Snippets

Vantage Snippets are short summaries of breaking news stories.

Keytruda’s cervical win goes beyond confirmation

Accelerated approvals of checkpoint-blocking antibodies have generated controversy when not confirmed in larger studies, but Merck & Co’s latest win should sweep away doubt, and then some. The Keynote-826 study of Keytruda plus chemo in cervical cancer has today been toplined positive for overall and progression-free survival, and spells a win on all fronts: in the front-line setting, with or without Avastin, and irrespective of patients’ PD-L1 status. Keytruda already carries a cervical cancer label, but this is for second-line use in tumours expressing PD-L1 at ≥1%, and on an accelerated basis. Thus Keynote-826 will not only confirm this conditional green light, but could also expand the Merck drug’s use to front-line all-comers who can tolerate chemotherapy. Full data, to be revealed at a scientific meeting or perhaps on Keytruda’s label if approval comes quickly, will show the extent of the survival benefit versus chemo alone, and determine whether Avastin needs to be included in the mix. True, cervical cancer will account for just a fraction of Keytruda’s $26.9bn of forecast 2026 revenues, according to Evaluate Pharma sellside consensus, but the win is important: no other checkpoint antibodies carry a cervical cancer label.

Selected cervical cancer studies
Study Design Result
Keynote-158 Uncontrolled monotherapy trial in solid tumours Cohort E showed 14% ORR in 2L PD-L1 ≥1% cervical cancer (accelerated approval Jun 2018)
Keynote-826 Chemo combo +/- Avastin, vs chemo, in 1L cervical cancer Positive for OS & PFS, with & w/o Avastin, irrespective of PD-L1 expression (Jun 2021)
Keynote-A18 Chemo combo, vs chemo, in 1L cervical cancer Primary completion Feb 2024; OS & PFS co-primaries
Source: clinicaltrials.gov.

Theravance looks beyond Covid-19

After the miss of one inhaled pan-Jak inhibitor in asthma last year, Theravance is now mourning the failure of another in Covid-19. The data come from a phase 2 study in 210 hospitalised patients with Covid-19-associated acute lung injury and impaired oxygenation. The 106 patients treated with TD-0903, also called nezulcitinib, for just under a month had a median 21 respiratory failure-free days during the treatment period – but so did those treated with placebo. With a p value of 0.61, the difference, such as it was, was not statistically significant. Neither did TD-0903 improve all-cause mortality (p=0.08) or hit any of other secondary endpoints. Theravance touted a post-hoc analysis of patients who had baseline C-reactive protein levels below 150mg/l, in whom there was a nominal improvement in mortality and time to recovery. The company said it would take the data to regulators, but much of the talk of future development of TD-0903 on today’s conference call was focused on non-Covid-19 indications, including acute lung injury caused by Sars, Mers, flu or parainfluenza. The sole Jak that is authorised in hospitalised Covid-19 patients remains Lilly's Olumiant – but this is oral, not inhaled. 

Tarsus eyes a new market

Lotilaner is already used to control fleas in animals. Tarsus Pharmaceuticals’ efforts to get it approved in humans took a step forward today with a pivotal trial win for TP-03, a lotilaner eyedrop for Demodex blepharitis. There are currently no therapies for this eye disorder, which is caused by a Demodex mite infestation in the eyelashes. Saturn-1 met its primary endpoint, with TP-03 significantly reducing collarettes, or “eyelash dandruff” – the waste products of these mites – versus placebo. Tarsus plans to file the project in the US next year pending data from a second pivotal study, Saturn-2. Still, questions remain. Tarsus said adverse events were all mild, but a 12% rate of burning/stinging might raise alarm bells. Another question is how big this market really is. Tarsus, which floated last October, reckons there could be as many as 25 million US patients, but this is based on a 1,000-patient study, called Titan. This found that 58% of patients visiting eyecare professionals had collarettes, and Tarsus has extrapolated this to the 45 million visits to eyecare professionals each year. The group, whose stock was up 15% in premarket trading, fell 10% this morning.

Out of this world or back down to earth? Saturn-1 results with TP-03
Endpoint TP-03 Placebo  P value
Complete cure (collarette grade 0)* 43% 7% <0.0001
Clinically meaningful cure (collarette grade 0-1) 81% 23% <0.0001
Complete mite eradication 68% 18% <0.0001
Complete composite cure** 13% 1% <0.0001
Clinically meaningful composite cure^ 68% 20% <0.0001
All at day 43, based on 209 pts on TP-03 & 204 pts on placebo (212 & 209 pts respectively randomised). Note: *primary endpoint; **defined as grade 0 collarette and redness score; ^defined as grade 0 or 1 collarette and redness score. Source: company release.

Glaxo pays handsomely to join the Tigit chase

That Glaxosmithkline was prepared to part with $625m up front for Iteos’s phase 1 anti-Tigit MAb EOS-448 shows that the pharma giant considers this a "must own" immuno-oncology mechanism. The terms point to a highly competitive process, which also means that there must be other large developers shopping in this space. The big three I-O players already have assets in their pipelines, but there are plenty of others, like Astrazeneca and Pfizer, that would presumably be interested. That is great for news for those unencumbered projects, and it is no coincidence that Mereo shares opened up 15% today, a surge that soon settled down to a 5% rise. Still, while the Glaxo-Iteos deal sounds rich, it is worth remembering that the small biotech has agreed to pay 40% of the R&D costs associated with an “aggressive” pre-agreed global development plan; in return, Iteos will jointly commercialise EOS-448 in the US and get 50% of the profits from the region. A further $550m is available if certain clinical and regulatory hurdles are crossed, with another $900m attached to sales milestones. The tiny Belgian developer has long been a proponent of Tigit, and this deal certainly justifies its enthusiasm: Iteos shares surged 30% in early trade.

Chasing Tigit: few unencumbered assets remain
Project

Company

Project source and status

Available to the highest bidder?
Ociperlimab Beigene In-house; wholly owned, in ph3
Etigilimab Mereo Oncomed originated; Celgene turned down option in July 2019, now wholly owned, in ph1/2
IBI939 Innovent In-house; wholly owned, in ph1
SGN-TGT Seagen In-house; wholly owned, in ph1
COM902 Compugen In-house; wholly owned, in ph1
AGEN1327 Agenus In-house; wholly owned, preclinical 
Already wrapped up…
Tiragolumab  Roche In-house; wholly owned, in ph3
Vibostolimab Merck & Co In-house; wholly owned, in ph3
Domvanalimab Arcus Gilead option; data and decision due soon. Otsuka owns certain Asia rights, in ph2/3
BMS-986207 Bristol Myers Squibb In-house; Ono owns certain Asian rights, in ph1/2
M6223 Merck KGaA In-house; wholly owned, in ph1
EOS-448 Iteos Licensed to Glaxo in Jun 2021 deal, in ph1
AGEN1777 (bispecific) Agenus/Bristol Myers Squibb Licensed to Bristol Myers in May 2021, preclinical
AB308 Arcus Gilead has an option under a 2020 deal, in ph1
JS006 Junshi/Coherus Junshi originated; Coherus bought an option over the project in a Feb 2021 deal. Preclinical.
Source: Evaluate Pharma & company presentations.  

(This story has been updated to include the Junshi Tigit project.) 

Asco 2021 – Alpine hopes to banish the ghost of Tegenero

The notorious 2006 blow-up of a phase 1 trial of Tegenero’s CD28-agonist MAb TGN1412, in which volunteers suffered severe inflammatory reactions, has cast a long shadow. 15 years later Alpine Immune Sciences is hailing early data with ALPN-202 as evidence that CD28 can, after all, be hit safely. ALPN-202 is a protein inhibiting PD-L1 and CTLA-4, as well as co-stimulating CD28, its premise being that just removing the immune system brake is not enough, and T cells need an additional signal. Today’s Asco presentation of the Neon-1 trial concerns 23 on average fifth-line subjects with various cancers, and shows just one partial response, in ovarian/fallopian tube cancer, that relapsed 40 days later. The much better news is ALPN-202’s relative safety, with only one related grade 3 toxicity despite evidence of maximal CD28 co-stimulation at most doses. While Alpine claims this to be the first demonstration that clinical CD28 agonism can be safely achieved for cancer immunotherapy, many successful Car-T projects also use CD28 co-stimulation, so perhaps Alpine is simply repeating this trick with an antibody-like approach, and with endogenous T cells. This is a promising start, but stronger efficacy data are still needed.

Source: Dr Justin Moser & Asco.

Grail launches pan-cancer screen – for those who can pay out of pocket

Grail’s liquid biopsy today became the third pan-cancer blood test to be launched in the US. But it is being sold for a slightly different use versus the two approved tests. Galleri, which is not approved by the FDA but sold under a Clia waiver, is on sale as a screen, and can be used to test people aged over 50 at elevated risk of cancer. The other two tumour-agnostic liquid biopsies are used in patients who already have a confirmed cancer diagnosis, as a way to assess the mutations a tumour carries and therefore help assign targeted drugs. Grail is pitching its Galleri test at $949, quite a bit cheaper than both its rivals: Roche’s FoundationOne Liquid CDx sells at $5,800 and Guardant’s Guardant360 around $1,000 more than that. But the latter two have formal FDA approval, granted last August, making reimbursement easier – no reimbursement is yet in place for Galleri. Meanwhile Illumina’s $8bn bid to acquire Grail is no nearer closing. The FTC recently withdrew a lawsuit seeking to block the acquisition, which sounds like good news, but is in fact the opposite. The suit will likely be refiled later, delaying the deal's close further.

Selected pan-cancer liquid biopsies – progress update
Company Liquid biopsy Use Status in US Company notes
Guardant Health Guardant360 Helps assign targeted therapy Approved Aug 7, 2020, price approx $6,800 $550m VC funding; floated in 2018
Foundation Medicine (Roche) FoundationOne Liquid CDx Helps assign targeted therapy Approved Aug 27, 2020, price $5,800 $115m VC funding; bought by Roche for $2.5bn in 2015
Grail Galleri Screening for early detection and identification of tumour origin Launched as LDT Jun 4, 2021, price $949 $2.1bn VC funding; bought by Illumina for $8bn in 2020
Unnamed Postsurgical, detects disease recurrence In development
Thrive Earlier Detection (Exact Sciences) CancerSeek Early detection FDA breakthrough device status $367m VC funding; bought by Exact Sciences in 2020 for $1.7bn
Natera Signatera Postsurgical, detects disease recurrence FDA breakthrough device status $152m in VC funding; floated in 2015
Archer DX (Invitae) Stratafide Helps assign targeted therapy FDA breakthrough device status $150m VC funding; bought by Invitae in 2020 for $1.4bn
LDT = lab-developed test. Source: EvaluateMedTech & company websites.

Asco 2021 – Keytruda’s adjuvant kidney win is the real deal

Those fretting about the magnitude of Keytruda’s disease-free survival win in Keynote-564, the first positive phase 3 trial of an adjuvant immunotherapy in renal cancer, need not have worried. The study’s just unveiled Asco late-breaker has shown a 32% reduction in risk of disease progression versus placebo (p=0.0010), the likely approvable primary endpoint. Just as important is the secondary endpoint of overall survival, which is showing a 46% reduction in risk of death. True, at p=0.0164 this was not statistically significant – but this was a result of a high bar set at this early interim analysis, corresponding to a December 14, 2020 cutoff. In reality, the strong hint is that Keytruda really is helping renal cancer patients live longer when given as adjuvant for a year within 12 weeks of surgery. The results further underscore the Merck & Co drug’s widening lead against its kidney cancer rivals, in particular Opdivo, though it should be stressed that competitor phase 3 adjuvant studies are under way and start reading out next year.

Source: Dr Toni Choueiri & Asco.

US FDA approval tracker: May

Last month ended with a flurry of US FDA decisions and one, the green light for Amgen’s Lumakras, came over two months early. The accelerated approval in NSCLC patients with a Kras G12C mutation was given to the 960mg dose; a 240mg dose is the subject of a postmarketing study to see whether it has a similar clinical effect. Two other oncology drugs gained first-time accelerated approvals: J&J’s Rybrevant and Bridgebio’s Truseltiq. Both have confirmatory trials under way. After two previous complete response letters it was finally good news for Heron’s pain therapy Zynrelef, an extended-release bupivacaine combined with the anti-inflammatory meloxicam. To try and gain market share Heron is pricing Zynrelef at a 22-28% discount to Pacira’s Exparel; Evercore ISI analysts note that this price will also allow Heron’s drug to compete with generic bupivacaine. With May now over all eyes rest on aducanumab’s June 7 Pdufa, the biggest regulatory event of the year (Go or no go? Aducanumab’s day of reckoning, May 27, 2021).

Notable first-time US approval decisions in May
Project Company Indication 2026e sales by indication ($m) Outcome
Lumakras
(sotorasib)
Amgen NSCLC with Kras G12C mutation after at least one systemic therapy 1,756 Approved (~2.5mth early, accelerated)
Myfembree (relugolix) Myovant Uterine fibroids 490 Approved
Zynrelef
(HTX-011)
Heron Therapeutics Post-op pain relief 471 Approved
Lybalvi
(ALKS 3831)
Alkermes Schizophrenia and bipolar 1 disorder 380 Approved
Empaveli (pegcetacoplan) Apellis PNH (including treatment naive) 309 Approved
Truseltiq
(infigratinib)
Bridgebio Pharma 2L cholangiocarcinoma 253 Approved (accelerated)
Rybrevant
(amivantamab)
J&J NSCLC with EGFR exon 20 insertion mutations 250 Approved (~2mth early, accelerated)
Pylarify (PyL) Lantheus Holdings Prostate cancer diagnostic imaging agent 233 Approved
Zonisamide oral suspension Eton/Azurity Pharmaceuticals Partial seizures in epilepsy - No decision yet
Dehydrated alcohol injection (DS-100) Eton Methanol poisoning - CRL (CMC)
Camcevi Foresee Pharmaceuticals Advanced prostate cancer - Approved
Source: Evaluate Pharma & company releases.

 

Advisory committee meetings in May
Project Company 2026e sales by indication ($m) Outcome Note
Vynpenta
(avacopan)
Chemocentryx 639 Efficacy vote split (9-9), safety profile and benefit-risk votes slightly in favour (10-8) ANCA-associated vasculitis, Pdufa in July (Chemocentryx’s future in doubt as avacopan foundation crumbles)
Teplizumab
(PRV-031)
Provention Bio - Voted 10-7 that benefits outweigh risks in support of approval  Delay of clinical type 1 diabetes in at-risk individuals (Provention’s diabetes project takes a tentative step forward)
Source: Evaluate Pharma & FDA adcom calendar

 

Supplementary and other notable approval decisions in May
Product Company Indication (clinical trial) Outcome
Opdivo Bristol Myers Squibb Adjuvant oesophageal/gastroesophageal junction cancer (Checkmate-577) Approved
Zeposia Bristol Myers Squibb Ulcerative colitis (True North) Approved
Nurtec ODT Biohaven Prevention of migraine (Study 305201) Approved
Ferriprox Chiesi Transfusional iron overload due to sickle cell disease or other anaemias in adults and paediatrics aged 3 and older Approved
Keytruda + Herceptin + chemo Merck & Co 1L Her2+ gastric or gastroesophageal junction adenocarcinoma (Keynote-811) Approved (accelerated)
Cosentyx Novartis Moderate-severe plaque psoriasis in children and adolescents (NCT03668613, NCT02471144) Approved
Nuzyra Paratek Oral only dosing regimen for the treatment of community-acquired bacterial pneumonia Approved
MSB11455 (Neulasta biosimilar) Fresenius Reduce the incidence of infection associated with febrile neutropenia No decision yet
Esbriet Roche Unclassifiable interstitial lung disease (NCT03099187) No decision yet
Aubagio Sanofi Paediatric relapsing MS (Terikids) No decision yet
Alecensa Roche First-line Alk-positive NSCLC (Bfast) No decision yet
Source: Evaluate Pharma & company releases.

 

FDA Covid-19 EUAs
Product Company 2026e sales by indication ($m) Note
Comirnaty Pfizer 1,784 Expanded to include 12 to 15-year-olds
Sotrovimab
(VIR-7831)
Vir/GSK 1,212 Treatment of mild-moderate Covid-19 in adults and paediatrics (US appetite for Covid-19 treatments remains undiminished)
Source: Evaluate Pharma & company releases.

Roche's liquid biopsy pips Guardant's on companion nods

Friday’s US approval as a companion diagnostic for Amgen’s Kras inhibitor Lumakras is the third such nod for Guardant360 CDx. Guardant’s liquid biopsy can be used to pick out patients with advanced non-small cell lung cancer whose tumours harbour the Kras G12C mutation, thought to be present in around 13% of this population. But Guardant360 CDx is some way behind Roche’s FoundationOne Liquid CDx, approved in the US for no fewer than seven drugs in four different cancers. A look at forecast sales, compiled by Evaluate Pharma, for these targeted therapies gives a loose indication of how the two tests might sell: the drugs with which Roche’s test may be used are forecast to generate $14.5bn of collective revenue in 2026, whereas the corresponding figure for Guardant’s assay is a comparatively paltry $10.8bn. Naturally not all patients with these cancers will respond to these therapies – the Alk arrangements amenable to treatment with Alecensa occur in just 3-7% of advanced NSCLC cases, for instance – but many more patients will undergo liquid biopsy testing.

Liquid biopsy US approvals as companion diagnostics
Test (company) Indication Drug 2021e sales by indication ($m) 2026e sales by indication ($m) Date of test approval as CDx
Guardant360 CDx (Guardant Health) NSCLC Tagrisso 5,355 9,059 Aug 7, 2020
Rybrevant - - May 21, 2021
Lumakras 92 1,756 May 28, 2021
FoundationOne Liquid CDx (Roche) NSCLC Iressa 240 126 Aug 26, 2020
Tagrisso 5,355 9,059 Aug 26, 2020
Tarceva 98 40 Aug 26, 2020
Alecensa 1,707 2,122 Oct 26, 2020
Prostate cancer Rubraca 19 185 Aug 26, 2020
Lynparza 263 1,435 Nov 6, 2020
Ovarian cancer Rubraca 174 419 Oct 26, 2020
Breast cancer Piqray 421 1,114 Oct 26, 2020
SBI = sales by indication. Source: Evaluate Pharma, FDA & company releases. 

This article has been corrected to remove a misattributed approval for FoundationOne Liquid CDx.