Roche Plans Price Reduction for SMA Therapy Amid Intensifying Competition Among Gene Therapy, RNA-Based Treatment, and Oral Drug

Recently (January 13–16, 2020), the 38th J.P. Morgan Healthcare Conference was in full swing at the Westin St. Francis on Union Square. In an interview, William Anderson, CEO of the Swiss pharmaceutical giant Roche, stated that the company’s strategy in the competitive market for spinal muscular atrophy (SMA) therapies is to reduce costs. This draws attention to the therapeutic market for SMA.

Spinal Muscular Atrophy (SMA)

Spinal Muscular Atrophy (SMA) is a rare hereditary neuromuscular disorder caused by biallelic deletion or mutation of the SMN1 gene, which encodes the survival motor neuron (SMN) protein. This mutation blocks the production of the SMN protein, which is essential for transmitting motor signals from the brain to the muscles. Consequently, the disease is characterized by the loss of motor neurons in the spinal cord and lower brainstem, leading to severe, progressive muscle atrophy and wasting, often accompanied by impairments in movement, respiration, and swallowing. The debilitation caused by SMA is often fatal. Approximately one in every 10,000 live births is diagnosed with SMA, and the disease affects individuals of all ages.

In addition to the SMN1 gene, the human body also contains a similar gene, SMN2. Most of the SMN protein produced by SMN2 is non-functional and cannot compensate for the deficiency in SMN protein caused by SMN1 mutations. Fortunately, the functional protein produced by the SMN2 gene can delay the onset of the disease and alleviate its symptoms. Therefore, targeting the SMN2 gene can help slow down disease progression.

This disease can be classified into four types based on the age of onset and severity. Type I is the most common and also the most severe, with symptoms becoming apparent within the first few months after birth. It often leads to early respiratory failure and death in infants; most patients with Type I SMA do not survive beyond two years of age, with a mortality rate of 50% by seven months and 90% by twelve months. Type II has an onset between 6 and 12 months of age, and patients may live into their 20s or 30s. Patients with Type III (older children and young adults) and Type IV (adults and the elderly) typically have a normal life expectancy.

Each has its pros and cons; pricing is particularly important.

Currently, there are two approved treatments for spinal muscular atrophy (SMA): Biogen’s Spinraza and Novartis’s gene therapy Zolgensma. Spinraza is priced at $750,000 for the first year and $375,000 annually thereafter. Novartis’s Zolgensma, considered a one-time curative therapy, is priced at $2.125 million per dose, making it the most expensive drug in the world.

Zolgensma — Novartis

Zolgensma is designed to deliver a functional copy of the human SMN gene by loading a transgene capable of normal SMN protein expression into an AAV9 viral vector, with the transgene modified to enhance its ability to produce SMN protein. It is the first and only gene therapy approved by the FDA for the treatment of spinal muscular atrophy (SMA) (approved exclusively for SMA Type I), which halts disease progression by enabling sustained in vivo expression of SMN protein through a single intravenous infusion, thereby addressing the genetic root cause of SMA.

This gene therapy has received Breakthrough Therapy designation from the U.S. FDA, PRIME medicine designation from the European Union, and SAKEGAKE (pioneer drug) designation from Japan. Since its market launch, Zolgensma has sparked widespread discussion due to its high price; currently, 20 insurance coverage plans have been implemented. In December 2019, Novartis proposed a lottery-based selection process for infants with the disease to receive this gene therapy, which not only surprised the public but also aroused extensive curiosity and attention toward the treatment. According to Novartis's third-quarter performance report, Zolgensma has been used to treat more than 100 patients since its launch and generated $160 million in revenue for the company in Q3 2019.

Spinraza —— Biogen

Spinraza (nusinersen) is a modified antisense oligonucleotide (ASO) that binds to pre-mRNA transcribed from the SMN2 gene, thereby altering mRNA splicing and increasing the production of full-length functional SMN protein. The drug is administered via intrathecal injection, delivering it directly into the cerebrospinal fluid (CSF) surrounding the spinal cord. Spinraza is indicated for all types of spinal muscular atrophy (SMA).

In December 2016, Spinraza received approval from the U.S. FDA for marketing to treat pediatric and adult patients with spinal muscular atrophy (SMA), becoming the first new drug approved in the United States for SMA treatment and currently the only therapy approved for infants, children, and adults with SMA. In July 2019, after four years of treatment, Biogen announced breakthrough results: 100% of children treated with the drug were able to sit upright, and 88% of patients could walk independently without assistance.

Spinraza is currently marketed in more than 40 countries, and it was approved in China at the end of February 2019. Since its launch in 2016, Spinraza’s sales have grown rapidly, far exceeding early expectations. Global sales reached $1.8 billion in 2018, and revenue totaled $547 million in the third quarter of 2019, representing a 17% year-over-year increase and a 12% quarter-over-quarter increase.

Risdiplam —— Roche

Roche’s SMA candidate product, risdiplam, has not yet received formal approval for marketing. Risdiplam is an investigational survival motor neuron 2 (SMN2) splicing modifier designed to increase and maintain SMN protein levels throughout the central nervous system and peripheral tissues. On November 25, 2019, the U.S. FDA accepted the New Drug Application (NDA) for risdiplam and granted it Priority Review, with a decision on approval expected by May 24, 2020. Previously, the FDA had granted orphan drug designation to risdiplam in January 2017, followed by Fast Track designation in April 2017. If approved, risdiplam would become the first oral medication for the treatment of patients with spinal muscular atrophy (SMA).

In November 2019, Roche announced positive data from Part 2 of the pivotal SUNFISH study, which evaluated the oral drug risdiplam in patients aged 2–25 years with Type II or Type III spinal muscular atrophy (SMA). The results demonstrated that the study met its primary endpoint, defined as the change from baseline in the Movement Function Measure 32 (MFM-32) scale score: after one year of treatment, patients receiving risdiplam showed significant improvement in motor function compared with those in the placebo group. To date, no treatment-related safety findings leading to discontinuation from the studies have been identified across all clinical trials evaluating risdiplam. The safety profile of risdiplam is consistent with known safety information, and no new safety signals have been observed.

Roche Plans to Compete on Price

In terms of administration, Novartis’s Zolgensma, a gene therapy, is administered via a single intravenous infusion and is theoretically a one-time curative treatment; Biogen’s Spinraza requires dosing every four months and lifelong treatment; Roche’s Risdiplam is an oral medication.

In terms of pricing, the cost of Spinraza treatment is $750,000 for the first year and $375,000 annually thereafter, while Zolgensma treatment costs $2.125 million. Since Spinraza requires lifelong administration, Zolgensma proves more cost-effective in the long run; compared with regular treatments, patients may prefer one-time gene therapy. More importantly, the significant increase in newborn SMA screening is expected to drive future revenue for Zolgensma. Novartis previously stated that over 50% of patients receiving Zolgensma had discontinued Spinraza treatment, preferring the one-time therapy.

However, regarding indications, Zolgensma is approved only for the treatment of patients under 2 years of age with Type I SMA; Spinraza is approved for all four types of SMA; and Risdiplam is currently in multiple clinical stages for the treatment of Type I, II, and III SMA. Zolgensma was also being evaluated in older patients, but the trial was halted due to safety concerns; nevertheless, Novartis expects the FDA to approve the resumption of this trial. With the emergence of additional clinical data, it is predicted that Novartis will submit a marketing application for Zolgensma for the treatment of Type II and Type III SMA in 2020.

Currently, both Zolgensma and Spinraza face competition from the orally administered Risdiplam, particularly Spinraza.

Zolgensma, as a one-time curative gene therapy, offers distinct advantages. However, data integrity issues that emerged in August 2019 sparked considerable controversy and drew unusual criticism from the U.S. Food and Drug Administration (FDA). Nevertheless, the FDA maintained that the therapy should remain on the market, as these issues did not affect its safety or efficacy.

Both risdiplam and Spinraza modulate SMN2 and have similar indications, so they may be considered treatment options for older patients. As an oral medication, risdiplam may offer advantages over Spinraza, which requires administration every four months.

Previous analyses projected that Risdiplam’s sales would reach $760 million in 2024, while Zolgensma’s sales during the same period were expected to climb to $1.57 billion. Spinraza currently generates annual sales of approximately $2 billion; however, under competitive pressure from these two drugs, its sales in 2024 may decline to $1.5 billion.

Roche CEO William Anderson has not yet disclosed the actual expected price of Risdiplam, but stated that the company will adopt the same pricing strategy it used in 2017 for its hemophilia drug Hemlibra, when it needed to compete with Novo Nordisk and Takeda Pharmaceutical. In an interview at the JPMorgan Healthcare Conference, Anderson said, “Our goal is to make our price satisfactory.”

Currently, the pricing of Risdiplam is particularly critical. Roche expects to obtain approval from the U.S. FDA by May 24, 2020, and has stated its intention to price the drug lower than those offered by Biogen and Novartis to strengthen its position in the third-largest market. Notably, a 2009 study found that with proper nutritional and respiratory care, a greater proportion of these patients survive beyond two years of age. Patients with Type II and Type III spinal muscular atrophy (SMA) typically live into adulthood and may have a normal life expectancy, although they require substantial medical care.

In addition, Novartis is also studying an oral drug for the treatment of SMA, named Branaplam. Previously, Novartis BiopharmaMedicineJay Bradner, the institute’s director, hinted that the company was less interested in the drug, stating, “Novartis does not see a significant opportunity for oral therapy in this field; otherwise, we would further develop this molecule.” Novartis later reversed its stance somewhat, announcing that it would continue the trials of branaplam and decide whether to proceed based on data to be released later this year. This development has made the SMA treatment market more intriguing.

With the market launch of Risdiplam on the horizon, the SMA field is set to witness a new round of market competition!

References:

https://www.biospace.com/article/roche-plans-to-beat-biogen-and-novartis-on-sma-therapy-price/?keywords=Roche

https://www.evaluate.com/vantage/articles/analysis/spotlight/threats-spinraza-are-mounting-biogen-still-has-cards-play

Source: E-Health Guest