sensitivity to others in the industry pipeline, making it a potentially more useful diagnostic tool. Navidea plans to take AZD4964 into Phase III testing early in 2013 ([A#14120228006]).

Massive Trial Requirements “A Bridge Too Far”

As for the trials, the enormous cost of conducting a trial that is long enough and includes enough patients to show a pro-cognitive benefit is causing developers to become risk-averse, argued Barbara Tate, vice president of biology for Cambridge, Mass., start-up Satori Pharmaceuticals Inc. Additionally, said Tate, “we don’t get enough iterations in that later stage to really inform the discovery phase” of drug development.

Lilly’s failed Phase III trial for the gamma secretase inhibitor semagacestat is notable for its cost as much as for the mechanism being tested, Kees Been, CEO of Watertown, Mass., CNS drug company EnVivo Pharmaceuticals Inc., said in an interview following the panel discussion. “What this trial did show is what it takes to prove a disease-modifying effect in Alzheimer’s, which is 4,000 patients dosed over two years at a cost of around $350 million. And that has become a bridge too far.”

Ultimately, the question of how to get these drugs to market will require “a debate, discussion and dialogue with the regulatory agencies at large, because we have to come up with endpoints that are feasible,” Been stressed. Currently, the regulatory definition of a disease-modifying drug is that the time and cognitive decline curves diverge. To show that divergence, the trial has to allow enough time to measure a natural decline in cognition, and then “you have to measure the effect [of your drug] on that natural decline,” Been explained, adding that the process “is going to take two years on many patients.”

It is generally accepted that people with mild cognitive impairment and positive amyloid scans have a high risk of progressing to a more severe form of disease within about 18 months.

While there can be no shortcuts on safety, a combination endpoint of biochemical measures and scans potentially could be used to show that the experimental therapy has a sustained effect on a surrogate endpoint, such as Abeta-42 levels, for the purpose of approval, Been suggested. Then, the drug’s pro-cognitive effect could be confirmed “as you start dosing patients.”

If results expected later in the year from much-anticipated tests of the industry’s two lead Alzheimer’s prospects are negative, “I’m not sure what that proves [in terms of disease theory], but it’s going to significantly abate pharma’s appetite” for risk, Been said.

Bapineuzumab And Solanezumab

Lilly is invested in Alzheimer’s in a big way. Following on the semagacestat failure in 2010, the company went ahead with solanezumab, a monoclonal antibody that works by a different mechanism of action, drawing amyloid out of the brain and “soaking it up” in the plasma. Using biomarker data, the company demonstrated Abeta clearance in CSF and plasma in Phase II.

Two Phase III studies, EXPEDITION and EXPEDITION-2, each of which enrolled 1,000 patients with mild disease (judged through imaging), aim to demonstrate improvement in cognition over 18 months using established testing and cognition scales. Top-line data are expected in the third quarter, with full presentation later at a scientific meeting. Lilly has been cagey about expectations for solanezumab, though CEO John Lechleiter told analysts in December that the company plans to give the biologic “every chance” ([A#29120117003]).

Analysts put the chance for the program’s success at anywhere from 10% to 25%, similar to their estimates for bapineuzumab, the biologic that now belongs to Pfizer Inc., in partnership with Elan and Johnson & Johnson Also see "J&J And Elan Strike A Deal On Key Alzheimer's Disease Assets" - Pink Sheet, 6 July, 2009..

Both solanezumab and bapineuzumab are considered passive immunotherapies.

Bapineuzumab induces an immune response to clear beta-amyloid plaque buildup in the brain. Phase II data for the drug were mixed: it failed to meet its primary efficacy endpoints, though its developers maintained it showed statistically significant and clinically meaningful benefit in a subgroup of patients who test negative for apolypoproteinE4 (ApoE4), a gene associated with a higher risk for the disease.

Over 4,000 patients, both ApoE4 positive and negative, are enrolled in the bapineuzumab Phase III program. Data from the two U.S. trials, being conducted by J&J, are expected mid-year.

Curiously, autopsies from the Phase II program showed some patients’ brains were clear of amyloid plaque, yet they died of dementia, supporting the theory that the disease becomes irreversible once plaque deposits begin and Alzheimer’s is diagnosed. The term “amyloid hypothesis,” a chicken and egg debate over the place of amyloid in the etiology of the disease, has evolved along with the science. Generally it is now believed that amyloid aggregation is involved in disease progression, but whether it is a cause is anyone’s guess. The presumptive mechanism underlying many experimental Alzheimer’s drugs is to interfere with the so-called amyloid cascade, in which the “sticky” Abeta-42 proteins clump to form plaque. The most popular working hypothesis is that getting upstream of that process will prove disease modifying Also see "Pipeline Of Alzheimer's Drugs Targeting Amyloid-Beta Protein" - Pink Sheet, 18 July, 2011..

A number of companies are now working in the area of pre-diagnosis mild cognitive impairment.

Roche is using a CSF biomarker strategy to find and treat mild cognitive impairment patients with its Abeta peptide antibody gantenerumab. The company is developing a companion diagnostic based on research by the Alzheimer’s Disease Neuroimaging Initiative, which has identified a threshold of Abeta in spinal fluid that is a predictor for Alzheimer’s risk. Phase II data are not expected until 2015 Also see "Roche Is Sudden Pioneer In Alzheimer's Research With New Trial In Early Patients" - Pink Sheet, 12 May, 2011..

Also targeting very early stage disease, Bristol-Myers Squibb Co. is working on a gamma secretase inhibitor (BMS-708163) it says avoids the selectivity flaw that caused Lilly’s semagacestat to fail. A Phase II trial is fully enrolled with 270 patients, and data are now anticipated at the end of 2013 Also see "Bristol Opens A Phase III Door Into Gamma Secretase As Lilly Closes Another" - Pink Sheet, 25 July, 2011..

Don’t Abandon A Generation

While that early-stage path of inquiry is inviting, “We can’t abandon a whole generation” of Alzheimer’s patients by only going after those strategies, asserted Satori’s Tate. While she acknowledged that the idea of treating patients early in the disease process should be pursued, Tate advised an approach that includes therapies to help remediate the symptoms of the disease while looking for disease-modifying therapies. “People [now] in their 50s and 60s are going to benefit from symptomatic approaches,” she said. For disease-modifying efforts, Tate urged that rather than setting out to find a new mechanism, well-described targets should be better exploited by “looking for the proper patient for the proper approach.”

Privately held Satori came on the scene in 2009 Also see "Alzheimer’s Player Satori Wades Into Fray With Mystery Technology – And $22 Million" - Pink Sheet, 12 January, 2009.. The company’s lead compound, which wasn’t at first revealed, is a “very selective and novel” gamma secretase modulator, Tate said.

Gamma secretases work naturally by cutting up amyloid precursor proteins into fragments, one of them being Abeta 42. An inhibitor can totally stop production of those fragments, including Abeta, but it also affects the other proteins, making specificity a problem. Modulating the target may be the key to mastering the mechanism.

For its part, EnVivo aims to make a difference by slowing cognitive decline. The firm’s lead candidate, EVP-6124, is a partial agonist of the alpha-7 nicotinic receptor. It works by sensitizing acetylcholine receptors in the brain to produce a normal response to lower amounts of the neurotransmitter, creating a pro-cognitive effect. A Phase IIb trial in patients with mild to moderate Alzheimer's has completed enrollment and the company expects to release top-line data in coming weeks, with a full report in July at the Alzheimer’s Association International Conference in Vancouver.

If the drug creates a curve separate from the natural decline of the disease for one or two years, “we have a very significant drug on our hands, especially for patients,” Been said.

The candidate has already produced positive results against the cognitive and functional symptoms of schizophrenia and is headed into a global Phase III trial for that indication soon.

EnVivo’s efforts at a disease-altering effect on Alzheimer’s include a gamma-secretase modulator that has completed a Phase I trial to identify the maximum tolerated dose. In Phase Ib, the company plans to take the compound into elderly volunteers to test its ability to lower Abeta levels in the CSF.

Amyvid Approval Just The Start Of A Critical Year For Alzheimer’s

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