Healthcare Policy, Market Access, Outcomes & Research

The Efficacy Sticking Point in the Post-Glybera Era for Gene Therapies and Ultra Orphan Drugs

The Efficacy Sticking Point in the Post-Glybera Era for Gene Therapies and Ultra Orphan DrugsThis April, Glybera (alipogene tiparvovec), a gene therapy developed by Dutch firm Amsterdam Molecular Therapeutics (AMT) for use in patients with lipoprotein lipase deficiency (LPLD), finally received a negative approval recommendation from the EMA’s approvals committee CHMP. Glybera, which had been expected by some to become the first gene therapy approved in Europe, took something of a circuitous and protracted path through the EMA—one with potentially important lessons for gene therapies and (ultra) orphan drugs more generally.

Efficacy Criteria and (Ultra) Orphan Drugs
The CHMP previously issued two negative recommendations for Glybera. April’s recommendation came after considering approval in a subset of patients at the request of the European Commission Standing Committee. While it is significant—and a testament to scientific progress—that serious concerns over safety did not figure in the CHMP’s recommendation, questions over efficacy did—something which has proved to be a sticking point before, notably in the case of Ark Therapeutics’ Cerepro, another candidate once hoped to be the first gene therapy to be approved in Europe.

LPLD, currently lacking treatment options, is an ultra-rare autosomal recessive disorder in which failure to metabolise chylomicrons leads to severe hyperlipidaemia and recurring pancreatitis. AMT relied on three trials for its evidence base:

  • CT AMT-010: enrolled 8 patients and assessed reduction in median fasting plasma triglyceride concentration;
  • CT AMT-011-01: enrolled 14 patients and also evaluated effect on fasting triglyceride; and
  • CT AMT-011-02: enrolled 5 patients and evaluated the effect on postprandial chylomicron metabolism, as well as plasma fatty acid and glycerol appearance rates

In its final recommendation, the CHMP considered that there was insufficient evidence of persistence of effect shown in a ‘clinically relevant manner,’ and that improvements in pancreatitis risk could have been due to other factors. The CHMP also determined that long-term data were not available for a sufficient number of patients.

One can wonder whether, in reaching this conclusion, the CHMP has not set the bar too high for many ultra-orphan drugs. As an ultra-rare disorder, LPLD is estimated to affect around one to two people per million, therefore challenging attempts to recruit sufficient patient numbers. In terms of clinical trial design, there has been some debate over choice of endpoints, with the correlation between plasma triglycerides levels and incidence of pancreatitis called into question. Indeed, prior to the final CHMP outcome, the CEO of AMT is quoted as saying that he believed the EMA would accept chylomicron levels as a better marker for reduction in pancreatitis risk; the company had hoped that post-hoc analysis of chylomicron levels in patients not in the CT AMT-011-02 trial would address CHMP concerns over efficacy. As pointed out by Alastair Kent OBE, Director of Genetic Alliance UK and President of the European Genetic Alliances’ Network, AMT had in fact availed itself of scientific advice on trial design made available by the EMA.

And Let’s Not Forget What Lies Downstream…
Having recently participated in our study on what payers look for in relative effectiveness assessment, I would be interested to know how these stakeholders would respond to the evidence base supplied by AMT…especially given our finding that, though a number of countries may in theory have policies for relaxing reimbursement decision-making criteria for orphan drugs (or ‘rules of rescue’ may operate for those diseases with no existing treatment options), in practice, there are many examples of candidates failing at this hurdle.

With a growing number of candidates in the gene therapy pipeline, it shouldn’t be long before another aims to make it past the regulatory post—and, when this occurs, it will be very interesting to see how European payers react to the efficacy issue.

About Cameron Lockwood

Cameron Lockwood is an analyst within the multi-client study team. He has a background in the life sciences, experience in market access, and specialises in the healthcare policy environment.


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