Vantage Snippets are short summaries of breaking news stories.
Biotech investors should be accustomed to it by now: Tyme Technologies releases data on its pancreatic cancer project SM-88, and shares crash. This time it happened ahead of a poster to be published later today at the Asco-GI conference, showing a low response rate in a single-arm trial in patients receiving the combination therapy in second, third and fourth-line settings. In 17 evaluable patients, two saw target lesions shrink enough to meet the definition of a partial response by Recist criteria. An earlier version of the poster showed no Recist responses out of 21 patients. The company said the first version of the poster was incorrect because it included four patients who were not evaluable according to trial protocol because they did not have two month scans. A placeholder abstract from the same trial reported three of four patients responding, as per Recist or another measure, PET SUV. A comparable drug, Ipsen’s Onivyde, has achieved a 7.7% objective response rate. Tyme touted the fact that at a median of 4.3 months of follow-up 19 of 28 patients were alive – by comparison, Onivyde patients have shown median overall survival of 6.1 months. This did not convince investors, who pushed shares down 32% in mid-morning trading today. Tyme was undeterred; executives said they would speak with the US FDA to discuss the design of a pivotal trial.
When it comes to oncology the US FDA has been extremely reluctant to rescind accelerated approvals, even for drugs whose subsequent confirmatory trials fail. Lilly’s Lartruvo, which today flunked just such a study, will be the next test of the agency’s stance. The drug was approved in 2016 for first-line soft tissue sarcoma on the basis of a small, open-label trial called JGDG, which showed an 11.8-month median overall survival improvement over control. Today, however, the phase III, double-blind Announce study, in 460 subjects, was said to have failed to extend survival either in all-comers or in a subgroup of patients with leiomyosarcoma. Lilly said it would incur a $70-90m first-quarter charge as a result, suggesting that at least part of the value of Lartruvo carried on its balance sheet was being written off. This will reflect the expectation that Lartruvo sales will be hit – presumably either by market withdrawal or by reduced prescribing. EvaluatePharma sellside consensus saw the drug generating $603m in 2024. Lilly, which previously referred to Lartruvo, Cyramza and Verzenio as the foundations of its oncology strategy, saw its stock fall 3% this morning.
|Lartruvo studies in soft tissue sarcoma|
|JGDG (phase I/II)||1st-line, on top of doxorubicin||Open-label, 11.8mth mOS benefit vs doxorubicin||NCT01185964|
|Announce (phase III)||1st-line, on top of doxorubicin||Double-blind, failed to beat mOS of doxorubicin||NCT02451943|
|Announce-2 (phase II)||3rd-line, on top of doxorubicin + gemcitabine||Double-blind, measures OS (ongoing)||NCT02659020|
When your only tool is a hammer, every problem looks like a nail. In Lipocine’s case, the hammer is testosterone-raising agents; the group's Tlando has been knocked back twice in hypogonadism, so the Nash nail no doubt looked like it needed some bashing. A 41% share increase today suggested that Lipocine had been successful with LPCN 1144 in a phase II Nash trial, but there are plenty of reasons to wait before declaring this trial a success, including missing patients, small patient numbers, and the lack of placebo control. Lipocine reported eight-week data from seven patients in a 16-week study of LPCN 1144 in hypogonadal men who had baseline liver fat of at least 10%, putting them at risk of developing Nash. Two patients who had completed eight weeks' treatment were not included in the analysis because they were unable to schedule an MRI-PDFF appointment. In the seven men who were evaluable the study found an absolute mean reduction from baseline of 7.6% liver fat, and demonstrated a 38% relative mean liver fat reduction from baseline as measured by MRI-proton density fat fraction. The baseline liver fat of these patients was 21%. The study is scheduled to enrol 36 patients in total.
|Upcoming phase III results in Nash|
|Ocaliva||Intercept||Data from Regenerate trial||Q1 2019|
|Selonsertib, GS-0976, GS-9674||Gilead Sciences||Data from Stellar trials||H1 2019|
|Cenicriviroc||Allergan/Takeda||Data from Aurora trial||Mid-2019|
|Elafibranor||Genfit||Data from Resolve-It trial||Q4 2019|
Homing in on a narrower indication appears to have paid off for Amgen, at least in terms of getting its osteoporosis project Evenity past the US FDA. Whether the company will be able to recoup its investment is another matter. Yesterday’s 18-1 advisory committee vote in favour of Evenity, which contains the active ingredient romosozumab, came despite fears of cardiovascular side-effects. Still, the panel highlighted a need for post-marketing follow-up – whether this means another trial is unclear. And Evenity’s potential market is not what it used to be: Amgen originally filed the project for osteoporosis in postmenopausal women, but after a complete response letter in July it narrowed this down to postmenopausal women at a high risk of fracture. Since the CRL analyst forecasts have come down dramatically, EvaluatePharma sellside consensus shows. And any questions over whether Evenity will be profitable are complicated by the fact that Amgen will have to share the proceeds with a partner, UCB. Meanwhile, Radius Health guides that its rival subcutaneous product Tymlos, which was approved in April 2017, will book US sales of $155-175m this year.
|Evenity's changing forecasts|
|Annual sales ($m)|
|Launch year||Year 1||Year 2||Year 3||Year 4||Year 5|
|Forecasts before July 2017 CRL||37||154||304||425||572||698|
The near record-breaking rush of biotech flotations in 2018’s second quarter saw ever-riskier bets jump on the bandwagon. Today one of these, the neurology-focused Aptinyx, reminded investors that wild parties tend to be followed by nasty hangovers as its lead asset, the small-molecule NMDA modulator NYX-2925, flopped in the clinic. In the phase II study in 300 diabetic peripheral neuropathy subjects NYX-2925 failed to reduce neuropathic pain versus placebo. The company said 50mg, the middle of three doses tested, showed the best improvement versus placebo in the primary efficacy measure, reduction from baseline in average daily pain on a numerical rating scale after four weeks, but even this did not come close to showing nominal significance. Aptinyx had been spun out of Naurex when the latter was acquired by Allergan mainly for its peptide chemistry work including the antidepressant project rapastinel. Aptinyx's premium-priced IPO raised $102m, and the stock climbed 26% on the first day of trading; perhaps the most glaring sign of the misplaced expectations is that at its peak, the company was worth over $1bn. A phase II NYX-2925 trial in fibromyalgia is due to read out by mid-2019.
When was the last time a small biotech with around $270m in the bank had to restructure and cut costs? The fact that Five Prime resorted to such a move yesterday speaks volumes about the behind-the-scenes crisis of confidence that the company has suffered over the past year or so. It all started with the debacle around disclosure of cabiralizumab data at the 2017 SITC meeting, which precipitated a 40% stock collapse (“Surprise” SITC late-breaker breaks Five Prime, November 8, 2017). Shortly afterwards the group’s chief executive, Rusty Williams, was replaced by Aron Knickerbocker, and Marc Belsky, chief financial officer, resigned. But the shares lost another 50% in 2018; Five Prime’s biggest problem is that it serves as a proxy for novel immuno-oncology drugs, whose promise is fading fast. A bullish JP Morgan pitch last week saw it claim 56,870 gastric cancer patients addressable with bemarituzumab, an asset that targets FGFR2B-positive tumours, but investors were not sold, and presumably were not keen to participate in another equity raise. Five Prime burned through $130m last year, and restructuring is designed to save an annual $10m and allow it to end 2019 with cash of around $150m.
FDA approval of Abbott’s Amplatzer Piccolo means that even the smallest patients with patent ductus arteriosus now have a device to close the hole in their heart. The minute device is approved for use in premature babies, including those weighing as little as 2lb – and since open-heart surgery is of course very risky in such tiny patients the Piccolo, which is implanted via the femoral artery in a much safer minimally invasive procedure, will be hugely appealing. That said, the device is unlikely to be a huge money-spinner for Abbott since only around 12,000 babies are born each year in the US with PDA severe enough to warrant treatment. The device is the latest in the Amplatzer range of products designed to plug various kinds of holes in the heart, also including the Amplatzer Duct Occluder II, which treats PDA in larger paediatric patients, and the Amplatzer PFO Occluder, used to treat patent foramen ovale.
Investors reading today’s clinical trial result announcement from Verona Pharma – at least those who got beyond the “encouraging topline data” claim in its headline – might be excused for thinking that the biggest problem is that ensifentrine failed. In fact, the asset faces a more fundamental crisis, namely that it has been in development for so long that it has only another year or two of patent life remaining. This likely explains why ensifentrine (until recently known by the lab code RLP554) is still unpartnered, a situation that must be reversed if a large pivotal study in respiratory disease is to take place. The phase II COPD trial that failed today added ensifentrine on top of Boehringer Ingelheim’s LAMA/LABA combo Stiolto Respimat, and was to have backed up last year’s success in a mid-stage study that required subjects to forgo LABAs (Verona’s transformation clears its first hurdle, March 26, 2018). One concern with that earlier trial was the lack of a dose response; if anything today’s failure will exacerbate such fears, as the numerical success Verona claims concerns 1.5mg – the lower of two doses tested. Undaunted, the group called the data “clinically meaningful and unprecedented”; its stock fell 30% this morning.
|Selected ensifentrine studies in COPD|
|NCT03443414||Versus placebo (no LABA use allowed)||0.75mg, 1.5mg, 3.0mg & 6.0mg doses all hit day-4 FEV1 endpoint|
|NCT03028142||On top of Spiriva||1.5mg & 6.0mg doses hit day-3 FEV1 endpoint; 6.0mg hits avg FEV1 co-primary|
|NCT03673670||On top of Stiolto Respimat||1.5mg & 6.0mg doses fail day-3 FEV1 endpoint; numerical benefit claimed for 1.5mg|
Having recently untangled itself from a hopeless alliance with Intrexon, the cell therapy laggard Ziopharm made an aggressive pitch at JP Morgan, claiming that the only way to make CAR-T economically viable was to ditch viral transduction and use a non-viral method, like its Sleeping Beauty system. Investors are being asked to put their faith in CAR-T therapy with two-day manufacturing and no lymphodepletion, and a complex personalised T-cell receptor approach licensed from the NCI’s Dr Steve Rosenberg. Both use Sleeping Beauty, and will be in clinical trials this year, Ziopharm’s chief executive, Laurence Cooper, said on Thursday. The market, however, is used to Ziopharm’s broken promises; the group has made glacial progress since licensing Sleeping Beauty from MD Anderson four years ago, and spent part of last year on clinical hold (Ziopharm stalls its CAR yet again, June 19, 2018). And, while Sleeping Beauty is theoretically more convenient, it has underwhelmed clinically, and electroporation, the means of delivering it to cells, is notoriously inefficient. At least Ziopharm has now extricated itself from Intrexon and a $157m preferred stock commitment, though it lost Merck KGaA as a partner in the process.
The zinc finger specialist Sangamo is often touted as a takeover target, at least among its army of retail investors, and being name-dropped by both Gilead and Sanofi during JP Morgan presentations had caused excitement. But an update today disappointed: Sangamo fans hoping for important data imminently will have to wait until later this year. The group’s lead assets, SB-913 and SB-318, being developed in mucopolysaccharide diseases, are being profiled at the World Symposium in February, but its chief executive, Sandy Macrae, told JP Morgan today that this readout would only reveal biochemical and safety data. Results in ERT-withdrawal patients will not come until an unspecified time later this year. The company needs to show that the projects produce results in patients who have been weaned off enzyme-replacement therapy (ERT), the standard of care, and Mr Macrae stated: “Until we’ve stopped filling up with ERT we won’t know the true benefit.” Sangamo has a CAR-T alliance with Gilead, as well as having teamed up with the Sanofi-owned Biogen spin-off Bioverativ in haemoglobinopathies, and with Pfizer in haemophilia A. Nevertheless, investors sent its stock down 14% today.