Ionis collaborator Flamingo is ready to take flight with 3 antisense drugs in the clinic and mysterious RNA in its sights
As the biggest name in antisense technology, Ionis has long focused on testing the interplay between oligonucleotides and RNA for therapeutic effect. But one class of RNA has mostly stumped researchers — until now.
Flamingo Therapeutics officially debuted Thursday with three clinical and one preclinical cancer drugs handed off from antisense guru Ionis, and an intriguing if unproven discovery engine gunning for mysterious long non-coding RNA targets.
It’s not common to see a biotech launch with three clinical drugs in the fold, but Flamingo’s short history and close relationship with Ionis puts it in a unique position for success. The company was founded in 2019 with some time in incubation before that, and it was co-founded by the research institute VIB, Ghent University, KU Leuven, the University of Michigan, Kurma Partners and PMV.
Now, the team is headed by CEO Mike Garrett and CSO Rob MacLeod, with Ionis co-founder Chris Mirabelli currently serving as chairman of the board. For Mirabelli, who left Ionis way back in 1993 but was there early in the antisense movement, Flamingo represents a major breakthrough for ASO technology and a sign of how the field has come in the past few decades.
“It really is a rich area for drug discovery and particularly oncology,” Mirabelli told Endpoints News. “When I got reintroduced to take a look at this particular company, it was this sort of introduction to lncRNAs and my re-introduction to have far the field had come with oligonucleotides and how much each challenge had been met and knocked down. It was the ability to get back to my roots.”
The biotech’s lead “Gen 2.5” ASOs target gene transcription factors and what are known as splice-site variants, but the work gets really interesting with its only declared preclinical candidate targeting MALAT1 — an lncRNA target Flamingo thinks could have a big therapeutic benefit in breast cancer and other tumor types. The drug is a product of research out of David Spector’s lab at Cold Spring Harbor, the fertile ground from which Ionis and Biogen’s Spinraza sprung.
The mysterious lncRNA — pronounced “link RNA” — is a form of RNA which has a function still little known to science. You may remember it in its circular form as the backbone behind Flagship startup Laronde, which is aiming to design programmable “eRNA” based on the lncRNA design. But Flamingo wants to test lncRNA’s connection to cancer, a still nascent scientific field but one the biotech believes could offer a major therapeutic breakthrough.
“Oncology typically leads the cutting edge because of access to tumor tissue and materials so more is known about lncRNA in oncology than any other therapeutic area,” MacLeod told Endpoints. “Moreover, with functional screens, CRISPR screens and other ways to functionalize the genome, it’s becoming clear that there are driver lncRNAs important in certain malignancies and subsets of certain malignancies.”
The Flamingo team thinks that antisense oligonucleotides could have a therapeutic effect on lncRNA, once thought to be an undruggable target. So far, the results against MALAT1 are preclinical, but the team thinks those early data could prove winning in humans given early results showing a connection between MALAT1 genetic depletion and a “dramatic phenotype” in breast cancer models, MacLeod said.
“We’re going initially into breast cancer, but there are a large number of opportunities for MALAT1 throughout oncology — it’s been implicated in many solid and hematological studies,” MacLeod said. The team expects a potential Phase I to start as early as late 2022.
Developing even more lncRNA-targeted drugs is the long-term goal, but the first checkpoint for Flamingo will be its three clinical drugs targeting STAT-3, Androgen Receptor (AR) and IRF4 — two transcription factors and a splice-site variant.
Both the STAT-3 and AR candidates have turned out early human data, and Flamingo sees a path forward in developing both as personalized medicines for pre-selected patients as well as pursuing an aggressive combination program with other drugs. In the case of the STAT-3 candidate, dubbed danvatirsen, the drug has shown some benefit when partnered with AstraZeneca PD-1 drug Imfinzi, and the biotech is interested in teaming up with other immune checkpoint inhibitors to test efficacy.
Meanwhile, Flamingo’s IRF4 candidate is just now entering human testing, and Flamingo thinks it could be a natural combo drug as cancer meds like Revlimid require IRF4 knockdown to function properly.