In the context of the COVID-19/SARS-Cov-2 pandemic, many biopharma companies throughout the world try to bring therapeutic options, on top of the topic of testing, which will not be focused on here. Some European listed companies have joined this international effort over the past weeks, and especially since the month of March.
Vaccine development has started in many companies, academia, or in the frame of a consortium with several stakeholders. Vaccination is theoretically the solution to obtain the "herd immunity" against the virus, if the "immunity" is confirmed, and knowing that the levels and duration of the "immunity" would still have to be characterized. There is quite a large number of vaccines in development already. It seems that the most advanced candidate in Europe comes from a British consortium led by Jenner Institute, University of Oxford. Oxford Biomedica recently joined this consortium, to bring its experience for the manufacturing, given that "at risk" production could start before the full results of the forthcoming clinical trial of this vaccine candidate are known. In the scenario where everything would go perfectly, this consortium would be ready to release the first vaccine batches in the Autumn of this year, which would be an extremely compressed timeline. Other vaccine initiatives by Moderna Therapeutics (together with the US NIH), Johnson and Johnson, CanSino, or BioNTech/Pfizer have been publicized over the past weeks. The timelines for these 2 other candidates are nevertheless more stretched, since early 2021 has been mentioned as the best-case scenario for a potential Emergency Use Authorization for Johnson and Johnson, and more mid-2021 for Moderna's vaccine to be "ready".
Concerning the virus itself and the clinical implications for the symptomatic cases, several avenues are pursued, starting with the most appropriate to address the emergency: drug repurposing. A number of papers have been published in the past weeks to propose existing drugs to be potentially repurposed to fight the COVID-19/SARS-Cov-2 coronavirus and the associated pathologies. These concerns currently approved drugs or investigational drug candidates. So far, several hundred of clinical trials have been launched, but unfortunately, no candidate has established a proven favorable benefit/risk ratio yet (at least not in the frame of an RCT). Given the increasingly large effort to find therapeutics, one may just be hopeful that several options will emerge, beyond the multiple case reports and observational studies published until now, for which it's hard to conclude anything that would be "practice-changing". Unsurprisingly, the repurposing of existing candidates is the approach of almost all the companies listed below.
The exceptions are listed the following cases:
• the UK's consortium joined by Oxford Biomedica for the ChAdOx-1 nCov19 vaccine candidate, which is a new development by definition, since the virus is new (the viral vector was already used in other candidates)
• Biotest and the internal consortium the company formed recently with Takeda, CSL and other plasma-derived product players (unique branded product based on antibodies from recovered/healed patients)
• Pharnext, whose hybrid approach consists in combining several repurposed drugs to propose new drug candidates to be tested (concept of "Pleodrugs"), using its AI/Big Data know-how
• Immupharma, via its subsidiary UREkA Pharma who recently joined a consortium to run research on viral-specific peptides, with a potential application on COVID-19 according to the company (this project seems very early and the plan seems quite vague so far)
• Avacta, for which the application is not for therapeutics but for testing
While the rationale for repurposing or for the development of new options seems interesting for some companies, it seems more questionable for others. Given that most of the companies are rushing to initiate the clinical development of their potential options, the level of evidence can only be globally low, if existing. Some companies haven't published any supporting data, which should be a minimum, even on a preprint or on the company website. One exception might be the Biotest case, for which the approach seems relatively de-risked, relying mainly on the execution. In contrast, the risk level seems more important for the approach pursued by Vicore (and likely also by Biophytis), betting on a potential role of an imbalance in the Renin-Angiotensin System induced by a "hijacking" of ACE2 by the virus, which is basically unproven at this date. In fact, the RAS (or RAAS) system has rapidly been the subject of a controversy, as ACE inhibitors and ARBs were shown to upregulate ACE2 expression on cell surface, possibly in the lungs. As ACE2 is one cell entry of the virus, there were concerns about a potentially increased risks of bad outcome for infected patients treated with these anti-hypertensive therapies (Vaduganathan et al., NEJM). However, a study published this week, in which patients under ACE inhibitors and ARBs did even better that those who did not, seemed to support the alternative thesis by Vaduganathan et al. Their thesis proposes, on the contrary, that ACE inhibitors and ARBs could help maintaining the balance between ACE2 (downregulated by the virus), and Angiotensin II, by decreasing the activity of the latter. If confirmed with more data or other studies, this could indeed give some credit to the concept of RAS imbalance, however ACE inhibitors and ARBs would also be straightforward and immediate solutions. Another point is that ACE inhibitors and ARBs potentially upregulate ACE2 expression, so how one contribution would offset the other? In short, there is no definitive conclusion on the RAS system involvement, and more studies are needed, but things do not always work as expected initially.
Our comments on the low level of evidence applies also for all the other companies with in vitro data only. In fact, there is no gold standard models for SARS-Cov-2 animal models, which is why there is no data in vivo for this virus. The development of such models is also a challenge. Then you have companies with some in vivo experiments, but in animal disease models for which the relevance is often hard to appreciate, due to the mechanisms inducing these diseases that would not recapitulate what happens with the virus. But do we really know what happens? More Interestingly, a few companies can find some support in human data, within the collection of off-label cases reported (see table references), like for the antibodies collected from healed patients, or the anti-cytokines, in particular anti-IL-6/IL-6Rs.
At the end of the day, some approaches might be invalidated or weakened in terms of rationale, even before launching the clinical trials. One can mention the case of Kaletra, studied in the Discovery trial piloted by the French INSERM, whereas RCT data published in the NEJM before the trial launch seemed to indicate a weaker-than-thought rationale. The risk mainly comes from the many unknowns on the virus, the research on the virus is still in its infancy and the knowledge of tomorrow might already challenge the assumptions we hold today. However, the investors' appetite for "the COVID stocks" has been important over the past weeks, and it could have led to some excess of optimism in terms of valuation. The most interesting example being the one of MedinCell, whose valuation jumped by 100 mEUR just on the disclosure of their research project. This program concerns the repurposing of ivermectin in a long-acting injectable, and is only based, for now, on in vitro experiments by an academic institution. Probably one of the most profitable Petri dish work ever in the history of biotech, since it costed 0 EUR to the company.
Therefore, the list established today is certainly called to expand even further in the next weeks. As no one really knows if the virus will come back periodically on a seasonal basis, how immunity has developed so far in the populations, how long it may last, and how far we are from a decent vaccine solution, the gap remains to be filled. This leaves an open door for speculation that some companies have already used, generally opportunistically. This door will close progressively over time when some agents will emerge, so the investors interest will fade at some point, but the timeframe for which the window will remain open in the investors' mind is currently undefined. Another caveat inviting to moderation is that many clinical trials will be performed in a small number of patients, in populations probably not optimally defined, so the expectations in terms of outcome should be globally relatively moderate. There is also the issue that after the mitigation measures, the number of cases in many Western countries could remain low (at least this is the plan), making clinical investigations more difficult to run in the coming months. Meanwhile, one can only endorse the current effort, wishing these companies the best.
The table below keeps track of the different programs disclosed by the European listed companies (mainly listed in European stock markets). Most of these companies are covered in the frame of our service. You will find the main information on these programs, as well as some relevant market data. The data -all accessible to the public- will be updated as data comes in.
On 20/04/2020, Molecular Partners disclosed a program for trispecific DARPin® molecules targeting the spike protein of COVID-19/SARS-Cov-2. This program could be one of the most promising, and not only for the European biotechs, but more globally, while waiting for an efficacious vaccine. As big biotechs/pharmas will develop biologics for the same purpose (neutralizing the virus by blocking the known cell entries, with multi-specific constructs or not), as disclosed by Regeneron, the DARPin approach of Molecular Partners could be a tour de force, adding multi-specificity for a potentially improved efficacy. On top of that, GMP manufacturing could be ready relatively rapidly (Q3 2020), competing with the most aggressive timelines for biologics manufacturing.
Then Valneva, together with Dynavax on 22/04, and Scancell on 24/04, both announced their respective vaccine programs. Of note, China Sinovac already entered in the clinics last week with an inactivated-virus vaccine (the same approach as Valneva). Sinovac's preprint on their vaccine candidate was also recently published. In addition, still on the topic of vaccines, you can have a look at these 2 posts by Derek Lowe on his Science blog (recommended one), here (prospects) and there for a review of the most advanced vaccine programs. According to another recent lanscape review on the COVID-19 vaccines, as of 08/04, there were not less than 115 vaccine programs, of which 78 confirmed. On 05/05, OSE Immunotherapeutics has joined the efforts towards the development of prophylactic vaccines. Given the number of vaccines in development, and the financial means of these companies, the expectations towards crossing the finish lines should be relatively low. Valneva and Dynavax will likely seek some more financing. Scancell has already said that they would need to partner their program at some point, and so would OSE Immunotherapeutics.
On 14/05, ABIVAX announced a broad phase 2/3 in 1034 patients, to investigate the efficacy and safety of ABX464 in a range of COVID-19 patients. The study was approved to begin in France, expected to be expanded in Europe in the short term. Of note, the company also managed to collect a sizeable amount of 36mEUR of grants and loans from BPIfrance, mainly to finance the costs of the study and support the costs associated with the scale-up of the manufacturing.
Since our end of May update, GSK started a clinical trial of otilimab. Remdesivir was approved on 25/06 in Europe (approved since early May in the US). Dexamethasone was shown to reduce mortality risks by around 30% in critically-ill patients (RECOVERY RCT), whereas the testing of hydroxychloroquine has been withdrawn by most of the institutions, due to a lack of efficacy.
Since our end of June update, the preliminary human data from the most advanced vaccine candidates from AstraZeneca/Oxford University/jenner's Institute (Lancet - July'20), Moderna (NEJM - July'20), CanSino (Lancet -July'20), Pfizer/BioNTech (Nature - August'20 - BNT162b1 paper but BNT162b2 picked for phase 3), Novavax (MedRXiV preprint - August'20), Sinovac (MedRXiv preprint - August'20), Sinopharm (JAMA - August'20) have been released.
Finally, one may find more information on clinical trials against COVID-19 on 2 external resources, here and there. RA Capital also kindly shares a great "live map" of the whole therapeutic landscape here. The New York Times also has an interesting COVID-19 vaccine tracker, other vaccine data are also shares on raps.org. Finally, the Milken Institute also has a nice database of the current therapeutics & vaccines (also accessible here).
Since our August update, many vaccine candidates have started their pivotal trials, with the first results expected in the coming days or weeks. The timings depends on the protocol for each vaccines, as well at the behavior of the enrollees, and the variable situation of the pandemic where the enrollees are located, which makes it hard to provide a precise date for each vaccine. We only know that the first interim analysis should occur "soon". In terms of therapeutics, only few progress was done overall, especially for the repurposed drugs. The neutralizing antibodies have nevertheless shown potentially interesting results in a patient population going up to those requiring a low-flow oxygen supplementation, but not in more severe patients. The COVID-19 "Cytokine Storm" remains to be cracked. The IL-6 blockade has failed to provide any mortality benefit. The IL-1 blockade has also yielded negative results last week. PharmaMar claimed positive results recently, but the study was exploratory and did not include a contro arm. Relief Therapeutics and theis US licensee NeuroRx filed for an EUA in the US, only based on data from patients from an EAP for RLF-100 (no news since). The WHO's SOLIDARITY trial yielded negative results for Interferon Beta 1a IV, but the population was apparently more late-stage versus the one studied by Synairgen (plus Synairgen's IFN Beta 1a is inhaled, not IV). Vicore completed a POC study in around 100 patients, where a signal was observed in a reduction of the need for mechanical ventilation (a registrational study is in preparation). The results of the AstraZeneca vaccine (for which Oxford Biomedica is involved in the manufacturing) was approved in the UK at the end of December 2020 (results published in The Lancet on 08/12/2020). Many clinical trials are ongoing or were launched in the past months, as we are advancing into the third wave on the old continent.
As of 04/01/2021, 55 (+2 versus 08/11/2020) European biotech companies -mostly within our coverage, or 37% of the total- have officially initiated a program relating to COVID-19, out of approximately 158 listed biotech companies (2020 perimeter). 1 program was approved for emergency use, in the UK (AZD1222). 31 programs are in active clinical development (+9 versus 08/11/2020).
Table updated on 13/01/2021
Conflict of interests: at the moment of initial publication (14/04/2020), the author of this post, Bertrand Delsuc, owns shares in some companies mentioned in the table (no significant ownership, none related to any COVID-19 program). The data in this post are no investment recommendations.
image credits: Centers for Disease Control and Prevention (CDC) / unsplash