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A mural for Rare Disease Day in Brazil, Feb 2021(Source:PTC Therapeutics)

Biopharma companies often have an opportunity to reach out to markets in the rest of the world (RoW), where they can act quickly following a US FDA or EU EMA approval for a drug, to capture some pre-registration sales as they await an approval decision in those RoW regions.

“Especially in the orphan space, it’s a no-brainer,” said Julius Steffen, principal at the consultancy Bionest Partners. The business case can make a lot of sense, he said, but sometimes, in the midst of other things to worry about – especially for a biotech start-up in the early phases of commercialization – “it doesn’t always take the space it should.”

In the Middle East (including Turkey), for example, fast market entry for rare disease drugs may be possible at pricing levels similar to those in the US. But with few exceptions (e.g. the high prevalence of sickle cell disease in the region), those markets do not have large enough patient populations to warrant setting up an affiliate. Rather, the model is to engage a distributor and thereby give up a significant percentage of revenues and control over sales strategy.

Asia-Pacific is also an interesting region for US biotechs to explore, given the size and long-term potential of its individual markets. But here, pre-registration opportunities offered through early access pathways may be limited to out-of-pocket costs, and local research and development is usually required.

For several reasons, the Latin American (LATAM) market may be among the most compelling to explore – especially if the business case for setting up a direct affiliate makes sense. A direct relationship in a country can help a company establish a brand. “Branding is not just of the product, but so that the company is credible to be able to engage the right health authorities and relevant people within the government so they want to listen to you and play with you,” says Anny Bedard, an advisor to early-stage companies developing drugs for orphan diseases.

For many rare conditions, LATAM can provide a significant patient population. Because of extensive diagnostic testing and the fact that its health service covers the whole population, Brazil is good at identifying patients with many rare diseases. “That’s good for clinical research,” says Roberto Giugliani, professor in the department of genetics at Universidade Federal do Rio Grande do Sul, in Porto Alegre.

Brazil has one of the largest populations of Duchenne muscular dystrophy (DMD) patients, for example. “It’s one of our top countries,” says Eric Pauwels, chief business officer at PTC Therapeutics, Inc., along with the US, Germany and France. Similarly, a high prevalence of hereditary transthyretin (TTR) amyloidosis exists in Brazil; there is an ethnic Portuguese component to this with a particular mutation called val30met, which means a high prevalence of young patients in Brazil that have TTR amyloidosis polyneuropathy. “When we saw that, we looked not only at Brazil but all of Latin America,” Pauwels said. With about 6,000 patients in the region, it is more than any single country in the world.

The Brazilian health regulatory agency, ANVISA, approved 11 rare disease drugs in 2020 (see Exhibit 1). That is about the same as awarded in 2018, but half of the number for 2019.

Entering The Market

In Brazil, some of the first DMD patients were treated through the judicialization process, a pre-authorization pathway, as advocacy groups worked with judges to get treatments. “We assessed that the immediate and long-term investment in Brazil and Latin America is worth it in the same way as it was in France with an ATU (Temporary Authorization for Use) or Italy with the 648 List early-access mechanism,” Pauwels said.

PTC Therapeutics started conducting clinical studies in Brazil and other parts of LATAM in 2014. It established a direct presence in March 2015, and has expanded its footprint ever since. Today, it has operations in Argentina, Colombia and Chile, as well as Brazil, and is establishing a direct business in Peru and Mexico.

“We didn’t go in for early access and then walk away,” said Pauwels. “We wanted to establish a sustainable business,” he added, anticipating an expanding portfolio and registrations in Europe or the US. PTC Eyes Transition From Capital-Raising To Money-Making Company

PTC received approval in Brazil for Translarna (ataluren) for DMD and Tegsedi (inotersen) for hereditary TTR amyloidosis in 2019, and has registered Waylivra (volanesorsen) for familial chylomicronemia syndrome, acquired via a deal with Akcea Therapeutics (now part of Ionis Pharmaceuticals, Inc.). Roche Holding AG, which licensed Evrysdi (risdiplam) for spinal muscular atrophy) from PTC and the SMA Foundation, received approval for that drug in Brazil last year.

Alnylam Pharmaceuticals Inc., whose Onpattro (patisiran) was approved in Brazil last year for hereditary TTR amyloidosis, has adopted a different strategy. Prior to the pandemic, it had no LATAM presence. It could have acquired a local company, as Amgen, Inc. did (in acquiring oncology company Bergamo, with mature brands, for $215 million in 2011). “That can be very expensive because you have to employ a lot of capital upfront,” said Norton Oliveira, Alnylam's SVP, head of Latin America, revealing one reason why the company did not consider it.

Alnylam could also have started with a “greenfield” approach, building all the needed capabilities locally, as it had done in other geographies. However, using this option in Brazil would have taken several years to get the necessary permits and licenses to be able to file for regulatory approvals. “That was not in line with our sense of urgency to help patients,” saids Oliveira. It could also have partnered with local companies and have them run the business on Alnylam’s behalf. But the distribution margins these companies ask are higher, and Alnylam’s products – and brand – would then be only a part of a basket of products in a sales call.

Instead, it adopted a hybrid strategy. Alnylam opened a legal entity, which allowed it to hire employees relatively fast, then partnered with a wholesaler that has all the import permits and licenses to be able to be the market authorization holder, host regulatory submissions and also manage the order-to-cash process. It did that in Brazil in 2019, a few months after receiving US and EU approvals for Onpattro, extending a similar model a year later to Argentina, and in 2021, to Colombia.

With this strategy in place, Alnylam made its first three regulatory submissions in Brazil in less than a year. In 2020 it received two approvals, for Onpattro and Givlaari (givosiran) and approval for Oxlumo (lumasiran), is expected later this year.

Exhibit 1. 

Named Patient Importations In Decline

In many LATAM countries, named patient importation (NPI) programs are tried and true ways to provide early access. The pathway allows companies having a product approved in Europe or the US to begin making it available through laws that guarantee citizens access to drugs through a judicialization process of petitioning the courts. The emphasis on NPI has diminished in importance in Brazil as regulators have sought to encourage development of rare-disease drugs.

In 2017, ANVISA implemented the orphan drug resolution, RDC 205/17, creating an accelerated pathway for approval. In addition, it waived requirements for the regulatory pathway for synthetic drugs that basically oblige companies to establish a local quality control lab. Under 205/17, companies can do this testing centrally. “Before this resolution, establishing quality was an expensive and painful process, adding months or years to your go-to-market timeline,” Oliveira said. “It used to take more than five years to get a drug approved in Brazil after the first commercial approval in the US,” he said. “Here, we are talking about no more than one year from the first approval.”

With the adoption of RDC 205/17, biotechs became more interested in entering Brazil, not only for commercialization but also for clinical trials, said Toni Daher, president of Febrararas, the Brazilian Federation of Rare Diseases Associations.

Around the same time, NPI – and pharma companies generally – got a black eye in Brazil following accusations that they abused the judicialization process. Brazils Spiraling Access Suits And The Potential Impact On Companies Aegerion Pharmaceuticals (now part of Amryt Pharma plc), for example, had received a US approval for its drug Juxtapid (lomitapide) in 2013, but appeared to drag its feet in securing approval in Brazil in order to perpetuate early sales under NPI. (The drug was finally approved in Brazil in 2020.) At the same time, Alexion Pharmaceuticals Inc. was probed for promoting Soliris (eculizumab) prior to its approval in Brazil in 2017.

The perception was that some companies decided to use NPI as the primary business model. In a single payer market, that could be perceived as the company indirectly generating demand at the government’s expense.

“Since those incidents, companies are more concerned about compliance and support more programs for public policy and to make their work happen in Brazil,” Daher said. “The organization between the patient communities and the scientific community is better.”

“Educational initiatives help support the perception that a foreign company is coming into Brazil and helping patients, not trying to squeeze the system with high-priced drugs to generate revenue,” Bedard added.

Sarepta Therapeutics, Inc. which is developing a portfolio of drugs for DMD, developed a high-impact education program around the disease that has been picked up by celebrities including the popular cartoonist Mauricio de DeSousa, who created a series of comics called “Monica’s Gang” to raise awareness of DMD in Brazil. Before PTC and Sarepta, it was almost impossible to get information about DMD, said Sheila Vasconcelos, patient advocate with the DMD patient group Aliança Distrofia Brasil.

“With this strategy, we were able to reach the patient advocates who were able to distribute these materials and talk about how it matters,” Fabio Ivankovich, general manager atSarepta, told In Vivo last year. “They are organizing events with our money.” As of last October, for a public relations investment of less than $500,000, Sarepta had distributed almost two million comic books and received 500 million views from TV and Internet.

Sarepta has three FDA-approved exon-skipping drugs to treat subgroups of the patient population. The company also started in 2020 to focus on LGMD (limb-girdle muscular dystrophy), supporting some investigator initiatives around registry activities. The first two, Exondys51 and Vyondys53, were denied in Brazil: ANVISA wanted more data to support the submission than the company had at the time. (The company is now focusing its efforts on the US.)

More Change Needed

Since COVID-19, Brazil has seen a proportional decrease in clinical trials activity. In 2018, the country had 2.1% of the worldwide volume of trials. That percentage was down to 1.8% as of the close of 2020, said Paolo Fernandes, IQVIA’s clinical trials site management head, Brazil.

Generally speaking, the approval process for clinical research remains cumbersome, said Giugliani, with a local ethics committee, a national ethics committee, local biosafety committees, national biosafety committees and ANVISA all running in parallel. “The process is becoming more effective in terms of timelines but is still a very complicated process to get approval for a clinical trial, especially in gene therapy,” he says. A bill to reduce bureaucracy in clinical research and cut the time it takes to secure approval for conducting studies, first introduced in 2017, is still pending. Brazilian Industry Pushes For Clinical Research Bill To Proceed

The 2017 regulations for ultra-rare diseases, which no longer require the sponsor of a clinical trial to provide the drug for life, has spurred interest. But that only holds for a narrow category of drugs. A January 2020 report from the Brazil trade association Interfarma noted that, despite the fact that CONEP, the Brazilian ethics overseer, published resolution 563/2017, which regulates some aspects of supply of the test drug after the clinical trial in ultra-rare diseases, the absence of a broad legislation that establishes rules, responsibilities and mainly deadlines for post-trial supply, generates a series of costs and logistical problems.

Despite regulations aimed at assuring post-trial access to rare disease treatments for five years, post-approval drug supply continues to be a significant issue, Fernandes said. “It no doubt benefits patients because now industry can estimate their costs for post-trial access,” he said. The new rules add predictability, but under the definition used in Brazil, are very specific to ultra-rare diseases, he saids, and do not embrace other drugs, especially those for chronic diseases with higher treatment costs.

“Because there is no post-trial access provision, industry will always consider coming to another country instead of Brazil,” Fernandes said. “With a timeframe, we would be more competitive,” he added. Developers could predict costs, timeframe and duration and then consider these factors in their launch strategy.

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