Zolgensma Provides No Proven Benefit Over Spinraza In SMA, Says German HTA
IQWiG Laments Lack Of Comparative Data
Executive Summary
IQWiG, Germany’s health technology appraisal institute, has found that Novartis’s gene therapy Zolgensma offers no additional benefit compared with Biogen’s Spinraza for treating spinal muscular atrophy, while Roche’s Evrysdi offers a hint of benefit in one patient group.
Novartis AG says it wants a rethink of the way medicines are valued, and Roche Holding AG would like the German system for evaluating medicines to be more open to real world evidence.
The comments come after the German health technology appraisal institute, IQWiG, carried out separate benefit assessments comparing Roche’s Evrysdi (risdiplam) and Novartis’s gene therapy Zolgensma (onasemnogene abeparvovec) with Biogen’s Spinraza (nusinersen) for the treatment of spinal muscular atrophy, a rare progressive disease.
According to IQWiG, Evrysdi, an oral disease modifying therapy, offers a hint of unquantifiable added benefit over Spinraza for SMA type 1, but no added benefit for Zolgensma has been proven over Spinraza for any type of SMA.
IQWiG pointed to a lack of comparative data that made it difficult to understand which of the three products might be suitable in different situations. “It is good news that three drugs for this severe disease have come onto the market in a short time, but the currently available data are insufficient, even for SMA type 1," said Thomas Kaiser, head of IQWiG’s Drug Assessment Department.
He said that differences between populations across different studies made indirect comparisons more difficult. “Sometimes children were included in whom the respiratory system was already severely affected, and sometimes they were not. And no comparative studies have been conducted for either of the new drugs in [comparison with] nusinersen… This does not make it easy for physicians and parents to choose the suitable therapy for these very young patients."
IQWiG’s assessments were part of the AMNOG benefit assessment process, which compares a new drug’s benefits with those offered by treatments already on the German market. This is an important process for companies marketing products in Germany as the ratings the product receives can impact the final price that the company can charge following the statutory 12 months of free pricing.
Orphan drugs that generate less than €50m ($60m) in sales in Germany are exempt from a full assessment and undergo an abridged process that does not require comparative datawith some level of additional benefit automatically conferred. IQWiG conducts an initial assessment but the G-BA, the committee in charge of pricing and reimbursement, makes the final decision on the drugs’ additional benefits before price negotiations with health insurers begin.
The full Zolgensma assessment comes after the gene therapy exceeded the €50m threshold following high sales last year. (Also see "Zolgensma Loses Orphan Benefit in Germany After 'Very High Sales'" - Pink Sheet, 10 Dec, 2020.)
Zolgensma
Zolgensma targets the root cause of the disease, with a modified virus delivering intact versions of the SM1 gene to the cell nuclei.
The comparator chosen for Zolgensma in SMA types 1 and 2 and in pre-symptomatic babies was Spinraza. For SMA type 3, the comparator was the physician’s choice between Spinraza and best supportive care (BSC). According to IQWiG, no suitable data were available for three of the four groups.
IQWiG pointed to a number of issues with the data. For example, for children with SMA type 1, the manufacturer compared individual arms of studies on Zolgensma and Spinraza. “Such comparisons are only interpretable if the study populations are sufficiently similar. This was not the case here,” the institute said.
It explained that children treated with Zolgensma were “notably younger” when they received treatment than the children in the Spinraza study were when they received their first dose of treatment. IQWiG said that outcomes were more favorable the earlier treatment was started.
In addition, the inclusion and exclusion criteria for ventilation and respiratory symptoms differed between the studies. Children receiving Spinraza had a less favorable prognosis than those treated with Zolgensma.
However, Novartis told the Pink Sheet that it believes the studies it included in its submission to IQWiG were “sufficiently similar to allow for an assessment of the additional benefit of Zolgensma over nusinersen.”
It said that when the clinical trial program for Zolgensma was designed, there were no available disease modifying treatments for SMA. “Therefore single arm studies were deemed to be appropriate,” it declared. “Since IQWiG has decided to assess the additional benefit of Zolgensma over nusinersen, such an assessment can only be conducted via an indirect treatment comparison.”
Novartis went on to say that Zolgensma has demonstrated a significant and clinically meaningful therapeutic benefit in pre-symptomatic and symptomatic SMA. “This includes prolonged event-free survival and achievement of motor milestones unseen in natural history of the disease and, to date, sustained for more than five years post-dosing.”
The company pointed out that real world evidence is being gathered to support the use of the drug in clinical practice. Last year the product became the first to be affected by new legislation that would allow the G-BA to mandate companies marketing orphan or conditionally approved medicines to collect real world evidence to close any evidence gaps. (Also see "Zolgensma First To Be Subject To New German Data Collection Rules" - Pink Sheet, 18 Aug, 2020.) The data will include children with pre-symptomatic and symptomatic SMA treated with Zolgensma or Spinraza collected through three studies: RESTORE, the SMART Study and the long-term follow-up studies LT001 and LT002.
Novartis says it is looking forward to collaborating on this “innovative project” and to ongoing dialogue with health authorities and payers to allow access to transformative treatments like Zolgensma.
Evrysdi
For children with SMA type 1, there was a hint of non-quantifiable added benefit for Evrysdi compared with Spinraza. IQWiG said this was largely because Evrysdi comes as a soluble powder that is taken orally once a day, whereas Spinraza is delivered via injection into the spinal canal. This means that treatment with Evrysdi “eliminates” the risks of repeated injections into the spinal canal.
Roche said it had expected IQWiG’s conclusions for SMA type 2, noting that the Pivotal SUNFISH study showed that Evrysdi showed a clinically relevant benefit over best supportive care in type 2 and 3 patients.
“An indirect comparison versus nusinersen was not feasible due to the different characteristics of the patients included in the risdiplam (SUNFISH) and Nusinersen (CHERISH) studies - the SUNFISH population being significantly older and with more advanced disease status. Therefore, no suitable data to derive an additional benefit is available for patients with SMA Type 2 or Type 3,” the company noted.
Meanwhile, for SMA type 3, Roche said that after it had submitted its dossier, IQWiG changed the appropriate comparative therapy from best supportive care to therapy according to physician’s instructions, with the choice of nusinersen or best supportive care.
“Since SUNFISH only compares risdiplam versus best supportive care, IQWiG did not recognize an additional benefit for methodological reasons,” the company said. It added that a clinically relevant benefit of risdiplam over BSC was demonstrated in the SUNFISH trial for SMA Type 3 patients.
IQWiG also did not recognize any additional benefit in pre-symptomatic patients compared with Spinraza or therapy according to physician’s choice with selection of best supportive care or Spinraza because no suitable data was available.
However, according to Roche, the RAINBOWFISH study, which is still recruiting, is evaluating pre-symptomatic patients treated with the drug. Recently presented preliminary data show that of the five babies treated with Evrysdi for at least 12 months, all achieved sitting without support, rolling and crawling, said Roche.
The company is preparing a written statement to address IQWiG’s assessment and preparing for an oral hearing due to take place in early September, where the company will try to reinforce its position that Evrysdi shows additional benefit compared with Spinraza for SMA Type 1 and compared with BSC for SMA Type 3 patients, and that it has high value in clinical practice for treating all SMA patients.
The Case For Change
Roche says it fully supports the AMNOG process to ensure pharmaceutical products add value to the healthcare system. However, “at the same time (and generally speaking), we would welcome a process that is more open to additional forms of real-world evidence.”
Meanwhile, Novartis says that the introduction of one-time gene therapies requires a re-think of how the value of treatments is defined, as well as how the healthcare system manages diagnosis, treatment, care and associated costs for patients with ultra rare diseases.
Gene therapies, when compared with contemporary medicines, could potentially cut the financial burden on both patients and healthcare systems by replacing chronic treatment with a single administration, says Novartis. However, despite these advantages, how to pay for these novel treatments remains a challenge, it added.
“Many healthcare systems have not established the infrastructure needed to reimburse one-time treatments that may have lifelong benefits and therefore new payment models have been developed, such as annuities that can spread the cost over multiple years or pay-for-performance approaches that allow the option to pay in installments over several years, with the possibility to refund payment if the treatment is not successful.”
Novartis says its “Day One” access program was designed to allow rapid access with “customizable” options that are designed to work within local pricing and reimbursement frameworks while still recognizing the novel nature of a one-time gene therapy that treats a “devastating and progressive disease.”
The Day One program includes options such as retroactive rebates; deferred payment and installment options; outcomes-based rebates; robust training for the treating institutions; and access to the RESTORE registry of patients diagnosed with SMA.
“To date, access pathways in 12 European countries are established, representing 47% of the European population, including in England, Scotland, Germany, France and Italy, as well as in six countries in the Middle East and Africa including Israel and Egypt,” said Novartis.