Vantage Snippets are short summaries of breaking news stories.

Asco 2023 – six months on Gilead/Arcus’s Tigit deflates

The run-up to this year’s Asco meeting saw a remarkable resurgence of interest in the Tigit mechanism, but today’s update on Gilead/Arcus’s Arc-7 study in NSCLC could puncture the enthusiasm. With 7.4 months’ additional median follow-up, and six more patients in each cohort, the PFS data for domvanalimab plus zimberelimab have deteriorated versus zimberelimab monotherapy. The anti-Tigit/PD-1 doublet that at December’s Asco virtual plenary had shown a 45% reduction in risk of progression or death, and a 6.6-month increase in median PFS versus the Arcus PD-1 alone, now stands at a 33% reduction and 3.9-month delta, today’s Asco update revealed. Not only that, but the confidence interval upper bound is now 1.13, having earlier stood precariously at 1.00 exactly. True, the shape of the PFS curves and small numbers of patients make it evident that just one or two early progressers might be making the difference. But the meaningfulness of Arc-7 was already in doubt, and the optics of a dataset that is clearly not improving will not go down well with fickle investors. Roche’s Morpheus-liver data, the cause of the recent run-up, will be presented in full at Asco tomorrow.

Gilead/Arcus's deteriorating Arc-7 dataset
  Tigit + PD-1 PD-1
Number enrolled 44 44
Date Dec 2022 (11.8mth median follow-up)
Median PFS 12.0mth 5.4mth
Stats for PFS HR=0.55 (0.31-1.00)
Number enrolled 50 50
Date Jun 2023 (18.5mth median follow-up)
Median PFS 9.3mth 5.4mth
Stats for PFS HR=0.67 (0.40-1.13)
Source: Asco.

Pfizer’s antibiotic combo could be a last resort

Just over a week after Innoviva gained approval for a novel antibiotic combination Pfizer has shown that it too has skin in this game. Two phase 3 trials of its aztreonam-avibactam might permit approval in hard-to-treat patients – a setting in which only a big pharma is likely to want to play. The Revisit trial tested Pfizer’s combo with or without metronidazole in serious infections caused by Gram-negative bacteria, including some multi-drug resistant strains, comparing it with the established regimen of meropenem alone or alongside colistin. Pfizer’s project beat control in both abdominal infections and pneumonia when analysed on an intention-to-treat basis, but lost out in pneumonia when only evaluable patients were analysed. Perhaps the most interesting finding was a marked benefit on 28-day mortality rates among the pneumonia patients. In the much smaller Assemble study, five of 12 patients given Pfizer’s therapy were cured at the final visit, versus none of three patients on best available therapy. The group intends to file for approval this year, but Evaluate Pharma’s consensus forecasts are small – $76m in 2028 – as befits the likely last-resort use of this project. Abbvie owns rights to the combo in the US and Canada. 

Revisit (NCT03329092) data
  Aztreonam-avibactam ± metronidazole  Meropenem ± colistin Delta
Cure rate in pts w cIAI - ITT analysis (%) 76.4 74.0 2.4
Cure rate in pts w cIAI - CE analysis (%) 85.1 79.5 5.6
Cure rate in pts w HAP/VAP - ITT analysis (%) 45.9 41.7 4.3
Cure rate in pts w HAP/VAP - CE analysis (%) 46.7 54.5 -7.8
All-cause 28-day mortality rates in pts w cIAI (%) 1.9 2.9 -1.0
All-cause 28-day mortality rates in pts w HAP/VAP (%) 10.8 19.4 -8.6
Serious adverse events (%) 19.3 18.2 -
cIAI=complicated intra-abdominal infections; HAP=hospital-acquired pneumonia; VAP=ventilator-associated pneumonia; ITT=intention to treat; CE=clinically evaluable. Source: company release. 

US FDA approval and panel tracker: May 2023

Last month the FDA granted approval for the first and second ever respiratory syncytial virus vaccines, from GSK and Pfizer respectively. Both companies have committed to conducting postmarketing studies to assess signals of Guillain-Barré syndrome and other immune-mediated demyelinating conditions. Another big event for the jabs is looming, with the CDC's advisory committee on immunization practices due to meet on 21 June to discuss how the vaccines should be used. Both companies anticipate launch before the upcoming RSV season. Separately Pfizer also gained a positive adcom for Abrysvo’s use in very young children, via maternal vaccination. Sarepta had its ups and downs in May: after a favourable adcom for its DMD gene therapy contender SRP-9001, the FDA decided to postpone the final decision until 22 June. An accelerated approval is now expected to be restricted to patients aged 4-5 years old. And Intercept's Nash dream came crashing down again as an adcom voted against obeticholic acid, causing shares to sink to a record low. The final nail in the coffin, another CRL, is expected later this month.

This snippet has been updated to include Pfizer's postmarketing plans for its RSV vaccine in older adults.

Notable first-time US approval decisions in May 2023
Project Company Indication(s) 2028e SBI ($m) Outcome
SRP-9001 (delandistrogene moxeparvovec) Sarepta Ambulatory patients with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene 2,036 Delayed from 29 May until 22 June, positive adcom
Veozah (fezolinetant) Astellas Moderate-to-severe vasomotor symptoms associated with menopause 1,904 Approved
Arexvy GSK Prevention of lower respiratory tract disease caused by RSV in adults ≥60 years 1,729 Approved
Abrysvo Pfizer Prevention of lower respiratory tract disease caused by RSV in adults ≥60 years 1,306* Approved
Epkinly (epcoritamab, DuoBody-CD3xCD20) Genmab/Abbvie Relapsed/refractory large B-cell diffuse lymphoma after ≥2 lines of systemic therapy 1,187 Approved (accelerated)
Bimzelx UCB Plaque psoriasis 718 FDA issued a Form 438 relating to manufacturing deficiencies
Vyjuvek (B-Vec, beremagene geperpavec) Krystal Dystrophic epidermolysis bullosa 636 Approved
Inpefa (sotagliflozin) Lexicon Heart failure (HFrEF & HFpEF pts with/out diabetes) 333 Approved
Alhemo (concizumab) Novo Nordisk Haemophilia A and B with inhibitors 198 CRL (additional information requested)
Xacduro (sulbactam-durlobactam, Sul-Dur) Innoviva (Entasis) Hospital‐acquired and ventilator‐associated bacterial pneumonia caused by Acinetobacter baumannii‐calcoaceticus complex in adults 82 Approved
Mydcombi Eyenovia Drug-device combination for in-office pupil dilation (mydriasis) 54 Approved
Elfabrio (pegunigalsidase alfa, PRX-102) Chiesi/Protalix Fabry disease - Approved
Trastuzumab duocarmazine (SYD985) Byondis Her2-positive unresectable breast cancer - CRL (additional information requested)
Brixadi Camurus Opioid use disorder - Approved
Anktiva (N-803) Immunitybio BCG-unresponsive non-muscle-invasive bladder cancer - CRL (manufacturing deficiencies and CMC problems)
Miebo (NOV03) Bausch & Lomb Dry eye disease - Approved
Posluma (flotufolastat F 18/ 18F-rhPSMA-7.3) Blue Earth Diagnostics/ Bracco PSMA-targeted PET imaging agent for prostate cancer - Approved
*Older adults and maternal setting not split out. SBI: sales by indication. Sources: Evaluate Pharma & company releases.


Advisory committee meetings in May 2023
Project Company Indication 2028e SBI ($m) Outcome
SRP-9001 (delandistrogene moxeparvovec) Sarepta Ambulatory patients with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene 2,036 8-6 in favour
Abrysvo Pfizer Prevention of (severe) lower respiratory tract disease caused by RSV in infants from birth through 6 months by active immunisation of pregnant individuals 1,306* In favour, 14-0 on effectiveness and 10-4 on safety
Ocaliva (obeticholic acid) Intercept Pre-cirrhotic liver fibrosis due to Nash 663 12-2 against (benefits do not outweigh the risks)
15-1 vote to defer until outcomes data are available
Epinephrine nasal spray (Neffy) ARS Pharmaceuticals Emergency treatment of allergic reactions (type I) including anaphylaxis in adults and children ≥30 kg - 16-6 in favour (adults), 17-5 in favour (children)
Opill Perrigo Daily oral contraceptive (progestin-only) - 17-0 in favour of making Opill available for OTC use
*Older adults and maternal setting not split out. SBI: sales by indication. Sources: FDA adcom calendar, Evaluate Pharma & company releases.


Supplementary and other notable approval decisions in May 2023
Product Company Indication (clinical trial) Outcome
Lynparza + Zytiga + prednisone/prednisolone Astrazeneca/Merck & Co 1st-line Brca-mutated metastatic castration-resistant prostate cancer (Propel) Approved
Kalydeco Vertex Cystic fibrosis in children from 1 month to <4 months of age Approved
Paxlovid Pfizer Patients who are at high risk of progression to severe disease from Covid-19 (additional analyses of Epic-HR and Epic-SR trials) Approved
Rexulti Otsuka/
Agitation associated with Alzheimer’s dementia Approved
Ayvakit Blueprint Indolent systemic mastocytosis (Pioneer) Approved
Opvee (OPNT003 nasal nalmefene) Indivior (Opiant) Opioid overdose (NCT04759768, NCT05219669, NCT04828005) Approved
Rinvoq Abbvie Adult patients with moderately to severely active Crohn's disease (U-Exceed, U-Excel, U-Endure) Approved
Farxiga Astrazeneca Heart failure with preserved ejection fraction (Deliver) Approved
Yuflyma (high concentration Humira biosimilar) Celltrion RA, juvenile idiopathic arthritis, PsA, ankylosing spondylitis, Crohn’s disease, UC, plaque psoriasis and hidradenitis suppurativa Approved
RA: rheumatoid arthritis; PsA: psoriatic arthritis; UC: ulcerative colitis. Source: Evaluate Pharma & company releases.

This table has been updated to include Lynparza's approval.

Abbvie gets a win and a loss in lupus

Abbvie’s attempts to add systemic lupus erythematosus to the half dozen indications for which Rinvoq is already approved seem to be on course, judging by data from the phase 2 Sleek trial, released today. The Jak will enter phase 3 here – but a combination of Rinvoq with the BTK inhibitor elsubrutinib, known as ABBV-599, is heading for the scrapheap. Both arms hit the primary endpoint of SLE Responder Index (SRI-4) and the use of no more than 10mg of steroids once a day at 24 weeks, as well as the key secondary of achievement of Bicla response at 48 weeks, each of which are measures of disease severity. But Abbvie said it would drop the combo, since elsubrutinib added nothing to Rinvoq’s efficacy. Unfortunately that efficacy is hard to put into context since trials of different lupus projects use different endpoints. One comparison might be the Bicla measure, since that was the primary endpoint of the pivotal trial of Astrazeneca’s anti-interferon type I MAb Saphnelo, albeit with a slightly different time cutoff. While a cross-trial comparison is always imprecise, Rinvoq does seem to have eclipsed Saphnelo, which was approved for the disease in 2021. Saphnelo sales are forecast to breach $1bn in 2028, according to consensus from Evaluate Pharma.

Abbvie vs Astrazeneca in lupus: cross trial comparison
Company Abbvie Astrazeneca
Trial  Sleek (Ph2, NCT03978520) Ph3 (NCT02446899)
Project Rinvoq ABBV-599 Saphnelo
Pbo-adj SRI-4 and steroid dose ≤10mg QD at 24wk 17.5 11.2 -
    p value 0.028 0.081 -
Pbo-adj SRI-4 and steroid dose ≤10mg QD at 48wk 13.4 18.5 -
    p value 0.075 0.012 -
Pbo-adj Bicla* 30.8 22.9 16.3
    p value <0.001 <0.001 0.001
*Sleek Bicla data at 48wk, Saphnelo at 52wk. Source: company release & NEJM.

Sanofi tries a new mechanism in multiple sclerosis

The notion of flipping an immuno-oncology mechanism on its head to treat an autoimmune disorder was highlighted last week by the mid-stage success of Lilly’s arthritis project peresolimab; this week it is Sanofi’s turn. A hit with the anti-CD40L antibody frexalimab (SAR441344) in multiple sclerosis, also in phase 2, adds to a resurgence in this mechanism’s popularity. The CD40/CD40L costimulatory pathway is thought to regulate immune cell function; blocking it has yielded a recent win for Horizon in Sjögren’s syndrome. Other projects include Novartis’s iscalimab, being trialled in Sjögren’s as well as hidradenitis suppurativa among other indications. UCB and Biogen are further advanced, with their agent dapirolizumab pegol having started phase 3 in lupus. Sanofi will push frexalimab, which it licensed from Immunext in 2017, into phase 3 in MS next year. Sanofi could do with another late-stage asset: its BTK inhibitor tolebrutinib remains on partial US clinical hold. The opposite mechanism, CD40 agonism, is being investigated by several companies for various cancers, though one of these groups, Apexigen, bit the dust in March.

Ph2 (NCT04879628) data on Sanofi's frexalimab
  Frexalimab high-dose Frexalimab low-dose
Reduction in new gadolinium-enhancing T1-hyperintense lesions, vs pbo, at 12wk* 89% 79%
   p value 0.0004 0.0021
Freedom from new GdE T1-lesions at 24wk 96% Undisclosed
*Primary endpoint. Source: company release.

Further manufacturing woes could spell disaster for UCB

The last thing UCB needs is yet another delay to its entry into the US psoriasis market, but continuing issues at one of its manufacturing facilities could potentially see bimekizumab hit with a second complete response letter. The FDA has issued another Form 438 relating to manufacturing deficiencies. While these appear to be less severe than those that earned UCB a CRL in May 2022, another FDA rejection could push bimekizumab’s US approval to the second quarter of 2024, two years later than hoped. This would see bimekizumab lose even more ground in psoriasis to the likes of Abbvie's Skyrizi and Novartis’s Cosentyx. Further delay would also stall UCB’s expansion plans for bimekizumab in the important hidradenitis suppurativa (HS) indication, where Jeffries analysts are predicting peak sale of €3bn ($3.2bn). Cosentyx is already filed in this indication and Acelyrin’s rival IL-17 antagonist izokibep could potentially launch in the next two or three years. Shares in UCB were down 4% today, but as bimekizumab is UCB’s best hope of ameliorating the current and future patent losses of some of its biggest products including Cimzia and Vimpat, another CRL could see the shares really drop. 

UCB's top five products ranked on 2028 sales
      Annual WW Sales ($m)      
  Product Therapeutic category 2023 2028 CAGR Phase Patent Expiry
1 Bimzelx Immunosuppressants 230 1,811 51% Marketed Jan 2030
2 Cimzia Other anti-rheumatics 2,192 1,041 (14%) Marketed Dec 2024
3 Zilucoplan Immunosuppressants 29 742 91% Filed Dec 2034
4 Fintepla Anti-epileptics 268 726 22% Marketed May 2033
5 Keppra Anti-epileptics 507 357 (7%) Marketed Nov 2008
Source: Evaluate Pharma

BenevolentAI turns ruthless to conserve cash

Another day, another Spac disappointment, with news of restructuring at BenevolentAI following Apexigen’s all-stock takeover yesterday. But while Apexigen never really stood a chance as a listed entity, arriving on Nasdaq with modest cash, Benevolent was not so disadvantaged. It went public in Amsterdam last year with around $200m in the bank (albeit only enough to last around 18 months), cash flow from a broad research deal with Astrazeneca and big names on its board. Cost cutting felt inevitable after the failure of its lead internal candidate last month, but arguably this should have happened sooner; the financing climate in Europe is considerably worse than in the US, and Benevolent’s stock is thinly traded. The stock has lost 81% since the Spac merger closed, with the group now worth just €270m ($290m). The shakeup, which includes the exit of the company’s chief finance officer, will see up to 180 staff cut, helping cash last until at least July 2025. Internal projects have been culled and earmarked for licensing out, while its AI drug discovery platform is another potential revenue generator. Plenty of biopharma groups have struggled with the mixed developer-platform business model, and Benevolent too has yet to make it work.

Benevolent AI's "prioritised" internal pipeline
Project Description  Status
BEN-8744 PDE10 inhibitor for ulcerative colitis To enter ph1 in Q3 2023
BEN-28010 CHK1 inhibitor for glioblastoma multiforme IND-ready by Q4 2023
The group has earlier-stage assets in amyotrophic lateral sclerosis, Parkinson’s disease and fibrosis. Source: company statement.

Mirati seeks to shrug off sitravatinib flop

Mirati’s broadly acting tyrosine kinase inhibitor sitravatinib always looked like a long shot, so perhaps the most surprising thing about yesterday’s Sapphire trial failure is that it caught investors unawares: the group’s stock fell 13% this morning. The project looks dead despite an ongoing study in treatment-naive patients and Beigene-backed trials of tislelizumab combos. Much more important to Mirati, though, is the launch of Krazati in second-line NSCLC, expanding that product’s use into earlier lines and new indications, and the group’s remaining pipeline. This month, Krazati’s first full quarter of sales beat expectations, but there are already signs of a broad Kras flatlining. Expanding into the potentially lucrative first-line NSCLC market is therefore key for Mirati, but Keytruda-combo data here looked lacklustre; SVB analysts suggested that the addition of chemotherapy, being tested in Krystal-17, might help. Mirati has yet to nail down its strategy in first-line lung, and investors will hope that things move more quickly than in colorectal cancer, where a filing is now due by year-end. As for the pipeline, data on a PRMT5 inhibitor are up next, although this mechanism has disappointed in the past.

Bigger events: what's coming up for Mirati
Project/product Description Setting Note
Krazati (adagrasib) Kras G12C inhibitor 1L NSCLC Updated data from Krystal-7 + Keytruda in H2 2023; ph3 studies to start H2 2023
3L+ CRC US filing due YE 2023
2L+ NSCLC Confirmatory PFS data due H1 2024
Sitravatinib  Tyrosine kinase inhibitor 2L+ non-squamous NSCLC Sapphire + Opdivo vs docetaxel failed May 2023
MRTX1719 PRMT5 Inhibitor MTAP-deleted cancers Initial data from ph1/2 due H2 2023
MRTX1133 Kras G12D inhibitor G12D-mutated solid tumours Initial ph1 data due H1 2024
MRTX0902 Sos1 inhibitor Kras/MAPK-mutated cancers Ph1/2 started Q4 2022; adagrasib combo starting 2H 2023
Source: company presentation &

Normal service resumes in amyotrophic lateral sclerosis

Two recent FDA approvals in amyotrophic lateral sclerosis bucked the usual trend of disappointments in the neurodegenerative disease. But it was back to business as usual this week, with two stumbles in quick succession from Wave Life Sciences and Apellis. In fact, a look at an Evaluate Vantage analysis of the late-stage ALS pipeline, carried out almost a year ago, shows that over half of these projects have since failed. Some developers are pressing on, with Prilenia and Clene still seeing a future for their assets. Such an optimistic stance is no doubt helped by the fact that Biogen and Ionis’s Qalsody (tofersen) got accelerated approval for Sod1-mutated ALS despite the antisense therapy failing its phase 3 trial, Valor. Perhaps the most optimistic of all is Brainstorm Cell Therapeutics, which after FDA knockbacks chose to file its project Nurown under protest, setting up an advisory committee meeting; a date has not yet been set. No such drama from Wave and Apellis, which have thrown in the towel on WVE-004 and Empaveli respectively. Notably one dose of WVE-004 performed statistically worse than placebo, echoing findings with Biogen and Ionis’s similarly-acting BIIB078 last year.

Late-stage ALS projects and recent failures
Project Mechanism Company Status
Phase 3
Masican (masitinib) CD117, FGFR3 & PDGFR antagonist AB Science AB19001 ends Dec 2023
Jacifusen (ION363) Fused in sarcoma antisense Ionis NCT04768972 ends Jun 2025
Phase 2/3
SLS-005 (IV trehalose) Natural disaccharide Seelos Therapeutics Healey ALS Platform Trial – Regimen E*; data due Q4 2023
MN-166 (ibudilast/Ketas) Phosphodiesterase inhibitor Medicinova Combat-ALS completes Dec 2023
Recent failures
Empaveli  Complement factor C3 inhibitor Apellis/Sobi Meridian failed May 2023; discontinued
WVE-004** C9orf72 antisense  Wave Life Sciences Focus-C9 failed May 2023; discontinued
Reldesemtiv  Troponin activator Cytokinetics Courage-ALS failed Mar 2023; discontinued
Pridopidine Sigma-1 receptor agonist Prilenia Healey ALS Platform Trial – Regimen D* failed Feb 2023; Prilenia still seeking path forward
CNM-Au8 Elemental gold nanocrystals Clene Nanomedicine Healey ALS Platform Trial – Regimen C* failed Oct 2022; Clene still seeking path forward
Verdiperstat Myeloperoxidase enzyme inhibitor Biohaven Healey ALS Platform Trial – Regimen B* failed Sep 2022
Zilucoplan Complement factor C5 inhibitor UCB Healey ALS Platform Trial – Regimen A* failed Mar 2022
*Investigator-sponsored trial; **Had been in development for C9orf72-associated ALS. Source: Evaluate Pharma &
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