Ash 2018 preview – smaller groups get their turn in the spotlight

Swedish Orphan Biovitrum made waves yesterday by getting its rare disease asset emapalumab into the Ash late-breakers – and bagging approval soon afterwards.

The Ash late-breaking abstracts are often dominated by big groups developing cancer drugs. So one name on yesterday’s list raised eyebrows: emapalumab, being developed by Swedish Orphan Biovitrum (Sobi) for the obscure rare disease primary haemophagocytic lymphohistiocytosis.

In an even bigger surprise, the asset received US approval just a few hours later, likely increasing the interest that will now be paid to the Ash data. Elsewhere, Acceleron also has a chance to make a mark, with its Celgene-partnered project luspatercept bagging a prestigious Ash plenary slot.

Selected non-oncology focused Ash abstracts
Project Company Details Abstract Time
Saturday, 1 Dec
Luspatercept  Acceleron/Celgene Believe ph3 trial in beta-thalassemia 163 2:00pm
Lentiglobin  Bluebird Northstar phase1/2 trial in beta-thalassemia (original manufacturing) 167 3:00pm
Sunday, 2 Dec
Luspatercept  Acceleron/Celgene Medalist ph3 trial in myelodysplastic syndromes  1 2:00pm
APL-2 Apellis Complement C3 inhibitor for PNH, ph1 trial 2314 6:00pm
MGTA-456 Magenta CD34+ expanded cord blood product, ph2 trial 3467 6:00pm
Monday, 3 Dec
Voxelotor Global Blood Therapeutics Part A ph3 Hope trial in sickle cell disease 505 7:00am
BCL11A Bluebird shRNA, first human data in sickle cell disease 1023 6:45pm
Lentiglobin  Bluebird Northstar-2/3 ph3 trials in beta-thalassemia (new manufacturing) 1025 7:15pm
Lentiglobin  Bluebird HGB-206 ph1 study in sickle cell disease 1026 7:30pm
Tuesday, 4 Dec
Emapalumab  Sobi/Novimmune IFN-gamma antibody for pHLH, ph2/3 trial LBA-6  7:30am

Primary haemophagocytic lymphohistiocytosis (pHLH) is a life-threatening condition characterised by hyperinflammation driven by overactive T and NK cells and previously treated with dexamethasone and etoposide. Sobi now has the first approved therapy for the disease.

Emapalumab is an anti-interferon-gamma antibody designed to combat the high levels of this protein seen in the disease, and after the FDA's blessing will be sold as Gamifant.

Its 34-patient, open-label trial had a primary endpoint of overall response, defined as normalisation or at least a 50% improvement in symptoms including fever, splenomegaly and cytopenias. A response was seen in 65% of patients, above a 40% threshold set.

Overall survival came in at around 71%, and 65% of patients proceeded to a haematopoietic stem cell transplant. The lack of a control arm makes it difficult to gauge the true impact of Gamifant; however, a recent trial of dexamethasone/etoposide plus cyclosporine A found five-year survival rates of around 60%, not far off what was seen with the Sobi project.

Nonetheless the data were obviously enough for the FDA, in the absence of other therapies. Sobi bought emapalumab from Novimmune for $50m up front in June, with the originator company retaining rights to a priority review voucher that the FDA will now issue. Sellside consensus sees 2024 sales of $187m, and no other IFN-gamma antibodies are in active development, according to EvaluatePharma.

Gold Medalist

Meanwhile, Celgene got some rare good news in June when it reported that the novel anaemia therapy luspatercept had achieved the primary endpoint in the Medalist trial in myelodysplastic syndromes (Celgene ends its losing streak, courtesy of Acceleron, June 29, 2018).

And the fact that the study will feature in Sunday’s plenary session at Ash means that expectations are high. The data available so far, with a May 8 cut-off, are promising. 38% of luspatercept-treated patients hit Medalist’s primary endpoint of red blood cell transfusion independence of at least eight consecutive weeks during the first 24 weeks, versus 13% in the placebo arm.

This was in line with Leerink analysts’ expectations of a 35% response, though the placebo arm did better than they had expected. And 28% of luspatercept patients achieved transfusion independence for 12 weeks or more, compared with 8% in the placebo group.

Medalist enrolled patients with ringed sideroblasts – a high-responder group – who had failed on or were ineligible to receive erythropoietin-stimulating agents. A potentially more important readout for luspatercept awaits, from the Commands trial in a broader population of patients who have not received such agents.

Meanwhile, data from the Believe trial of luspatercept in beta-thalassaemia, also being presented at Ash, were deemed less impressive by Leerink. A 21% response on the primary endpoint, a 33% or greater reduction in transfusion burden during weeks 13-24, fell well short of the 41% seen in phase II.

Acceleron and Celgene still have a chance to improve on this with updated figures, as the placeholder Ash abstract has a cut-off of May 11.

Flying high or feeling Blue?

Another beta-thalassaemia player, Bluebird, has made Ash its go-to conference in recent years, and 2018 will be no exception. The group’s most eagerly awaited Ash update concerns CAR-T, but it will also present data with its gene therapy Lentiglobin.

In sickle cell disease Bluebird is looking at accelerated Lentiglobin approval for patients with a history of vaso-occlusive events, and to this end is expanding its HGB-206 study to include 50 subjects. Data from this, specifically from patients receiving Lentiglobin produced using a new manufacturing process as of May 15, appear to be an improvement over earlier results using an older production method.

Filing for approval on the back of the expanded HGB-206 trial might still be a stretch, Evercore ISI analysts noted. Also keenly awaited, given the potential for early filing, are full results from the Hope study of Global Blood's sickle cell disease asset voxelotor; the FDA will decide by the end of the year whether the dataset qualifies for accelerated approval.

Other non-oncology specialists will also come under the spotlight, including Magenta’s MGTA-456, a cell therapy designed to improve stem cell engraftment. This is showing good efficacy in phase II, but emergence of autoimmune cytopenia in some children caused the company’s stock to dip 6% when the abstract went live.

For live updates from the Ash conference, taking place in San Diego on December 1-4, follow and @ByMadeleineA and @JacobPlieth on Twitter.

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