Rocket is bringing lenti back

The resurgence of lentiviral-based gene therapies might be one of the comeback stories of 2022. Bluebird bounced back from toxicity scares to secure US approvals for Skysona and Zynteglo, and ranked among the winners at December's Ash meeting.

Also doing well at at Ash was Rocket Pharmaceuticals, which had data on its three lentiviral contenders. This company gets more attention for its AAV-based Danon disease project, but “we think we’re in a position to bring lenti back”, its chief executive, Gaurav Shah, told Evaluate Vantage at the conference.

Investors have largely kept the faith with Rocket, even as other gene therapy players suffered; the group’s stock sank 10% across the year, something that could be seen as a victory of sorts compared with the performance of other names in the space.

Still, a somewhat vague update at the tail end of 2022 on the Danon asset, RP-A501, spooked backers who had apparently hoped for more details on pivotal trial design. 

Cancer risk

As for the group's lentiviral projects, one reason for caution about this approach is a theoretical risk of insertional mutagenesis; namely that the gene therapy could trigger cancer. Although Bluebird’s Zynteglo has been exonerated here – most recently at Ash – there are lingering concerns.

Mr Shah talked down these worries, saying the only lentiviral gene therapy that has directly been linked with cancer was Bluebird's Skysona, which was approved last year for cerebral adrenoleukodystrophy, albeit with a black box warning for haematologic malignancies.

He contended that Rocket’s lentiviral projects had been “discounted” by investors “because of all the news around other lenti programmes”. But he believes that there is still a place for this modality, and gene therapy in general, despite the negative sentiment.

However, he was scathing about attempts to develop gene therapies for less serious disorders, or those that are already well served. “Gene therapy doesn't work as a nice to have. It has to be reserved for fatal diseases, or highly morbid diseases where patients have no other good alternatives.”

Fanconi anaemia

Fanconi anaemia, where Rocket plans a filing in the second half of 2023 for RP-L102, is a good example. The disorder leads to gradual bone marrow failure and is associated with an increased risk of leukaemia. The only potentially curative therapy is a bone marrow transplant, but even if this is successful patients can develop solid tumours.  

“Why not try this?” Mr Shah says of RP-L102, which notably does not require a conditioning regimen, unlike many other ex vivo gene therapies. He added that bone marrow transplant would remain an option for RP-L102 non-responders.

Phase 2 data were presented at Ash, showing efficacy in six of 10 patients evaluable at one year – this was defined as increased resistance to mitomycin-C, a DNA-damaging agent to which Fanconi patients are particularly sensitive. An additional patient went on to show resistance at a later timepoint.