European listed biotech landscape: 2020 review and outlook for 2021

The vaccines developed by public European biotech companies:

Concerning the vaccines, there is not a plethora of vaccine companies in our covered landscape, so we can shortly talk about each of them.

Oxford Biomedica, a British company mainly offering services for gene therapy companies using viral vectors (but also having a few internal and partnered gene therapy programs), was rapidly selected by the Oxford University and the Jenner Institute for the manufacturing of the ChAdOx-1 nCoV vaccine candidate (codename AZD 1222 or COVID-19 vaccine AstraZeneca. The company had to accelerate the building and the qualification of their brand new OxBox facility. The AZD1222 program was not originated from Oxford Biomedica but their efforts remain key, since this vaccine candidate is still one of the main hopes for many low and middle-income countries (by far, one of the cheapest vaccines in the world, with an “at cost” sale by AstraZeneca, which is singular). The first conditional/emergency approvals were granted in the UK, in India, and in Argentina. An authorization was filed in Brazil on January 8th, 2021. According to the EMA, AstraZeneca should file in Europe next week and could potentially be granted a Conditional Marketing Approval by the end of the January 2021. In the US, the EUA will depend on the completion of the US trial, for which the timeline isn’t very clear.

Two European vaccine specialists also announced their COVID-19 vaccine: Valneva and Bavarian Nordic (BioNTech is definitely European but our landscape only focuses on the companies whose main stock listing is in Europe, which is not the case of BioNTech who flotaed directly on Nasdaq in New York). Though the commitment of both companies is quite different. While Valneva already has an order from the UK government for its adjuvanted inactivated vaccine candidate -phase 1 started in December 2020-, Bavarian Nordic decided to leverage a third-party technology, which relies on virus-like particles (or VLPs) from Adaptvac, with whom a license agreement was signed during the Summer. Though Bavarian Nordic had not communicated on the progress, and more importantly, the Danish vaccine manufacturer indicated that they would not purse the development of their vaccine candidate past phase 1 (or phase 1/2 whatever it is called), if they could not find a partner. Which indeed does not seem to be warranted. Still, Bavarian Nordic seems to be late on their initial schedule, which was to enter in clinics by the end of 2020.

Finally, three other companies originally focused on immunology, and notably for cancer vaccines, also decided to repurpose their vaccine or vaccine-like platforms for COVID-19: the French OSE Immunotherapeutics, the British company Scancell, and recently Vaccibody from Norway.

OSE’s vaccine approach relies on a previous cancer vaccine candidate named Tedopi, which aimed at generating T cells specific for tumor cell epitopes commonly found in various cancer types. With the company’s COVEPIT vaccine, the aim is to induce T cells specific for 11 selected immunodominant SARS-Cov-2 epitopes, located in several regions (RBD, Spike, Nucleocapsid). The selection was established after the analysis of the immunodominant and mostly conserved epitopes with respect to mutation possibilities thanks to their collab with the French deeptech MAbSilico. The entry in clinics was delayed into Q1 2021, from potentially the end of 2020. Scancell and Vaccibody approaches are quite similar, since the idea is to inject DNA plasmids coding for immunogenic proprietary structures also relating to multiple SARS-Cov-2-specific epitopes and aimed at being taken up directly by APCs, and especially dendritic cells (“Immunobodies” for Scancell and “Vaccibodies” for Vaccibody). However, the epitopes are apparently specific for the spike and the nucleocapsid in the case of Scancell, whereas Vaccibody focused on the RBD and the spike only. Scancell’s SN14 candidate is planned to enter the clinics in Q1 2021, and there is no disclosed timeline yet for Vaccibody’s VB10.COV2 candidate (but it seems it could definitely happen in 2021).

The therapeutics developed by public European biotech companies:

Most of the efforts of the European biotech companies in our universe concern therapeutic interventions. While the earlier efforts were towards the repurposing of already approved drugs, many companies also envisaged the repurposing of their investigational drug candidates for COVID-19, as the characterization and the understanding of the pathophysiology of COVID-19 increased. Only a few dedicated new therapies (other than vaccines) are currently in active development:
• the multi-specific anti-SARS-Cov-2 DARPin ensovibep/MP042 (and MP0423) from Molecular Partners (Switzerland) – phase 1 ongoing
• the ACE2-fc fusion protein FYB-207 from Formycon (Germany), in clinics in Q3 2021
There is also potentially an anti-SARS-Cov-2 Affimer program from Avacta (UK) but there is no recent news on whether this would be advanced or not, as the company already focuses on Affimers as reagents, notably for rapid tests.

Almost all the other approaches are either repurposed agents with assumedly an antiviral activity (usually with weak in vitro evidence) against SARS-Cov-2, or with anti-inflammatory properties (also with very few evidence) that could potentially help in the most severe cases affected by the “cytokine storm” associated with COVID-19, commonly associated with an acute respiratory distress. There are also other mechanisms of action not falling directly into these categories, but these are the 2 main ones. One program even claims both properties (ABX464 From Abivax, in phase 2/3), but there is no paper published to really assess the strength of these claims (there’s even a third claim, which is tissue repair of lung cells).

Among the most advanced agents, one may mention:
• Synairgen (UK)’s inhaled interferon beta 1a SNG001 (data published in the Lancet in November 2020, with some positive findings on odds of improving on the WHOI’s ordinal scale in hospitalized patients not in ICU), which is just entering into phase 3. Of note, Faron (Finland)’s intravenous interferon beta 1a didn’t show any benefit on reducing mortality in the SOLIDARITY trial (seemingly limited use of Faron’s product but other branded IV IFN-beta didn’t seem to work either), but it is still investigated in the REMAP-CAP study.
• in October, Pharmamar claimed having some positive results on a reduction of the viral load, thought to be supportive to launch a phase 3 for plitideptin (tested in Multiple Myeloma otherwise). But it was from a small single arm study. The Spanish company expanded this initial study with a few more patients (results should be disclosed in the coming weeks). In the meantime, Pharmamar is to discuss the next steps with the authorities.
• in December 2020, Vicore (Sweden) also disclosed some positive findings (reduction of the risk of needing oxygen supplementation) in a small pilot RCT for their AT2R agonist C21. These findings will have to be confirmed in larger RCTs.
• GSK’s anti-GM-CSF otilimab (licensed from German Morphosys) is also investigated in large randomized controlled phase 2 with data anticipated in Q1 2021, according to enrollment information available on

The main other programs with antiviral properties include:
• the SK2 inhibitor opagnib (option to license for Cosmo -Italy- from RedHill, readout in Q1 2021), the AXL inhibitor of Bergenbio (Norway) currently tested in 2 phase 2 studies (readout in Q1 2021),
• the LSD1 inhibitor from Oryzon Genomics (Spain, phase 2 ongoing),
• the multi-kinase inhibitor masitinib of AB Science (France, phase 2 ongoing),
• or the repurposing of a long acting ivermectin (positioned as prophylactic use) from Medincell (France) – continuous oral administration tested in phase 1.

The main other programs with anti-inflammatory properties are:
• the anti-C5a advoralimab from Innate Pharma (France) – currently in phase 2,
• the anti-C2 inhibitor ARGX-117 of argenx (Netherland) tested in a small ongoing IST phase 2,
• Pharming (Netherland)’s RhC1 esterase inhibitor Ruconest (one IST phase 2 in Switzerland and one phase 2 sponsored by Pharming in the US),
• the live biotherapeutic MRx004 from 4D Pharma (UK, also tested in asthma) currently in phase 2,
• the dual PDE3-4 inhibitor ensifentrine from Verona (UK, delisted from AIM since) currently in phase 2,
• the anti-CX3CR1 KAND567 from Kancera (Sweden) - also in phase 2,
• the Nrf2 activator/STAT3 inhibitor SFX-01 from Evgen (UK) - in phase 2/3,
• the NET inhibitor alvelestat from Mereo (UK, delisted from AIM since), currently investigated in a single center phase 1/2),
• and Tiziana (UK) tests its anti-CD3 foralumab (and potentially later their inhaled anti-IL6) with detailed data in Q1 2021 (Brazilian study just completed).

Among the other MoAs:
• the MAS Receptor agonist BIO-101/Sarconeos of Biophytis (France) is in phase 2/3 (rationale seemingly similar to Vicore's),
• Puretech’s deuterated pirfenidone LYT-100 aims at tackling the “Long COVID” symptoms (phase 2 recently launched),
• Biotest (Germany, not in our coverage anymore) has repurposed its polyclonal hyper immunoglobulin Trimodulin from ARDS to COVID-19 (they are also part of a multi-company consortium aiming at developing a new polyclonal hyper immunoglobulin but it is not clear whether the program is still committed or ongoing),
• and Paion/Cosmo/Acacia’s remimazolam (Byfavo, FDA approved in 2020) is tested to support the shortage of hypnotic drugs like midazolam and propofol.

Finally, there is the UFO named Relief Therapeutics. At the end of 2019, the stock of this Swiss company was trading in the low third decimal (0.0016 CHF), with no cash, a junk pipeline, and a CEO who resigned during the year. In short, no perspective except the one for the shareholders to get diluted with a never-ending equity line. A real zombie in the SIX Swiss Exchange listing. A few tiny licensing deals were signed in the past years though. The thing is that NeuroRx apparently believed there was a rationale to repurpose aviptadil, a 20-year-old drug use in erectile dysfunction, for the ARDS associated with COVID-19. Aviptadil is a naturally occurring vasoactive intestinal polypeptide (VIP). It binds to VPAC1 receptors on the pulmonary Alveolar Type 2 (AT2) cells which are critical for oxygen transfer, surfactant production, and maintenance of Alveolar Type 1 (AT1) cells. Given that these AT2 cells are particularly damaged by the coronavirus since they express the ACE2 receptor, NeuroRx thought there was a rationale to test aviptadil in COVID-19. They filed and IND as soon as March 2020 to run a phase 2, later upgraded in phase 2/3 (supposedly registrational). It is not even clear when they signed a collaboration with Relief but the fact is that the company managed to have a few ICU patients dosed with aviptadil within a compassionate use program. Then NeuroRx and Relief reported anecdotes of recoveries in some critically ill patients and the action on the stock went crazy. From a 3.1mEUR market cap at the end of 2019, the valuation was 810mEUR 12 months later! Not having data of a single randomized study in hands, NeuroRx and Relief filed for an Emergency Use Authorization to the FDA in September 2020. On 30 December 2020, in a management comment buried in a press release for which title referred to the completion of the enrollment of the phase 2/3 trial, Relief disclosed that the EUA had been rejected. The readout for the primary completion is to occur around the end of the January 2021. So, it is likely that the results in around 200 patients will be available a few days or weeks later. As a reminder, the commercialization agreement with NeuroRx includes a 50/50 profit split in the US, Israel, and Canada, where it is 85% Relied/15% NeuroRx in Europe and 80% Relief/20% NeuroRx in the rest of the word.

As one can see, the mechanisms of action are quite broad. While the question of the reliability of the positive findings disclosed so far can still be questioned, given the scarcity of positive news in terms of therapeutic options for COVID-19, one might just hope that these will be confirmed, and that more positive findings will be disclosed during 2021. The sizes and the designs of the studies vary a lot, so caution warranted, unless large effect sizes can be demonstrated.

Finally, to end the COVID-19 part of this review, we also have a post dedicated to the follow-up of the vaccine (pre-)orders for Europe, the US, Canada, Australia and Japan. You can also find some info on the main vaccine approvals, and figures about the vaccine prices/contracts.

So, forgotten the pre-COVID-19 macro concerns. The US/China trade war was quite far in 2020. There is still some action in the foreground though. When Donald Trump talked about China in 2020, moreover an election year, it was more to talk about “the Chinese virus”. Donald Trump, that almost everyone thought would easily be elected for a second mandate, eventually lost it seat, after a long suspense that lasted almost a full week. A seat that he did not lose only due to COVID, but his management of the situation probably was not adequate, especially at the beginning (see the poll we had as soon as March 12th, 2020), and probably also around the election days, since the US President managed to be infected himself, along with his wife and many staff members!

The Brexit was only a topic in the very last few weeks, with a deal announced for Christmas. Instead, it was all about “whatever it costs” (French Macron’s phrase in reference to Draghi’s “whatever is takes” – now followed by Lagarde) to save the economy, with monster fiscal stimulus in the US and in Europe. Which of course was appreciated by the markets, along with ultra-low rates.

From this point in our review, let COVID-19 aside now, and let us focus more on what represents the fundamentals of the European public biopharma sector. In the next pages, we will parse some highlights and lowlights for 2020, with a short outlook on what to expect in 2021.