Recent successes in the development of Alzheimer’s disease treatments make it easy to forget sometimes just how difficult it is to drug that disorder and bring new therapies to market.
Athira Pharma (ATHA) received a fresh reminder of that sad reality the hard way this past week. Athira announced last Tuesday that its lead candidate fosgonimeton failed the Phase II/III LIFT-AD clinical trial (NCT04488419)—an outcome that sent the company’s shares tailspinning 81% between Wednesday and Friday.
Fosgonimeton is a once-daily, subcutaneous candidate initially targeted for the potential treatment of Alzheimer’s disease. According to topline results, fosgonimeton (also called “fosgo” or ATH-1017) missed the trial’s primary endpoint—the Global Statistical Test (GST), a combination of results from measures of cognition (ADAS-Cog11) and function (ADCS-ADL23).
Fosgonimeton also missed the study’s key secondary endpoints by failing to reach statistical significance compared with placebo at 26 weeks, as measured by the 11-task Alzheimer’s Disease Assessment Scale (ADAS-Cog 11) and the 23-item Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale (ADCS-ADL23).
“These are not the results we hoped for,” Javier San Martin, MD, Athira’s chief medical officer, acknowledged in a statement. “The lack of clinical decline in the placebo group, combined with the short duration of the study, may have impacted the trial’s ability to translate the effect of fosgonimeton treatment into meaningful clinical benefit.”
Yet Athira also expressed a commitment to double down on development of fosgonimeton despite the failed Phase II/III trial. One reason: In pre-specified subgroups characterized by more rapid disease progression, such as patients with moderate Alzheimer’s and APOE4 carriers, cognition and function improved or stabilized in the fosgonimeton-treated group, Athira reported.
The company also said that data across three biomarkers of protein pathology (Aβ42/40, p-Tau181, and p-Tau217), inflammation (GFAP), and neurodegeneration (NfL) showed directional improvements with fosgonimeton treatment that are consistent with the broad neuroprotective mechanism of hepatocyte growth factor (HGF) modulation.
“We believe the totality of the data continues to suggest that positive modulation of the HGF pathway has the potential to translate into improvement in parameters of neuronal health and may mitigate disease progression,” San Martin added.
Full data from LIFT-AD is set to be presented at the Clinical Trial Alzheimer’s Disease (CTAD) Conference set for October 29-November 1 in Madrid.
Plummeting stock
Athira’s reasons for hope did not sit well with investors, who sold off enough shares to send the stock plummeting 78% on Wednesday from $2.83 to $0.61. In the days that followed, Athira shares fell another 11%, cratering to $0.55 on Friday as of 1:40 p.m. ET.
“We see modest trends on the two key FDA-approvable [secondary] endpoints,” Andrew Tsai, equity analyst with Jefferies, wrote in a research note, adding that the trends did not reach statistical significance.
“A natural investor question is how Fosgo’s efficacy will be maximized in a subsequent study. In any case, Street expectations were low,” Tsai observed, using a metaphor for the investor community derived from Wall Street.
A more positive outcome or “upside scenario,” Tsai added, was to see the GST primary endpoint reach statistical significance, with ADAS-cog11 and ADCS-ADL23 showing clear directional trends. That outcome could have propelled Athira stock five-fold, from the $108 million market capitalization it had before the trial results, toward $500 million-plus, he projected.
Market capitalization is the product of the share price and the number of outstanding shares. Since announcing the LIFT-AD topline results, Athira has seen its market cap plunge to $20.853 million.
Instead, GST showed a change of -0.08, which while favoring fosgonimeton was not enough to reach statistical significance. In function, the fosgonimeton-treated group showed an increase or improvement of 0.65 as measured by ADCS-ADL23 versus a decline of -0.02 in placebo, but that difference also did not meet statistical significance.
Fosgonimeton fared better in cognition, showing a decrease or improvement from baseline as assessed by ADAS-Cog11 of -1.09 for fosgonimeton patients vs. -0.39 for placebo patients.
“The best-case scenario was seeing stat-sig [statistical significance] across all three endpoints (GST, ADAS-cog, ADL), driving at least 10x stock upside (a $1B+ valuation),” Tsai wrote.
Tsai maintained Jefferies’ “Hold” rating on Athira shares. However, three other analysts downgraded Athira on the news from LIFT-AD:
- Elemer Piros (Rodman & Renshaw)—To “Neutral,” just two weeks after initiating coverage with a “Buy” rating.
- Jason Butler (JMP Securities)—To “Market Perform” from “Market Outperform.”
- Thomas Shrader (BTIG)—To “Neutral” from “Buy.”
“We don’t see Fosgo with a way forward in an area of drug development where trials are expensive, and investors are relatively skeptical,” Shrader wrote, while Butler added: “We do not expect the company to invest further in fosgonimeton,” according to Seeking Alpha.
LIFT-AD was a randomized, placebo-controlled, double-blind study designed to assess the efficacy and safety of once-daily subcutaneous injections of fosgonimeton (40 mg) in 312 mild-to-moderate Alzheimer’s patients not on acetylcholinesterase inhibitors (AChEIs) compared to placebo over a 26-week treatment period.
Difficult indication
Alzheimer’s has been a notoriously difficult indication for drug developers. Only a handful of drug successes have ever reached the market, most of which have merely slowed progression of symptoms by six to twelve months.
A 2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for AD drug candidates between 2002 and 2012. That study found high attrition rates for AD treatments, with 72% of agents failing in Phase I, 92% failing in Phase II, and 98% failing in Phase III.
Fosgonimeton’s clinical failure contrasts with more successful outcomes generated by three biopharma giants in Alzheimer’s. Eisai (4523:JP) and Biogen (BIIB) won FDA approval last year for Leqembi® (lecanumab-irmb) as the first disease-modifying treatment authorized for Alzheimer’s. Leqembi 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).
Last month, Eisai and Biogen received mixed news from the U.K. The Medicines and Healthcare Products Regulatory Agency (MHRA) approved Leqembi for the treatment of Alzheimer’s disease, but the National Institute for Health and Care Excellence (NICE) refused to authorize Leqembi for use by the National Health Service, deeming the drug too costly.
Eli Lilly (LLY) won FDA authorization in July for Kisunla
(donanemab-azbt), 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.
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.
In contrast to Lilly and Eisai/Biogen, as StockWatch reported in August, Cognition Therapeutics (CGRX) shares lost more than two-thirds of their value in late July after the company released results from its Phase II, 153-patient SHINE trial (COG0201; NCT03507790) that rattled investors. In an interview with GEN Edge, Cognition’s top two executives defended the results as showing consistent positive changes for its lead candidate CT1812 in patients with mild to moderate Alzheimer’s disease.
Based in the Seattle suburb of Bothell, WA, Athira focuses on developing small molecules designed to restore neuronal health and stop neurodegeneration—led by fosgonimeton, a novel small molecule being developed for Parkinson’s disease, dementia, and dementia with Lewy bodies, in addition to Alzheimer’s.
Leaders and laggards
- Dyne Therapeutics (DYN) shares tumbled 31% from $46.09 to $31.94 Tuesday despite the company announcing positive data from its ongoing Phase I/II DELIVER trial (NCT05524883) assessing DYNE-251 in Duchenne muscular dystrophy patients amenable to exon 51 skipping. Dyne said the results demonstrated “unprecedented” dystrophin expression and functional improvement in multiple cohorts. Patients treated with 20 mg/kg of DYNE-251 every four weeks showed a mean absolute dystrophin expression of 3.71% of normal (unadjusted for muscle content), >10-fold higher than the 0.3% reported in a clinical trial of the weekly standard of care, Sarepta Therapeutics (SRPT)’s Exondys 51® (eteplirsen). Dyne also announced an executive shakeup in which Doug Kerr, MD, PhD, was appointed chief medical officer, succeeding Wildon Farwell, MD, who is stepping down but will remain at Dyne full-time through year’s end. Johanna Friedl-Naderer is joining Dyne as chief commercial officer while Lucia Celona has been named chief human resources officer.
- Illumina (ILMN) shares stayed all but flat, dipping 0.9% from $131.40 to $130.26 Tuesday after the European Court of Justice ruled that Illumina did not have to pay the €432 million ($480 million) fine imposed by the European Commission against it and its then-subsidiary Grail (GRAL) for breaching European Union (EU) rules by agreeing to merge with the cancer blood test developer before receiving EC approval for the $7.1 billion deal. Shares of Grail—which was spun off from Illumina in June—fell 6%, from $14.11 to $13.26. Illumina maintains a minority share of 14.5% in Grail.
- Vaxcyte (PCVX) shares jumped 36% from $80.76 to $110.15 Tuesday, after the company announced that it would advance its 31-valent pneumococcal conjugate vaccine candidate VAX-31 to a Phase III trial based on positive topline results from a Phase I/II trial (NCT06151288). VAX-31 showed robust opsonophagocytic activity (OPA) immune responses for all 31 serotypes at all doses studied. At the middle and high doses, VAX-31 met or exceeded OPA response non-inferiority criteria for all 20 serotypes common with Pfizer (PFE)’s Prevnar 20® (PCV20). At the VAX-31 high dose, average OPA immune responses were greater for 18 of 20 serotypes compared to PCV20 (geometric mean ratio [GMR] >1.0), with seven of the serotypes achieving statistically higher immune responses compared to PCV20.
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