Vantage Snippets are short summaries of breaking news stories.
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.
Whether Opdivo sales would fall in 2019 was a question that had troubled Bristol-Myers Squibb investors, but the fact full-year revenues rose 7% will give them little solace. In fact the curve is on a decidedly downward trajectory, as evidenced by the PD-1 drug’s flatlining of quarterly sales since the middle of 2018, and a 2019 fourth-quarter decline of 2% year on year, and 3% quarter on quarter. On an analyst call today Bristol said this was due to the US second-line NSCLC opportunity being eroded by first-line immunotherapy – basically Merck & Co’s Keytruda – and that a similar effect was expected in SCLC and head and neck cancer. It added that 30-35% of NSCLC patients were still eligible for second-line Opdivo, and that its share would settle at around 30%, though the patient pool would shrink. Remarkably, Yervoy sales climbed 12% last year. Bristol continues to hope for a front-line NSCLC approval of Opdivo plus Yervoy, though in the EU after the recent filing withdrawal its focus has switched from the Checkmate-227 study to Checkmate-9LA. EvaluatePharma sellside consensus reflects the rosy view that Opdivo sales will dip 2% this year, before accelerating to hit $10.5bn in 2024.
An important patent win for Biogen looks to have secured vital US Tecfidera revenues to 2028; the multiple sclerosis drug is the company’s biggest seller, but generic challengers were hoping to launch low-cost versions as early as 2021. Two more legal challenges are pending, but the 17.5% jump in Biogen shares yesterday, adding around $9bn to the company’s market cap, shows that investors consider the threat largely extinguished. The sellside agrees, with several banks having already lifted their numbers, and the chart below, from EvaluatePharma Vision’s NPV Analyzer, shows how consensus could shift even higher. Biogen’s thin pipeline has left it open to criticism in recent years: Tecfidera’s longevity might be secured, but the company’s next most important asset, Spinraza for SMA, is also under threat. Roche confirmed the efficacy and clean safety with its rival therapy, risdiplam, today. Risdiplam could reach the market in a matter of months, and the Swiss firm has made no secret of its intention to compete on price. None of this might matter if the miraculously resuscitated Alzheimer’s antibody aducanumab gets to market; confirmation that the FDA will accept the project for review is the next piece of good news that investors need.
As head of Roche’s pharma division, Daniel O’Day was notoriously cautious about Car-T, refusing to take his company into any cell therapy deals. It will come as cold comfort that his first year as chief executive of Gilead will have proved his scepticism to have been well placed. 2019 sales of Gilead’s Car-T therapy Yescarta yesterday came in at $456m, missing sellside consensus of $474m, according to EvaluatePharma, and comprising an anaemic 3% quarter-on-quarter increase; this means that Yescarta revenues have been flat for three straight quarters. And Gilead’s financials revealed another Car-T-related impairment: $800m, “primarily related to the treatment of indolent non-Hodgkin lymphoma”, adding to an $820m write-off for the discontinuation of the BCMA-targeting Car-T asset KITE-585 a year ago. Gilead’s immediate Car-T hopes now rest on KTE-X19 – the Yescarta construct but with a modified manufacturing process – which is filed for mantle cell lymphoma, and on Zuma-7, a phase III study that reads out in the second half and seeks to expand Yescarta’s lymphoma use from third to second line. Ultimately, Mr O’Day will have to decide how much funding to devote to Gilead’s cell therapy pipeline, or indeed to business development in this area.