Cell Therapies Hope to Be Next Frontier for Alzheimer Disease
As cell therapy investigations mature in the field of AD, some programs show promising signs of efficacy.
Alzheimer disease (AD) is a growing problem, affecting nearly 7 million people in the United States. In 2021, AD was the fifth-leading cause of death among people aged 65 years and older.1
Deborah Phippard, PhD
Prior to 2023, the field of research for AD had stood relatively stagnant for 10 years until the FDA approved the controversial anti-amyloid therapy aducanumab (Aduhelm).
The Rise of Anti-Amyloid Therapies
Aducanumab had only met the primary endpoint of slowing AD progression in 1 of 2 pivotal trials used as the basis of approval and has since been pulled from the market by its manufacturer, Biogen.2,3
“Everyone's well aware that AD and Parkinson disease (PD) trials have often been very disappointing with small molecules and even with some of the biological treatments we have now, so gene therapy is poised to be useful... It’s a very rich, promising field,” Deborah Phippard, PhD, chief scientific officer of the clinical research services organization Precision for Medicine, told CGTLive®.
Two other anti-amyloid therapies, donanemab and lecanemab (Leqembi; Eisai), have been approved in the years since with more promising efficacy, but some research has also turned to cell and gene therapy development with loftier goals of achieving a more dramatic slowing of progression or even effectively halting it.4
Investigating NK Cell Therapy for AD
Although no studies investigating cell or gene therapies are powered to assess efficacy yet, there are a couple of promising therapies currently in phase 2 trials. One such therapy, SNK01 (NKGen), is a natural killer (NK) cell therapy comprised of autologous NK cells that are not genetically engineered but have enhanced cytotoxicity and activating receptor expression. The therapy, which is also being investigated for the potential treatment of PD, was cleared by the FDA to proceed to phase 2 trials in May 2024.5
Paul Y. Song, MD
“We've now dosed almost, I would say, 100 patients between all of our cancer trials, Alzheimer trials, and our compassionate use trials, and [we’re] not seeing any side effect related to our treatment at all. There is no pretreatment, unlike a lot of cell therapies where you have to give some lymphodepletion or some type of low dose chemotherapy or even some cytokine support. We do not have to do any pretreatment, because it's your own natural killer cells that are not genetically modified. So, it's a very simple outpatient infusion in and out. And we find our patients, thus far, have been really, really tolerating [SNK01] extremely well with no side effects,” Paul Y. Song, MD, the chairman and chief executive officer of NKGen, told CGTLive.
NKGen recently presented data from the phase 1 ASK-AD trial (NCT04678453) of SNK01 in people with AD at the 2024 Alzheimer’s Association International Conference (AAIC), held July 28 to August 1, in Philadelphia, Pennsylvania.6
The data are from 10 evaluable participants out of 11 enrolled (5 male, 6 female) with a median age of 79 years (range, 56-85). Participants receive intravenous SNK01 every 3 weeks for a total of 4 treatments using a 3+3 dose escalation design (1, 2 and 4 x 10 cells). SNK01 was well-tolerated, with no treatment-related adverse events observed.6
Even at lower doses (70% of participants were treated with low dose SNK01)in a safety-focused study, SNK01 does seem to have demonstrated some clinical activity. At week 11, 1 week after the final dose, 90% of all evaluable subjects had either stable or improved (±0.1) composite AD Composite Score (ADCOMS) scores and 60% had a decrease in cerebrospinal fluid (CSF) α-syn compared to baseline values. In 5 of 6 evaluable participants, the decreases in α-syn corresponded to stable/decrease in ADCOMS.6
In 5 of 6 patients for whom data were available, these levels continued through week 22 for α-syn. At week 22, an additional participant had a decrease in CSF α-syn compared to baseline.6
"We’ve found that when we measure cells for a certain receptor that they need in order to allow the NK cell to cross into the brain... when you take the cells from the patient at the beginning, they don't have that chemokine receptor. But after we've had a chance to put it through our process, we see upregulation of this chemokine receptor that is required for NK cells to then be able to traffic into the brain. And this is one of the ways we've been able to show our NK cells do cross the blood brain barrier and can start to affect all these positive changes,” Song said.
Joshua M. Hare, MD, FACC, FAHA
Early Signs of Efficacy With MSC Therapy
Another cell therapy that has shown some promise for treating AD is Longeveron’s allogeneic medicinal signaling cell therapy (MSC) product Lomecel-B. The company also presented data from the phase 2 CLEAR-MIND trial (NCT05233774) at the AAIC meeting, with some disease measures even improving.7
“There is directional, actual improvement in some of the cognitive scores... not just a slowing of decline, but actually an increase towards the positive direction... These are very early days, and we don't want to [read too into] it, but we're very excited about that. Of course, we'll be looking at that very carefully in the next larger study that we do, which will be powered around the efficacy endpoint,” Joshua M. Hare, MD, FACC, FAHA, cofounder, chief science officer, and chairman, Longeveron, and professor of medicine, Miller School of Medicine, University of Miami, told CGTLive. “If we have an agent here that can actually improve cognitive function in the mild AD patients, that would be a very exciting outcome, one very clinically meaningful for affected patients and their families.”
The data were from 49 participants: 12 in the placebo arm, 13 in the low dose arm (1 dose x 25 million), 13 in the low, multi-dose arm (4 doses x 25 million), and 11 in the high, multi-dose arm (4 doses x 100 million). The therapy was well-tolerated, with no serious adverse events (AEs) related to Lomecel-B in participants receiving up to 4 infusions.7
Treated participants had better scores on Composite Alzheimer’s Disease Score (CADS), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and AD Cooperative Scale-Activities of Daily Living (ADCS-ADL) than those receiving placebo. Specifically, participants in the high, multi-dose arm performed statistically significantly better on ADCS-ADL (P = .04) than placebo with trends of improvement on MMSE and participants in the low dose arm performed statistically significantly better on MoCA (P = .009) with trends of improvement in CADS at 39 weeks.7
The data were announced soon after the FDA granted both fast track and Regenerative Medicine Advanced Therapeutic (RMAT) designations.8,9
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“The hippocampus is a region that's heavily implicated in AD outcomes. It undergoes atrophy as part of the disease, and we slowed that atrophy rather substantially. This was a very exciting finding, and furthermore, we could show that the slowing of the atrophy correlated with clinical improvements in the cognitive scores. So, in summary, we definitely exceeded our expectations with the outcomes of the small study, and our conclusion is that we will go on and do a much larger, more clinically powered study now as our next step,” Hare said.
Other Novel CGT Programs in Development
While SNK01 and Lomecel-B are currently some of the most advanced programs being developed for AD, there are a number of other novel therapies being investigated for the indication. (FIGURE)
In fact, one such program comes from Biogen, aducanumab’s sponsor - antisense oligonucleotide (ASO) therapy BIIB080 targeting tau, which is one of the company’s new priorities after discontinuing aducanumab. BIIB080 also recently entered phase 2 trials and has demonstrated an ability to safely lower tau levels.10
Other notable therapies in phase 1 trials include AAV2-BDNF gene therapy, which is sponsored by the University of California, San Diego, and is being evaluated in a trial (NCT05040217) at Ohio State University; and Regeneration Biomedical’s RB-ADSC, an autologous, Wnt-activated adipose-derived stem cell therapy, which was administered to the trial’s (NCT05667649) first patient in April 2024.11,12
