N.C. Scientist Awarded ‘Part the Cloud’ Research Grant

“I like to label us as ‘the little mouse that roared,’” begins John Didsbury, Ph.D., and Chief Executive Officer at T3D Therapeutics, a clinical stage drug development company engaged in the development of T3D-959, a new orally administered metabolic-focused treatment for Alzheimer’s disease in Raleigh, NC.  With more than 5 million Americans living with Alzheimer’s disease today, including 180,000 in North Carolina, there is an urgent and pressing need to develop treatments that will stop or slow the progression of the disease.  

Clinical trials investigating 16 promising therapies for Alzheimer’s and dementia are taking off thanks to $24 million in new grant funding from the Alzheimer’s Association’s Part the Cloud global research grant program and Bill Gates.  T3D Therapeutics is a first time grant recipient of Part the Cloud receiving $740,000 to support the study to evaluate whether a chemical compound can alter brain energy levels to stop or reverse the progression of Alzheimer’s.

“It is an honor to have won this highly competitive award from the Alzheimer’s Association Part the Cloud-Gates Partnership Grant Program and the recognition that improving inherent metabolic defects in Alzheimer’s disease is a vital and largely unexplored therapeutic avenue to treat Alzheimer’s disease.”

Dr. John Didsbury

Making a connection

The biomarker studies supported by the grant are an integral part of the upcoming Phase 2 PIONEER study (Prospective therapy to Inhibit and Overcome Alzheimer’s Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration).   “Scientists in the field have, in my opinion, paid insufficient attention to metabolism changes in the brain, metabolism research is my background.  I’m not a neurologist but rather versed in metabolic diseases such as diabetes and dyslipidemia.”  Didsbury notes that the connection to brain was quite obvious to him for two reasons:  the brain is the most metabolically-active, energy-demanding organ in the body on a weight to weight basis (ten times that of any other organ) and, the brain is half lipid (fat), lipids are vital to the structure and function of the brain. These facts direct one to a logical supposition that they are major vulnerability points for malfunction. “A new approach to me – an outsider looking in – is to treat Alzheimer’s as a metabolic disease of the brain.” 

While Didsbury has no known personal connection to Alzheimer’s disease, he admits that it was pure scientific logic that excited him.  The logic is based on considering Alzheimer’s disease as a massive feedback loop of three main events in the brain:  1) metabolic dysfunction (glucose and lipids); 2) structural changes (plaques and tangles); and 3) stress changes (inflammation, possibly from infectious agents).  “Each of these three main component changes are highly interrelated and interconnected – they feed on each other.”  He believes that the key is to break the loop at some critical intervention point.  “Researchers have largely maintained that the intervention point be on the eliminating the structure changes (plaques and tangles); perhaps that’s not the correct place to break the loop as we are not seeing the effectiveness that one would have predicted.”   He sees recent movement toward looking at stress changes, for example, inflammation, but what causes the inflammation in the first place? His answer is metabolic dysfunction in the brain.

“Putting all this information together – a light bulb went off,” offers Didsbury.  “There’s a drug I was formerly working on as an antidiabetic medication which was going to be dropped because the company working on it had changed business models.   This particular compound was ‘a needle in the haystack’, a molecule that had an attractive safety profile, the ability to control glucose and lipid metabolism and had ideal pharmaceutical development properties such as being administered orally just once a day. I’m adding two plus two and it equals 20 for Alzheimer’s disease.” Subsequently, Alzheimer’s research was initiated with the compound and now the birth of the PIONEER Study.

Ingenuity in the time of COVID-19

Plans were for 256 subjects with mild to moderate Alzheimer’s disease to participate in the study.  They were on track – enrollment started in the 2^nd week of February 2020 with projections that nine months would be needed to get all of the subjects in the study enrolled.  However, five weeks into enrollment (mid -March) – receptivity to this study was so great that full enrollment was now projected to be completed in just five months instead of nine, by the end of June.   Then the COVID-19 pandemic hit and operationally hindered a number of clinical trial sites.  With a patient population that was most susceptible [to the pandemic] they couldn’t adequately ensure patient safety and get comparative data from a phone call versus a clinic visit.  The study was put on pause.

Didsbury notes that in the meantime they are creating changes to the way PIONEER will be conducted, with COVID-19 contingencies. Contingencies that maintain the ability to adequately assess and monitor patients should clinical site visits become impossible  for patients for whatever reason. These include the use of Zoom video conference interface with iPads, home health care nursing, all electronic data capture, etc. “We are using the latest in technologies in an avant-garde approach. Simply put, we are mimicking the clinic in an at-home setting, to be used in the event of a future pandemic emergency”.

Alzheimer’s Association leading the way

With this new funding through the Alzheimer’s Association’s Part the Cloud global research grant program, research teams from around the world, like Didsbury and T3D Therapeutics, are exploring high risk, high reward therapies that focus on how brain cells use energy and fuel, how brain cells remove waste and debris from the brain, and how blood supply in the brain is maintained.

“We must leave no stone unturned when it comes to finding treatments for Alzheimer’s and all other dementia, and Part the Cloud is designed to explore every feasible option in order to drive research forward to get potential treatment options to people living with Alzheimer’s faster,” said Maria C. Carrillo, Ph.D., Alzheimer’s Association chief science officer.

Learn more about the Alzheimer’s Association research at alz.org/research, and to how to get involved in support of such research at alz.org/get_involved.