Experts advise caution over early, emerging treatments

The American Academy of Dermatology (AAD), Lupus Foundation of America, American College of Rheumatology, and Arthritis Foundation, sent a letter to the White House Coronavirus Task Force March 24, outlining concerns about a growing shortage of medications required for managing patients with lupus and rheumatoid arthritis.

After President Donald Trump said in a March 19 press conference that an anti-malaria drug could treat the coronavirus disease COVID-19, pharmacists began reporting surges in demand for hydroxychloroquine.

Hydroxychloroquine is approved by the U.S. Food and Drug Administration (FDA) for the treatment of malaria, lupus and rheumatoid arthritis, and tens of thousands of Americans depend on the medication to manage symptoms.

“For patients with lupus, hydroxychloroquine is the only medication shown to increase survival,” the letter reads. “[It] is the cornerstone of therapy, used in most patients.”

Following a series of small studies indicating the drug’s potential benefit for the treatment of COVID-19, hospitals began purchasing large quantities, pharmacists reported depleted supplies and manufacturers are reporting back orders.

“Patients are indicating that they are not able to fill their prescriptions and are concerned about continued access to their treatment. We are encouraged that manufacturers - who are currently manufacturing or authorized to manufacture hydroxychloroquine - will be increasing supply to not only meet the needs of patients with COVID-19 but also patients with lupus and rheumatoid arthritis,” Bruce Harris Thiers, M.D., FAAD, president of the American Academy of Dermatology tells Dermatology Times.

Patients with these conditions need this drug to effectively manage their health conditions. If patients can’t fill their prescriptions, they could face flares that significantly impact quality of life, says Alison Ehrlich, M.D., MHS, a dermatologist in Washington, D.C.

The organizations have requested the White House Task Force to work with the pharmaceutical industry, pharmacies and the FDA to take several steps that are aimed at mitigating the effects of the shortage, including increasing monitoring and timely reporting of shortages; utilizing existing authorities to increase the production and supply of the drugs; and taking action to ensure current supplies are allocated for patients taking them for indicated uses.

Hydroxychloroquine is currently being investigated as a treatment to reduce the duration of symptoms and viral shedding in patients with mild-to-moderate COVID-19. However, recent data from a small study of 30 patients, reported March 24, by Bloomberg News, showed that hydroxychloroquine was no more effective than managing patient symptoms conventionally.

The study, which was conducted by researchers from the department of infection and immunity at the Shanghai Public Health Clinical Center, involved 15 patients treated with hydroxychloroquine and 15 controls who were managed with bed rest, oxygen inhalation, anti-viral drugs recommended in China’s treatment guidelines, and antibiotics when necessary. Of the 15 patients treated, 13 tested negative after one week of treatment vs. 14 patients in the control group who were managed conventionally. One patient in the treatment group progressed to severe disease and four patients developed diarrhea and signs of possible liver damage. The researchers concluded that a larger-scale investigation is required to better understand the drug’s benefit and risk profile.

“Our scientific clinical trials data is not as robust as the media attention,” Dr. Ehrlich says. “We are already seeing some of the dangers of unsupervised use as witnessed in toxicity cases in Nigeria (3 patients) and Arizona (2 patients).”

She says, that while chloroquine and its less toxic derivative, hydroxychloroquine, are generally safe when dosed correctly, the clinical trials data is still limited for this indication. The studies that have supported recommendations for the drug’s use in the treatment of the current pandemic are not high-quality well controlled studies.

While there are no drugs approved to treat, cure or prevent COVID-19, at this time, there are several potential treatments that may help ease the symptoms from a supportive care perspective, the organization reports. The FDA says it is working closely with the scientific community around the world and several clinical trials are underway.

According to Dr. Ehrlich, several other drugs being studied are interesting. For example, “IL-6 blocking agents may have a role in decreasing pulmonary inflammation,” she says. Interleukin-6 (IL-6) may play a role in driving the overactive inflammatory response in the lungs of patients who are critically ill with COVID-19.

Regeneron and Sanofi have initiated a phase 2/3 clinical trial evaluating the IL-6 inhibitor sarilumab (Kevzara) in patients with severe COVID-19.  Regeneron Pharmaceuticals also announced March 17 its progress in developing a multi-antibody cocktail for prophylaxis exposure to COVID-19, as well as treatment. Researchers have isolated virus-neutralizing, fully human antibodies from lab mice, genetically-modified to have a human immune system, as well as humans who have recovered from COVID-19. Researchers will select the top two antibodies for a cocktail treatment, which the company says allows for targeting of different parts of the virus and may help protect against multiple viral variants.

The FDA has approved the initiation of a phase 3 trial for the immunosuppressive drug tocilizumab (Actemra) to evaluate its safety and efficacy in combination with standard of care in hospitalized adult patients with severe COVID-19 pneumonia. Tocilizumab is an IL-6 receptor agonist approved for the treatment of rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis.

Finally, remdesivir (Gilead), an investigational monophosphoramidate prodrug of an adenosine analog that was developed in response to the 2014-2016 Ebola outbreak, is also being investigated. There are four clinical trials enrolling patients in the United States. The drug was available for compassionate use until the company suspended that access due to overwhelming demand. Gilead expects to set up a broader access program, but critically ill patients are now left in limbo.

The bottom line is that “we just don’t know what’s really going to pan out and what will be the most helpful right now,” says Dr. Ehrlich. “We just don’t have really strong clinical trial data yet. Until we have strong clinical trial data to support specific therapies for Covid-19 , it’s going to be  very challenging.”