Vantage Snippets are short summaries of breaking news stories.
Another delay to Genfit’s Resolve-It trial of elafibranor looks suspicious, but you can hardly blame the French company for wanting to give the study the best possible spin. After all, the Nash trial’s odds of success are low, given elafibranor’s phase II flop, the failure of most other Nash projects and the discontinuation of Cymabay’s similarly acting seladelpar. Resolve-It’s readout had already quietly been delayed from the end of last year (Genfit’s liver disease Hail Mary approaches, September 19, 2019). Yesterday the group revealed a plan to sit on the blinded dataset until the second quarter “to incorporate the latest FDA insights”. Presumably this is to allow Reduce-It’s endpoints to be tweaked at the last moment – permissible before unblinding – should evidence emerge that this would increase the trial’s chances of showing an effect on Nash. More clarity is possible when Genfit reports 2019 financials on April 8, but a likely timeline will see Resolve-It results only after Intercept’s Ocaliva faces a US adcom on April 22, or after the FDA’s verdict on that drug. Lots more should then be known about the agency’s thinking, and not all of it will be favourable to Genfit.
|A Nash timeline|
|Mar 2015||Elafibranor's phase 2 Golden study fails|
|Feb 2016||Gastroenterology paper published post-hoc analysis of Golden study, suggesting a path forward|
|Mar 2016||Genfit's phase 3 Resolve-It study begins|
|Apr 2018||Resolve-It recruits 1,000 Nash subjects necessary for interim analysis, data expected by end 2019|
|Feb 2019||Gilead’s Ask1 inhibitor selonsertib fails|
|Jun 2019||Conatus collapses after failure of emricasan|
|Sep 2019||Genfit delays Resolve-it readout to Q1 2020|
|Nov 2019||Cymabay discontinues PPAR delta agonist seladelpar|
|Dec 2019||Gilead's multi-project Atlas study fails|
|Dec 2019||Boehringer discontinues AOC3 inhibitor BI 1467335|
|Feb 2020||Genfit delays Resolve-it readout to Q2 2020|
|8 Apr 2020e||Genfit to report 2019 financials|
|22 Apr 2020e||US adcom for Intercept's Ocaliva|
|26 Jun 2020||US FDA action on Intercept's Ocaliva|
|Q2 2020e||Resolve-It to read out|
|Source: company announcements.|
Teleflex’s contract manufacturing business is neither its biggest nor its fastest-growing unit, but a $260m tuck-in acquisition could give it a lift. The diversified company paid cash for IWG High Performance Conductors, the market leader in insulated ultra-fine wires and micro-diameter tubing – components used in the fields of electrophysiology, other vascular technologies and pain management. As such IWG should be complementary to Teleflex’s OEM segment, but unlike that business it is growing at double-digit rates. It also carries operating margins in excess of Teleflex’s own, which are themselves at an all-time high of 27%, chief financial officer Thomas Powell said on the group’s quarterly call yesterday. There could be many more deals to come, quite possibly this year: the group's chief exec, Liam Kelly, said Teleflex had the capacity for more M&A on its balance sheet, and that acquisitions was the preferred option for capital deployment. It will have to: sales growth of one of its main products, the UroLift prostate implant, is forecast to slow despite a planned marketing blitz, and sterilisation facilities and the coronavirus outbreak are also expected to drag on revenues.
|Annual sales ($m)|
|Vascular, anaesthesia, urology & critical care||1,223||1,338||1,582||1,827||+8%|
|Devices for original equipment manufacturers||220||232||257||281||+5%|
|Total company revenues||2,595||2,780||3,182||3,585||+7%|
Tourette’s syndrome, like most neurological conditions, has proven resistant to pharmacological intervention, so the failure of Teva’s attempt to extend Austedo into this disorder might not be wholly surprising – unless you are an equity analyst. The sellside had forecast 2024 Austedo revenues in Tourette’s of $175m, around 17% of the VMAT2 inhibitor’s total sales that year. But Artists 1, a phase II/III study, and the phase III Artists 2 have both failed to show a reduction in motor and phonic tics with Austedo over placebo in children with moderate to severe Tourette’s. Loss of the potential Tourette’s sales means that Austedo could miss the sellside's overall 2024 blockbuster forecasts. The twin trial misses also leave the pipeline for Tourette’s in a pretty dismal state. Data on Neurocrine’s VMAT2 inhibitor Ingrezza and Lundbeck’s Lu AG06466 should come this year, and on Otsuka’s antipsychotic Abilify, which already has Tourette's on its label, in 2021, but the omens for many are not good; no significant banks have yet been willing to assign sales for these drugs in Tourette’s.
|Selected active projects in Tourette's|
|Abilify||Partial 5-HT1A, D2 agonist & 5-HT2 antagonist||Otsuka||NCT03661983 (Data due 2021)|
|Austedo||VMAT2 inhibitor||Teva/Nuvelution||NCT03452943 (Artists1, failed)|
|NCT03571256 (Artists2, failed)|
|Ingrezza||VMAT2 inhibitor||Neurocrine||NCT03530293 (T-Force Platinum, update due Q2)|
|NCT03325010 (T-Force Gold, failed)|
|Lu AG06466||MGLL inhibitor||Lundbeck (ex Abide)||NCT03625453 (data due 2020)|
|Ecopipam||D1 & D5 antagonist||Emalex Biosciences||No active trials|
|THX-110||Cannabinoid receptor agonist||Therapix Biosciences||NCT03651726 (not yet recruiting)|
The mere fact that Merck & Co’s mighty Keytruda received a US complete response is reason enough for surprise, but in reality it amounts to little. The slapdown, issued after market close yesterday, concerned an every six weeks dosing regimen (rather than the current three-week schedule) for monotherapy use only, and Mizuho analysts reckon it will have had no effect on the drug’s two biggest growth areas, non-small cell lung cancer and renal cell carcinoma. As the chart below shows, Keytruda is well entrenched, with global sales estimated to total an incredible $22.3bn in 2024, according to EvaluatePharma sellside consensus. Still, this has not deterred challengers, as evidenced by Roche’s pursuit of Tecentriq monotherapy for first-line NSCLC; a US filing for this was yesterday accepted, with the FDA setting a June 19 action date. This is backed by the Impower-110 study that read out positively for overall survival versus chemo alone in patients whose tumours expressed PD-L1 at ≥1%. Keytruda monotherapy is already available in this precise setting, thanks to the Keynote-042 trial, and in all-comers as part of a chemo combo, so the Roche threat looks relatively minor for now.
Today Vifor Pharma said it had bought a priority review voucher. What it did not say, however, is from whom it bought it, how much it paid, or the use to which the voucher is to be put. Fortunately educated guesses can be made regarding all these unknowns. The table below reveals that 21 unused vouchers are thought to be in existence, and might thus have been sold to Vifor. As to price, the vouchers that changed hands last year went for about $100m – Vifor presumably would have paid around the same amount. When it comes to the project for which Vifor’s voucher might be used, the obvious candidate is vadadustat, in US phase III trials for the treatment of anaemia due to chronic kidney disease. Notably, one of the main candidates for use of the priority review voucher Astrazeneca bought from Sobi last year is the similar project roxadustat – though when Fibrogen, Astra’s partner, announced the filing it did not mention priority review. Perhaps this is a chance for Vifor, and its US partners Akebia Therapeutics and Otsuka, to steal a march on the competition.
|Disclosed priority review vouchers thought not to have been redeemed|
|Date issued||Issued company||Action|
|Feb 2014||Biomarin||Sold for $68m to Sanofi & Regeneron|
|Sep 2015||Wellstat||Transferred to Astrazeneca in licensing deal|
|Apr 2017||Biomarin||Sold for $125m to undisclosed party|
|Dec 2017||Spark||Sold for $110m to Jazz Pharmaceuticals|
|Apr 2018||Ultragenyx||Sold for $81m to undisclosed party|
|Jul 2018||Siga||Sold for $80m to Lilly|
|Jun 2018||Medicines Development||Sold to Novo Nordisk|
|Nov 2018||Novimmune||Asset sold to Sobi, which sold PRV for $95m to Astrazeneca|
|Sep 2019||Bavarian Nordic||Sold for $95m to undisclosed party|
|Feb 2017||Marathon||None; asset sold to PTC Therapeutics|
|Aug 2017||Insud Pharma||None|
|Aug 2019||TB Alliance||None|
|Dec 2019||Merck & Co||None|
Jenavalve Technologies’ latest funding round provided $50m for the development of a catheter-mounted aortic valve. But it also highlighted the fact that the company, unlike many of its peers, has been unable to find a buyer. Jenavalve, New Valve Technology and Meril Life Sciences are the three groups whose transcatheter aortic prostheses have been approved in Europe but which have not been taken out by one of the big players here. Meril, owned by a single family and self-funding, does not want a buyout; but Jenavalve’s management has made no secret of its desire for an exit – and since its product was CE marked far earlier than these others its investors must be getting restive. Still, a consortium led by Bain Capital appears to have faith that it will get there in the end, presumably buoyed by the FDA awarding breakthrough device designation to the device last month. A US filing for humanitarian device exemption is planned for the second half of this year, as are supplementary EU filings.
|CE marked transcatheter aortic valves|
|Company||Product||Originator and date of acquisition||First CE mark date|
|Medtronic||CoreValve franchise||Corevalve, 2009||May 2007|
|Edwards Lifesciences||Sapien franchise||In-house||Sep 2007|
|Boston Scientific||Acurate franchise||Symetis Technologies, 2017||Sep 2011|
|Jenavalve Technologies||JenaValve||In-house||Sep 2011|
|Abbott||Portico||St Jude Medical, 2017||Nov 2012|
|Direct Flow Medical||Direct Flow valve||In-house; company folded in 2016||Jan 2013|
|Boston Scientific||Lotus franchise||Sadra Medical, 2011||Oct 2013|
|New Valve Technologies||Allegra||In-house||Apr 2017|
|Edwards Lifesciences||Centera||Development abandoned, July 2019||Feb 2018|
|Meril Life Science||MyVal||In-house||Apr 2019|
|Source: EvaluateMedTech & company websites.|
|Jenavalve's VC funding|
|Feb 2020||Series F||50.0||Bain Capital Life Sciences; Andera Partners; Gimv; Legend Capital; Neomed Management; RMM Consulting; Valiance; VI Partners|
|Aug 2017||Series E||9.4||Undisclosed|
|Aug 2016||Series D||10.0||Undisclosed|
|Aug 2015||Series C||99.0||Atlas Venture; Edmond de Rothschild Investment Partners; Gimv; Investor (Rudi Mariën); Legend Capital; Neomed Management; Omega Funds; Sunstone Capital; Valiance; VI Partners|
|Mar 2010||Series B||25.8||Atlas Venture; Edmond de Rothschild Investment Partners; Neomed Management; Sunstone Capital; VI Partners|
|Sep 2007||Series A||18.5||Atlas Venture; Edmond de Rothschild Investment Partners; Neomed Management|
This morning’s discontinuation of Astrazeneca’s lung cancer study combining oleclumab with AZD4635 should be of interest to Corvus and Novartis. The latter two companies are also pursuing combinations of in-house projects that have the same mechanisms of action: co-blocking CD73 and the A2A receptor. The two pathways are thought to be related, and there is some preclinical rationale behind blocking them both. Astra today stressed that it was continuing to work on combinations, and indeed a separate oleclumab/AZD4635 trial in prostate cancer is continuing. The group has also recently begun new studies combining oleclumab with Imfinzi, as well as with Innate Pharma’s anti-CD39 MAb IPH5201. Corvus’s A2A approach, once implied only in Parkinson’s disease, had earlier disappointed in combination with Tecentriq (AACR – Parkinson’s approach to cancer needs more work, Aptil 5, 2017). And yesterday the company disappointed further, falling 5% after the same combo posted just one partial remission among 35 subjects with very late-line prostate cancer, according to an abstract at Asco’s Genitourinary Cancers Symposium.
|Selected anti-CD73 and A2A receotpr inhibitor projects|
|Company||CD73||A2A||Combo work?||Clinical study summary|
|Astrazeneca||Oleclumab||AZD4635*||Yes||Discontinued combo in EGFRm NSCLC|
|Corvus||CPI-006||Ciforadenant||Yes||Phase I as monotherapies & combo (also with PD-1)|
|Arcus||AB680||AB928||No||Studies as monotherapies and in combo with PD-1 or Tigit|
|Novartis||SRF373/ NZV930**||PBF 509/ NIR178||Yes||Phase I as monotherapies & combo (also with spartalizumab)|
|Bristol-Myers Squibb||BMS-986179||(none)||NA||Phase I monotherapy & Opdivo combo|
|I-Mab/Tracon||TJD5||(none)||NA||Phase I Tecentriq combo|
|Source: EvaluatePharma. *Licensed from Sosei; **licensed from Surface Oncology.|
If Astrazeneca still insists that CTLA-4 inhibition is a valid part of an immuno-oncology combination its private stance seems to be somewhat different. The reality has been laid bare by EvaluatePharma Vision’s estimate of the clinical trial costs of Astra’s tremelimumab, suggesting that R&D investment in this CTLA-4 MAb peaked in 2018 and is now winding down. The estimate is based on enrolment numbers in previous and ongoing trials, and an estimate of the per-patient cost. Tremelimumab is notorious for not recording any resounding clinical wins despite an extensive study programme, and notwithstanding a recent purported success in Astra’s Poseidon study (Poseidon scores, but tremelimumab’s role is still unclear, October 29, 2019). One of the biggest ongoing bets on CTLA-4 inhibition is by Yervoy’s owner, Bristol-Myers Squibb, which is additionally pursuing the afucosylated MAb BMS-986218, and BMS-986249, a CTLA-4 probody licensed from Cytomx, through the clinic. A definitive picture might not emerge until Merck & Co’s Keynote-598 trial combining Keytruda with Yervoy reads out in 2023, and should this be positive Merck has its own CTLA-4 MAb, MK-1308, waiting in the wings.
*EvaluatePharma Vision’s R&D model estimates the cost of individual clinical programmes using real-world data, combining disclosed product-level spend and clinical trial subject numbers.
Roche, looking to regain lost ground in immuno-oncology, probably did not need Merck & Co to challenge it on its home turf of breast cancer. But it looks like this has happened with today’s hit for Keytruda in the Keynote-355 study in first-line triple-negative disease. Still, the victory is equivocal, Keynote-355 extending progression-free survival only in ≥10% PD-L1 expressers. The study presumably failed in all-comers and in the ≥1% population, while its co-primary endpoint of overall survival has yet to be revealed. Roche’s Tecentriq, in combination with Abraxane, already carries a first-line TNBC label in ≥1% PD-L1 expressers thanks to the Impassion-130 trial, so perhaps the Keytruda threat does not yet amount to much. But Keytruda might also steal a march on Tecentriq in perioperative TNBC use, thanks to the separate Keynote-522 study, whose positive result stands in contrast to Tecentriq’s recently failed NeoTRIPaPDL1 neoadjuvant trial (Perioperative use proves elusive for Tecentriq, February 10, 2020). And Keytruda earlier flunked the second-line TNBC study Keynote-119 in all-comers, so today’s news suggests that Roche cannot afford to rest on its laurels.
|Merck vs Roche in triple-negative breast cancer|
|Impassion-130||Tecentriq + Abraxane||1st-line||Hit on mPFS in ≥1% PD-L1; US & EU approved|
|Keynote-119||Keytruda monotherapy||2nd/3rd-line||Fail; exploratory OS hit in ≥20% PD-L1|
|Keynote-355||Keytruda + chemo||1st-line||Hit on mPFS in ≥10% PD-L1|
|Keynote-522||Keytruda + chemo||Neoadj + adjuvant||Hit on pCR, 13.6-point improvement, p=0.00055|
|NeoTRIPaPDL1||Tecentriq + chemo||Neoadjuvant||Miss on pCR|
|Impassion-031||Tecentriq + Abraxane||Neoadjuvant||Upsized by 120 subjects; data late 2020|
Myriad Genetics’ share price performance over the past 12 months has been erratic to say the least, but the major disappointments in its second-quarter results, released after market yesterday, have pushed the stock to its lowest price since April 2017. Second-quarter revenues of $195m were not only 10% lower than a year earlier, but they were far below Myriad’s own guidance of around $211m. The group blamed billing changes to do with its prenatal testing business, which it gained via its $375m acquisition of Counsyl in 2018; revenues form this unit almost halved year-on-year. Its chief executive, Mark Capone, is to step down immediately, with finance chief R Bryan Riggsbee taking the helm in the interim. The new leadership will doubtless wish to stabilise the company’s stock. A 54% jump in the price late last July, when United Health said it would reimburse the group’s GeneSight multi-gene panel, was wiped out a week later by disastrous fourth-quarter financials. Indeed, every quarterly update by the company since November 2018 precipitated a crash, and investors will surely be tiring of this volatility.