Mid-stage failure a year ago crushed the stock of Seres Therapeutics, but now Rebiotix, a private group also focusing on the microbiome and also targeting Clostridium difficile infection, reckons it can do better.
Seres’s failure notwithstanding, both companies have gone into phase III, and Lee Jones, Rebiotix’s chief executive and co-founder, is blunt in drawing distinctions. “We’re building on three successful phase IIs... they’ve had one phase II programme that failed, and they have no other ones. What they’re choosing to do is really risky,” she tells EP Vantage.
This is not to say that Rebiotix’s own mid-stage data are unequivocal. Like Seres Rebiotix reported positive open-label results, its lead asset, RBX2660, prompting 87% of high-risk patients to have no recurrence of C diff infection after eight weeks; remarkably, this 87% response is precisely what Seres saw in its trial of SER-109.
That placebo response again
But controlled studies is where things get tough, partly owing to a high response among placebo recipients. In Seres’s blinded trial SER-109 yielded a 44% response versus 53% for placebo (Seres failure a kick in the gut to microbiome field, August 1, 2016).
Rebiotix did better: its 46% placebo response rate was beaten both by the 67% seen in patients given one dose of RBX2660 and by 61% in those given two doses. However, only the latter squeezed through statistically, with p=0.048, while the former missed significance; the lack of a dose response will also be noted, though in fairness this was a small trial.
And Ms Jones says important lessons were learned: “We didn’t know what to expect. We powered our study for 40% [placebo response], and it was almost 50%. The true placebo rate – not just from our study – is really closer to the 50% number.” Still, no one knows why such high placebo responses have been seen in microbiome trials.
Ms Jones also stresses that the design of Rebiotix’s blinded study, which after the above efficacy readout allowed patients with disease recurrence to switch to active treatment, also showed an added benefit in those patients who crossed over.
There are also clear lessons for the pivotal study that has just begun, which will be identical to the blinded phase II, except with more patients and a single dose of RBX2660 versus placebo. It has yet to be decided whether a single phase III trial will be enough for filing.
In terms of efficacy the eight-week recurrence-free measure is what professional guidelines dictate. Patient selection could be a bit hit and miss, but Ms Jones is confident of selecting high-risk subjects on the basis of them having had a C diff primary episode and two recurrences, which is what the FDA requested.
|Trials of RBX2660 in prevention of Clostidium difficile recurrence|
|PunchCD||Open label, 31 subjects||87% response rate shown||NCT01925417|
|Punch open label||Open label, 132 subjects||Single or double dose, 79% response rate||NCT02589847|
|PunchCD2||Blinded, 127 subjects||Single dose (67% response) vs double dose (61%) vs placebo (46%)||NCT02299570|
|PunchCD3||Phase III, blinded, 270 subjects||Single dose vs placebo||NCT03244644|
|Note: all recruiting subjects at high risk of recurrence, measuring recurrence-free rate at 8 weeks.|
The microbiome, the genetic makeup of the microbes present in the human body, has been postulated to play an important role in a growing range of diseases. The precise mechanisms behind how it affects the balance of various factors whose dysregulation affects human health are still a mystery.
It has even been suggested that the microbiome affects people’s response to cancer drugs, and Ms Jones hints that oncology is an application Rebiotix has considered: “Our external head of research came out of the oncology area at Yale.”
For now, however, the lead focus is C diff, and RBX2660 has its origins in faecal transplantation, an area that the company had initially investigated. This project is a liquid suspension of microbes harvested from human donor faecal material, delivered in an enema; RBX7455 is an oral formulation, while the rest of Rebiotix’s pipeline comprises the same project for other indications.
The group has raised $30m – so far entirely from high-net worth individuals – and is pursuing its first institutional VC round, a $50m series C aimed at seeing RBX2660 through commercial approval.
“We are the first company that has had to take a product like this through the FDA. We had to pioneer all the regulatory processes,” says Ms Jones. Thanks to this early work it has become clear that the FDA will regulate microbiome products as drugs, via its CBER division, though in Europe this has yet to be decided.
And, she insists, this has paid off in yielding the data needed to pursue commercialisation: “I don’t know how Seres is feeling, but I’m glad I’m not in their shoes.”