StockWatch: Cognition Stays the Course as Shares Plunge on Alzheimer’s Data

Cognition Therapeutics (CGTX) shares lost more than two-thirds of their value this past week after the company released results from its Phase II, 153-patient SHINE trial (COG0201; NCT03507790) that rattled investors, but which the company is defending as showing consistent positive changes for its lead candidate CT1812 in patients with mild to moderate Alzheimer’s disease.

The proof-of-concept trial compared CT1812—a once-daily, oral, brain penetrant small-molecule antagonist of the sigma-2 receptor (S2R)—with placebo across cognitive and functional measures. The 153 patients, who had Mini-Mental State Examination (MMSE) scores of 18 to 26, were randomized 1:1:1 to 100 mg CT1812, 300 mg CT1812, or placebo.

Cognition’s results included was an acknowledgement that CT1812 did not achieve statistical significance on its first secondary efficacy endpoint—namely a slowdown in cognitive decline in a pooled population of patients dosed with either dose of the drug compared to placebo patients, as measured by the 11-task Alzheimer’s Disease Assessment Scale (ADAS-Cog 11).

CT1812 patients showed ADAS-Cog11 scores that declined by an average of 1.66 points, compared with the 2.7 point-decline shown by the placebo patients. Cognition presented the 39% slower decline in condition shown by CT1812 patients as a key positive finding.

“2.7 was the yardstick, of which we had a 1.6 score. So, about 40% of how poorly placebo patients did was rescued, if you will, by active treatment,” Lisa Ricciardi, Cognition’s president and CEO, told GEN Edge in an interview that included Anthony Caggiano, MD, PhD, the company’s chief medical officer and head of R&D.

But the resulting difference of 1.04 points between CT1812 and placebo was a marked drop from the three-point decline seen after six months in the first 24 patients enrolled in SHINE, according to data announced last November by Cognition.

Shares fall 69%

The decline rattled investors enough to spark a selloff that sent Cognition shares plunging 69% over five trading days—from $2.37 to $1.33 on Monday, then to $1.10 Tuesday, an even $1 Wednesday, 90 cents Thursday, and 73 cents at the close on Friday.

At deadline, three of the six analysts who cover Cognition sided with the bears: Charles Duncan of Cantor Fitzgerald downgraded his firm’s rating of Cognition shares from “Overweight” to “Neutral.” Two other analysts cut their firms’ 12-month price targets on Cognition stock: Raghuram Selvaraju chopped H.C. Wainwright’s target 30%, from $10 to $7, while Aydin Huseynov sliced Ladenburg Thalmann & Co.’s target 17%, from $6 to $5.

Both Selvaraju and Huseynov, however, kept their “Buy” ratings on Cognition’s shares.

As reported by TipRanks, Duncan cited questions on the duration of activity seen in patients dosed with CT1812, limited dose-response data, incomplete analysis of the correlation between activity and baseline cognitive burden, and safety (A Cantor Fitzgerald spokesperson at deadline had not responded to GEN queries seeking a copy of the report).

Addressing these questions may make subsequent studies large and costly, Duncan observed in a research note, adding that while the results provided a provocative signal of efficacy as a possible symptomatic treatment, safety data with the 300mg suggested that next studies will require further dose evaluation in larger sample sizes and possibly for longer durations.

Cognition is studying data from SHINE to determine what additional clinical trials it will need to conduct—and how large of a patient population those studies will need to evaluate, Ricciardi said.

Ricciardi and Caggiano acknowledge that they will need larger trials with more patients given the populations studied in Phase III trials for the two Alzheimer’s disease drugs approved since last year—a 1,795-patient study for Eisai/Biogen’s Leqembi^® (lecanumab-irmb), which won full approval in July 2023 six months after accelerated approval; and a 1,736-patient study for Eli Lilly’s Kisunla™ (donanemab-azbt), which won FDA authorization in July.

Leqembi—the first disease-modifying treatment approved for Alzheimer’s—is a recombinant humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody designed to treat Alzheimer’s by targeting aggregated soluble and insoluble forms of amyloid beta (Aβ). Kisunla is a once-monthly injection treatment indicated for adults with early symptomatic Alzheimer’s, including mild cognitive impairment or mild dementia stage of disease with confirmed amyloid pathology.

Comparing Cognition scores

Ricciardi added that the 39% difference in cognition scores between CT1812 and placebo compared favorably to the slowing of Alzheimer’s progression seen in studies of:

• Leqembi—The Phase III Clarity AD trial (NCT03887455) showed reduced declines first announced as 27% (later published in The New England Journal of Medicine as 25%) in patients 18 months after dosing compared with placebo on the CDR-SB global cognitive and functional scale.
• Kisunla—According to results published in JAMA last year, the Phase III TRAILBLAZER-ALZ 2 trial (NCT04437511) showed a 48% slowing of decline in 542 participants under age 75 on iADRS and 45% on CDR-SB. In 551 participants aged 75 or older, Kisunla slowed decline by 25% on iADRS and 29% on CDR-SB.

“No, Leqembi has not obviated the market. I’d say the opposite is true,” Ricciardi told GEN Edge last year, when asked where Cognition fit into an Alzheimer’s drug landscape reshaped by the Eisai/Biogen drug as well as Lilly’s treatment. “[Investors] see us advancing and that’s what makes them interested in continuing to speak to us.”

Addressing analysts on the first quarter earnings call in April, Ricciardi and Caggiano noted patients treated with Leqembi showed a slower cognitive decline of 1.44 points at 18 months compared to placebo (based on the 14-task ADAS-Cog14 scale)—a result Ricciardi noted Cognition surpassed in its initial three-point decline seen in the SHINE trial’s first 24 patients.

“What we have seen with our oral once-a-day, small molecule, easily manufactured drug is that it confers a benefit similar in size to what the more complex regimens confer for patients. And to us, that looks like a really positive result,” Ricciardi said.

SHINE met its primary endpoints of demonstrating a favorable safety and tolerability profile. The overall percentage of patients experiencing any adverse event was similar between the pooled CT1812 treatment arms (76.5%) and placebo (78%). Most adverse events were mild or moderate in severity, according to Cognition.

Clinical trials in progress

SHINE has been one of four clinical trials in progress for CT1812. The Phase II, 130-patient SHIMMER trial (COG1201; NCT05225415), is assessing two dosages of the drug (100 mg and 300 mg) in patients ages 50-80 diagnosed with mild to moderate DLB. SHIMMER—which has been funded with an approximately $29.5 million grant from the National Institute on Aging—is set to read out data later in the second half.

Cognition said it is actively recruiting patients for two additional trials of CT1812, for which data readout time frames have not yet been disclosed:

• Geographic atrophy caused by dry AMD—A 200 mg dose of CT1812 is under study in the Phase II MAGNIFY trial (COG2201; NCT05893537), which is expected to enroll approximately 246 adults. The first patient was dosed last year.
• Early-to-mild Alzheimer’s—CT1812 is under study in the Phase II START trial (COG0203; NCT05531656), which is projected to enroll 540 participants to be randomized 1:1:1 to receive either 100mg or 200mg of CT1812 or placebo.

In the START trial, Caggiano said, “We’re allowing folks to have been on lecanemab [Leqembi] and pretty soon, donanemab [Kisunla] prior to entering the study. So we’ll be able to get a nice picture for safety and tolerability and combination, as well as whether there’s any potential for an added benefit when either of those are used together with CT1812.”

Results from the Phase II trials will help Cognition decide what dosage of CT1812 it will ultimately use in Phase III trials, Caggiano added.

Cognition also cited as successful outcomes data generated by its cerebrospinal fluid (CSF) biomarker program, which showed favorable changes in neurofilament light chain (NfL), a marker of neurodegenerative disease, and significant changes for the 300mg dose. But the company added that data from several other CSF biomarkers did not approach significance, including neurogranin, synaptotagmin, SNAP25, pTau, total Tau and GFAP.

Cognition insists its development program for CT1812 remains on track, and that the results from SHINE were less a setback than a springboard for future clinical success.

“The objective of the [SHINE] study was to see a nice signal of disease, modification, or slowing disease, progression as measured on cognitive scales to show safety and tolerability of the molecule and use, and then to explore certain biomarker signals. And we think we were able to achieve all of those,” Caggiano said.

Leaders and Laggards

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• Immunon (IMNN) shares nearly tripled, zooming 181% from $1.18 to $3.32 on Tuesday after the company announced positive topline results from the Phase II OVATION 2 Study (NCT03393884) assessing IMNN-001 in patients with advanced ovarian cancer. IMNN-001 met the trial’s primary endpoint of progression-free survival (PFS) by demonstrating a three-month improvement compared with standard-of-care alone. Patients in the intent-to-treat population (ITT) showed a hazard ratio of 0.79, indicating a 27% improvement in delaying progression for the IMNN-001 treatment arm. Immunon said it plans to hold an End-of-Phase II meeting with the FDA “as soon as possible” to discuss the protocol for a Phase III study that the company anticipates will begin in the first quarter of 2025.
• Lipella Pharmaceuticals (LIPO) shares more than doubled, rocketing 117% from 42 cents to 90 cents July 29 after the company announced the enrollment of the first patients in its multi-center Phase IIa trial (NCT06233591) assessing LP-310 as a treatment for Oral Lichen Planus (OLP). LP-310 is a liposomal-tacrolimus oral rinse formulation of the company’s lead candidate LP-10 for hemorrhagic cystitis.  The primary endpoint is safety assessed by incidence of Treatment-Emergent Adverse Events through study completion, an average of 10 weeks. The trial is anticipated to conclude by mid-2025, with topline data expected to be released by the end of this year.
• Novavax (NVAX) shares tumbled 26% from $16.42 to $12.20 on Tuesday after J.P. Morgan analyst Eric Joseph downgraded his firm’s rating of the stock from “Neutral” to “Underweight.”  He concluded that the value of Novavax shares had grown beyond the value it can generate from its COVID-19 vaccine Nuvaxovid. The downgrade ended a surge that sent Novavax shares leaping nearly five-fold before settling for a 267% gain since May, when Sanofi inked an up-to-$1.2 billion co-exclusive licensing agreement with Novavax to co-commercialize Nuvaxovid—$500 million upfront, up to $700 million in development, regulatory, and launch milestones. Sanofi also took a sole license to Novavax’s adjuvanted COVID-19 vaccine for use in combination with Sanofi’s flu vaccines; and a non-exclusive license to use Novavax’s Matrix-M adjuvant in vaccine products. In addition, Sanofi took a <5% equity stake in Novavax.
• PepGen (PEPG) shares sank 33% from $16.98 to $11.43 Wednesday, the first trading day after the company’s Tuesday post-market announcement of positive data from the first dose cohort (5 mg/kg) in the ongoing CONNECT1-EDO51 Phase II open-label trial (NCT06079736), evaluating PGN-EDO51, the company’s lead pipeline candidate for Duchenne muscular dystrophy (DMD) whose mutations are amenable to exon 51 skipping. Investors reacted to data that reportedly fell short of PepGen’s dystrophin objective. The company reported that PGN-EDO51 achieved a mean muscle-adjusted dystrophin level of 1.49% of normal and a 0.70% change from baseline after four doses, measured at week 13—as well as a mean absolute dystrophin level of 61% of normal and a 0.26% change from baseline after four doses, measured at week 13 by Western blot analysis.
• Vaccinex (VCNX)shares nosedived 37% from $8.06 to $5.10 Wednesday after the company reported data from its Phase Ib/II SIGNAL-AD trial (NCT04381468) assessing its pepinemab, a humanized IgG4 monoclonal antibody SEMA4D inhibitor, in patients with mild dementia due to Alzheimer’s disease. Vaccinex said SIGNAL-AD met its designated primary endpoint of safety by showing pepinemab to be well-tolerated by patients with AD. But CEO Maurice Zauderer, PhD, added in a statement: “Pepinemab may be most effective in patients with very early-stage symptoms, e.g. mild cognitive impairment (MCI) due to AD, but not subsequent dementia.” Vaccinex added that it was actively exploring the potential for continuing late-stage development of pepinemab in AD together with a major pharmaceutical partner.