Snippets

Vantage Snippets are short summaries of breaking news stories.

The T-cell test bronze goes to Qiagen

Qiagen today became the third company to launch a T-cell-based test for prior Covid-19 infection and also to assess individuals’ response to vaccination. The Quantiferon Sars-Cov-2 assay, which detects CD4+ and CD8+ T-cell responses elicited by the virus, is now available in Europe, joining Perkinelmer’s T-Spot Discovery Sars-CoV-2 product. Neither of these is yet available in the US, however, where the only T-cell test with FDA emergency authorisation is Adaptive Biotechnologies’ T-Detect Covid assay. Qiagen says its blood test, which has grown out of the Dutch group’s year-old collaboration with Tscan Therapeutics, is differentiated from the competition as it does not require a purification step for the lymphocytes. Testing for Covid-19-reactive T-cells is believed to be a useful adjunct to antibody testing since the response declines more slowly than antibody response, but also appears beforehand, since CD4+ T-cells help B cells generate anti-Covid antibodies. Quantiferon Sars-Cov-2 could indicate how severe the course of a Covid infection will be, according to Qiagen, as well as how long immunity might last. But there is as yet no definitive evidence linking T-cell readings to resistance to subsequent infection with Covid-19. 

Marketed Covid-19 T-cell tests
Company Test Status 
Perkinelmer T-Spot Discovery Sars-CoV-2 CE marked Mar 2021; awaiting US EUA
Adaptive Biotechnologies T-Detect Covid  US EUA granted Mar 2021
Qiagen Quantiferon Sars-Cov-2 CE marked Dec 2021
Source: FDA, company releases.

Novartis gets in on alpha-synuclein

Novartis is hardly known for novel CNS projects. But today the group took a punt on a potentially disease-modifying mechanism for Parkinson’s, via a deal with UCB. The target, alpha-synuclein, has had its fair share of setbacks, with Roche and Prothena last year reporting mixed data with their antibody, prasinezumab, and Biogen this year discontinuing BIIB054. At least Novartis has not paid top dollar: the company is giving UCB $150m up front, although it is on the hook for up to $1.5bn in milestones. In return, the Swiss company gets global co-development and co-commercialisation rights to UCB0599, an oral, brain-penetrant alpha-synuclein misfolding inhibitor, and an option on UCB7853, an anti-alpha-synuclein antibody. The two projects could complement each other, UCB noted. As well as Roche and Prothena, which are pressing on with prasinezumab, other companies looking at this target include include AC Immune, which struck its own deal here in July. Annovis Bio’s ANVS401, meanwhile, inhibits amyloid-beta and tau as well as alpha-synuclein – that group is planning phase 3 trials in both Parkinson’s and Alzheimer’s, but phase 2 data have been far from convincing.

Alpha-synuclein-targeting projects in clinical development
Project Company Description Trial details
Phase 2
ANVS401 Annovis Bio Small molecule amyloid precursor protein, alpha-synuclein & Tau inhibitor Ph2 PD data reported Oct 2021, ph3 planned
Prasinezumab (PRX002/RO7046015) Prothena/Roche Anti-alpha-synuclein Mab PD: Ph2 Pasadena failed, Ph2b Padova began May 2021
ENT-01 Enterin Small molecule alpha-synuclein aggregation inhibitor Ph2 Karmet in PD-related constipation completed Jul 2021; Ph2 planned in PD+psychosis & PD+dementia
Lu AF82422 Lundbeck/Genmab Anti-alpha-synuclein Mab Amulet in multiple system atrophy completes May 2023
UCB0599 Novartis/UCB (licensed from Neuropore Therapies) Small molecule alpha-synuclein misfolding inhibitor Ph2 in PD completes Jul 2024
Phase 1
ACI-7104 (PD01 ) AC Immune (via Affiris) Anti-alpha-synuclein vaccine Ph1 completed, ph2 to start "shortly"
MEDI341 (TAK-341) Astrazeneca/Takeda Anti-alpha-synuclein Mab MAD trial in PD completes Jul 2022
ION464 (BIIB101) Biogen/Ionis Alpha-synuclein antisense Horizon in multiple system atrophy completes Jul 2022
UB-312 Vaxxinity Anti-alpha-synuclein vaccine Ph1 in healthy volunteers & PD pts completes Dec 2022
UCB7853  UCB (Novartis has option) Anti-alpha-synuclein Mab Ph1 in healthy volunteers & PD pts completes Jun 2023
ABBV-0805 Abbvie/Bioarctic Anti-alpha-synuclein Mab Ph1 withdrawn for "strategic reasons", project still listed on pipeline
Source: Evaluate Pharma & clinicaltrials.gov.

Why molnupiravir could still work for Merck

A narrow squeak through its adcom yesterday means Merck and Ridgeback’s Covid-19 pill molnupiravir is odds-on for US authorisation. Uptake is another question. The drop in efficacy from 50% at interim to just 30% at the final readout might render the drug a distant second, in terms of demand, to Pfizer’s far more effective-looking Paxlovid. Indeed, data presented yesterday showed that among patients assessed between the interim and final analysis, those given molnupiravir were more likely to suffer hospitalisation or death than those given placebo. As worrying as the sharp decline in efficacy was the inability of Merck scientists' to explain it, with one researcher telling the panel he did not have “a satisfying answer” to this question. Neither will the discussion of molnupiravir’s potential side effects have done Merck any favours. Embryo foetal toxicity seen in animal studies means the FDA could refuse to approve the pill for use in pregnancy, or at least recommend against its use. But there is one reason to expect molnupiravir, if authorised, to ramp acceptable initial sales: the US Government has already committed to spending $2.2bn on the pill by early 2022.

Source: FDA.

US FDA approval tracker: November

The FDA dished out three Pdufa extensions and four knockbacks in November, including a CRL for Beyondspring’s plinabulin in chemotherapy-induced neutropenia. Beyondspring said today that the FDA had requested a second clinical study of plinabulin; this news sent the company's shares down 55% in early trading and follows disappointing NSCLC data at Esmo. On the flip side, Biomarin’s Voxzogo gained accelerated approval in patients aged five and older with achondroplasia. Assessing final adult height is part of the post-marketing requirement and Biomarin has said it will use the ongoing open-label extension studies versus natural history for confirmatory data. Merck’s Keytruda also gained another string to its bow last month with an adjuvant approval in renal cell cancer. The decision came three weeks early and puts Keytruda further ahead of rivals, which will start reporting phase 3 data next year.

Notable first-time US approval decisions in November
Project Company Indication(s) 2026e SBI ($m) Outcome
Ciltacabtagene autoleucel
(cilta-cel)

Johnson & Johnson/
Legend Biotech
3L+ multiple myeloma 1,692 Extended to Feb 28 (updated analytical method)
Voxzogo
(vosoritide)
Biomarin Achondroplasia 720 Approved (accelerated)
Doria
(risperidone ISM)
Laboratorios Farmacéuticos ROVI Schizophrenia 375 CRL (manufacturing inspection)
Enpaxiq
(pacritinib)
CTI Biopharma Myelofibrosis patients with severe thrombocytopenia 368 Extended to Feb 28
(data submission)
Livtencity
(maribavir)
Takeda Post-transplant cytomegalovirus infection in those that are refractory, with or without resistance 355 Approved
Oleogel-S10
(Filsuvez)
Amryt Epidermolysis bullosa 269 Extended to Feb 28 (review of additional data analyses)
Erwinaze Clinigen/
Porton Biopharma
ALL patients who have developed hypersensitivity to E. coli-derived asparaginase 211 CRL
Eohilia
(TAK-721)
Takeda Eosinophilic oesophagitis 188 No decision yet
Pedmark Fennec Cisplatin-induced ototoxicity for paediatric patients 165 CRL
(manufacturing deficiencies)
PreHevbrio
(Sci-B-Vac)
Opko Health/
VBI Vaccines
Hepatitis B 164 Approved
Plinabulin + G-CSF Beyondspring Prevention of chemotherapy-induced neutropenia  138 CRL
(more data requested)
Yutrepia (LIQ861
/treprostinil inhalation powder)
Liquidia Pulmonary arterial hypertension 126 Tentative approval*
Cytalux
(OTL38/
pafolacianine sodium injection)
On Target Laboratories Adjunct for identifying ovarian cancer during surgery - Approved
Eprontia (topiramate oral solution
/ET-101)
Azurity Pharmaceuticals/
Eton Pharmaceuticals
Tonic-clonic seizures, partial-onset seizures, and as preventative treatment of migraine - Approved
Besremi (ropeginterferon alfa-2b) Pharmaessentia Polycythemia vera - Approved
Fyarro
(ABI-009)
Aadi Bioscience Advanced malignant PEComa - Approved
Epsolay Sol-Gel Papulopustular rosacea - No decision yet
*Final FDA approval may occur in Oct 2022 or earlier upon resolution of ongoing litigation with United Therapeutics. SBI=sales by indication, CMC=chemistry, manufacturing and controls.
Source: Evaluate Pharma & company releases.

 

Advisory committee meetings in November
Project Company Indication Outcome
LV-101
(intranasal carbetocin)
Levo Hyperphagia, anxiety, and distress behaviours associated with Prader-Willi syndrome 12-1 against approval
Molnupiravir Merck/
Ridgeback
EUA for the treatment of mild to moderate Covid-19 in adults who are at risk for progressing to severe Covid-19 and/or hospitalisation 13-10 for EUA
Source: FDA adcom calendar, Evaluate Pharma.

 

Supplementary and other notable approval decisions in November
Product Company Indication (clinical trial) Outcome
Dyanavel XR tablets Tris Pharma ADHD Approved
Keytruda  Merck Adjuvant treatment of RCC at intermediate-high or high risk of recurrence (Keynote-564 Approved
(3 weeks early)
Pobevcy
(BAT1706)
(Avastin biosimmilar)
Bio-Thera Solutions Metastatic colorectal cancer (+ chemo), 1L non-squamous NSCLC, recurrent glioblastoma, met renal cell carcinoma (+ interferon alfa), persistent, recurrent or met cervical cancer No decision yet
Source: Evaluate Pharma & company releases. 

TG’s rollercoaster ride veers off the track

The story of TG Therapeutics’ Unity-CLL trial of its combo cancer project U2 has already taken several turns, encompassing design changes, delays and recently a surprise benefit. Yesterday the FDA added another twist, demanding an advisory committee that at the very least will delay U2’s approval. An approval decision had been due by March 25. The project comprises ublituximab plus Ukoniq, the former an anti-CD20 antibody also being developed in MS and the latter a recently approved PI3K delta inhibitor. The FDA wants the panel to review Ukoniq in its approved lymphoma settings but, more ominously, is concerned about a lack of survival benefit with U2 in Unity-CLL. The agency had requested an early analysis of OS from the trial, and found an imbalance favouring control with a non-significant hazard ratio of 1.23. This improved to 1.04 when Covid-related deaths were excluded, and TG stressed that the finding was preliminary, with the study not powered for OS. This clearly bodes poorly, however, and TG shares tanked 35% yesterday. Ublituximab’s potential in MS is considered TG’s biggest opportunity, and execs confirmed yesterday that the FDA had informally accepted this filing. Investors must hope that the agency’s concerns do not extend beyond oncology.

Olema's fake news problem

Olema was punished today for confusion about data with its sole project, OP-1250, with a 56% share price crash showing just how jittery the markets are for biotech stocks. It all started when data from a phase 1/2 dose-escalation study, due for presentation at the San Antonio Breast Cancer Symposium next week, were apparently leaked yesterday. Remarkably, the company later claimed the poster had been falsified and put out its own, slightly worse, results today. Olema plans to start phase 2 trials of ’1250, a complete oestrogen receptor antagonist and selective oestrogen receptor degrader, as monotherapy and in combination with a CDK4/6 inhibitor at the start of 2022. But the November 1 cut also showed that three patients had grade 4 neutropenia attributed to study drug by the investigator. Combination with CDK4/6 inhibitors will likely be necessary for future success, a class that is already associated with high rates of neutropenia, meaning this signal could also have worried investors. Still, even if the data did not warrant such an extreme reaction, the optics on the whole situation are terrible. This is a clearly a black mark against Olema, which was presenting its first results as a public company.  

The Olema mystery: phase 1/2 data on OP-1250
Source Data cut-off Results
Poster leaked to Inspire.com on Nov 29, later claimed by Olema to be falsified Oct 01 17% ORR, 3 confirmed PRs
Official Olema poster, released Nov 30, to be presented at SABCS next week Oct 01 17% ORR, 2 confirmed PRs, 1 unconfirmed PR
Olema statement, released Nov 30 Nov 01 17% ORR, 2 confirmed PRs, 1 unconfirmed PR

Blueprint takes a long shot at a small niche

Blueprint Medicines' ability to make a success of LNG-451, a preclinical EGFR exon 20 inhibitor it obtained yesterday via its $250m purchase of Lengo Therapeutics, depends on a number of other projects failing. Aside from the two bispecifics already approved for this particular lung cancer niche there are half a dozen in mid-stage trials and a few preclinical assets that might be ahead of '451. Stifel analysts suggest that that the approved drugs for this setting “have clear deficiencies”, but add that the EGFR exon 20 non-small cell lung cancer market is worth less than $500m annually. Leerink analysts were vastly more optimistic, forecasting peak sales of $600m in the exon 20 NSCLC niche and an NPV of $1bn, if the drug makes it all the way to market. There might be an advantage for ’451 in that it is said to be brain-penetrant – none of the approved or clinical-stage projects are known to have demonstrated meaningful CNS responses. But for Blueprint to get more than a small fraction of a tiny market LNG-451 needs to show remarkable benefits over those already available, when it does eventually yield clinical data.

NSCLC therapy landscape for EGFR+ exon 20 ins
Drug Company Status
Exkivity (mobocertinib) Takeda/Ariad Approved in US for 2L treatment of pts w EGFR+ exon 20 ins
Rybrevant J&J Approved in US for 2L treatment of pts w EGFR+ exon 20 ins
Poziotinib Spectrum Ph2 Zenith20 trial failed in EGFR+ exon 20 ins cohorts
JMT101 Shanghai JMT-Bio Ph2 data due late 2023 
Tarlox (tarloxotinib) Rain Therapeutics Ph2 trial enrolment paused
CLN-081 Cullinan/Otsuka Ph1/2 trial data due mid-2022
BDTX-189 Black Diamond Therapeutics Ph1/2 trial (MasterKey-01) data due 2023
DZD9008 Dizal Pharmaceuticals Ph1/2 trial (Wu-Kong1) data due 2023
LNG-451 Blueprint Medicines Preclinical; first clinical data could come 2023
STX-EGFR-Exon20 Scorpion Therapeutics  Preclinical; could reach clinic in 2023
Source: Evaluate Pharma, clinicaltrials.gov, company websites.

Immunogen’s perseverance pays off

Targeting folate receptor α seemed to be a dead end until developers threw antibody-drug conjugates at the problem, and a clinical win from Immunogen with mirvetuximab today could make the company first to market here. The pivotal Soraya trial, in FRα-high platinum-resistant ovarian cancer, met its primary endpoint, easily surpassing a minimum threshold (12% on the lower bound of the confidence interval). Five complete responses were seen, impressive considering that patients had received three prior lines of therapy, including Avastin. Median duration of response needed to reach six months for this result to be considered clinically meaningful, and that was almost achieved; Immunogen believes that with longer follow up mDOR might hit seven months. A 7% discontinuation rate due to adverse events is also encouraging, given the known toxicities of ADCs. Immunogen shares jumped 25% in early trade on hopes for accelerated approval next year, though the FDA might choose to wait for a second-line trial, Mirasol, to read out in the third quarter of 2022. Immunogen insists that combination strategies could unlock bigger potential for mirvetuximab and this mechanism, which is presumably what Bristol Myers Squibb was also thinking when it paid $650m for a similar asset from Eisai. 

Soraya trial or mirvetuximab: top-line results 
ORR by investigator  32.4% (CI: 23.6%, 42.2%)
ORR by BICR 31.6% (CI: 22.4%, 41.9%)
mDOR 5.9 months (CI: 5.6, 7.7)
Treatment-related AEs....
Blurred vision 41% all grade, 6% grade 3+
Keratopathy 35% all grade, 9% grade 3+
Nausea 29% all grade, 0% grade 3+
...Leading to….
Dose reductions 19% of patients
Dose delays 32% of patients
Discontinuations 7% of patients 
Note: Median follow-up time 8.1 months, as of data cut-off almost half of responders remain on therapy. BICR=blinded independent central review; DOR=duration of response; ORR=overall response rate. Source: company statement. 

Diagnostics groups square up to Omicron

One group of medtechs were largely resistant to Friday’s bloodbath on the markets: Covid-19 test developers. Several have been quick to clarify that their tests can accurately detect the new Omicron variant despite its many mutations, with Qiagen stating that all of its PCR tests for the virus had been assessed successfully against the variant using public genetic databases. Thermo Fisher went further, pointing out that its TaqPath PCR assays could distinguish Omicron infections from those caused by Delta, thanks to the so-called “S gene drop out”. The Alpha and Omicron variants have this genetic quirk, but Delta does not, and since Delta is now so prevalent any drop out samples seen recently are likely from patients with Omicron. Currently this has to be confirmed with full sequencing of the viral genome, but Thermo Fisher is also working on specific genotyping assays for Omicron. And on Friday, Eurofins launched a new test that can differentiate Omicron from Delta. Called GSD NovaType Select P681H, this assay can be used as a large-scale screening test for PCR-positive samples. Eurofins also sells tests that can distinguish Omicron from other variants of concern, and its US listing closed up 13% on Friday.

Diagnostics companies vs the markets
Company Selected molecular Covid-19 tests SP move on Friday
Eurofins Scientific GSD NovaType Select P681H* 12.7%
Oxford Nanopore Technologies LamPore Covid-19 4.8%
Quest Diagnostics Sars-Cov-2 rRT-PCR 3.6%
Qiagen QIAstat-Dx Respiratory Sars-Cov-2 Panel; NeuMoDx Flu A-B/RSV/Sars-Cov-2 VantageAssay 3.4%
Siemens Healthineers Fast Track Diagnostics Sars-Cov-2 Assay 1.9%
Illumina CovidSeq Test 1.2%
Thermo Fisher TaqPath Combo*; TaqPath CE-IVD RT-PCR* 0.9%
Abbott Abbott RealTime Sars-Cov-2 assay 0.6%
Becton Dickinson BD Sars-Cov-2 Reagents for BD Max  0.3%
Roche Cobas Sars-Cov-2; Cobas Sars-Cov-2 & Influenza A/B 0.2%
*Can distinguish Omicron from Delta. Note: the S&P 1500 HealthCare Equipment & Supplies index was down 2% on Friday.

Cholesterol “win” does Ionis and Pfizer a fat lot of good

Investors were unconvinced by yesterday’s apparent mid-stage success with Ionis and Pfizer’s cholesterol-lowering project vupanorsen. On the face of it the anti-ANGPTL3 antisense did what it needed to do in the dose-ranging Translate Timi 70 trial, statistically lowering non-HDL cholesterol at all doses tested versus placebo at week 24. However, Pfizer’s commitment to the asset is far from clear: the big pharma left Ionis to report the results, and also seemed lukewarm about further development, only saying it was reviewing the findings before determining next steps. In another potential red flag, the study found liver enzyme elevations, primarily at the highest doses tested, as well as increases in hepatic fat fraction at “certain doses”. Ionis said there were no Hy’s law cases. More information is needed, but there must now be fears that the group might not be able to find a therapeutic window for vupanorsen; Ionis’s stock sank 2% yesterday and another 2% after hours. The liver findings could also throw doubt on ANGPTL3 as a target. However, the pivotal trial of Regeneron’s Evkeeza in homozygous familial hypercholesterolaemia was not marked by liver enzyme worries, something that could provide solace to other developers of anti-ANGPTL3 projects, though of course Evkeeza is a MAb, unlike the other projects in this space. 

ANGPTL3 modulators in clinical development for cardiometabolic indications
Project Company Description Indication  Trial details
Approved
Evkeeza (evinacumab) Regeneron Anti-ANGPTL3 MAb HoFH Elipse, 49-point reduction in LDL-C vs SOC 
Phase 2
Vupanorsen (AKCEA-ANGPTL3-LRx/ PF-07285557) Ionis/Pfizer ANGPTL3 antisense oligonucleotide Dyslipidaemias Translate Timi 70, "statistically significant" reduction with all dose vs placebo at week 24
ARO-ANG3 Arrowhead Anti-ANGPTL3 RNAi therapeutic Dyslipidaemias Arches-2, completes Oct 2022
Phase 1
LY3561774 Lilly/Novo (Dicerna) Anti-ANGPTL3 small interfering RNA Dyslipidaemias NCT04644809, completes Apr 2022
HoFH=homozygous familial hypercholesterolaemia. Source: Evaluate Pharma & clinicaltrials.gov.
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