4 In Pipeline

Dexamethasone (Corticosteroid): So far corticosteroids have not been recommended because of their immuno-suppressive effects, but low dose dexamethasone has now been proven to reduce complications in critically infected COVID-19 patients by RECOVERY (NCT04381936), the world’s largest randomized clinical trial. Over 2104 patients received 6mg of dexamethasone once per day for ten days. Dexamethasone was able to reduce mortality from 40% to 28% in patients on ventilation. It shows little effect on patients with mild symptoms. It is a huge prospect as dexamethasone is a cheap and widely available drug36.
Supplements: By now it has been well established that many of the complications of COVID-19 such as ARDS are the result of oxidative stress in turn due to a cytokine storm. Timely use of large dose of intravenous Vitamin C has the ability to oppose these effects as it is an antioxidant. High dose oral vitamin C also has some effect. Neither oral nor intravenous administration are associated with any side effects37.
There is an ongoing trial being conducted in Wuhan to investigate efficacy of Vitamin C in treating COVID-19 associated pneumonia. A total of 140 patients have been recruited, of which some have been randomized to a placebo group. Primary outcomes such as ventilation free days within the first 28 after initiation of treatment and secondary outcomes such as organ failure scores and 28-day mortality will be compared38. In another ongoing clinical trial (NCT04342728), randomized patients (Age group 18 and above) have been randomized to four groups: those who received Vitamin C (ascorbic acid), those who received Zinc Gluconate, those who received both in combination and the last group that just received standard care. Primary end point is the time taken for 50% symptom reduction.
Vitamin D, N-acetylcysteine and Zinc supplements have been hypothesized in the treatment of SARS-CoV-2 infections because of their anti-inflammatory effects. According to ClinicalTrials.gov a phase III interventional randomized control trial (NCT04344041) has begun recruiting 260 COVID-19 patients (Age group 70 and above). They will be randomized into two groups: one receiving high dose of cholecalciferol (200,000IU) and the other receiving the normal standard dose (50000IU). The primary outcome will be the number of deaths by any cause during the fourteen days after inclusion and intervention.
Thymosin Alpha one (Tα1) , a peptide produced by the thymus gland can increase CD4+ and CD8+ T cells and has been tested on COVID-19 patients. In 34 cases studies, Thymosin Alpha 1 was seen to cause an increase in CD4 and CD8 positive T cells in COVID-19 patients with severe lymphocytopenia. However, it was only seen to be beneficial for patients with counts of CD8+ and CD4+ cells population below 650/µl and 400/µl, respectively. Moreover, the case files of 76 critically ill patients were also retrospectively analyzed. The patients were divided into two groups; treatment group received 10mg of Tα1 subcutaneous injection daily for at least 7 consecutive days as well as antiviral and anti-bacterial treatment while the control group received all forms of treatment provided to the first group except Tα1. The mortality rate in the group receiving Tα1was lower, 11.11% vs 30% 39. Currently, 3 trials have been proposed to test the prophylactic or the therapeutic potential of thymosin. One of these has started recruiting patients. Anti-viral T cells have also been identified in COVID-19 patients so vaccines eliciting a T-cell response could also be useful40.
Baricitinib , a JAK and AAK1 inhibitor, has been suggested as possible candidate for treatment of COVID-19. AAK1 may impede the entry of the virus into cells via endocytosis 41. Some registered clinical trials of JAK inhibitor such as “Baracitinib in Symptomatic Patients Infected by COVID-19” NCT04320277.
Dapagliflozin is an anti-diabetic drug that is hypothesized to prevent the progression of COVID-19 as many of the complications occur in patients already suffering from cardiovascular, metabolic and renal problems 42. Currently this drug is being tested in a phase III clinical trial involving hospitalized adult patients with COVID-19 (DARE-19 NCT04350593).
Vaccine development against SARS-CoV-2 has been essentially a continuation of the work against SARS-CoV-1 and MERS. After the outbreak of SARS-CoV-2 the structure of the S protein was rapidly determined. It has been established from previous studies that this S protein would be an ideal target for future vaccines. This is because the S protein interacts with an ACE-2 receptor, after binding the ACE-2 receptor mediates the entry of the virus into target cells. Potential S-protein based vaccines would stimulate an immune response against the viral S protein and would resultantly inhibit infection of target cells.
However, it is an mRNA-based SARS-CoV-2 candidate, mRNA-1273 (NCT04283461), a collaboration between Moderna and the Vaccine Research Center at the National Institutes of Health, that is among some of the furthest along in development. It involves inoculation of host cells with encapsulated viral mRNA that will then be transcribed into proteins using host machinery. These host proteins will then trigger an acquired immune response. It has recently finalized the protocol for the phase III clinical trial and based on the phase I trial a 100ug dose has been selected to best stimulate the immune system. Moderna is aiming to supply 500 million doses each year 43.
Ad5-nCoV (NCT04341389) an adenovirus vaccine is in its Phase 2 trial. BNT162(NCT04380701) an mRNA vaccine, INO-4800 (NCT04336410), a DNA virus vaccine, PiCoVacc (NCT04352608), an inactivated virus vaccine and NVX-CoV2373 (NCT04368988) a protein subunit, based vaccines are all undergoing phase 1 or 2 clinical trials 44.
Researchers at Oxford’s Jenner Institute are in the process of development of an adenovirus vaccine vector ChAdOx1(NCT04324606). This vector has been used to develop vaccines against several other infectious agents. ChAdOx1 (recently renamed as AZD1222) contains the genetic sequence of the viral S protein which will be produced in the body after administration of the vaccine stimulating the immune response. Phase 1 trial with ChAdOx1 vaccine commenced in April of this year with more than 1000 healthy adult volunteers, many were the frontline staff of the NHS. Follow-ups are in process. Phase II and III trials are set to begin. Phase II trials will include a larger population with a wider age range 45.
Imperial College London has begun phase I clinical trials of its COVID-19 vaccine candidate this month. 300 volunteers will receive two doses four weeks apart. It consists of the use of a revolutionary RNA amplifying technology. The RNA coding for the S protein will be extensively amplified and translated resulting in higher levels of antigens produced for a longer period of time which will mimic a natural infection. This self-amplifying technology shows the same efficacy in providing immune protection as conventional mRNA vaccines but with a much lower dose of RNA. Three hundred candidates will receive two doses46.
Sanofi and GSK are collaborating to develop a vaccine that contains the viral S protein that will trigger an immune response directly in candidates. Phase 1 trials are planned to begin in the later half of 2020. Around 100 vaccines are in the pre-clinical stage of development according to the WHO. Only 6% of vaccines make it out of development to be approved for public use 44.

5 Discussion and Conclusion

While we have seen many previous pandemics and epidemics the SARS-COV-2 has brought the world at a standstill and sparked a global health crisis that has taken many by surprise with many health care systems being unable to cope. The death toll is on a continual rise and the race is on to find effective treatments. Till now the main focus has been on the prevention of spread through testing, tracing and case monitoring. Treatment has mostly involved supplemental oxygen and ventilatory support.
Rapid research is being carried out to investigate potential therapies and to re-purpose old ones. Repurposing of drugs has been the main-stay of this pandemic. With soft-ware for computational analysis available it is now possible to compare and assess the binding ability of molecular structures of available drugs to potential target sites. Several drugs have shown promising effects while numerous others are under investigation. Till present no specific guidelines by the WHO or the CDC, have been set in place about what exact treatment to be used.
According to ClinicalTrials.gov, 2,351 studies are registered which will investigate the COVID-19, as of June 29, 2020. It is clear that the foremost hurdle is not insufficient research but actually the lack of data from meticulously controlled clinical trials and peer reviewed research. Many studies include great deal of bias, show variable outcomes, have very small sample sizes, do not have control groups and patients are simultaneously treated with other therapeutic agents and respiratory support so it is difficult to analyze the true effect of a single drug that is under investigation. In a high-mortality situation, patients may simply not want to take part in randomized control trials with placebo groups.
In the light of current events it seems that the credibility of current research is also uncertain as can be seen by the withdrawal of the infamous Lancet paper on the 4th of June that stated that the Hydroxychloroquine (a drug that has been under the spotlight in recent days) increased the risk of mortality. The reason being was the refusal for an independent review of its dataset.
Many view a vaccine and subsequent global immunization as the end of this pandemic. However, vaccine development takes time, a compressed regulatory pathway will have to be rapidly conceived. Manufacturing vaccines in large quantities will be costly, developing countries will likely find themselves in trouble. As yet, no global organizations have taken responsibility of such a task but discussions with global stakeholders are in process and steps are being taken. If Imperial’s low-cost vaccine is successful it will increase affordability and availability 47.
Drug availability and shortage is also another problem in developing countries such as Pakistan. Remdesivir and Tocilizumab have been approved for use in severe infections in Pakistan. Remdesivir is in short supply while a single dose of Tocilixumab is 11,952 Pak rupees (USD 72). With a large majority of the population under the poverty line and a deteriorated government health care system such therapy is not widely available. Access to this therapy may increase after the proposed local manufacture of Remdesivir begins.
While tangible progress has been made there will have to be an even greater coordinated and co-operative global effort to identify and establish the most effective treatments.
There are unique challenges in resource limited developing countries such as Pakistan, a country which has one of the lowest funding allocated to it’s health-care system as a fraction of it’s GDP in the world. The inadequacy of the system can be seen by the fact that there are only 0.6 beds per 1000 patients and 1503 ventilators available in government hospitals for a total population of 212.82 million. With a lack of immediate response mechanisms in place, non-existent infection tracing and tracking systems and insufficient public health centers manned by under-trained staff, the system is truly under pressure that it has never faced before. Treatment puts forth a whole set of new problems, even with regulatory bodies preventing over-pricing of drugs that are already in short supply such as Tocilizumab (priced at 11,952 Pak rupees (USD 72) and Remdesivir and others that are being hoarded they will still most likely be inaccessible to the 24.3% of the population that lives under the poverty line. Pakistan will have to develop a holistic strategy to enhance the capacity of its pharmaceutical sector as home production seems to be a credible solution of unfortunately one of several problems. It seems in cases such as this, prevention is truly better than cure. (Noreen et al., 2020)