Friday Five – ASH special

The annual meeting of the American Society of Hematology (ASJ) took place in Atlanta December 9-12  and, based on the clinical data presented, was arguably the most important medical meeting of 2017.

BioMarin sparks ASH into life

BioMarin Pharmaceutical presented very promising dose-escalation data for its gene therapy valoctocogene roxaparvovec, prompting the New England Journal of Medicine to proclaim "a cure for haemophilia is within reach."

Roche's recently approved antibody therapy Hemlibra is poised to mark a paradigm shift in how haemophilia A patients are treated, but BioMarin and others, including Spark Therapeutics and Pfizer, are looking to take this revolution a step further with one-off gene therapies that can potentially provide a cure.

Data for valoctocogene roxaparvovec is in just nine severe patients, with follow-up out to 78 weeks, but each of them were able to stop using clotting factors and bleeding rates fell to zero or near-zero, while clotting factors were restored to normal levels. Results caught investigators off-guard; John Pasi – director of the Royal London Hospital Haemophilia Centre said "this is way more than we wanted to achieve."

It is safe to assume BioMarin could be a takeout target for either Shire or Roche, both of whom could have a lot to lose if a gene therapy for haemophilia A successfully reaches the market; the biotech would also fit Shire's orphan drug blueprint, while Roche has previously proffered its interest in rare disease-focused acquisitions.

Spare a thought for Spark, which presented its own competing data at ASH showing a lack of consistent dose response for SPK-8011. With BioMarin set to initiate two single-arm Phase III trials of valoctocogene roxaparvovec, the key questions is whether Spark's misfortune enhances BioMarin's leadership in this race or is endemic of development challenges that lie ahead.

See ViewPoints: Back to the drawing board for Spark with SPK-8011 and ViewPoints: Spark’s pain is BioMarin’s gain in haemophilia A – or is it?

The CAR-T crowd

Gilead Sciences and Novartis both presented follow-up data showing sustained responses to their CAR-T therapies Yescarta and Kymriah, respectively, in diffuse large B-cell lymphoma (DLBCL) patients; Yescarta is already approved in the US for this indication, while Kymriah is under regulatory review (but approved in paediatric and adolescent acute lymphoblastic leukaemia).

Data look remarkably similar, suggesting that other factors such as toxicity profile and logistical support provided to centres certified to administer CAR-T will play an important role in determining commercial success.

See ViewPoints: Novartis touts safety as key advantage in its CAR-T showdown with Gilead

One as yet unanswered question is whether Juno Therapeutics, which lost ground on Novartis and Gilead (then Kite Pharma) last year, can differentiate its own offering – JCART017 – as a best-in-class CAR-T product in DLBCL to avoid becoming an also-ran.

Data from a small number of patients published earlier this year suggested the former was a possibility, both in terms of superior efficacy and safety, but at ASH Juno failed to land a knockout blow with its updated results, which showed a marked decline in response rates to fall more broadly in line with Gilead and Novartis' numbers.   

Juno did outline ongoing efforts to treat patients with JCAR017 in an outpatient setting as part of its ongoing pivotal-stage study, but Novartis rained on this parade by confirming that around a quarter of patients in its JULIET trial have also been treated outside the hospital setting – ViewPoints: Juno claims a niche position for JCAR017, only to find Novartis is already there.

While the science behind CAR-T therapies continues to impress, question marks around commercial execution remain and are unlikely to go away if other drugs such as Roche's polatuzumab vedotin combination, which are more convenient to administer, produce impressive data.

See Physician Views: Clinical data for CAR-T therapies in DLBCL grows at ASH and KOL Views: Reassessing CAR-T leaders in light of ASH data dump.

bluebird soars

By comparison, new data for bluebird bio's BCMA-targeting CAR-T bb2121, being developed for multiple myeloma, showed deepening responses in heavily pre-treated patients and a robust safety profile. Just prior to the ASH meeting, bluebird and its partner Celgene confirmed that they are moving bb2121 into a pivotal-stage trial and during the conference talked up the opportunity of eventually moving CAR-T into earlier lines of therapy via head-to-head trials versus established myeloma therapies.

Among 21 patients treated with bb2121, 10 and six patients achieved complete and partial responses, respectively, versus four and 12 complete and partial responses among 18 patients in data presented at the ASCO annual meeting in June.

With BCMA as a promising target in myeloma emerging as a key theme at ASH (see below), delivery of impressive bb2121 data keeps bluebird in an advantageous position; one it is now looking to drive home. Enrolment in its pivotal-stage study will not be limited to patients with high BCMA expression, the company has confirmed, thereby potentially broadening bb2121's applicability if data are positive.

In addition, bluebird bio provided an update on its evolving manufacturing process for its LentiGlobin gene therapy, being developed for sickle cell disease and beta thalassaemia, which was met enthusiastically by investors and analysts – ViewPoints: bluebird steers LentiGlobin back on track.

Is GlaxoSmithKline back in the game?

Against the backdrop of BCMA as an emerging target in myeloma, GlaxoSmithKline presented promising Phase I data for its BCMA-targeting antibody drug conjugate GSK2857916; a product it hopes will springboard it back into the cancer market, but which was somewhat overshadowed by new data for bb2121 at ASH – ViewPoints: Heading out of ASH, GlaxoSmithKline claims to be back in the oncology game.

GlaxoSmithKline's decision to divest its portfolio of marketed oncology products to Novartis in 2015 casts a shadow across its current aspirations in this therapy area and if '916 looks like it may be 'the right product at the wrong time,' then development delays stemming from that deal may be to blame.

Axel Hoos, who heads up GlaxoSmithKline's oncology business, believes that '916 is more than capable of competing with other mechanisms, including CAR-Ts, which will prove more commercially challenging.

Celgene's partnerships prove valuable

At the end of a challenging year for Celgene, the company was one of the leading beneficiaries exiting ASH, thanks to development collaborations with both bluebird and Juno. Promising data for bb2121 and JCAR017, the former in particular, have firmed up potential growth trajectories for Celgene into the next decade, chorused analysts, while simultaneously positioning the company at the top table in CAR-T – ViewPoints: Celgene gets a boost from its CAR-T friends.

Further reading - KOL Views Results: Leading oncologist sees rapid Darzalex uptake in front-line MM but not necessarily at Revlimid’s expense and Physician Views Poll Results – AbbVie, Roche will exit ASH with practice-changing data for Venclexta


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