NEW YORK ─ Italian startup Diadem is looking to take on an obstacle in the ability to treat Alzheimer's disease: the lack of diagnostic tests that can detect early-stage disease to slow down its progression.
Based in Milan, the company plans to launch its AlzoSure blood-based test that uses an antibody to target changes in the p53 protein. Specifically, the test detects unfolded p53, a conformational change of P53 that reflects the production of amyloid beta in the brain, Diadem's newly appointed CEO Paul Kinnon said in an interview.
The development of the test comes as blood-based biomarkers for early Alzheimer's disease detection and drugs for treatment are taking center stage in efforts to slow disease progression.
Last week St. Louis-based C2N Diagnostics established a benchmark by becoming the first company to bring a blood-based test for Alzheimer's to market. Its PrecivityAD test uses mass spectrometry and measures levels of amyloid beta and apolipoprotein E in patient blood.
In a separate development involving an antibody to target amyloid beta, Biogen’s stock soared on Wednesday after FDA staff appeared to support the approval of the company’s experimental Alzheimer’s drug. Aducanumab, expected to be most helpful for people experiencing early signs of Alzheimer's, would become the first new Alzheimer's therapy in nearly two decades.
The potential advance for Biogen "reinforces the need for real prognostic testing" that will enable doctors and clinicians to advise patients early about the likely onset of dementia and Alzheimer’s, even in healthy asymptomatic patients, Kinnon said, adding that many drugs developed for Alzheimer's over the years have failed during clinical trials, partly because of the lack of a suitable test to help identify appropriate patients.
For sales of its test, Diadem will target physician clinics and hospitals for diagnosis and pharmaceutical companies to enable patient stratification during the development of drugs to slow Alzheimer's progression.
Kinnon said its test is capable of detecting the disease between three and five years before the onset of symptoms, and would, therefore, provide vital information that enables early intervention and targeted care.
Scientists at the University of Brescia led by Daniela Uberti, cofounder and chief scientific officer at Diadem, began developing the biomarker test more than 10 years ago and founded the company as a spinout in 2012.
At the university, the scientists discovered that the biomarker was highly specific for the onset of Alzheimer’s and for identifying patients who are pre-symptomatic.
In studies completed so far, the tool has demonstrated an area under the curve (AUC) of greater than 90 percent, Kinnon said, adding that its performance in clinical studies has been a contributing factor to his decision to take the reins as Diadem's CEO.
"This company is a stereotypical diamond in the rough," said Kinnon, who until recently was CEO of Cambridge, UK-based PredictImmune, a developer of tests for immune-mediated diseases.
In early studies, AlzoSure provided a yes or no answer to whether symptomatic and asymptomatic patients were progressing to early-stage Alzheimer's, the firm said. So far, the company has evaluated its test in about 250 patients enrolled in a seven-year longitudinal study, said Kinnon.
On the back of encouraging early performance data, Diadem plans to begin offering the test beginning late next year from a CLIA-certified laboratory in the US.
The company would supply antibody test kits to labs to detect the biomarker by mass spectrometry, said Kinnon, who was named CEO in October. "It's a simple test that involves sending a 1-milliliter blood sample to the lab," he said. "The lab extracts plasma from the sample and puts it through an immunoseparation and precipitation process before detection with mass spec." The firm anticipates that the test's turnaround time would be less than four days.
In 2018, Diadem raised €1.5 million ($1.8 million) in a Series A financing round led by Milan-based Panakès Partners. The funding has enabled the company to attract advisors and board members, including Chairman Gerald Möller, former CEO of Boehringer Mannheim; Francesco Granata, former group vice president for Schering-Plough Europe and Canada; Antonio Boniolo cofounder of DiaSorin; and Antonella Fassio, former director of regulatory affairs at DiaSorin.
The financing has allowed Diadem to continue with the validation and launch of its kit. "We've got enough money in the bank to bring it to market," Kinnon said, adding that it will look to raise about €10 million from private investors before June 2021 to help it to continue growing the business.
The company is evaluating companies for strategic partnerships and anticipates first connecting with its academic collaborators who would offer the test from their labs. Diadem also has plans to discuss the potential for collaboration with large reference laboratories and smaller regional labs because such partnerships could enable a more rapid launch of the test.
Kinnon said that to support commercialization, the company is embarking on clinical validation trials involving several hundred additional patients and in the future intends to submit to the US Food and Drug Administration for clearance to market the test, as well as to obtain CE marking.
If clinical validation studies confirm AlzoSure's performance, the test will allow for discrimination of Alzheimer's from other forms of dementia and distinguish itself from positron emission tomography (PET) imaging, which is expensive and not readily available in all settings, Kinnon said.
By enabling testing via a blood draw, the test is also likely to be more broadly used than tests that require spinal fluid, he said.
Additionally, the Diadem test has the potential to enable drug companies developing anti-Alzheimer's drugs to more quickly screen large numbers of patients and select those with early-stage Alzheimer's most likely to respond to their therapies, Kinnon said.
Currently, clinicians prescribe approved cholinesterase inhibitors that can temporarily alleviate symptoms in the treatment of patients with Alzheimer's, Douglas Galasko, a clinician researcher in the department of neurosciences at the University of California, San Diego, said in an interview. "Beyond that, there are recommendations about lifestyle interventions, diet, sleep, exercise, and about management of vascular risk factors."
In the hands of a good clinician, "the clinical diagnosis of Alzheimer's disease is about 80 to 90 percent accurate," he said.
On the other hand, the diagnosis of earlier symptoms, such as mild cognitive impairment, "is quite a bit harder, and that is when a biomarker can be particularly useful," he added.
Galasko, who is not affiliated with Diadem, is developing an assay for the detection of α-synuclein aggregates, a marker of Parkinson's and Lewy body dementia, in patients’ cerebrospinal fluids.
He noted that many biomarker tests are in development for early-stage Alzheimer's disease, and the launch of the C2N test establishes a benchmark for blood-based tests for this indication.
C2N appears to be well ahead of Diadem on the path to commercialization, he said. Further, the Diadem test is difficult to evaluate because of the lack of available peer-reviewed data on clinical studies, but at a minimum it would need to demonstrate performance and clinical utility in future studies, he added.
Kinnon said it is important to note that Diadem's tool is prognostic and predicts the onset of Alzheimer’s in advance of its symptomatic detection. "Therefore, we believe our test could be used in advance of, or in a complementary way with, the C2N diagnostic test by doctors and clinicians to identify and treat Alzheimer’s patients," he said.
Jeff Cummings, founding director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a research professor at the University of Nevada, Las Vegas, said that "the preliminary data on the Diadem test look good."
If the test continues to do well in clinical trials, it has potential for adoption especially given that it can be inexpensive and done frequently, said Cummings, who is a consultant to Diadem.
With that said, "early data always look better," he noted. So far, the firm has validated its assay in patients with known amyloid beta status, but further validation is needed involving people presenting at clinics with various levels of cognitive decline.
"In this way, we will see how well the test predicts who will be fine and who has amyloid in the brain," said Cummings, who has also consulted for a number of drug and biomarker test companies in the Alzheimer's disease space. "That's what doctors are going to need if this is going to be a widely available, very useful blood test." Â
Publishing scientific papers based on its studies is a focus area for the company as it continues to take the test through validation in the US and Europe. Though its scientists have described the potential of the test in preliminary studies, they have not published the results of recent studies, Kinnon said.
In its efforts to drive adoption after launch, the firm expects to use its clinical validation data not only to obtain regulatory approvals but also to seek reimbursement from the US Centers for Medicare & Medicaid Services and private payors.
"Given recent progress with treatments, there's massive potential in being able to indicate when Alzheimer's is starting to progress," Kinnon said. Test pricing has not yet been determined but "the strategy is to make it cheap enough and accurate enough so that everyone who needs the test can get it," Kinnon said.