Snippets

Vantage Snippets are short summaries of breaking news stories.

Esmo 2021 – Beyondspring experiences winter of discontent

Beyondspring’s pledge to file plinabulin with the FDA next year has failed to reassure investors. The group’s shares sank 33% yesterday, after full results from the Dublin-3 trial were presented at Esmo – a stark contrast to the 176% surge Beyondspring enjoyed after toplining the data in August. Even then there were questions around the results' relevance given that fewer than a quarter of the Dublin-3 patients had failed on a PD(L)-1 regimen, which is standard of care in first-line use; the trial largely recruited in China. A new subset in PD(L)-1 treated patients was unveiled, showing a 32% reduction in death, albeit with no significant median survival difference between the two arms. Esmo discussant Dr Maurice Pérol of the Léon Bérard Cancer Centre in France did not sound wholly convinced, pointing out that plinabulin achieved similar efficacy to Cyramza, the Lilly drug that is already approved third line, but with different safety profile. "It is difficult to know in which subset of patients [plinabulin] might be of interest... maybe frail patients where the haematological toxicities of [Cyramza] are a concern," he told the cancer conference. With so few options for these late-stage patients plinabulin might yet convince regulators, but it seems that not everyone is on side.

Dublin-3 trial
Intent-to-treat population    Subset PD(L)-1 analysis n=129
 
Docetaxel    
Docetaxel
Primary endpoint       Primary endpoint    
Mean OS 15.1 mths 12.8 mths   Mean OS 18.3 mths 14 mths
Median OS 10.5 mths 9.4 months   Median OS 12.3 mths 12.1 mths
Log rank p value 0.039   Log rank p value N/A*
Hazard ratio 0.82   Hazard ratio 0.68
*Sample size too small. Source: company presentation.

Pfizer/Biotech's Covid vaccine data looks good enough for FDA, but parents?

The devil is often in the detail, and no more so when it comes to balancing the risks and rewards of treating children. As such, Pfizer Biontech’s latest phase 2/3 data in 5-11 year old patients, showing that two 10µg doses of the Covid-19 vaccine Comirnaty stimulated similar antibody responses to 16-25-year-olds might not be enough to convince all parents, especially as there were no data on reduction of serious illness. While children are being hospitalised with the Delta variant, the numbers remain very low, and children, particularly younger children, are still at much lower risk than adults of serious illness and complications following Covid-19 infection. Add to this that mRNA vaccines have been linked to myocarditis – albeit in small numbers – this incidence of which in this age group is almost impossible to gauge from a clinical trial setting. If this latest data divides opinion on whether or not to vaccinate young children, trial results in 2-5 year olds and 6-24 month olds, due at the end of the year, could see those divisions widen further. Pfizer, however, is planning a regulatory filing within weeks, for for a vaccine that Evaluate Pharma forecasts will make $31.8bn this year, a consensus figure that looks likely to rise with the prospect of boosters for adults. 

Selected paediatric Covid-19 trials
Project Company/Sponsor Trial Age (years) Enrolment
Comirnaty (BNT162b2)  Biontech/Pfizer NCT04368728 12 - adult 43,998
Comirnaty (BNT162b2)  Biontech/Pfizer NCT04816643 6 months - 11 years 4,500
Ad26.COV2-S J&J NCT05007080 12-17 4,350
Spikevax Moderna/BARDA NCT04649151 12-17 3,732 
Nanocovax Nanogen NCT04683484 12 - adult 620
SARS-CoV-2 vaccine Sinovac NCT04551547 3-17 552
Covaxin (BBV152) Bharat Biotech NCT04471519 12 - adult 755
Vaxzevria (AZD1222) Astrazeneca/Oxford Uni COV006 6-17 300
Source: Evaluate Pharma, clinicaltrials.gov.

Holding back doesn’t lessen the pain for Protagonist

Protagonist's admission that a cancer signal had prompted the FDA to halt trials of rusfertide, or PTG-300, caused its shares to slump 62% on Friday, erasing $1.4bn from the biotech’s market cap. Further detail, inexplicably released after markets closed in an SEC filing, only add to concerns. The company disclosed that four cases of cancer had been seen across clinical trials of rusfertide; the earlier press release only referenced findings in mouse models. The cancer cases had been previously assessed as unrelated to rusfertide, and it is true that the project’s lead indication, the myeloproliferative disorder polycythemia vera, can, rarely, progress to cancer. The sellside came to the company’s defence, pointing out examples of other drugs that had showed similar preclinical cancer signals in the same mouse model but which went on to reach the market. But it is clear that investors believe rusfertide, a hepcidin mimetic, to be dead; after La Jolla effectively abandoned work on its synthetic hepcidin a couple of years ago, this appears to be an avenue of research now closed. Attention for Protagonist now turns to PN-943, an oral integrin antagonist, on which mid-stage results are not due until next year at the earliest.

Protagonist's clinical pipeline
Status Product Mechanism of Action Indication(s)
Phase II PTG-300 (rusfertide) Hepcidin mimetic Polycythemia vera (NCT04057040, NCT04767802), hereditary haemochromatosis (NCT04202965)
  PN-943 Alpha-4 beta-7 integrin antagonist Ulcerative colitis (NCT04504383)
  PTG-200* IL-23R antagonist Crohn's disease (NCT04102111)
Phase I PN-235* IL-23R antagonist Healthy volunteers (NCT04621630)
  PN-232* IL-23R antagonist Healthy volunteers (NCT04819620)
*In collaboration with J&J. Source: company website, clinicaltrials.gov.

Mirati moves for an independent future

Stronger than expected response rates with Mirati’s Kras inhibitor adagrasib in colorectal cancer, unveiled at Esmo this weekend, had analysts speculating about accelerated approval. Today executives confirmed this plan, telling investors that FDA talks will be held before year end. Mirati believes that data in around 100 patients, in both combination and monotherapy settings, will be required. Another big unveiling today concerned the first look at phase 2 lung cancer data, and a 43% response rate should please. This puts adagrasib in the same ballpark as Amgen’s Lumakras, which was approved on a 36% ORR; Kras G12C-mutant NSCLC will form Mirati’s other accelerated approval application before year end. Full presentation of this data remains important, however, including a closer look at safety. The company promised this in early 2022. This means a busy period awaits new chief executive David Meek, a surprise appointment that also emerged today. The former Ipsen boss's mixed track record notwithstanding, some could be disappointed that Mirati is “building up” rather than seeking a sale or partnership, the prospect of which remains the bull case for many investors. With the stock opening 9% higher, those considerations are apparently for another time.

Cross-trial comparison of Kras inhibitors in second-line+ KRAS G12C-mutated NSCLC
  Adagrasib: Krystal-1 Lumakras: Codebreak 100 
  Ph 2 cohort 600mg BID (n=?) (registrational)  Ph1/1b cohort 600mg BID (n=19)  (not registrational*)  960mg QD (n=124) 
ORR 43% 58% 36%
mDoR ? 12.6 months  10 months 
mPFS  ? 8.3 months  6.8 months
*Investigator assessed. ORR= overall response rate; mDoR= median duration of response; mPFS=median progression free survival. Source: company press releases, drug label. 

Building for an independent future? Mirati's near term plans

Source: Mirati investor presentation.

Esmo 2021 – look out Agenus, Keytruda is about to put up a roadblock

Merck & Co’s Keytruda is the only anti-PD-(L)1 drug with a cervical cancer label, and it could move from second to first-line use, suggests a just unveiled Esmo late-breaking abstract on the Keynote-826 study. The full data are crucial to Agenus, which is seeking approval for its own anti-PD-1, balstilimab, in second-line cervical cancer, based only on remission rates in an uncontrolled trial that the FDA is due to review by a December 16 action date. In Keynote-826 Keytruda plus chemo beat chemo in terms of overall and progression-free survival in all-comers, and in PD-L1≥1% and PD-L1≥10% expressers, though the abstract does not split out survival for PD-L1 non-expressers. One quirk of this trial is that it also allowed Avastin in both cohorts, with no stratification, but the abstract states that Keytruda’s benefit was seen regardless of the Roche drug. Keynote-826 should see Keytruda approved front line as well as confirming its second-line accelerated green light. Will the FDA nod balstilimab through on an accelerated basis at a time when there could already be a marketed competitor boasting formal approval backed by a survival benefit? This is the daunting question Agenus will likely face.

Anti-PD-1 MAbs in cervical cancer
Project Setting Trial Data 2026e cervical cancer sales
Keytruda (Merck & Co) 2nd-line Keynote-158 cohort E 14% ORR (9 PRs, 2 CRs) $94m*
1st-line (chemo combo, +/- Avastin) Keynote-826 (all-comers) mOS 22.4 vs 16.5 mth (HR=0.67, p<0.001); mPFS 10.4 vs 8.2 mth (HR=0.65, p<0.001)
Keynote-826 (PD-L1 ≥1%) mOS NR vs 16.3 mth (HR=0.64, p<0.001); mPFS 10.4 vs 8.2 mth (HR=0.62, p<0.001)
Keynote-826 (PD-L1 ≥10%) mOS NR vs 16.4 mth (HR=0.61, p=0.001); mPFS 10.4 vs 8.1 mth (HR=0.58, p<0.001)
Balstilimab (Agenus) 2nd-line NCT03495882 14% ORR (24 PRs, 3 CRs) $143m^
Note: *out of a total $27.0bn; ^100% of 2026 forecast. Source: Esmo, Evaluate Pharma & prescribing information.

Esmo 2021 – poziotinib could add first-line string to its bow

Spectrum’s poziotinib keeps throwing up surprises. Its multi-cohort Zenith20 lung cancer study had whiffed twice and yielded one surprising hit, on the basis of which the group plans a US filing this year. But a late-breaking Esmo abstract just made public suggests that the project could have broader potential: cohort 4, in first-line NSCLC patients whose cancer harbours Her2 exon 20 insertion, is also positive. The stated 44% confirmed remission rate in 48 subjects appears comfortably to hit Spectrum’s success criteria, and there are another two responses as yet unconfirmed. Twice-daily dosing in cohort 4 continues, but the Esmo data relate to once-daily, the same dose that Spectrum will take to the FDA in a filing focused on relapsed Her2 exon 20 insertion NSCLC. As for competition, Takeda’s now approved Exkivity (mobocertinib) and Cullinan’s CLN-081 have put up impressive results in EGFR exon 20 insertions, the niche where poziotinib failed, but little data exist on exon 20 insertions in Her2. How significant could the latter opportunity be? The sellside once expected poziotinib to sell over $500m by 2024, according to Evaluate Pharma, but now its 2026 consensus is $285m. The late-breaking data will be presented in full on Saturday.

Poziotinib's Zenith20 study in NSCLC (possibly registrational cohorts)
Cohort Setting Subjects Confirmed ORR mDOR Result
1 Relapsed, EGFR exon 20 insertions 115 14.8% 7.4mth Fail: missed undisclosed threshold
2 Relapsed, Her2 exon 20 insertions 90 27.8% 5.1mth Success: lower bound of CI >17%
3 1st-line EGFR exon 20 insertions 70 27.8% 6.5mth Fail: lower bound of CI <20%
4 1st-line Her2 exon 20 insertions 70 43.8%* 5.4mth Apparent success
6 EGFR Tagrisso failures 30  
7 Atypical EGFR or Her mutations 30  
Source: Spectrum & Esmo. Note: *data from 48 evaluable subjects, with a further 2 CRs taking unconfirmed ORR to 48%; ORR=overall remission rate; mDOR=median duration of response; CI=confidence interval.

Esmo 2021 – Mahogany loses its polish for Macrogenics

Macrogenics is already struggling to justify a role for Margenza in Her2-positive breast cancer, and it seems that gastric tumours will prove no less difficult. New data in front-line gastroesophageal adenocarcinoma (GEA) at Esmo do not stack up favourably against Zymeworks’ zanidatamab – another anti-Her2 project hoping to take share from Roche’s Herceptin. In a phase 2 trial testing zanidatamab on top of three different chemotherapy regimens the bispecific antibody posted an objective response rate of 75%. Margenza, administered with Macrogenics’ anti-PD-1 MAb tretifanlimab, could only muster an ORR of 53% in module A of the phase 2/3 Mahogany trial. One caveat is that these are early data cuts, each concerning a few dozen evaluable Her2-positive patients, so the situation could shift. Still, Zymeworks’ stock rose 10% as the data boosted hopes for zanidatamab's potentially registrational phase 3 trial, which is to begin by year end. Macrogenics's shares, meanwhile, dropped 25%. Margenza’s best hope might be as a chemotherapy-free option in this setting, given the toxicity profile, according to the sellside. But Her2-positive gastric cancer is a small and crowded space, and the data need to get much better to look competitive.

Cross-trial comparison of Esmo data in 1st-line Her2-positive GEA
  Zanidatamab (n=28) Margenza* (n=40)
Objective response rate 75% 53%
   Complete responses 1 4
   Partial responses 20 17
Median duration of response 16 mth 10 mth
Median progression-free survival 12 mth 6 mth
Source: Esmo posters #1379P#1380P. Note: *combo with anti-PD-1, in PD-L1-positive patients.

The other shoe drops for Theravance

After the failure of Theravance’s gut-selective Jak inhibitor izencitinib last month the company’s hopes hinged on getting a result with ampreloxetine in neurogenic orthostatic hypotension. Today the latter project was also revealed to be a dud, and the group has slashed its headcount and R&D efforts in response. Such an outcome was entirely predictable given unconvincing phase 1/2 ampreloxetine data, and a restructuring had also been foreseen by Leerink analysts. More surprisingly, Theravance does not seem to have learned its lesson: the group’s core assets now include the inhaled Jak inhibitor nezulcitinib, which is in development for acute lung injury despite recently failing a Covid-19 trial. More sensible, if unexciting, is a focus on the approved respiratory products Trelegy, on which Theravance receives royalties from Glaxosmithkline, and Yupelri, sold in partnership with Viatris. Theravance hopes that its streamlining will allow it to become “sustainably cash flow positive” by the second half of 2022, but many investors are not hanging around to find out. The company, already worth less than half of what it was at the start of the year, fell another 22% this morning.

The new-look Theravance
Project Description Setting Trial details
Still in play
Nezulcitinib (TD-0903) Lung-selective Jak inhibitor Acute lung injury Failed ph2 in Covid-19, development continues in acute lung injury
Unnamed Dry-powder Jak inhibitors Asthma Preclinical
Out of favour
Ampreloxetine (TD-9855) Norepinephrine reuptake inhibitor Neurogenic orthostatic
hypotension
Failed ph3 Sequoia; ph3 Redwood being closed out
Izencitinib (TD-1473)* Gut-selective Jak inhibitor Ulcerative colitis, Crohn's  Failed ph2b Rhea in UC; ph2 Dione in Crohn's reads out Q4'21/Q1'22
TD-8236 Lung-selective Jak inhibitor Asthma Failed in ph2a asthma allergen challenge trial; development "paused"
TD-5202* Gut-selective Jak inhibitor Coeliac disease Ph1 in healthy volunteers completed; deprioritised
Inhaled ALK5i Inhaled Alk5 inhibitor Idiopathic pulmonary fibrosis Ph1; presumed deprioritised
*Being developed in partnership with J&J. Source: Evaluate Pharma & clinicaltrials.gov.

Redhill gets a rude awakening in Covid

Redhill had hoped that its sphingosine kinase-2 inhibitor opaganib might become one of the first oral therapies for Covid-19. Those hopes are in tatters after the project flunked its phase 3 study in hospitalised patients. The trial did not meet its primary endpoint, the proportion of patients not requiring supplemental oxygen at 14 days with opaganib versus placebo, but Redhill pointed to a subgroup trend, and looks like it might press ahead in patients with earlier disease. The results reinforce that hospitalised Covid is very tough setting: Merck & Co abandoned efforts here with its oral antiviral molnupiravir, although data are due soon from a pivotal trial in Covid outpatients. Redhill, meanwhile, has another oral Covid candidate, RHB-107, in phase 2/3 in non-hospitalised patients. A pill would be handy here given the logistical difficulties in administering intravenous antibodies, a barrier that has contributed to disappointing uptake. If this does not work out Redhill, which had just $72m in cash in June, will have to go back to plan A: its lead project, RHB-204, is in phase 3 for nontuberculous mycobacteria disease. Unimpressed investors sent the group’s stock down 31% this morning.

Selected antiviral projects in development for Covid-19
Project Company/ies Note
Opaganib  Redhill Biopharma Failed ph3 in hospitalised pts
Molnupiravir (MK-4482) Merck & Co/Ridgeback Company discontinued Move-In in hospitalised pts; data from Move-Out in outpatients due Oct 2021; data from Move-Ahead in post-exposure prophylaxis due H1 2022 
PF-07321332 Pfizer Ph2/3 in high-risk & low-risk outpatients complete Oct 2021
AT-527 Roche/Atea Ph2 data in hospitalised pts released Jun 2021; data from ph3 Morningsky in outpatients due end 2021
RHB-107 (upamostat) Redhill Biopharma Ph2/3 in outpatients completes Sep 2022
Source: Evaluate Pharma & clinicaltrials.gov.

No sleepless nights for Asahi Kasei over $538m Itamar deal

Covid-19 has revolutionised the fortunes of manufacturers of respiratory technologies such as ventilators and sleep apnoea devices. This is doubtless behind yesterday’s acquisition of Itamar Medical by Asahi Kasei for $538m in cash. Itamar does not make the air pumps that treat sleep apnoea – instead it has a technology, WatchPat, which diagnoses the condition. And one particular version of this tech, called WatchPat One, is particularly well suited to the Covid-19 era, being not only home-based as all the WatchPat devices are, but also fully disposable. Itamar’s 2020 revenues were up 31%, and sales from disposables, including WatchPat One, made up 77% of WatchPat US revenues in 2020, versus 64% a year earlier. There is an angle beyond Covid-19, however. Asahi Kasei will integrate Itamar into its Zoll Medical subsidiary, which specialises in cardiovascular technologies; sleep apnoea is associated with increased rates of coronary heart disease, heart failure, stroke and atrial fibrillation. Zoll says around 60% of cardiovascular patients have sleep apnoea, and most are undiagnosed. The strategy here is clear, and Asahi will hope to increase sales enough to justify the purchase of a company yet to break even.

Itamar's WatchPat One system