Tiny dataset, massive lifeline for Annovis

Sceptics may question the robustness of an early glimpse of mid-stage data for a well-worn neurodegenerative disease candidate but it is tough to doubt how real the upside has been for Annovis Bio.

The backstory

ANVS401 (formerly known as posiphen) is the positive enantiomer of the next-generation acetylcholinesterase (AChE) inhibitor phenserine, which was shelved by Annovis (then known as QR Pharma) after failing a Phase III trial for Alzheimer’s disease (AD) in 2009.

The follow-on compound, which like phenserine is believes to block production of a precursor of beta-amyloid and other inflammatory markers, has been tested in human trials for 15 years. Prior to an ongoing Phase IIa trial, it had been evaluated in two safety studies in 120 volunteers and another in five patients with mild cognitive impairment (MCI).

What’s new?

Late last week, Annovis reported an initial cut of data from the first 28 patients – 14 each with AD and Parkinson’s disease (PD) – enrolled in a double-blind, placebo-controlled Phase IIa trial evaluating once-daily doses of oral ANVS401.

The finding that attracted the most attention was Annovis’ report that AD patients treated with ANVS401 for 25 days achieved a statistically significant 4.4-point improvement on the Alzheimer's Disease Assessment Scale–Cognitive Subscale 11 (ADAS-Cog11) from baseline after 25 days.

Why this matters

Annovis was not shy about broadcasting its interpretation of the results. In fact, the company took the unusual step of comparing ANVS401’s benefit on ADAS-Cog11 to those demonstrated – in separate studies involving different endpoints and patients with distinct baseline characteristics – by several competing AD therapies.

One was the Phase III EMERGE trial of Biogen/Eisai’s aducanumab in which the anti-beta-amyloid mAb achieved a 1.4-point improvement on ADAS-Cog13 after 52 weeks. Annovis also noted that Cassava reported its sumifilam improved ADAS-Cog11 scores by 1.6 points over six months.

In its press release, Annovis remarked that “while we do not know how ANVS401 will affect cognition after more than one month of treatment, the present results show promise that the drug may improve or stop the course of AD.”

The promotional effort paid off – handsomely. Annovis shares shot up as much as 270% to $97.97 on May 21. Within hours the company announced plans to raise money in a public offering, eventually raising $50 million through the sale of 1 million shares at $50 on May 24.

The key question

Is ANVS401 for real? That is the big question mark that investors are weighing in on, and there are some notable reasons for Annovis to hold off on the parade for the time being.

First and foremost only 14 patients have been treated for one month with ANVS401, which is a rather tiny dataset to use to make bold assertions about efficacy. It is also curious that the placebo effect observed in the Phase IIa study appears to have been almost as strong as the treatment effect in the Biogen and Cassava trials.

Annovis’ decision to only report findings on the ADAS-Cog11 endpoints and not the handful of others being evaluated in the study may also raise some question marks, as will the company’s acknowledgement that ANVS401 did not actually achieve significance when lined up against placebo (p=0.13).

The bigger picture

Some observers will inevitably harbour lingering doubts about ANVS401, at the very least until a more robust readout is made available.

In the meantime, though, Annovis leveraged the preliminary data – red flags and all – into some desperately needed capital. The company finished the 1Q21 with $5.6 million in cash and a burn rate of $2.5 million for the quarter.

This week’s financing greatly extends Annovis’ runway and should at a minimum give the company an opportunity to turn over more cards with ANVS401.