Prothena said today it will terminate development of its lead drug, the amyloid light-chain (AL) amyloidosis candidate NEOD001, after it failed a Phase IIb trial and appeared headed for another failure in a Phase III study, touching off a 63% plunge in the company’s stock price.

Prothena acknowledged that NEOD001 missed its primary endpoint and three secondary endpoints in the Phase IIb PRONTO study (NCT02632786), a global, multicenter, randomized, double-blind, placebo-controlled clinical study designed to compare the treatment versus placebo in 129 previously treated patients with AL amyloidosis and persistent cardiac dysfunction. Patients were randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 (n=66) or placebo (n=63) via intravenous infusion every 28 days.

Just 39.4% of patients treated with NEOD001 met the primary endpoint of cardiac best response (NT-proBNP, modified consensus criteria) through 12 months of treatment, compared with 47.6% of placebo patients, Prothena said.

NEOD001 also failed to outperform, or generated statistically insignificant improvement over, placebo after 12 months of treatment in the trial’s secondary endpoints of mean change in Short-form 36 (SF-36v2) Physical Component Summary Score (PCS) (0.19 vs. 0.97 for placebo); change in 6-Minute Walk Test distance (meters) after 12 months of treatment (median) (19.25 vs. 8.00); and NT-proBNP rate of change (slope) through 12 months of treatment (9.80 vs. 81.42).

Following the failure of PRONTO, Prothena said, it asked the independent data monitoring committee (DMC) of the Phase III VITAL Amyloidosis Study (NCT02312206) to review a futility analysis of that ongoing trial. The DMC recommended ending VITAL based on futility.

VITAL was a global, multicenter, randomized, double-blind, placebo-controlled clinical study. The study intended to compare NEOD001 versus placebo in 260 newly diagnosed, treatment-naïve patients with AL amyloidosis and cardiac dysfunction. Patients were randomized on a 1:1 basis to receive 24 mg/kg of NEOD001 or placebo via intravenous infusion every 28 days, with both groups receiving concurrent standard of care therapy.

VITAL’s composite primary endpoint was event-based, with all-cause mortality or cardiac hospitalizations as events. Secondary endpoints of the study included Short Form-36v2 Physical Component Summary Score, 6-Minute Walk Test distance, and NT-proBNP best response.

Prothena responded to the failure of PRONTO and projected failure of VITAL by halting all development of NEOD001, including VITAL as well as open-label extension studies.

“Surprised by the Results”

“We are deeply disappointed by this outcome, particularly for patients suffering from this devastating disease,” Prothena president and CEO Gene Kinney, Ph.D., said in a statement. “We are surprised by the results from these two placebo-controlled studies and will continue to analyze the resulting data to share insights with our collaborators in the scientific, medical, and advocacy communities.”

NEOD001 was an investigational monoclonal antibody designed to target the circulating soluble and deposited aggregated amyloid that accumulates in patients with AL amyloidosis and can cause organ damage and failure.

Prothena had cited preclinical studies showing that NEOD001 reacted only with a “cryptic” epitope found on the misfolded light-chain proteins produced by clonal plasma cells in the course of the rare, and typically fatal, bone marrow disorder.

News of the clinical setbacks touched off a stock selloff that sent Prothena shares plummeting 62% from Friday’s closing price of $36.84, to $13.69 in premarket trading as of 9:29 a.m.

“Prothena has a deep pipeline of novel therapeutics in clinical and preclinical development, including several partnered with leading strategic collaborators,” stated Prothena chairman Lars Ekman, M.D., Ph.D.

The most recent collaboration was launched last month, when Celgene agreed to team up with Prothena to develop new treatments for neurodegenerative disorders, including Alzheimer’s disease, through a partnership that could generate just over $2 billion  for the Irish-based biotech.  

Prothena’s pipeline includes a single additional clinical-phase drug—the Roche-partnered Parkinson’s disease treatment PRX002/RG7935, now under study in the Phase II PASADENA trial (NCT03100149)—and three preclinical candidates partnered with Celgene.

Among the Celgene-partnered candidates, furthest along in discovery phase is a tau protein–targeting treatment designed to fight Alzheimer’s disease, progressive supranuclear palsy, frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE).

Also partnered with Celgene are two earlier-phase discovery candidates—TDP-43, a potential treatment for amyotrophic lateral sclerosis (ALS) and FTD, and a candidate with an undisclosed target for a neurodegeneration disorder.

“We have the resources and scientific expertise to continue to advance our pipeline through meaningful development milestones toward our goal of transforming patients' lives,” Dr. Ekman added.

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