Vantage Snippets are short summaries of breaking news stories.

Tofersen adcom raises hopes of even more FDA flexibility

So much for a new, stricter regimen at the FDA’s neurology division after the departure of Billy Dunn, who was something of a patron saint of lost causes. Biogen/Ionis’s tofersen looked finished 18 months ago, but now seems set for accelerated approval in Sod1-mutated ALS at the very least: at yesterday’s FDA advisory committee meeting panellists were unanimously in favour of using the controversial biomarker neurofilament light chain to predict a clinical benefit. Full approval looks like a longer shot, but could still happen after a close vote – it seems incredible that this was even discussed, given the project’s phase 3 failure. Biogen is already carrying out the Atlas trial in presymptomatic patients, which could be used as a confirmatory study, owing to the difficulties in carrying out a new study in such a small population. The rarity of Sod1 ALS means tofersen is not expected to become a big money-spinner, but the panel outcome appears to signal continuing flexibility at the FDA around CNS biomarkers. This could be good news for the likes of Uniqure, Denali, Dyne, Pepgen and Alector, as well as other pipeline assets from Biogen and Ionis, Stifel analysts noted.

Heading for accelerated approval or more? Tofersen's adcom outcome
Question Approval type Yes No Abstain
Is a reduction in plasma NfL concentration reasonably likely to predict clinical benefit of tofersen? Accelerated 9 0 0
Do data from the placebo-controlled study and long-term extension study (+ biomarker data) provide substantial evidence of tofersen's effectiveness? Full 3 5 1
Source: company releases.

Dupixent pushes towards a big new use

Success in the Boreas study is a big step forward for Sanofi/Regeneron’s Dupixent in a potentially large new setting: chronic obstructive pulmonary disease. The statistically significant 30% reduction in exacerbations, versus placebo, easily beat the mid-teens range that analysts at Wolfe Research said would be required for a clinically meaningful result. With Sanofi trading 5% higher in a down market, and Regeneron opening up 7%, the topline data were clearly stronger than many expected. Hopes were low because biologicals have previously failed in the progressive lung condition. Selecting for patients with an eosinophilic phenotype was presumably the key here, though it is as yet unknown whether the result was driven by former or current smokers; the study recruited both patient types. Either way, Dupixent probably needs to hit in a second identical trial before approvals can be sought; Notus reports in 2024. Past COPD disappointments mean a similar result is far from guaranteed, though the strength of the signals in Boreas will raise hopes. But it will be some years before the door to this potentially multibillion-dollar market is fully opened, and by then other biologicals could also be knocking.

Dupixent in COPD: the Boreas data so far
Primary endpoint: annualised exacerbation rate  30% reduction vs placebo (p=0.0005)
Key secondary endpoints:  
Lung function (FEV1) improvement from baseline at 12 weeks 160ml at 12 weeks compared to 77ml for placebo (p<0.0001)
Lung function (FEV1) improvement from baseline at 52 weeks  Improvements sustained (p=0.0003)
Note: Dupixent met all endpoints tested in the hierarchy, including improvement in patient-reported health-related quality of life scales. Source: company press release. 

Cognito gets $73m and hopes to do better this time

Cognito Therapeutics’ VC haul of $73m yesterday is notable for a couple of reasons. Like the deal between Roche and Lilly it shows that appetite for technological approaches to Alzheimer’s disease remains strong. Secondly, it highlights the overall paucity of VC funding available to the medtech sector in 2023. The round is the third biggest so far this year; this time last year it would have ranked ninth. Indeed the total venture cash raised by medtech companies this year sits at just $819m – by 23 March 2022 the total was $2.3bn. Still, Cognito is one of the lucky ones, and its series B round will go towards the phase 3 trial of its neuromodulation technology. CogTx-001 is a wearable device that delivers gamma frequency light and sound, which the group says incites increased brain activity, potentially boosting memory and perception. The Hope trial, which kicked off last month, tests this versus sham, with the aim of improving symptoms on a couple of rating scales after a year’s treatment. Investors have clearly not been put off by CogTx-001’s showing in phase 2: it missed significance on all three of the Overture trial’s primary endpoints.

Top 5 medtech VC rounds of 2023 so far
Date Company Investment ($m) Round Focus
19 Jan Setpoint Medical 80 Series F Neurology
26 Jan Alleviant Medical 75 Undisclosed Cardiology
22 Mar Cognito Therapeutics 73 Series B Neurology
9 Jan Sonivie 60 Series C Cardiology
1 Feb Ronovo Surgical 50 Series B General & plastic surgery
Source: Evaluate Medtech.

Merkel cell provides Incyte’s laggard a way in

A few years ago the first approval of an anti-PD-(L)1 drug would have been trumpeted far and wide. But with seven already on the US market Incyte did not even disclose that it had filed the Macrogenics-originated retifanlimab, and the announcement yesterday that the drug had been approved as Zynyz for Merkel cell carcinoma thus came as a surprise. Investors received it with a shrug, presumably because Merkel cell is such an insignificant use. Still, this is not the point; Incyte needed retifanlimab to be approved not so it could have a monotherapy challenger but to give it an in-house PD-1 backbone for future combinations. The key lesson for laggards pursuing similar strategies is that Merkel cell – where only Merck & Co’s Keytruda and Merck KGaA/Pfizer’s Bavencio are approved, both through the accelerated pathway – remains a viable niche indication in which a quick nod is possible. Incyte had tried and failed to get retifanlimab greenlit in another peripheral use, squamous cell carcinoma of the anal canal, but a US adcom slammed its data in 2021, and a complete response letter followed.

Anti-PD-(L)1 laggards in the US
Project Company Lead indication(s) US status
Toripalimab Coherus/ Shanghai Junshi 1st-line chemo combo & 3rd-line monoRx nasopharyngeal carcinoma 2 May 2022 CRL; new Pdufa date 23 Dec 2022 missed because of Covid travel restrictions
Tislelizumab Novartis/ Beigene 2nd-line oesophageal squamous cell carcinoma 12 Jul 2022 Pdufa date missed because of Covid travel restrictions
Penpulimab Akeso/ Sino 3rd-line nasopharyngeal carcinoma 2022 Pdufa date missed, presumably because of Covid travel restrictions
Cosibelimab* Checkpoint (Fortress) Cutaneous squamous cell carcinoma 4 Jan 2024 Pdufa date, no adcom
Envafolimab* Tracon/ Alphamab/ 3D Medicines 1st-line biliary tract cancer (gemcitabine combo) Ph3 ends Jan 2024 (delayed from Dec 2021)
Serplulimab Shanghai Henlius/ Fosun 1st-line SCLC, vs Tecentriq Ph3 ends Jun 2024
Zimberelimab Arcus (via Wuxi/ Gloriabio) 1st-line PD-L1+ve NSCLC (+/- domvanalimab) Ph3 trial ends Feb 2024 (earlier Dec 2025)
Sasanlimab Pfizer Non-muscle-invasive bladder cancer (BCG combo) Ph3 ends Jun 2025 (delayed from Jun 2024)
Cetrelimab (JNJ-63723283) Johnson & Johnson Muscle-invasive bladder cancer (TAR-200 combo) Ph3 trial ends Dec 2026
Ezabenlimab (BI 754091) Boehringer Ingelheim Various, Lag3 & VEGF/Ang2 combos Ph2 trial ends May 2024
Balstilimab Agenus 2nd-line cervical cancer Filing pulled 22 Oct 2021
Sintilimab Innovent 1st-line non-squam NSCLC (Alimta combo) 24 Mar 2022 CRL
Sugemalimab* Cstone/ EQRX 1st-line NSCLC US filing plan abandoned
Spartalizumab Novartis Melanoma (Tafinlar+Mekinist combo) Failed Combi-I trial Aug 2020 (deprioritised)
Note: *anti-PD-L1; all others are anti-PD-1. Source: company disclosures &

Roche and Lilly Eapp into Alzheimer’s testing

Both Roche and Lilly have so far failed get their therapies for Alzheimer’s on the market. Now they are working together with the aim of diagnosing rather than treating the disease. Today the two announced their development collaboration for the Elecsys Amyloid Plasma Panel, intended to help healthcare professionals diagnose patients more quickly. As a blood test this could offer advantages over the current FDA-cleared technologies – two of which are sold by Roche – which detect either amyloid or tau in cerebrospinal fluid samples. Despite its name the test does not use amyloid as its biomarker; instead it measures levels of phosphorylated tau and apolipoprotein E4. Elevations in the former occur in early stages of Alzheimer’s, while ApoE4 is the most common genetic risk factor for the disease. Roche told Evaluate Vantage that its research team tested a number of potential biomarkers and these were the most promising at indicating increased amyloid-beta levels in a patient’s brain.

Selected IVDs for Alzheimer's disease
Company Test Biomarker Sample Status
The three FDA-cleared tests…
(HU Group)
Lumipulse G β-Amyloid Ratio Amyloid beta 42/40 ratio CSF Granted de novo clearance Apr 2022
Roche Elecsys β-Amyloid (1-42) CSF II Amyloid beta 1-42 CSF Granted 510(k) clearance Dec 2022
Roche Elecsys Phospho-Tau (181P) CSF Phosphorylated tau 181 CSF Granted 510(k) clearance Dec 2022
And Roche and Lilly's other assays…
Roche/Lilly Elecsys Amyloid Plasma Panel (Eapp) Phosphorylated tau 181 and apolipoprotein E4 Blood In development
Lilly P-tau217 test Phosphorylated tau 217 Blood Used in-house to aid trials of Alzheimer's drugs
Source: Evaluate Medtech & company releases.

Second pivotal hit brings Claudin18.2 closer to approval

With confirmation of a hit in its second pivotal trial Astellas’s zolbetuximab appears set to become the industry’s first approved drug targeting Claudin18.2. Astellas said last night that the Glow trial had replicated the success of Spotlight, unveiled at January’s Asco-GI conference, in showing progression-free and overall survival benefit advantages when adding zolbetuximab on top of chemo. The first-line gastric/gastroesophageal junction (GEJ) cancer patients enrolled had to have Claudin18.2-positive tumours, amounting to around 39% of this population, and approval would require testing for this antigen to become standard. Baseline characteristics likely account for the numerical PFS and OS differences between Spotlight and Glow, which used slightly different chemo regimens, but statistically both results hit significance and were in line with the phase 2 Fast study data. More concerning is the 66-69% rate of nausea and vomiting reported in Glow (Spotlight had seen 65-81% rates, including 16% at grade 3 or above). Other quirks of Spotlight included no activity in the subset of GEJ patients, and no benefit at all in terms of overall response rate; for Glow this detail will hopefully be revealed when the full data are presented at an Asco virtual plenary series this afternoon.

Zolbetuximab in Her2-ve, Claudin18.2+ve* gastric/GEJ adenocarcinoma
  Spotlight Glow
(Folfox combo) (Capox combo)
mPFS (primary endpoint) 10.6mth vs 8.7mth 8.2mth vs 6.8mth
Stats HR=0.75, p=0.0066 HR=0.69, p=0.0007
mOS (secondary endpoint) 18.2mth vs 15.5mth 14.4mth vs 12.2mth
Stats HR=0.75, p=0.0053 HR=0.77, p=0.0118
ORR (secondary endpoint) 60.7% vs 62.1% TBC
Note: *defined as moderate-to-strong membrane staining in ≥75% of tumour cells by IHC. Source: Asco.

Mereo’s regulatory boost means little without a partner

Mereo spent much of last year battling activist investors and planning to keep the lights on – 40% of the UK developer’s staff are being culled to help cash last into 2026 – so today’s update comes as a small fillip. US and EU regulators have agreed that alvelestat might win full approval on a single phase 3 trial, having completed phase 2 in alpha-1-antitrypsin deficiency-associated lung disease. The problem: a partner must be found before the pivotal study can start. The search has begun, executives said on a call today, without elaborating further. The AATD pipeline has seen activity in the past few years, though the disease has proved tough to target, and most focus on liver manifestations. Augmentation therapy is approved for those with AATD lung disease, but this is controversial and not widely reimbursed. All of which means alvelestat could attract attention; clarity on what the pivotal trial needs to look like should also help. The FDA and EMA want different primary endpoints, and Mereo expects the trial to recruit some 200 patients and last up to 18 months. Given the company's weak position long-suffering shareholders must hope that interested parties emerge quickly.

Alvelestat in AATD lung disease: proposed phase 3 design (240mg versus placebo)
Two independent primary endpoints:
FDA  Patient-reported outcome of the St George’s Respiratory Questionnaire (SGRQ); activity domain or the full score to be used*
EMA Lung density measured by CT scan ("the EMA has indicated it would accept a more relaxed Type 1 error (i.e., p<0.1)") 
Note: will not be co-primaries, and trial will not need to hit both to be deemed successful; *score developed for COPD, and Mereo will need to validate it for AATD-LD before and during the phase 3 trial. Source: Mereo press release & conference call. 

Pear sets out its stall for potential sale

Friday’s announcement that Pear Therapeutics was effectively putting itself up for sale is the latest hammer blow to the digital health sector, which has recently seen numerous rounds of job cuts and company failures. Pear had been a poster child for digital therapeutics through its 2021 $1.6bn float via a merger with a special purpose acquisition company, as well as its three FDA-approved products. But enthusiasm for digital health, which reached fever pitch during the pandemic, has cooled significantly. Tougher economic conditions and tightening capital markets have dented sentiment for tech-focused companies and seen Spac valuations tumble. Pear, which posted a $30.7m third-quarter net loss, has been in distress since last year, when it trimmed its workforce by 30%, and last month announced the departure of its chief commercial officer. Pear’s products have experienced the same problem as other digital therapeutics of limited cover from health insurance companies, despite the group’s success in securing interest from commercial insurers. Shares in the company are now trading 97% below their list price, and with little appetite for risk in the market it is hard to see who will come to Pear’s rescue.

Prescription app makers' Spac deals
Target Spac (main backer)  Date merger announced Date merger closed Time to close (months) EV change since announcement
Sandbridge Acquisition Corp (Sandbridge Capital and Pimco)
16 Feb 2021
16 Jul 2021 4.9 -96%
Better Therapeutics Mountain Crest Acquisition Corp II (Mountain Crest Capital) 7 Apr 2021 29 Oct 2021 6.7 -88%
Pear Therapeutics Thimble Point Acquisition Corp (LJ10) 22 Jun 2021 6 Dec 2021 5.5 -97%
Akili Interactive Social Capital Suvretta Holdings Corp I (Social Capital and Suvretta Capital Management) 26 Jan 2022 22 Aug 2022 6.6 -89%
Spac=special purpose acquisition company. EV=enterprise value. Assumes $10 pre-announcement share price. Source: company statements.

Bad vibes continue for Merck

Yesterday Merck admitted that its Tigit-Keytruda coformulation MK-7684A was numerically inferior to chemo in the phase 2 Keyvibe-002 lung cancer trial, and the question now is what that means for other studies of the Tigit, vibostolimab. The trial was a long shot since patients had already failed on one checkpoint inhibitor and chemotherapy, and following the disappointing performance of vibostolimab in Keynote-001 three years ago. Data from the open-label arm of Keyvibe-002 showed that the vibostolimab-Keytruda combo was inferior to docetaxel on the primary endpoint of PFS in NSCLC patients who had progressed on anti-PD(L)1 and platinum-based chemo. Keyvibe-002 also has a blinded comparison of the combo plus docetaxel versus docetaxel alone, and Merck is continuing this. But attention will now shift to the much bigger phase 3 study Keyvibe-003, in the first-line treatment of NSCLC patients with PD(L)1 expression of at least 1%, and while this is a different setting the chance of success now looks even slimmer. That said, both Mizuho and SVB analysts point to the Keymaker-U02 substudy 02C in neoadjuvant stage III melanoma, data from which is expected at AACR next month, as giving closer read-through to the Keyvibe programme in an earlier setting. 

Selected Keyvibe trials of Merck's vibostolimab
Trial Arms Setting PCD
Keyvibe-001* Uncontrolled PD-(L)1-naive NSCLC Disappointed Sep 2020
Keyvibe-002** Vibostolimab + Keytruda +/- chemo, vs chemo PD-L(1)/chemo-experienced NSCLC  Failed Mar 2023
Keyvibe-003 Vibostolimab + Keytruda, vs Keytruda 1L PDL(1)+ NSCLC w PD(L)1 expression >1% Apr 2026
Keyvibe-006 Vibostolimab + Keytruda + CRT, vs Imfinzi + CRT Stage III inoperable NSCLC Sep 2028
Keyvibe-007 Vibostolimab + Keytruda + chemo, vs Keytruda + chemo 1L metastatic NSCLC Nov 2025
Keyvibe-008 Vibostolimab + Keytruda + chemo, vs Tecentriq + chemo 1L extensive-stage SCLC May 2025
Keyvibe-010 Vibostolimab + Keytruda, vs Keytruda Adjuvant treatment in resected stage II-IV melanoma  Oct 2027
*Ph1 trial. **Ph2 trial. All others Ph3. Source: Evaluate Pharma, 

Sarepta investors fear a panel beating

The FDA’s sudden decision to call a panel meeting to evaluate Sarepta’s Duchenne muscular dystrophy gene therapy SRP-9001 is perhaps a sign that the agency is tightening its scrutiny of approval applications that rely on surrogate endpoints in the wake of the Aduhelm controversy. Just last month Sarepta assured investors that the FDA had stated that no adcom would be needed, so the volte-face has prompted consternation; Sarepta opened down 20% today. The timing of the meeting will be key: SRP-9001 has a Pdufa date of 29 May, and even a successful adcom could be bad news if it pushes the decision date back. A more concrete risk comes from the fact that SRP-9001 is the first gene therapy for which accelerated approval has been sought on the basis of a surrogate endpoint – expression of dystrophin. This will probably be the panel’s main focus, and should the panellists decide that it is insufficient the panel could vote against approval, forcing Sarepta to resubmit when the confirmatory trial, Embark, reports functional data later this year. 

Sarepta's track record… and what's at stake
Product US status Adcom Confirmatory trial 2028 sales forecasts ($m)
Exondys 51 Gained accelerated approval Sep 2016 based on uncontrolled trial with surrogate endpoint Yes, voted against approval Mis51on, could report 2026 302
Vyondys 53 Gained accelerated approval Dec 2019 based on uncontrolled trial with surrogate endpoint No Essence, could report 2024 212
Amondys 45 Gained accelerated approval Feb 2021 based on pbo-controlled trial with surrogate endpoint No Essence, could report 2024 216
SRP-9001* Awaiting accelerated approval based on pbo-controlled trial with surrogate endpoint, Pdufa date 29 May 2023 Yes, date unconfirmed  Embark, could report 2023 2,036
*Gene therapy, all the rest are Exon skippers. Source: Evaluate Pharma, company communications. 
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