Bioanalysis Zone

COVID-19 is opening a door to a new era in drug development

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Tamal MahlakoivTanel Mahlakõiv, PhD – Celularity Inc (NJ, USA)
Tanel Mahlakõiv has an international and very collaborative background in biomedical research, having worked in six countries on three continents. He holds a PhD degree in virology and immunology from Freiburg University in Germany and an MSc in Biosciences from École normale supérieure de Lyon, France. He started his science career in molecular virology working on viruses that require the highest biocontainment level, including Ebola virus. His doctorate focused on the innate mechanisms the body uses to protect itself against pathogenic viruses that infect epithelial tissues, such as the lung and the gut. Various Influenza viruses and SARS were among the many viruses in his tool kit. He performed his postdoctoral research in Weill Cornell Medicine in New York City (USA) studying the interactions of immune cells with metabolism and the nervous system. Currently, Tanel is a senior scientist in a New Jersey based clinical-stage biotechnology firm Celularity, Inc that is developing cellular therapies to improve the quality of life and extend life expectancy in humans. He has published in top-tier journals, including Nature, Science Immunology and Immunity.

With coronavirus disease 2019 (COVID-19) shutting down countries and economies, the world is expectantly looking at scientist to come up with a solution. Although the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus is fast and deadly, there is a serious arsenal of antivirals the scientific community is charging at SARS-CoV-2. The weaponry includes novel RNA vaccines, broad-spectrum virus inhibitors and even a cell therapy.

Since Edward Jenner’s experimental work using cowpox to protect against smallpox in 1796, vaccines have drastically extended life expectancy and improved the quality of human life. Yet, despite significant scientific and biotechnological advances, it takes a tremendous amount of effort, resources and a long time to develop an efficacious and safe vaccine. Exemplified by decades of HIV vaccine struggles, sometimes not even that is enough.

For Moderna, a Massachusetts-based biotechnology company that is focused on developing messenger RNA based drugs and vaccines, it took a few days to come up with a SARS-CoV-2 vaccine candidate, termed mRNA-1273, and only 2 months to start testing safety and immunogenicity in human trials. Other small biotechnology companies including CureVac (Tbingen, Germany), Cepi (MA, USA), Novavax (MA, USA), CanSino (Hong Kong, China), Inovio (PA, USA) and pharmaceutical mammoths like Sanofi (Paris, France), J&J (NJ, USA), Gilead (CA, USA) and GSK (Brentford, UK) are not far behind. However, even if everything goes as planned and human trials demonstrate safety, immunogenicity and protection, a vaccine against SARS-CoV-2 will not reach the masses before 12–18 months. The development of neutralizing monoclonal antibodies takes a similarly long time. Blood serum from recovered COVID-19 patients has the potential to neutralize the virus in severe infections but is not an option for large-scale treatments. Therefore, a parallel race is on to develop antivirals to specifically suppress SARS-CoV-2 replication or drugs to control COVID-19 disease.

Much of the focus for developing antiviral treatments today still lies on small molecule drugs that block the molecular machinery of a specific virus. The outbreaks of SARS-CoV in 2003 and MERS-CoV in 2012 warned the world of the potential that coronaviruses could cause, involving a disease in humans with high morbidity and mortality, resulting in the initiation of drug development programs that have now been repurposed for SARS-CoV-2. High genetic and molecular similarity between these three pathogenic coronaviruses suggests that some drugs in development could be retargeted for SARS-CoV-2 and first candidates have already entered clinical trials in COVID-19 patients around the world. Furthermore, approved broad-spectrum antiviral drugs that target generic parts of the replication machinery of negative-strand RNA viruses could also inhibit SARS-CoV-2.COVID-19 hubIsolation of the novel SARS-CoV-2 in early January 2020 allowed the initiation of screening of experimental antivirals and existing drugs for their potential to block virus replication in cultured cells. This approach pre-selected molecules with a promising antiviral profile for testing in COVID-19 patients in Wuhan province, China. Among several other candidates, Gilead’s former experimental Ebola drug Remdesivir demonstrated a fast relief of symptoms in COVID-19 patients in two ongoing trials, first in China and later in the US [1]. Remdesivir belongs to a class of drugs known as nucleotide analogs and because it targets basic virus replication mechanisms, it has shown activity against multiple single-stranded RNA viruses in a test tube. At the moment, Remdesivir is viewed as the most promising molecule in development and has been promised fast-track evaluation by international authorities.

Abbvie’s (IL, USA) HIV drug Kaletra, a combination of two protease inhibitors Ritonavir and Lopinavir, gained much attention when entering trials in China but demonstrated little benefit in a randomized controlled trial over standard of care [2]. On the other hand, another antiviral, called Favipiravir, also termed Favilavir or Avigan, is an RNA polymerase inhibitor that was initially developed for treating influenza infection by Japanese Toyama Chemical, but has now been rapidly approved by the Chinese authorities for COVID-19 treatment based on successful trials. Other small molecule antivirals in clinical trials include Sofosbuvir and Ribavirin, approved for the treatment of HCV and RSV infections, respectively.

On March 19, President Trump announced that the FDA will fast track the approval of drugs and therapies with a potential against COVID-19, including the above-mentioned molecules and, paradoxically, also an anti-malaria drug hydroxychloroquine. The drug sold under the name Plaquenil is approved for malaria and autoimmune conditions, whereas, its antiviral effects have not been fully elucidated [3]. In the SARS-CoV outbreak in 2003, hydroxychloroquine exhibited an antiviral effect in the laboratory and was now put to test in humans, demonstrating safety, fast reduction of viral load and improvement of pneumonia symptoms [4,5].

The initial SARS outbreak in 2002–2003, as well as the current pandemic of SARS-CoV-2, demonstrated an evolution of the virus with genetic changes resulting in altered replication potential and disease severity [6,7]. We expect to see more virus diversity with the pandemic unfolding, therefore, raising the chances for the emergence of an escape mutant of functioning antiviral drugs. Whereas small molecule drugs are cheap to manufacture and administer, the virus-specific drugs often have off-target effects and toxicity, usually have a narrow spectrum and they are prone to the virus developing drug resistance. Immunotherapy drugs can circumvent these drawbacks.

In the cancer field, for decades, scientists’ focus was on the tumor side – trying to understand on the molecular level what makes tumor cells proliferate uncontrollably. Today, we are rapidly shifting towards harnessing the diverse mechanisms that evolution has provided our bodies with to fight cancer. Immunotherapy has rapidly revolutionized the way oncologists treat cancers, resulting in improved prognosis for patients.

The goal is to reinvigorate the dormant immune system in cancer patients or teach the immune cells to recognize certain tumor markers leading to tumor cell lysis and elimination. Checkpoint inhibitors in the form of monoclonal antibodies and chimeric antigen receptor (CAR)-T cells are the two main reasons behind the successes and rapidly revolutionizing cancer treatment. Whereas immunotherapy has come to stay in cancer treatment, it is not yet a treatment of choice in infectious disease, with the exception of vaccines.

Virus-specific effector T cells are part of an effective immune response against virus infection as they clear virus-infected cells. Chronic infections often result in T cell exhaustion and depletion. Small molecule drugs today keep chronic infections like HIV and HCV under control but the current therapies fail to cure due to viral dormancy in rare ‘invisible’ cells or occurrence of drug resistance. Pathogen-specific CAR-T cells present an attractive alternative to existing therapies, however, antiviral CARs are highly experimental and few are described in the literature, mostly targeting HIV [8]. Despite the successes of approved CAR-T therapies for the treatment of B cell leukemias, they come with a hefty price tag and weeks long manufacturing process tailored for each patient individually. Scientist are developing off-the-shelf CAR-T cells for cancer treatment, but at the moment these are far from reach for the current pandemic.

Cytotoxic T lymphocytes functionally resemble innate immune cells termed natural killer (NK) cells that are specialized in the recognition and elimination of stressed or malignant cells in the body, including tumor cells and virally infected cells. NK therapies against hematologic cancer and solid tumors are in development by several companies and now Celularity, a New Jersey-based biotechnology company, has submitted and a new drug application to the FDA to test their off-the-shelf placental stem cell-derived CYNK-001 cells in COVID-19 patients. If approved, it would be the first cell therapy in clinical trial for an acute viral infection.

Various recombinant cytokines have been used to modulate immune responses since the approval of recombinant interleukin (IL) 2, a T cell promoting cytokine, by the FDA in the beginning of the 90s. Among these are interferons (IFNs) that initiate strong antiviral responses and represent the first line of defense of the body against an invading virus. What makes IFNs attractive is the fact that they target the host immune response rather than a viral protein – one drug to treat them all. On the negative side, as IFN receptors are on all cells of the body, systemic treatment results in significant adverse effects. IFN alpha and beta were used to treat HCV and HBV infections but were pushed aside by specific small molecule drugs against these viruses. In the current outbreak, systemic IFN alpha has been used in combination with antivirals and a UK biotech firm Synairgen is about to test inhaled IFN beta in a clinical setting.

The IFN family of molecules also contains IFN lambda that mostly targets epithelial cells of the body and could potentially inhibit respiratory viruses without causing side effects as seen with IFN alpha and beta [9]. Eiger Biopharmaceuticals (CA, USA) is in clinical trials with IFN lambda as a hepatitis delta virus (HDV) drug. While there is no news about using IFN lambda in COVID-19 patients, it is a very attractive drug for respiratory infections, not only limited to the current SARS-CoV-2 outbreak.

Despite broad social distancing measures in most affected countries, the death toll continues to climb rapidly and warrants a need for an approved treatment that could reach the masses. The speed and scale of the response from the biopharma sector is unprecedented and will change the way drugs are developed. Several drugs already on the market have been repurposed and approved for the COVID-19 indication and many experimental treatments show promise in containing virus replication and alleviating symptoms in ongoing trials.


References:
  1. The COVID-19 Investigation Team, 2020, medRxiv: medrxiv.org/content/10.1101/2020.03.09.20032896v1.full.pdf
  2. Cao B, Wang Y, Wen D et al. A trial of Lopinavir-Ritonavir in adults hospitalized with severe covid-19. N Engl J Med. doi:10.1056/NEJMoa2001282 (2020).
  3. Yao X, Ye F, Zhang M et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2. Clinical Infectious Diseases. dio:10.1093/cid/ciaa237 (2020).
  4. Gautret P, Lagier J-C, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. J Antimicrob. Agents. doi: 10.1016/j.ijantimicag.2020.105949 (2020).
  5. Gao J, Tian Z, Yang X et al. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioSci. Trends. doi:10.5582/bst.2020.01047 (2020).
  6. Tang X, Wu C, Li X et al. On the origin and continuing evolution of SARS-CoV-2. Sci. Rev. doi:10.1093/nsr/nwaa036 (2020).
  7. Muth D, Corman V, Roth H et al. Attenuation of replication by a 29 nucleotide deletion in SARS-coronavirus acquired during the early stages of human-to-human transmission. Sci. Rep. 8,15177 (2018).
  8. Seif M, Einsele H, Loffler J et al. CAR T cells beyond cancer: hope for immunomodulatory therapy of infectious diseases. Front. Immunol. 10,2711 (2019).
  9. Klinkhammer J, Schnepf D, Ye L et al. IFN-ƛ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission. eLife. doi:10.7554/eLife.3354 (2018).

 

The opinions expressed in this feature are those of the author and do not necessarily reflect the views of Bioanalysis Zone or Future Science Group.

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