Vantage Snippets are short summaries of breaking news stories.
Promedior’s sale for $390m to Roche today is notable for the fact that the biotech was to have been bought by someone else entirely. Four years ago Bristol-Myers Squibb had handed across $150m by way of an option to acquire Promedior, but that deal never reached fruition. Now Promedior can be doubly pleased: Roche has come in with even more money, and Bristol’s $150m has turned into a clean source of financing that sustained the private group for several years. Promedior’s lead, PRM-151, is a phase III-ready asset for idiopathic pulmonary fibrosis, a key area of interest for Roche, which had gained the IPF drug Esbriet through the $8.3bn takeout of Intermune in 2014. PRM-151 is a recombinant form of human pentraxin-2, a protein thought to prevent scarring, and Roche says it is the first project to show significant lung function improvements on top of current IPF therapies. It is in earlier trials for myelofibrosis, Nash and fibrotic kidney disease, and perhaps a recent long-term trial analysis persuaded Roche to pay up. Bristol, meanwhile, had an early presence in IPF via BMS-986020, but this project is no longer in active clinical trials.
|Second time lucky for Promedior|
|31 Aug 2015||Bristol-Myers Squibb||Pre phase 2||$150m option fee||$1.1bn in funding and exercise fees|
|15 Nov 2019||Roche||Pre phase 3||$390m up-front fee||$1.0bn contingent payments|
Kiadis’s move to scrap development of ATIR101 yesterday makes perfect sense given the regulatory roadblock that all three such stem cell transplant adjuncts have hit. But, even though Kiadis is moving to discontinue ATIR101’s phase III Hatcy study, it will not be able to draw a simple line under its troubles: subjects already enrolled into Hatcy must, for ethical reasons, be followed to completion. The study enrolled the first of 250 patients two years ago, and had been due to yield results in 2021. Kiadis had already bought the private NK cell therapy player Cytosen, and logically this business now becomes its key focus, with two assets, K-NK002 and K-NK003, to enter the clinic next year. But this brings up Kiadis’s next problem: with a share price off 85% year to date how does the group raise the necessary cash? Also in the doldrums is Kiadis’s peer company Bellicum, which had now effectively switched fully to Car-T work. However, its lead asset here, BPX-601, is progressing slowly, and the follow-up BPX-601 is having a hard time gaining US IND clearance.
|Stem cell transplant add-ons|
|Molmed||Zalmoxis||"No further investment"; phase III TK008 study closed to new enrolment||CD44v6 (Car-T), Car-NK & NGR-hTNF|
|Kiadis||ATIR101||Terminated; phase 3 Hatcy study being wound down||K-NK002 (HCST adjunct) & K-NK003 (undisclosed NK cell therapy)|
|Bellicum||BPX-501||Partner sought, and Bellicum activities "reduced"; phase III Thrive study recruiting||BPX-601 & BPX-603 (inducible Car-T)|
|Source: company websites.|
Fibrogen and partners were probably hoping that the long-awaited cardiovascular safety analysis of the huge roxadustat clinical programme would silence concerns. But another highly critical report emerged yesterday; the authors are probably positioned to benefit from falling share prices, but it is notable that both Fibrogen and Astrazeneca moved to defend their data. The report concluded that roxadustat was unlikely to win approval in dialysis-dependent patients, pointing out that Pyrenees, a major trial that had the worst safety reading, had been omitted from the pooled analysis; it also claimed that the way the data were analysed understated the risk of death in this setting. Astrazeneca responded by saying the FDA had agreed to the Pyrenees exclusion, because of its different design; supportive equity analysts moved to defend other assertions of opaqueness. The sellside remains largely approving of Fibrogen, but roxadustat forecasts have come down substantially over the past 12 months. None of these debates will be settled until the regulatory verdicts are known, later next year, and until then many investors might decide to believe that there is no smoke without fire. Substantial postmarketing requirements are surely the best-case scenario here.
|Sales forecasts for roxadustat, and how they've changed|
|12-mth chg in 2024 forecast|
|Astrazeneca||WW ex Astellas regions, China co-promote with Fibrogen||160||893||-31%|
|Astellas Pharma||Japan, Europe, CIS, Middle East & South Africa||86||387||-47%|
|Fibrogen||WW royalties, China co-promote with Astra||32||155||-42%|
|Phase III roxadustat programme for US and EU regulators|
|Himalayas*||Fibrogen||Epogen||US, Europe, RoW|
|Rockies*||Astrazeneca||Epogen||US, Europe, RoW|
|Pyrenees||Astellas||Epogen or Aranesp||EU only|
|Olympus*||Astrazeneca||Placebo||US, Europe, RoW|
|*Included in Mace analysis for US FDA.|
A third clinical hold on Solid Biosciences’ Duchenne muscular dystrophy gene therapy SGT-001 leaves the company facing an existential question: what to do with a project that is ineffective at its low dose and appears to be dangerous at its high one? The company revealed today that the FDA had suspended the Ignite DMD trial after the sixth patient to be enrolled, and the third to receive the highest 2x1014vg/kg dose, suffered serious side-effects including complement activation, thrombocytopenia, decreased red blood cell count, acute kidney injury and cardiopulmonary insufficiency. Further data on all subjects, including biopsy information that will give an idea of how well the microdystrophin gene is being transfected, will be released by the year end, the company said. However, executives’ refusal to answer questions on a conference call this afternoon – on, for example, how the patient was rescued – will give investors little reason to hang around. Solid shares slumped 69% this morning to a record low. Sarepta, which is viewed as having the leading DMD gene therapy, SRP-9001, was up 3% in early trade.
Kadmon will head to US regulators next year with a strong case to make for accelerated approval of KD025 in graft-vs-host disease. Response rates easily cleared a 30% ORR threshold at an interim analysis of the phase II Rockstar trial, and Kadmon shares jumped 12% to a 14-month high. KD025 is thought to work by inhibiting Rock2, which modulates an inflammatory response pathway; these findings suggest efficacy at least in line with Imbruvica, which was approved on data generated in a less refractory population. Unless results substantially deteriorate at the final analysis, or an unexpected safety issue rears its head, a green light for patients who have received at least two prior lines of therapy looks likely; Imbruvica is approved in all steroid-refractory patients. Analysts have pencilled in KD025 sales of $473m in GVHD by 2024, EvaluatePharma’s sellside consensus shows, though this bullish outlook presumably depends on the absence of more effective rivals. Incyte is one to watch here, with trials of both Jakafi and its follow-on asset itacitinib ongoing, while Amgen has AMG 592, an IL-2 and IgG fusion protein, in a mid-stage chronic GVHD trial.
|Cross-trial comparison of chronic GVHD results|
|Imbruvica (Study 1129)||KD025 (Rockstar)|
|Steroid-refractory, ORR at median 13.9mth follow-up||ORR 2mth after completing enrollment|
|420mg once daily (n=42)||200mg once daily (n=63)||200mg twice daily (n=63)|
|Median prior therapies||2||3||4|
|Source: Company presentations, US drug label.|
Timing is everything, and luckily for Roche positive phase II results for Gazyva in lupus nephritis got out ahead of Astrazeneca’s unveiling of detailed Tulip 2 data for anifrolumab in systemic lupus erythematosus (SLE) later today. Although the main focus of Tulip 2 will be SLE, the trial's new BICLA endpoint is based on an improvement in all organs, albeit partial, so any news on kidney function will be of interest. Gazyva achieved a 40% complete renal response at week 76, Roche said today. Another yardstick for Gazyva is just around the corner: Aurinia’s voclosporin is due to report phase III lupus nephritis data before the end of the year, but progress could be hindered by safety. Novartis’s iscalimab (CFZ533) is also in phase II and, not content with scoring the only approval in SLE in more than 50 years, Glaxosmithkline is running a pivotal 448-patient trial of Benlysta in lupus nephritis, which could report data by the end of next year. As such, Roche needs to move Gazyva into phase III quickly if it is to capitalise on today’s win.
|Selected lupus nephritis projects|
|Gazyva||Roche||Anti-CD20 MAb||Phase II||NCT02550652|
|Voclosporin||Aurinia||Calcineurin inhibitor||Phase III||NCT03021499|
|Benlysta||Glaxosmithkline||Anti-BLyS MAb||Phase III||NCT01639339|
|Iscalimab||Novartis||Anti-CD40 MAb||Phase II||NCT03610516|
|Anifrolumab||Astrazeneca||Anti-interferon type I MAb||Phase II||NCT02547922|
|Source: EvaluatePharma & clinicaltrials.gov.|
The anti-CGRPs are expected to be a big biopharma growth driver: the class as a whole is expected to add $1bn in new sales next year. However, the latest figures from the three marketed migraine-prevention MAbs suggest that, unless things change drastically, this prediction is unlikely to become reality. All three products failed to meet analyst forecasts in the third quarter and look set to fall short of EvaluatePharma sellside consensus for the full year, putting longer-term predictions into further doubt. The last company to report its quarterly results, Teva, yesterday blamed Ajovy’s poor performance on the lack of an autoinjector, which it hopes to get approved by the end of the year. But there is no escaping the fact that the entire class has failed to live up to early hopes, even as companies switch from giving away their drugs for free to making patients pay for prescriptions. Price concessions are not helping, and payers are no doubt benefiting from fierce competition between the makers. This is only set to increase, with a US approval decision on Alder/Lundbeck’s intravenous MAb eptinezumab due in February; Biohaven also expects migraine prevention data soon with its oral candidate, rimegepant.
|CGRP headaches: actual sales vs consensus ($m)|
|Q3 2019||9mth 2019||Annual sales forecasts|
|All CGRP targeting migraine products||822||1,857|
|*US sales, as reported by Amgen, only; Source: EvaluatePharma & analyst notes.|
Exact Sciences has recently been attempting to diversify away from its core stool test for colorectal cancer, which has been selling well but has so far been unable to lift the company out of loss-making territory. Today’s top-line data on one of these new programmes, the group’s hepatocellular carcinoma blood test, shows that when specificity was set at 90%, Exact’s test detected 80% of HCC cases across all stages and 71% of early stage cases. This was better performance than the most commonly used marker for HCC, serum alpha-fetoprotein (AFP). AFP testing is falling out of favour as an HCC diagnostic as imaging techniques improve and are beginning to take its place; indeed guidelines recommend ultrasound is used to screen at-risk patients, with AFP as an optional extra. Exact says that ultrasound plus AFP has demonstrated 63% sensitivity for early stage cancers, so its test would beat that, but whether the difference is significant enough for payers to back the new assay is as yet unclear. Exact plans to launch the test in the second half of 2020, but out to 2024, analysts do not see the company earning money from anything other than Cologuard.
|Top-line data with Exact's HCC liquid biopsy|
|All cancers||Early-stage disease|
|Ultrasound + AFP||-||-||63%||-|
|WW annual sales ($m)|
|Cologuard/laboratory service revenue||748||1,101||1,595||2,021||2,465||2,908||31%|
|Total company revenues||748||1,101||1,595||2,021||2,465||2,908||31%|
The most surprising thing about today’s failure of Anaptysbio’s lead asset, etokimab, is that investors were surprised. The group’s stock plummeted 72% this morning on the news that the anti-IL33 MAb had flunked the phase IIb Atlas study in atopic dermatitis, despite several red flags. For one, Anaptysbio started the study after testing the project in just 12 patients in phase IIa. There were also questions about IL-33 as a target after Sanofi/Regeneron’s REGN3500 recently failed to outperform Dupixent in asthma. This raised doubts about whether etokimab would be able to compete in a crowded sector, but this is now a moot point: Atlas failed to show any benefit with the project versus placebo. Today’s main winner is Dermira, which rose 22% on etokimab’s failure: that company’s IL-13-targeting agent, lebrikizumab, recently went into phase III in atopic dermatitis. Etokimab looks dead in the water but nasal polyp data, due in the first quarter, might allow Anaptysbio to drag things out for a bit longer. Perhaps the company will have better luck with its oncology pipeline, partnered with Glaxosmithkline; however, the most advanced project here, the PD-1 inhibitor dostarlimab, is hardly novel.
|Where now? Anaptysbio's clinical pipeline|
|Project||Indication||Mechanism||Status||2024e sales ($m)|
|Dostarlimab*||Endometrial, ovarian, non-small cell lung cancers||Anti-PD-1 antibody||Phase III||354|
|Etokimab||Atopic dermatitis, asthma, nasal polyps||Anti-IL33 antibody||Failed phase IIb in atopic dermatitis||386|
|ANB019||Generalised pustular psoriasis, palmoplantar pustulosis||Anti-IL36 antibody||Phase II||219|
|TSR-022*||Liver cancer, melanoma||Anti-TIM-3 antibody||Phase II||5|
|TSR-033*||Solid tumours||Anti-LAG-3 antibody||Phase I||-|
|C-90006**||Psoriasis||PD-1 agonist||Phase I||-|
|*Developed in collaboration with Tesaro (now Glaxosmithkline); **Licensed to Celgene.
Source: EvaluatePharma, company website.
Despite Observa’s best efforts to keep its lead project going nolasiban has finally run out of road. Today the oxytocin antagonist flunked its confirmatory European Implant 4 trial, prompting a halt to all work in IVF and a 43% share price fall. It had been hoped that adding nolasiban at day five of IVF embryo transfer would increase the number of pregnancies reaching the 10 week mark. Instead, the rate with nolasiban was roughly similar to that with placebo. Current low IVF success rates – only 29% of IVF-treated women under 35 celebrate a live birth – mean there is a real need for products that assist fertility. This could explain the $106m of sales forecast for nolasiban in 2024, despite ongoing questions around its efficacy. Nolasiban had previously failed a phase II trial and in February 2018 a phase III trial only showed benefits in patients undergoing embryo transfer at day five and not day three, prompting the confirmatory Implant 4 trial. With nolasiban now on ice in IVF, Obseva’s focus will switch to linzagolix in uterine fibroids, but given the competition here from Abbvie’s Orilissa and Myovant’s Relumina any further missteps with Obseva’s pipeline will not be taken kindly.
|Sales by indication uterine fibroids|
|WW sales ($m)|
|Relumina||Myovant Sciences||Phase III (marketed Japan)||33||194||438|