Saturday, June 15

New hope (and an old obstacle) for a terrible disease with terrible treatments

Three years ago, Jesús Tilano went to a hospital in a densely forested valley in Colombia with large open lesions on his nose, right arm and left hand. He was diagnosed with leishmaniasis, a parasitic disease that is transmitted by the bite of a female sand fly and that affects poor people who work in fields or forests in developing countries.

He was prescribed a medication that required three injections a day for 20 days, each one excruciatingly painful. Tilano, 85, had to make repeated and expensive bus trips to the city to get them. Then his kidneys began to fail, which is a common side effect of the medication, as is heart failure and liver damage.

“The cure was worse than what I had before,” Tilano said.

Leishmaniasis is a terrible disease, with terrible treatments that have barely changed in a century. The drug Tilano took was first administered 70 years ago. All treatments are a combination of painful, toxic, expensive or difficult to administer, requiring hospitalization or daily visits for a month.

Among so-called “neglected tropical diseases,” many experts believe leishmaniasis is unique in terms of the lack of progress, in the 120 years since it was first identified, to help the two million people who contract it each year. anus. year.

Now, finally, that’s starting to change: When Tilano’s grandson, 14-year-old Andrés Tilano, contracted leishmaniasis last year, he was treated at a Medellín clinic with an experimental therapy that cured his infection in a matter of days.

The treatment he received is one of several being developed by the Program for the Study and Control of Tropical Diseases, known as PECET, a small research institute based at the University of Antioquia in Medellín. In its effort to find new treatments for leishmaniasis, the program has partnered with the Drugs for Neglected Diseases Initiative (DNDi), a nonprofit research and development organization based in Geneva.

All of the experimental treatments that researchers are evaluating are much less toxic, burdensome, or expensive than those that exist now. But there is still a major obstacle preventing them from reaching the millions of people who need them.

None of the new treatments have been tested in a large-scale trial, approved by Colombia’s drug regulator, or adopted into national treatment guidelines. When a pharmaceutical company makes a drug, it will guide it through the costly and time-consuming regulatory process.

But you can’t make money on a drug for a disease that overwhelmingly affects the poor, and academic or public health institutes rarely have the resources to push a drug to the end of the process, said Marcela Vieira, a Brazilian IP. Lawyer with experience in development and access to medicines.

The global drug development system has long favored private sector companies that can fund experiments and diseases that afflict people with the money to pay for treatments. There is more and more new research on diseases such as leishmaniasis. From the public sector and academic institutions in middle-income countries., particularly Brazil, South Africa, India, Cuba and China, Ms. Vieira said. The Covid-19 pandemic, during which low- and middle-income countries were relegated to the back of the queue for vaccines and therapeutics, helped spur new investments to build drug development and production capacity.

“We need to do it, because no one will do it for us,” said Dr. Juliana Quintero, expert in leishmaniasis and PECET researcher.

The program’s research laboratories are located on six floors of a voluminous brick building at the University of Antioquia in Medellín. On the ground floor, Dr. Quintero cares for patients who arrive by bus from rural towns. He knows that few can afford to stay in the city for a month to receive the shots; He wants a treatment he can take home, ideally one they can take orally. Because funds for drug development for leishmaniasis are so scarce, he hopes for something that works for each of the 22 parasites in the family that cause variations of the disease in tropical countries around the world.

Leishmaniasis researchers have been inspired by the indigenous people of the region: a drug they are testing, a gel that is applied to lesions, is derived from a plant that indigenous people use to combat the parasite. The experimental treatment that cured Andrés Tilano is called thermotherapy and is similar to the traditional indigenous cure of burning lesions. At her clinic, Dr. Quintero used a handheld device that emitted heat at 50 degrees Celsius (122 degrees Fahrenheit) on the lesion, killing the parasite inside.

Today, Dr. Quintero prescribes two treatments that her institute has developed and provides them to patients under the so-called compassionate use model, since they have not yet been approved or registered by the Colombian government.

Mr. Tilano and his grandson suffered from cutaneous leishmaniasis, which is the least severe form of the disease. It can progress to mucosal leishmaniasis, when the parasite infects tissues such as the inside of the nose. Another species of the parasite migrates to the spleen, liver or bone marrow and causes what is called visceral leishmaniasis.

If left untreated, the visceral form of the disease is fatal in more than 95 percent of cases; It is estimated to kill about 6,000 people each year, most of them in Africa and Asia. The number of deaths has decreased significantly in recent years, mainly due to advances in the detection and treatment of leishmaniasis in India, where it is known as kala-azar.

Because existing treatments are so expensive and difficult to obtain, Dr. Quintero said, few patients complete treatment. That creates a newly drug-resistant parasite, which another sandfly can pass on to his family or other members of his community. When Dr. Quintero went to visit Mr. Tilano at her house not long ago, she met her daughter and her granddaughter, who had large circular scars from injuries that had finally healed.

Tilano’s son Luis, a logger who has become something of a local expert on the disease, asked Dr. Quintero to accompany him to the bank of the Cauca River to see a neighbor who he thought might also have leishmaniasis. . After navigating a curious cattle field and a steep river bank, he crawled through the twisted vines of a fig tree and encountered a group of older women panning for gold at the water’s edge. Her neighbor, María de las Mercedes González, 55, had large lesions on her face and Dr. Quintero used the flashlight on her cell phone to try to determine if the parasite had already moved to the cartilage of her her nose.

“Imagine an animal so small that a single bite can cause such a problem: it is a very irritating little creature,” González said after Dr. Quintero explained the risk he faced without treatment and gave him the news that he would have to spend 10,000 dollars. pesos (about $2.50, more than he normally earns in a day of mining) to make the daily trip to the city for treatment. The medications, at least, would be free through Colombia’s public health system.

DNDi, the nonprofit organization, has screened more than 2.5 million compounds (a standard first step in drug development) to find five chemical structures that, in early lab tests, appeared to work against the parasite that causes leishmaniasis. But of those five, only one or two will advance to larger clinical trials, said Jadel Kratz, who leads the organization’s drug discovery work in Latin America.

Early discoveries and preclinical studies cost $10 million to $20 million, he said, while getting through the first small clinical trials to determine safety and some signal of efficacy could cost another $6 million. The final phase, a large trial in patients to see if the drug works, costs a minimum of $20 million, far more than the public and academic research teams can fund.

“It is a huge risk for local research if only multinational corporations can do this work,” said Dr. Iván Darío Vélez-Bernal, who recently retired as director of PECET, the research institute.

But DNDi’s focus on leishmaniasis and the work of researchers in a network that includes India, Colombia and Brazil is beginning to bear fruit. Today there are five drugs in Phase 1 trials and another in Phase 2, which is unprecedented in the history of the disease.

It is not clear when or how the drugs will move to the next phase of the process. Medicines that leave public sector institutions tend to languish without an advocate, said Vieira, a researcher at the Center for Global Health at the University Institute of International and Development Studies in Geneva.

Medicines that originate from public health organizations in Brazil or India are often different in key ways from those developed by a pharmaceutical company in an industrialized country, Dr. Kratz said: The scientists who create them think about access from the beginning, knowing that whatever they design will have to be provided by a low-resource health system.

In Colombia and neighboring Brazil, leishmaniasis mainly affects farmers, loggers and miners, people whose work puts them in regular contact with the sand fly. But climate change is causing the fly’s habitat to expand rapidly, and Dr. Quintero is more frequently treating cases from semi-urban areas. During Colombia’s long civil war, much of which was fought in the jungles, the parasite also sickened soldiers, who accounted for up to half of cases nationwide. So the military was interested in finding treatment and helped test some of the experimental drugs.

The Colombian government is missing an opportunity by not funding the Phase 3 trial for experimental PECET therapies, Ms. Vieira said.

“Trials are expensive, but it is much less than what they would pay for a treatment if it was developed by a for-profit company, or everything they already have to pay, for people who are sick and do not have access to treatment,” said.