Snippets

Vantage Snippets are short summaries of breaking news stories.

Esmo IO – Mirati struggles to keep the first-line dream alive

When it comes to adagrasib's chances in the potentially lucrative first-line lung cancer setting, Mirati still has some convincing to do. Amgen set a low bar earlier this year at World Lung: adding its rival Kras inhibitor, Lumakras, to checkpoint inhibition came with worrying levels of liver toxicity and a meagre 29% overall response rate. Standard-of-care Keytruda presents a much bigger challenge, and topline data in an abstract, released ahead of a full presentation at the Esmo Immuno-Oncology conference tomorrow, point to adagrasib coming up short. SVB analysts described a 49% ORR for adagrasib plus Keytruda as “relatively modest” and in-line with Keynote-189, which tested the Merck & Co MAb plus chemo. Adagrasib needs to do much better for any hope of justifying front-line usage; Stifel analysts described a 56% ORR generated in six patients treated for more than six months as “trending in the right direction”. Responses stratified by patients’ PD-L1 expression levels will be scrutinised tomorrow, and perhaps point to a way forward. Mirati plans to launch a phase 3 trial in patients with low PD-L1 expression “soon”, according to Reuters. But with Mirati shares opening down 17%, it seems the market was expecting a lot more.

Cross-trial comparison of combination first-line non-small cell lung cancer trials
  ORR  ORR in TPS >50% ORR in TPS 1-49% ORR in TPS<1%
Krystal-7 (ph2, adagrasib + Keytruda)  49% (26/53)* ? ? ?
Krystal-1 (ph1b portion, adagrasib + Keytruda) 57% (4/7)** ? ? ?
Keynote-189 (ph3, Keytruda + chemo)  48% (184/387)*** 61% 48% 32%
*In patients with at least one on-study scan, median treatment duration two months, includes 5 unconfirmed partial responses. **median follow-up 19.3 months. ***median follow-up 10.5 months Source: Esmo-IO 2022 abstract, NEJM Gandhi et al, 2018.

US FDA approval tracker: November 2022

Apellis investors suffered a disappointment last month as the Pdufa for intravitreal pegcetacoplan was pushed out to February. The delay was caused by Apellis submitting longer term data from two geographic atrophy phase 3 studies, only one of which hit the primary 12 month measure. News was better for Immunogen, which gained an accelerated approval for mirvetuximab soravtansine, now called Elahere, in FRα-positive platinum-resistant ovarian cancer. A confirmatory study is already underway with data expected early next year. But the FDA’s crackdown on previous accelerated decisions continued in November, with Roche’s Tecentriq and GSK’s Blenrep and Zejula all being withdrawn in certain oncology indications after confirmatory studies failed. For Ardelyx’s Xphozah there were glimmers of hope after an earlier CRL and two appeals. An FDA adcom, convened in response to the second appeal, voted favourably for the project, which aims to control serum phosphorus in adults with chronic kidney disease on dialysis. The Office of New Drugs now has until mid-December to provide a response to Ardelyx's appeal.  

Notable first-time US approval decisions in November
Project Company Indication(s) 2028e SBI ($m) Outcome
Intravitreal pegcetacoplan Apellis Geographic atrophy secondary to age-related macular degeneration 2,567 Delayed until February (Apellis plans to submit 24-month efficacy data)
Tzield (teplizumab) Provention Bio Delay the onset of Stage 3 type 1 diabetes in patients aged 8 and older with Stage 2 952 Approved (previous CRL)
Elahere (mirvetuximab soravtansine) Immunogen Folate receptor alpha-high platinum-resistant ovarian cancer who have been previously treated with 1 to 3 prior systemic treatments 759 Approved (accelerated) (confirmatory Mirasol data due early 2023)
AT-GAA (cipaglucosidase + miglustat) Amicus Pompe disease 266 Previous delays, FDA type A meeting now expected before YE
Poziotinib  Spectrum Previously treated Her2 exon 20 insertion mutated NSCLC 137 CRL (another study needed)
Omblastys (omburtamab) Y-mAbs Therapeutics Treatment of neuroblastoma with CNS/leptomeningeal metastases 69 CRL (another study needed)
Hemgenix (etranacogene dezaparvovec) Uniqure/CSL Adults with haemophilia B - Approved
Rebyota (RBX2660) Ferring (private) Reduce the recurrence of Clostridioides difficile infection in adults following antibiotic treatment for recurrent C diff infection - Approved
SBI: sales by indication. Source: Evaluate Pharma, company releases.

 

Advisory committee meetings in November
Project Company Indication 2028e SBI ($m) Outcome
Zejula GSK Second-line ovarian cancer maintenance 1,034* Cancelled (FDA has asked GSK to restrict use to Brca +ve patients)
Xphozah (tenapanor) Ardelyx Control of serum phosphorus levels in adults with chronic kidney disease on dialysis 357 9-4 in favour of monotherapy, 10-2 in favour of combo with phosphate binders
PT027 (albuterol/budesonide) Astrazeneca/ Avillion As-needed treatment or prevention of bronchoconstriction and for the prevention of exacerbations in patients with asthma 4 years of age and older - Favourable vote for those aged 18 and older but against in ages 4-11, and 12-17 years
Sabizabulin Veru Treatment of SARS-CoV-2 infection in moderate to
severe Covid-19 infections at high risk of acute respiratory distress syndrome
- 5-8 against
*Forecasts not split by treatment line, restriction does not apply to Zejula's 1L maintenance use. Source: Evaluate Pharma, company releases, FDA adcom calendar.

 

Supplementary and other notable approval decisions in November
Product Company Indication (clinical trial) Outcome
Brexafemme Scynexis/ Merck & Co Recurrent vulvovaginal candidiasis (Candle) Approved
Libtayo Regeneron 1L NSCLC (+chemo; Empower-Lung 3) Approved
Vemlidy Gilead Chronic hepatitis B virus infection in paediatric patients 12 years of age and older with compensated liver disease (trial 1092) Approved
Cotellic Roche Histiocytic neoplasms (Erdheim-Chester disease, Rosai-Dorfman disease, and Langerhans cell histiocytosis) (Ph2 NCT02649972) Accelerated approval
Imfinzi + Imjudo + platinum-based chemo Astrazeneca Adult patients with stage IV NSCLC (Poseidon) Approved
Adcetris Seagen Paediatric patients 2 years and older with previously untreated high risk classical Hodgkin lymphoma, (in combo with chemo) (AHOD1331) Approved
Rylaze Jazz Additional dosing schedule, component of chemo regimen for ALL and lymphoblastic lymphoma patients who have developed hypersensitivity to E. coli-derived asparaginase Approved
Rezvoglar (Lantus biosimilar) Eli Lilly Interchangeability designation (improve glycemic control in type 1 and type 2 diabetes) Approved
Sezaby (phenobarbital sodium powder for injection)  Sun Pharma Treatment of neonatal seizures (Neolev2) Approved
Kineret Swedish Orphan Biovitrum Treatment of Covid-19 in hospitalised adults with pneumonia requiring supplemental oxygen who are at risk of progressing to severe respiratory failure EUA
Blenrep GSK Fourth-line relapsed or refractory multiple myeloma (accelerated approval) Withdrawn from market (confirmatory Dreamm-3 failed)
Tecentriq Roche 1L urothelial bladder (accelerated approval) Withdrawn from market (confirmatory Imvigor130 failed)
Source: Evaluate Pharma, company releases.

CTAD 2022 – donanemab could be the plaque clearer king

While Lilly awaits results of donanemab’s pivotal Trailblazer-Alz 2 study next year, investors now have a positive signal. Trailblazer-Alz 4, a small trial pitting donanemab against Biogen’s Aduhelm, has suggested that the Lilly project could clear amyloid more quickly than any other amyloid-beta MAb. Lilly had already toplined Trailblazer-Alz 4 as positive, and this evening the CTAD conference saw full results in what was billed as the first active comparator data on plaque clearance in early symptomatic Alzheimer’s. In just six months donanemab-treated patients saw a mean 63% reduction in brain amyloid – a figure Aduhelm and Eisai’s lecanemab only reached a year later in separate, pivotal trials. The mean six-month reduction for Aduhelm in Trailblazer-Alz 4 was 16% – broadly in line with both the negative Engage study and the arguably positive Emerge trial. 37.9% of donanemab patients achieved six-month plaque clearance, versus 1.6% on Aduhelm, and Aria-E and symptomatic Aria-E rates were around 20% and 3% respectively, similar across the two cohorts. The big question is: so what? Until donanemab shows evidence of activity on disease in a controlled study the plaque data will do little beyond backing its mechanism of action.

Plaque clearance by amyoid-beta MAbs across four studies
  Mean brain amyloid levels*  
Study Project Baseline 6mth 18mth Difference at 6mth**
Emerge Aduhelm 85 66 25 -22%
Engage Aduhelm 91 76 37 -17%
Clarity-AD Lecanemab 78 44 19 -44%
Trailblazer-Alz 4 Donanemab 98 36 NA -63%
Aduhelm 102 86 NA -16%
Notes: *units are Centiloids, which express the Standard Uptake Value Ratio used to quantify the PET signal; in Clarity-AD Eisai set 30 Centiloids as the threshold above which subjects are considered to have elevated brain amyloid; in Trailblazer-Alz 4 plaque clearance was defined as ≤24.1 Centiloids; **difference not adjusted for the placebo cohorts used in Emerge, Engage & Clarity-AD. Source: Aduhelm label & CTAD.

This story has been amended to correct the six-month value for Aduhelm in the Emerge trial.

Is a big deal on the Horizon?

Horizon Therapeutics has long been discussed as a takeover target, and now it’s official: the group yesterday confirmed that it was in “highly preliminary discussions” with Amgen, Johnson & Johnson and Sanofi. These talks might come to nothing, but it is noteworthy that three players are interested; Stifel analysts also cited Novartis and Abbvie as potentially good matches. One question is whether any bidder will pay what Horizon wants, with the group’s share price well off its all-time high of nearly $120 a year ago, though even before the deal talk it had been creeping up again following a second-quarter blip. Stifel reckons that $120 per share would be the minimum acceptable offer, putting the total takeout cost at $27bn. SVB is slightly less optimistic, mooting a potential price tag of $101-117 per share. Horizon’s net present value is $19bn, as calculated by Evaluate Omnium using sellside consensus, which always represents the bull case. Much cheaper, meanwhile, is Horizon’s thyroid eye disease rival Viridian, which traded up 15% this morning in sympathy – however, an even bigger rival might not be great news for that group. Horizon’s suitors have until January 10 to make their intentions known.

What's it worth? Putting a valuation on Horizon
Product/project NPV ($bn)
Tepezza 10.8
Krystexxa 2.4
Uplinza 2.6
R&D pipeline 1.3
Total 17.1
Horizon total NPV 19.1
Source: Evaluate Pharma.

Nestlé’s peanut exit makes DBV look brittle

The $2.6bn that Nestlé paid for the peanut allergy therapy developer Aimmune always looked a little bit nuts. Now reality is biting for the food giant, with the company announcing today that it is "exploring strategic options" for Palforzia following poor sales. While Aimmune investors got their exit, the same cannot be said for backers of the group’s peanut allergy rival, DBV, which now looks like it could have an even harder task of making its patch project, Viaskin Peanut, a success. Not that the French company has had an easy ride so far, with its latest setback a partial clinical hold for its new pivotal trial, Vitesse. Nestlé’s latest move suggests that even if Viaskin Peanut can make it past regulators – hardly a dead cert given its tortuous development path so far – it will have trouble drumming up demand. DBV stock fell only 2% today, but it is not far off all-time lows. Other players in peanut allergy might also want to take note: Novartis’s ligelizumab is in phase 3 here, although it has already failed in urticaria.

Selected projects in development for peanut allergy
Project Company Mechanism Status
Ligelizumab Novartis Anti-immunoglobin E antibody Ph3 ends Jan 2025
PRT120 Prota Therapeutics  IgE/Th2 inhibitor Ph2b completed in Australia; company seeking funds for further development 
Remibrutinib  Novartis BTK inhibitor Ph2 ends Sep 2024
PVX108 Aravax  "Next-generation, allergen-specific immunotherapy" Ph2 ends Nov 2024
ADP101  Alladapt Immunotherapeutics Oral immunotherapy Ph1/2 ends Nov 2022
VE416  Vedanta Oral immunotherapy Ph1/2* ends Jan 2023
CNP-201 Cour Pharmaceuticals Nanoparticle encapsulating purified peanut protein extract Ph1/2 ends May 2023
*Investigator-sponsored study. Source: Evaluate Pharma & clinicaltrials.gov.

 

The recent history of DBV's Viaskin peanut 
Date Event
Dec 2018 DBV pulls US filing for Viaskin Peanut
Oct 2019 FDA accepts refiling of Viaskin Peanut in 4-11 year olds; target action date Aug 5 2020
Aug 2020 CRL for Viaskin Peanut; FDA cites need for patch modifications and subsequent new human factor study
Jan 2021 DBV says FDA only requires two short studies to support new application
Dec 2021 DBV changes plan & starts pivotal study of modified Viaskin Peanut patch in children; withdraws EU marketing application
Sep 2022 DBV starts ph3 Vitesse trial using modified Viaskin Peanut patch; expects to screen 1st pt in Q4 2022 & topline results in Q1 2025
Sep 2022 FDA puts Vitesse on partial clinical hold, requesting protocol changes
Nov 2022 DBV says it will not meet target of screening 1st pt in Vitesse by YE 2022; has $213m cash
Source: Company releases.

Boston’s obesity acquisition is a leftfield move

Even before the approval of the first effective obesity drug, Novo Nordisk’s Wegovy, last summer, demand for devices to treat the disease was pretty slack. So Boston Scientific’s acquisition of Apollo Endosurgery for $615m in cash today is an unexpected move. Novo is having difficulty meeting demand for Wegovy and its diabetes drug Ozempic, which contains the same active ingredient, so perhaps Boston believes devices can step into the gap. But Apollo has had difficulty with obesity products over the years, selling its surgical obesity products at a loss in 2018 to focus on Orbera, its gastric balloon for obesity; Orbera ran into trouble as well. Apollo’s other main obesity device is its ESG system, a gastric sleeve that was approved in July but is not expected to see reimbursement until 2025. Stifel analysts believe that the ESG could have sales of up to $64m a year before that, even though the out-of-pocket cost is $2,500. Apollo also has devices that allow minimally invasive suturing and fixation during complex gastrointestinal procedures, which could augment Boston’s own endoscopy portfolio, which accounts for around 17% of its sales.

Apollo's Orbera balloon

Broken Halo sinks Cincor

The Halo trial in patients with uncontrolled hypertension was supposed to confirm the encouraging signals that Cincor found for baxdrostat in Brightn, a previous phase 2 study conducted in treatment-resistant hypertension and presented earlier this month. But Halo’s failure, and Cincor’s attempts to dig up a signal, raise the risks around this project as it heads into pivotal development. The company blamed a group of non-adherent patients, the majority of whom were Hispanic/Latino and who were enrolled at five study sites, for the trial’s miss. Cut out these patients – who represented 55% of the intent-to-treat population – and a nominally statistically significant reduction in blood pressure can be found, Cincor insisted. On a call executives said they believe adherence is the issue here rather than Hispanic/Latino biology; another possibility mooted was that Halo recruited patients whose high blood pressure is caused by something other than the aldosterone pathways on which baxdrostat works. Patients in Halo were less refractory to existing blood pressure medicines than those in Brightn, so this trial was always higher risk. But success could have opened up a much bigger market. Disappointed investors wiped out almost half the company’s market cap, or around $600m, this morning.

Source: Company presentation.

C4X gets another small deal from big pharma

After signing a licensing deal with Sanofi last year, C4X got more big pharma buy-in today from Astrazeneca. True, the up-front sums involved are small, but the UK group’s strategy of farming out preclinical assets is continuing to bear fruit. Astrazeneca, for its part, reckons that C4X’s Nrf2 activator programme could have disease-modifying potential in COPD; the group also has various other projects in development with this aim, including the IL-33-targeting tozorakimab. Nrf2 is described as a “master regulator” of the antioxidant response and has a role in fighting inflammation. Biogen’s multiple sclerosis drug Tecfidera is thought to work via its effects on Nrf2, while Reata is also pursuing this approach with both omaveloxolone and bardoxolone, with mixed results so far. The list of diseases that could be addressed by Nrf2 activation is large; C4X also cites atopic dermatitis, inflammatory bowel disease, sickle cell disease and pulmonary arterial hypertension. As for what might be next for C4X’s out-licensing efforts, its pipeline names oral Malt-1 and α4β7 inhibitor programmes – still, the latter field had a setback with the failure of Protagonist’s PN-943 this year, which that group has since deprioritised.

Preclinical deals by C4X
Partner Mechanism Up-front payment ($m) Total potential deal value ($m) Date
Astrazeneca Oral NRF2 activators 2 402 Nov 2022
Sanofi Oral IL-17A inhibitors 7 433 Apr 2021
Indivior Oral orexin-1 receptor antagonists 10 284 Mar 2018
Source: Evaluate Pharma, company releases.

Axsome soars on non-pivotal data

When Axsome decided to stop the Accord study of AXS-05 in Alzheimer’s disease agitation early, hopes for that trial took a nosedive. So it was clearly a pleasant surprise today when the company announced that the study had hit. Axsome’s stock opened up 33%, and some investors might be hoping for an earlier-than-expected filing, despite the fact that results from the pivotal Advance-2 study are not due until 2025. Accord had initially been intended as a second pivotal, alongside the previously completed Advance-1, but when the number of agitation events turned out lower than expected, management decided to switch focus to Advance-2. Despite this, Accord met its primary endpoint, time to relapse of agitation, and a key secondary, relapse prevention. One potential fly in the ointment could be Accord’s randomised withdrawal design; it comprised an open-label lead-in phase in which all 178 patients were given AXS-05, and those that had a sustained clinical response to the agent were randomised to either continue treatment or switch to placebo. AXS-05, a combination of dextromethorphan and bupropion, is approved in depression as Auvelity and moving into Alzheimer’s agitation would be an important expansion.

Accord data (from double-blind period)
  AXS-05 Placebo
N 53 55
Time to relapse Stat sig vs pbo -
     Hazard ratio 0.275 -
     P value 0.014 -
Risk of relapse 3.6-fold lower vs pbo -
Proportion of pts relapsing (%) 7.5 25.9
     P value 0.018 -
Rate of adverse events (%) 28.3 22.2
Discontinuations due to AEs (%) 0 1.9
Source: company release. 

Delfi enters the liver cancer blood test arena

Delfi Diagnostics’ mission to bring low-cost liquid biopsies to the market took another step forward last week with promising early results for its liver cancer screen. The blood test achieved sensitivity of 88% at a pre-set 98% specificity in more than 700 individuals at average risk of developing hepatocellular carcinoma. This test, like Delfi’s flagship lung cancer screen, uses the group’s fragmentomics technology, based on aberrant pieces of DNA from cancer cells. These can be pieced together using machine learning, allowing for a more cost-effective sequencing technique, Delfi says. There will be more to do to get this test to customers, of course, but a comparison with early data on other groups’ liver cancer blood tests shows Delfi’s test to have similar levels of accuracy. It is notable, however, that Exact Sciences is the only one of the more established liquid biopsy developers to have a liver cancer-only test. The most common choice for single-tumour liquid biopsies is colorectal cancer, followed by lung cancer.

Selected liquid biopsies for liver cancer
Company Liquid biopsy N Sensitivity Specificity
Delfi Diagnostics Unnamed 724 88% 98%*
Exact Sciences OncoGuard Liver 401 88% 87%
Laboratory for Advanced Medicine IvyGene Liver 151 95% 98%
Genetron  HCCscreen 1,615 88% 93%
Oncimmune  EarlyCDT Liver - ~40% ~90%
*Pre-set. Source: Vantage interviews, company releases, AACR.