Vantage Snippets are short summaries of breaking news stories.
The announcement of two deals today shows that Alexion has its eyes firmly on franchise protection. A partnership with Affibody builds Alexion’s existing presence in FcRn, an area that is still very much under development, while a collaboration with Zealand Pharma will see the companies develop novel peptide therapies for complement-mediated diseases, the big biotech’s existing area of expertise. Under the former deal Alexion has for $25m up front bought rights to ABY-039, a bivalent antibody-mimetic that targets FcRn. This hot area of research promises advances in the treatment of a range of IgG-mediated diseases; Alexion paid $400m for Syntimmune last September to gain Synt001, an IgG4 monoclonal antibody. The Syntimmune project is now called ALXN1830, and is administered intravenously, which is not ideal for chronic conditions. Step forward the subcutaneously delivered ABY-039, which Alexion describes as a high-affinity protein ligand with an extended half-life. Assuming that this field progresses successfully the Affibody deal could put Alexion in a very strong position in a few years’ time, particularly as there are very few clinical assets to choose from here. Argenx is considered to be leading, and this latest move by Alexion shows that the Belgian group cannot afford to trip up.
|Targeting FcRn: clinical-stage projects|
|Efgartigimod||Argenx||Anti-FcRn Ab fragment||IV; SC to enter phase II H1 2019|
|Rozanolixizumab||UCB||Anti-FcRn MAb||IV and SC; SC going forward|
|Synt001/ALXN1830||Alexion||Anti-FcRn MAb||IV; plans to pursue SC|
|M281||Momenta||Anti-FcRn MAb||IV; plans to pursue SC|
|ABY-039||Alexion/Affibody||Anti-FcRn bivalent Ab mimetic||SC|
|IV=intravenous. SC=subcutaneous. Source: EvaluatePharma, company websites.|
The launch date for Sage Therapeutics’ postpartum depression treatment Zulresso (brexanolone) looks set for June, but exactly how big an opportunity this new drug presents is far less clear. Its method of administration looks likely to limit use to very severe cases: Zulresso must be continuously infused over 60 hours. Meanwhile, the advancement of new oral medicines showing promise in this setting, including Sage’s own SAGE-217 and Marinus’s ganaxolone, makes forecasting sales further out even harder. As the first FDA approved treatment for postpartum depression the need for Zulresso is clear, at least, and clinical trials demonstrated an impressive reduction in symptoms, with a swift onset and sustained effectiveness. But it is obvious from the sellside forecasts, collated by EvaluatePharma, that analysts are divided on this opportunity. Those who believe it will remain a niche product do not expect sales to top $100m, while others appear to believe that Zulresso heralds a major treatment revolution, with projections soaring to $600m-plus in five years. Sage’s huge $8bn valuation rests mostly on SAGE-217, but with expectations so high the company needs to deliver a Zulresso launch that more closely follows the bull case.
Over the past few years Celyad has made much of its desire to become a player in off-the shelf CAR-T. But it was only yesterday, during the tail end of an R&D presentation, that it spelled out precisely what it planned to do and how. Three new allogeneic CAR-T projects were presented: CYAD-211 targeting BCMA, CYAD-221 against CD19, and CYAD-231, a bispecific construct versus NKG2D ligands and an undisclosed antigen. These are due to enter clinical trials in mid-2020, late 2020 and early 2021 respectively. All use a short hairpin RNA technology licensed last October from Horizon Discovery to knock out endogenous T-cell receptors – the cause of graft-versus-host disease – without gene editing. Meanwhile, a phase I trial of Celyad’s first allogeneic CAR, CYAD-101, also against NKG2D ligands, is ongoing, but to silence the T-cell receptor this asset uses a different mechanism, namely a “TCR inhibitory molecule”. A resurgence of interest in off-the-shelf CAR-T approaches saw Precision Biosciences outline the terms of its Nasdaq flotation yesterday. Celyad will compete against Precision and more established players, and said it was important to hit validated antigens before looking to novel targets.
|Celyad's allogeneic CAR-T assets|
|Target||NKG2D ligands||BCMA||CD19||NKG2D ligands x undisclosed bispecific|
|TCR silencing tech||TIM*||shRNA||shRNA||shRNA|
|Clinical trial||NCT03692429||mid-2020||Late 2020||Early 2021|
|Allogeneic competition||None||ALLO-715 (Cellectis/Allogene)||UCART19 (Cellectis/Allogene)||None|
|PBCAR269A (Precision)||ALLO-501 (Allogene)|
|P-BCMA-ALLO1 (Poseida)||PBCAR0191 (Precision)|
|Source: company filings; *TCR inhibitory molecule.|
“The best outcome we could have hoped for” is how Dermira executives described phase IIb data with the atopic dermatitis project lebrikizumab this morning, and investors appeared to agree: shares almost doubled in early trade, putting the group's valuation at $570m. Results suggest that the company’s IL-13 antibody has similar efficacy to Sanofi/Regeneron’s blockbuster Dupixent, but with a more convenient dosing schedule. On some safety and tolerability measures, like rates of conjunctivitis, lebrikizumab looks better. All of this needs to be confirmed in a pivotal study, of course, and Dermira plans to start such a trial before the end of the year. Results could emerge in late 2021, by which time Dupixent is expected to be selling $3bn in atopic dermatitis, or severe eczema; for any chance of seriously competing with such a successful product Dermira needs subsequent trials to be equally impressive. In the phase III study of lebrikizumab the company hopes to show that patients can be moved from a two-weekly loading schedule to a maintenance phase of injections every four weeks. Lebrikizumab has a chance of emerging as “best in category”, executives maintain. Watch out Sanofi and Regeneron.
Novartis is ensuring that Alcon gets the best start in life as an independent eyecare company, with yet another bolt-on acquisition. Today's beefing up involves the $285m takeout of Powervision, a privately held advanced intraocular lens company; in December Alcon added the dry eye specialist Tear Film for an undisclosed sum. Alongside these small additions to help grow sales, Novartis has been working on improving profitability at Alcon through an aggressive restructuring; last year the unit reported a 10% improvement in core operating income as sales rose 6% to $7.15bn. Alcon’s disengagement from the mothership is expected to happen in the second quarter of 2019, and the group is eyeing growth via the ageing Western population, increasing wealth levels in emerging economies and the rising prevalence of myopia and "digital eye strain" due to screen use. Independent Alcon is expected to be valued at $20-30bn, though those with longer memories will remember the $50bn plus that the former Novartis chairman Daniel Vasella originally shelled out for the company. Shareholders, who will receive one Alcon share for every five Novartis shares, will hope that the group does a better job at growing in value as a standalone.
Medtronic needed a win in the Wrap-It study to boost uptake of its Tyrx absorbable antibacterial envelope – and it has one. The trial found that the envelope, when used with implantable cardiac devices like pacemakers, significantly reduced major infection without increasing the risk of complications. Tyrx, which is already widely approved, is a bioresorbable polymer mesh pouch impregnated with the antibiotics minocycline and rifampin. Implantable devices are placed inside the envelope before being put into patients, with the aim of preventing infections. The 7,000-patient Wrap-It trial evaluated whether using Tyrx decreased the incidence of infection leading to device removal or revision, antibiotic therapy with infection recurrence, or death, one year after implantation. 25 patients in the Tyrx group experienced such an event, versus 42 in the control group, who received an implantable device without the envelope. The difference was statistically significant, with a p value of 0.04. Meanwhile Tyrx was non-inferior to control on the safety endpoint, procedure or system-related complications within a year. Medtronic will now have to wait and see if Tyrx will be added to cardiology guidelines, although this seems likely given its potential to reduce hospital readmissions.
How worried is Amgen about the potential for the Medicines Company’s twice-a-year cholesterol-lowering injection inclisiran to steal market share from Repatha? Worried enough that it is willing to initiate a new clinical trial, costing hundreds of millions of dollars, to break into a new market – prevention of cardiovascular events in high-risk patients who have not already had one. Earlier this week the group registered the new study with clinicaltrials.gov, and the filing reveals that the trial will enrol 13,000 patients with cardiovascular disease and elevated LDL, and follow them for four years. Composite endpoints measuring cardiovascular death, myocardial infarctions, strokes and revascularisation will be evaluated. In terms of patient numbers and outcomes, the new Amgen trial looks similar to the Medicines Company’s Orion-4 cardiovascular outcomes study, although that phase III trial reserves inclisiran for patients who have already experienced a myocardial infarction, stroke or peripheral artery disease. Amgen also thinks it can generate outcomes data by mid-2024 – six months earlier than Orion-4 – and thus be able to counter a potential marketing push against Repatha, as well as Sanofi and Regeneron’s Praluent, by the Medicines Company in the post-event population. The new Amgen trial may cost around $800m, according to an estimate using EvaluatePharma Vision’s R&D Cost methodology.
|Comparing the cardiovascular outcomes studies|
|Population||High-risk cardiovascular disease patients post-MI, stroke or peripheral artery disease||High-risk cardiovascular disease patients without prior MI or stroke||High-risk cardiovascular disease patients post-MI, stroke or peripheral artery disease|
|Endpoint||Cardiovascular death, MI, stroke, revascularisation or hospitalisation for unstable angina||Cardiovascular death, MI, stroke or revascularisation||Cardiovascular death, MI, stroke or revascularisation|
|Completion||Nov 2016||May 2024||Dec 2024|
At first glance a three-month delay to selinexor’s US FDA approval decision should be bad news for its developer, Karyopharm. But the group’s stock rose 30% today on hopes – however slim – that the multiple myeloma project might still be in line for accelerated approval by its new PDUFA date of July 6. Last month an FDA panel appeared to have put a quick go-ahead completely out of reach, voting to wait for results from the open-label Boston study before making a call on selinexor; data are due in late 2019 or early 2020. Since the adcom, Karyopharm has submitted more data to the FDA, and Leerink analysts speculated that these might have come from the Boston trial. Toxicity concerns could still stop selinexor from getting the approval and mean that even if it does, it might remain a last-ditch option. The project is under review for treatment of relapsed/refractory multiple myeloma patients who have received at least three prior therapies; Boston tests a combo with Velcade and dexamethasone in earlier-line relapsed patients. Selinexor is forecast to bring Karyopharm $1.2bn by 2024, according to EvaluatePharma – numbers that are looking increasingly unrealistic.
Stryker has struck its latest deal at an interesting moment. Its $110m cash takeout of the private company Orthospace is timed just before the pivotal trial of the target’s sole product, a shoulder implant called InSpace, is due to read out – perhaps Stryker got a sneak peek at the data and found them satisfactory. InSpace is a fluid-filled balloon similar in shape to a whoopee cushion, implanted arthroscopically at the site of irreparable rotator cuff tear. It is intended to cushion the bones and speed rehabilitation, and biodegrades as the shoulder heals. The US pivotal trial pits the device against arthroscopic partial repair of these tears in 184 patients; outcomes are safety and change from baseline on the Western Ontario rotator cuff index. Results are due next quarter, and a trial success, and/or US approval itself, will presumably trigger some of the $110m milestone payments also included in the deal. The fast-growing sports medicine sector is one of the areas in which Stryker is focusing its investment strategy. It clearly believes that this bet will pay off.
While Bellicum tries to get its lead cell therapy, Rivo-Cel, across the regulatory finish line it is continuing to talk up the early-stage pipeline. This week it revealed that a fifth pipeline asset, a CAR-T therapy called BPX-603, will target the Her2 antigen and enter the clinic this year. This might seem puzzling: Her2 is known to be expressed on healthy as well as cancerous cells, and the risk of on-target/off-tumour toxicity with a therapy as powerful as CAR-T is considerable. Indeed, an NCI study of a Her2-directed CAR that caused a patient death has been well documented. Nevertheless, several such trials are ongoing, including one at Bellicum’s academic parent, Baylor College. And Bellicum reckons it can overcome problems by using in BPX-603 a humanised binding domain that is more selective for Her2 than Baylor’s murine binder, as well as employing dual “on” and “off” switch domains. Still, there is little to suggest that an adverse event that occurs as fast as cytokine storm can be counteracted by this type of off switch, and in any case this technology does not appear to be proprietary to Bellicum.
|Selected Her2-directed CAR-T therapies|
|Sponsor||Project||Cancer types||Trial ID|
|Mustang Bio/NCI||HER2-CAR||Brain or leptomeningeal metastases||NCT03696030|
|Baylor College||HER2-CAR||Her2 +ve CNS tumors||NCT02442297|
|Seattle Children's Hospital||HER2-specific CAR||Her2 +ve CNS tumors||NCT03500991|
|Leucid Bio/King's College||T1E28z*||Head & neck cancer||NCT01818323|
|NCI||Anti-Her-2 cells||Colon cancer||NCT00924287**|
|Bellicum||BPX-603||Gastric & endometrial cancers||TBA|
|Source: clinicaltrials.gov; *targets Erb dimers including Her2; **study terminated owing to patient death.|