The failure four years ago of Seres’s bacterial formulation SER-109 threatened to end mounting exuberance over microbiome therapeutics. But the company pressed on into phase III, and that trial’s unexpected success yesterday could reawaken this field.
It has certainly reawakened Seres’s share price, which had crashed 70% on the 2016 disappointment. After drifting further for the next few years the stock yesterday surged 389% to value Seres at $1.7bn. This is quite the turnaround, and Seres is now gunning for a quick US regulatory filing, which it hopes will result in the first ever marketed microbiome therapeutic.
The development is curious for a number of reasons, the most obvious being that biotechs that insist on initiating pivotal development despite unconvincing or negative mid-stage data usually suffer punishing phase III failures.
A second is that the company had a backup compound, SER-262, which unlike SER-109 was synthetically designed and thought by some to be far more promising. But in the event SER-262 flunked a phase I Clostridium difficile infection trial two years ago, and ended up being abandoned, leaving remaining investor attention on SER-109.
Enough for approval?
Yesterday Seres said the SER-109 pivotal study, also in C difficile and called Ecospor III, had met its primary endpoint, reducing recurrence of infection at eight weeks by 30.2 percentage points versus placebo.
The overall risk of recurrence was cut by 83%, with a p value of <0.001, which despite being tested at a one-sided level looks impressive. Importantly, the FDA had apparently told Seres that a single study would suffice for approval as long as the upper bound of its hazard ratio range fell below 0.833; this value has come in at 0.51.
Seres had initiated Ecospor III after reviewing why SER-109 might have failed in phase II. Possible reasons ranged from manufacturing problems through clinical site variability to even a mix-up of trial samples. Ultimately Ecospor III tested a 10-fold higher SER-109 dose than had been used in phase II.
SER-109 is an oral formulation of purified, donor stool-derived, Firmicute bacteria spores, designed to germinate, repopulate the microbiome and inhibit germination and growth of C difficile. Seres says this is more convenient, less risky and better characterised than faecal transplant, though only a head-to-head trial can prove this.
Should Seres investors sitting on a fourfold gain be aware of any stumbling blocks? One is that, at just 105 subjects exposed to the SER-109 phase III dose, Seres’s safety database is about 200 patients short.
The group hopes that this requirement can be met through a post-marketing commitment, but at worst it will have to dose and analyse these extra subjects in an open-label phase before approval. Another is Seres’s funding requirement: second-quarter cash was $64m, enough to last only a year.
Then there is the competition. Among the numerous industry projects that aim to restore patients’ microbiome health is Ferring’s RBX2660, which is also in development for C difficile, and whose pivotal trial should read out imminently.
Ferring had acquired this through its 2018 takeover of Rebiotix, something that could soon look like a very smart move.
|Selected microbiome modulators in development|
|SER-109||Seres/Nestlé||C diff infection|
|RBX2660||Ferring (ex Rebiotix)||C diff infection|
|IBP-9414||Infant Bacterial Therapeutics||Necrotising enterocolitis|
|RBX7455||Ferring (ex Rebiotix)||C diff prevention|
|C16G2||Armata Pharmaceuticals||Dental caries|
|CP101||Finch Therapeutics||C diff infection|
|Blautix||4D Pharma||Irritable bowel syndrome|
|Source: EvaluatePharma and company reports.|