Vantage Snippets are short summaries of breaking news stories.

Inflarx pushes past the red flags to claim a win

Anyone with more than a fleeting experience of biotech investment should be familiar with the practice of post-hoc data dredging of a failed clinical trial to find hints of activity. Inflarx’s claim yesterday that its clearly negative study of IFX-1 in hidradenitis suppurativa did, after all, show robust efficacy is a particularly egregious example of this. Inflarx has moved to cast doubt on the HiSCR measure – its study’s primary endpoint, and the metric on which Abbvie’s Humira got a hidradenitis suppurativa label – and instead now tells investors to look at reduction of draining fistulas as evidence of activity. It backs this by carving out a subset of subjects with at least one draining fistula at baseline, given the highest IFX-1 dose, and claims that these yield a p value of 0.036 versus placebo. Inflarx seems to have carried out multiple post-hoc analyses to arrive at one that gave a nominal p value below 0.05, and despite the fact that this new result is meaningless until proved prospectively it calls it “statistically significant”. It is a given that this and other “multiple efficacy signals” are enough for the company, up 12% today, to continue developing IFX-1. Caveat emptor.

IFX-1 effect on reduction of draining fistulas at 16 weeks in the Shine study.
Note: one of multiple post-hoc analyses, looking at subgroup (n unspecified) with at least 1 draining fistula at baseline; primary endpoint failed; p value nominal.

Shareholders stimulated by Brainsway depression data

Brainsway’s transcranial magnetic stimulation system was approved in the US for depression in 2013, but the first data pitting it head-to-head against a different type of technology have only just emerged. An academic study compared Brainsway’s Deep TMS device, which uses a conformation of electromagnetic coils called H-1 with an unnamed system with coils arranged in a figure of eight. The 228-patient study, conducted in Croatia, found that patients treated with Deep TMS had numerically higher remission rates, the trial’s primary endpoint, than those treated with figure-8 TMS; both types of stimulation resulted in significantly better remission than medication alone. Whether the data will spur greater uptake of Deep TMS is not clear, though shareholders seem to think it might – Brainsway’s shares closed up 5% on the Tel Aviv exchange yesterday. The company is also trialling Deep TMS in smoking cessation and post-traumatic stress disorder, and is planning trials for opioid addiction, fatigue in multiple sclerosis and post-stroke rehabilitation. The system was cleared in the US for obsessive-compulsive disorder last year (Transcranial magnetic stimulators attract attention, August 21, 2018).

Brainsway head-to-head trial data
Therapy Brainsway's Deep TMS
(H-coil) system + medication
Figure-8 coil TMS system + medication Medication alone
No of patients 72 75 81
Remission rate (%)* 59.7 42.2 11.1
     Significance p < 0.001 vs medication p = 0.001 vs medication  
Response rate (%)** 66.7 44.0  
     Significance p = 0.04 vs Figure-8 coil    
Lowering in HAM-D17 score from baseline (%) 59.0 41.0 17.0
     Significance p < 0.001 vs medication;
p = 0.048 vs Figure-8 coil
P = 0.003 vs medication  
* Remission defined as a Hamilton Depression rating scale (HAM-D17) score of ≤ 7 after four weeks of therapy or 20 treatments.
** Response defined as ≥50% decrease in HAM-D17

Brainsway's Deep TMS system

Pixium makes a start with Prima

Pixium Vision switched to developing the sub-retinal implant Prima after its initial device, Iris II, was found to have a shorter lifespan than the group had hoped. Now data from the first feasibility trial of Prima are in, and while these are positive they have not allowed Pixium’s stock to rebound from the fall caused by the switch of devices. Prima consists of an photovoltaic chip containing 378 electrodes that is implanted under the retina. It detects light from images shot by a camera integrated into augmented reality glasses, improving vision in patients with age-related macular degeneration or retinitis pigmentosa. One year after the device was implanted, all five patients in the Paris-based Prima-FS trial had light perception in the central retinal area – none had had central visual activity at enrolment – meeting the study’s primary endpoint. Most of the patients could identify letters, and some sequences of letters. Crucially, there were no serious adverse events – a safety signal seen with the Orion system developed by Pixium’s main rival, Second Sight Medical Products, hurt that company back in April. Pixium’s feasibility trial will continue out to three years, and Prima is also in a similar five-patient US feasibility study.

Pixium vs Second Sight
    Annual sales ($m)  
Company Retinal implant(s) 2018 2019 2020 2021 2022 2023 2024 CAGR
Pixium  Prima  - - - 2 9 47 135 N/A
Second Sight  Argus II and Orion 7 7 7 11 18 42 98 +56%
Source: EvaluateMedTech.

Servier leaves Macrogenics again

Were it not for the lingering doubts about Macrogenics’ lead asset, margetuximab, Servier’s ending of a licensing deal for flotetuzumab yesterday would be a non-event. As it is, however, investors have another reason to fret over a share price that, since enthusiasm over margetuximab peaked in February, has slumped 40%. Flotetuzumab is an anti-CD123 bispecific, a mechanism that has proved extremely tricky to exploit without toxicities, as numerous companies have found (Xencor’s bispecific hold reignites debates over approach and target, February 21, 2019). Servier is not a major oncology player, so its decision might not mean much beyond the loss of $308m of possible milestone payments; $35m had already been received in up-front and option fees. Four years ago Servier pulled out of a separate deal covering Macrogenics’ anti-B7-H3 MAb enoblituzumab. Meanwhile, margetuximab, an anti-Her2 MAb, remains mired in concerns revealed at this year’s Asco that its highly touted Sophia trial is unlikely to show an overall survival benefit. The next evidence for or against flotetuzumab will emerge at December’s Ash conference, where a monotherapy trial in acute myelogenous leukaemia and myelodysplastic syndromes should yield updated results.

Selected CD123-targeting projects
Project  Company  Mechanism  Notes 
Elzonris Stemline Protein/drug conjugate  Two deaths in BPDCN cohort despite protocol modification
Phase III
Talacotuzumab Xencor/J&J MAb  Trial scrapped; J&J evaluating data to determine further steps
Phase I
UCART123   Cellectis/Allogene Allogeneic CAR-T   Clinical hold after patient death (Sep 2017), now lifted
MB-102   Fortress/Mustang Autologous CAR-T    
MIH911   Novartis   Autologous CAR-T   Study terminated for "lack of funding"
SGN-CD123A   Seattle Genetics  Antibody-drug conjugate   
IMGN632 Immunogen/Jazz Antibody-drug conjugate   
Flotetuzumab   Macrogenics   Bispecific MAb  Servier deal terminated
JNJ-63709178   Genmab/J&J Bispecific MAb  Two clinical holds (Sep 2016 & Aug 2018), both lifted
XmAb14045   Xencor/Novartis Bispecific MAb  Clinical hold after 2 patient deaths (Feb 2019), now lifted
KHK2823   Kyowa Hakko Kirin   MAb   
APVO436 Aptevo/Ligand Bispecific MAb   
SAR440234 Sanofi Bispecific MAb   
Source: EvaluatePharma. 

Vectura moves to appease long-term shareholders

Though it is rare to see money flow from biotechs back to shareholders, a pledge to buy back £50m ($54m) in stock failed to set Vectura alight this morning. True, the UK company had trailed such a move, made possible by a $90m boost in a patent settlement with Glaxosmithkline. But this generosity is presumably of little comfort to long-term investors, who have seen Vectura lose almost half its value since it bought its respiratory rival Skyepharma in 2016. The declines are down to issues like the collapse of the asthma project VR475, which incurred a £40m charge, and a three-year battle to win approval for a Hikma-partnered Advair generic. Data are nearing from an FDA-required trial and the project, VR315, is due to be re-filed shortly, although the protracted development means that hopes are very low. A deal has also been promised for the paediatric asthma asset VR647, and a Novartis-partnered asthma project, QMV149, should be filed in the US before year end. Vectura is also looking for a new chief executive, who will presumably be charged with coming up with a new use for the company's excess cash. In the meantime, investors will be happy to have it. 

Inovio cans cancer vaccine... but not for the obvious reason

Shifting Inovio’s therapeutic cancer vaccines to the back burner makes perfect sense given the appalling track record of such approaches. However, this is not the reason cited by the company; instead, Inovio told analysts on a call today that a phase I/II trial of INO-5401 in urothelial bladder cancer was being discontinued because of competitor developments, specifically citing Seattle Genetics/Astellas’s success with enfortumab vedotin in this setting, where the asset was filed yesterday. A study of INO-5401 in glioblastoma in combination with Libtayo and the electroporated IL-12 INO-9012 continues, though Inovio is likely casting an eye at Oncosec’s underwhelming melanoma trial of Tavo, which is based on its own electroporation technology. The shift in Inovio’s body language is clear: while oncology work will continue, the main focus becomes vaccines for HPV-related conditions, and 28% of the group’s workforce is being cut – a move applauded by Stifel analysts that nevertheless sent the stock down 10% this morning. Inovio has been on a long journey, floating over 20 years ago as Genetronics and later merging with VGX Pharmaceuticals, so it is high time that it focused on something likely to become a viable commercial product.

Inovio's selected pipeline assets
Project Description Indication Detail
VGX-3100 Vaccine vs E6 & E7 HPV-related cervical dysplasia Phase III Reveal trial reads out 2020
MEDI-0457 Therapeutic vaccine vs E6 & E7 Cancer Astrazeneca project; head & neck cancer data possible at 2020 AACR or Asco
INO-5401 Therapeutic vaccine vs WT1, PSMA & hTERT Cancer GBM (Libtayo combo) phase I; urothelial cancer (Tecentriq combo) discontinued
INO-3106/3107 Vaccine vs HPV6 Recurrent respiratory papillomatosis Phase I starting within 12 mth
INO-9012 Electroporated IL-12 Adjuvant Various combinations

Capricor doubles on Duchenne Hope

To hear Capricor Therapeutics’ chief executive Linda Marbán tell it, the company started its phase II trial of its Duchenne muscular dystrophy candidate CAP-1002 merely hoping for a suggestion of a trend towards efficacy. The statistically significant interim data the group reported today was apparently entirely unexpected, and drove its shares up 124%, though the group's market cap remains a tiny $25m. CAP-1002 is a cell therapy based on cardiosphere-derived cells taken from donor hearts, which Capricor believes can help patients’ muscles regenerate. The Hope-2 results are particularly interesting as the trial enrolled older, more severely affected DMD patients, a group in whom gene therapies might face challenges since very large doses would be required. As positive as the Hope-2 data are, the trial is too small for the group to request accelerated approval from the FDA, Ms Marbán said on a call today. Only seven patients received CAP-1002 at the trial’s dose of 150 million cells per intravenous infusion every three months, with 10 in the placebo arm. The trial will continue until the 12-month time point, and if final results are good enough the company just might be able to file on them.

Six-month Hope-2 interim data
  CAP-1002 Placebo p-value
Change in score on the mid-level performance of the upper limb PUL 2.0 -0.2 (1.17) -0.8 (0.75) 0.0389
Change in tip to tip pinch strength 3.3 (2.88) -0.3 (1.51) 0.0674
Change in grip strength 0.8 (4.54) -2.2 (1.83) 0.0389
Source: company communications.

Zejula win primes Glaxo’s Parp for a larger market

For Glaxosmithkline’s $5bn takeout of Tesaro to make sense a couple of pivotal trials of the US biotech’s Parp inhibitor, Zejula, had to succeed. The first can now be ticked off the list: Prima hit its primary endpoint, Glaxo said today, significantly extending progression-free survival in patients with ovarian cancer, regardless of their biomarker status. This is important because Lynparza, Astrazeneca and Merck & Co’s leading Parp inhibitor, is only indicated to treat BRCA-positive patients in this maintenance setting. Solo-1, the trial that won Lynparza approval here, generated a very impressive result but was started before researchers fully appreciated that Parp inhibitors had utility beyond BRCA-positive patients. Only 15% of newly-diagnosed ovarian cancers carry this particular tumour biomarker, and while these patients respond most strongly to Parp inhibition, others can also benefit. In later treatment lines Parp inhibitors are approved regardless of BRCA status but at Esmo last year, when Solo-1 was presented, doctors expressed caution about translating this to the front line setting without clear evidence (Esmo 2018 – Lynparza delivers a huge result in first-line ovarian cancer, October 21, 2018). Prima could provide this, though the full readout remains crucial. The Esmo cancer conference, which will be held in September, looks a likely venue.

Outlook for the Parp space
    Annual Sales WW ($m)
Product Company 2019e 2021e 2023e
Lynparza Astrazeneca/Merck 1,094 1,786 2,491
Zejula Glaxosmithkline 313 690 990
Rubraca Clovis Oncology 149 339 634
Talzenna Pfizer 55 243 389
  Total incl. others 1,632 3,156 4,822
Source: EvaluatePharma. 

Drug pricing concerns return for pharma

The fall in big pharma stocks more or less across the board yesterday is due not so much to what the Trump administration is doing as what it might do next. The US government has called off its plans to ban the rebates drug companies pay to pharmacy benefit managers in the Medicare and Medicaid programmes, which is, in itself, pretty neutral for drug companies – and is great news for insurers, many of which own PBMs and which are trading up on the news. The danger for pharma is what the government might do instead: one possibility is that a previously shelved plan to link US drug prices to an index of prices paid in other developed countries, which are generally much lower, might be reanimated. This would hit hard. As an example, an analysis by Bernstein found that if US prices for Novo Nordisk’s key insulin and GLP1 products – which are currently three or four times higher than the European prices – were to be limited to 25% above European levels, the company’s profits would fall by approximately 40%, assuming no change in market share. Novo’s shares were down 3% yesterday.

Novartis and Amgen abandon their Bace

All attempts to treat Alzheimer’s disease with anti-amyloid drugs have ended in failure, and Novartis and Amgen’s Bace1 inhibitor CNP520 is no different. The partners, along with their academic partner, the Banner Alzheimer’s Institute, have canned the asset after some patients had worsening of cognitive function. This has been seen with other Bace inhibitors; Eli Lilly cited such concerns when it scrapped a couple of similar assets last year. Also known as umibecestat, CNP520 was being tested in two phase III trials in preventative settings. The Generation S1 trial was testing CNP520 along with Novartis’s amyloid vaccine ACD106, and the Generation S2 study tested CNP520 alone; together they were set to enrol more than 3,000 patients. The situation is not great for Novartis but far worse for Amgen – to get the CNP520 collaboration Amgen granted Novartis joint marketing rights to the migraine drug Aimovig. The news raises the pressure on Biogen and Eisai, which have somewhat controversially pushed on with their Bace inhibitor, elenbecestat. This project is also in phase III, with data expected at the Alzheimer’s Association International Conference next week

Phase III trials of CNP520 and elenbecestat
Companies Drug Acronym N Trial ID
Novartis/Amgen CNP520/ umibecestat Generation S1 1,340 NCT02565511
    Generation S2 2,000 NCT03131453
Biogen/Eisai  Elenbecestat  MissionAD1 950 NCT02956486
    MissionAD2 950 NCT03036280
Source: EvaluatePharma.
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