ASH – Recent biotech floaters show their worth

The past year or so has seen a resurgence in US biotech flotations, and several of the recent entrants used the ASH meeting in San Francisco to showcase data on their most advanced clinical assets.

Another feature of ASH has been the huge presence of Celgene, a company that has licensing deals with four of these newcomers – Acceleron Pharma, Agios Pharmaceuticals, Bluebird and Epizyme. On the strength of ASH data, projects partnered with Acceleron and Agios targeting anaemia and haematological malignancies might enter pivotal studies next year.

Celgene’s deal with Acceleron was worth $75m up front and initially concerned sotatercept (ACE-011), before being expanded to luspatercept (ACE-536). Both projects are activin type II receptor fusion proteins that act on late-stage erythropoiesis to increase mature erythrocyte release into the circulation, and thus have potential to treat anaemia.

At ASH the setting was myelodysplastic syndromes (MDS) and beta-thalassaemia, which can both lead to severe anaemia.

In an open-label phase II MDS study sotatercept was given at 0.1-1.0mg/kg once every three weeks and resulted in overall haematological improvement in 24 of 53 evaluable patients, said Dr Rami Komrokji, of the Moffitt Cancer Center. Transfusion independence was achieved in five of 44 high-transfusion-burden patients and five of nine low-transfusion-burden patients.

Luspatercept, meanwhile, has been studied in phase II in beta-thalassaemia as well as MDS. In the beta-thalassaemia trial 10 of 30 patients given 0.2-1.0mg/kg saw an efficacy signal, defined as a more than 1.5g/dl haemoglobin increase for over two weeks for patients who were transfusion independent, or a ≥20% transfusion reduction in transfusion-dependents.

The result was driven by 0.8-1.0mg/kg doses, and by the effect in transfusion-dependents. While both trials aimed to identify the best dose and no statistical analysis was performed, the Turin University’s Dr Antonio Piga described the beta-thalassaemia data as important and clinically relevant.

He also highlighted luspatercept’s effects on iron overload reduction and healing leg ulcers. The session’s moderator, Dr Julie Panepinto, from the Medical College of Wisconsin said that progressing into pivotal studies was now warranted, at least in beta-thalassaemia.

Where sotatercept or luspatercept might fit into therapy is an open question, though their distinct action from erythropoiesis-stimulating agents (ESAs), and sotatercept’s effect in ESA-refractory patients, suggest a distinct approach.

Speaking to EP Vantage, Acceleron’s chief business officer, Steven Ertel, said the projects basically represented two shots on goal, with one likely to be prioritised over the other. Entry into phase III might represent a milestone trigger under the Celgene deal, though he would not confirm whether this was the case.

Class of 2013

Acceleron raised $84m in its IPO last year, while the Agios float brought in $86m; year to date the stocks are up 8% and 368% respectively.

Agios’s Celgene-partnered lead project is AG-221, an oral, first-in-class inhibitor of the IDH2 mutant metabolic enzyme, and phase I data in advanced IDH2 mutation-positive malignancies were enthusiastically received at ASH.

73 patients with relapsed or refractory AML or MDS, or untreated AML, have now been treated – an additional 38 since the last report. Long-lasting responses impressed, with three-month duration estimated at 90%; one patient’s partial response is continuing at almost nine months.

Overall response rate is 56%, including six complete remissions. However, safety is still closely watched, with 11 deaths reported – two of which were due to sepsis/hypoxia and atrial flutter and said to be “possibly related” to AG-221.

That said, presenting the update the Memorial Sloan-Kettering Cancer Center’s Dr Eytan Stein called AG-221’s mechanistic approach revolutionary. By virtue of targeting a specific genetic mutation AG-221 is able to progress from phase I to a “global registration programme” in 2015, Agios states.

Celgene announced today that it had extended its deal with Agios for an additional year to April 2016. Agios will receive a $20m payment.


For Acceleron there is a broader question of how a potential treatment for the effects of beta-thalassaemia might stack up against something far more revolutionary, such as a gene therapy. Another 2013 stock market entrant, Bluebird Bio, is to present hotly awaited data on its LentiGlobin gene therapy at ASH today.

Dr Piga admitted that if you could “cure” beta-thalassaemia with a gene therapy that would be spectacular, but as yet there was no safe and effective treatment. “Ours is a soft approach,” he said, “just improving the efficiency of red blood cell production.”

Bluebird’s Celgene deal covers a separate field: CAR T-cells. The group’s IPO raised $116m, and helped by a pre-ASH run-up the shares are up 120% since January.

Faring rather less well since its $76m IPO is Epizyme, another Celgene partner fighting for attention at ASH. Shares have been on a rollercoaster and are basically unchanged since the float.

Celgene has ex-US rights to Epizyme’s DOT1L inhibitor EPZ-5676 under a deal that was worth $90m up front, plus a $25m milestone when two complete responses were reported in January in a phase I dose-escalation trial in 36 leukaemia patients. However, information released in the ASH abstract revealed no further responses, causing some concern over the path forward.

Thus this group’s epigenetic approach, developing small-molecule inhibitors of histone methyltransferases of which DOT1L is one example, might take time to prove itself. However, it has generated big pharma interest: in addition to Celgene Epizyme counts GlaxoSmithKline and Eisai as licensing partners.

To contact the writer of this story email Jacob Plieth in San Francisco at [email protected] or follow @JacobEPVantage on Twitter

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