UniQure’s AMT-061 (etranacogene dezaparvovec) in haemophilia B is expected to achieve clinically significant results in its Phase III HOPE-B trial, despite divided expert opinion about the company’s decision to enrol patients with neutralising antibodies. While some experts said the decision broadened the target population, others were concerned the antibodies could counteract the drug’s mechanism of action (MOA).

According to a 28 June 2018 company press release, patients who enrolled in the open-label, single-dose, 56-patient HOPE-B trial (NCT03569891) trial were tested for the presence of pre-existing neutralising antibodies to adeno-associated virus serotype 5 (AAV5), a single-stranded DNA virus, but were not excluded from the trial based on their titers. The study tests etranacogene dezaparvovec in severe or moderately severe haemophilia B patients. Haemophilia B is a blood clotting disorder due to an inherited mutation of the gene for factor IX (FIX).

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Some experts expressed optimism about etranacogene dezaparvovec’s approval prospects and market uptake due to the sustained levels of FIX seen thus far in the Phase IIb data, but another saw a potential caveat to uptake in young adults, citing high alcohol consumption among this population. Etranacogene dezaparvovec could be priced between $2m and $5m if approved, experts said, adding the treatment would probably be reimbursed through an amortized scheme.

UniQure has a market cap of $2.43bn. Topline data from the HOPE-B trial is expected in 2020, according to a 3 September press release. Etranacogene dezaparvovec is expected to achieve peak sales of $710m in 2025, according to GlobalData consensus.

UniQure did not respond to a request for comment.

Clinical significance expected despite division on antibody inclusion

Most experts expected HOPE-B to have clinically significant results, despite the division of opinion about including patients with the antibodies. The Phase III trial measures FIX activity level as a primary endpoint.

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Preclinical data shows AAV5-based gene therapies such as etranacogene dezaparvovec may be clinically effective in patients with pre-existing antibodies to AAV5, according to the UniQure website. The inclusion of patients with antibodies was a strong feature of the trial design, said an investigator on the HOPE-B trial and Dr Lisa Boggio, assistant professor, Department of Pediatrics, Rush Medical College, Chicago, Illinois. It ensures patients with antibodies are not automatically excluded from future treatment, as is the case for many gene therapies for haemophilia, the investigator explained. Spark Therapeutics and Pfizer’s Phase I/II trial for their gene therapy SPK-9001 in haemophilia B excludes patients with the antibodies, according to ClinicalTrials.gov.

While patients will not be excluded from the HOPE-B trial based on their antibody titres, the cut-off point is undisclosed, according to a 6 July press release. As such, it is unclear whether the cut-off point is particularly high or low, and therefore whether it is significant, Boggio said. The proportion of the general population possessing these antibodies ranges between 20% and 50% depending on geographical location, the first and a second investigator said, with the second investigator adding the number is roughly 30% in the US.

The trial could potentially have poorer efficacy results due to the antibody exclusion criterion, said a second investigator and Dr Adam Cuker, associate professor of medicine, Hospital of the University of Pennsylvania, Philadelphia. When the viral vector carrying the gene is infused into the blood of a patient, those with antibodies will fight off the viral infection so the vector does not reach the liver or get deposited, which in turn does not allow for the increase of FIX levels, the second investigator explained.
However, assuming only patients with low levels of antibodies will be included and those with high levels of antibodies will be excluded, clinically significant results will likely be attained, Cuker said. The Phase IIb trial (NCT03489291) for etranacogene dezaparvovec saw clinically meaningful FIX activity levels observed in patients with antibody titers up to 1:341, according to an 11 July 2017 company press release.

The drug must attain an FIX level of 15% to protect against spontaneous bleeds, Cuker said, while the first investigator set the benchmark for clinical significance at 20–30%. Boggio and the third investigator set a higher standard of 30%, adding they thought this target would be achieved based on previous results.

At 36 weeks of follow-up, all three patients in the Phase IIb trial saw sustained increases in FIX levels after one-time administration, with two maintaining activity in the normal range at 54% and 51%, according to the July press release. Mean FIX activity for the three patients at 36 weeks after administration was 45%, the release stated. While neutralising antibodies should theoretically block the drug’s MOA, preceding trial results suggest it will achieve clinically significant results in HOPE-B, a third investigator said. However, long-term data from a larger population is needed to be certain on efficacy, Cuker and the third investigator said.

Mostly positive approval, uptake prospects despite alcohol caveat

Approval would likely be straightforward since FIX levels have not declined, suggesting the drug produces a steady response, Boggio and the first investigator said. In terms of patients with antibodies, previous studies suggest the therapy may be viable for at least 97% of haemophilia B patients, according to the 28 June 2018 press release.

However, it is unclear whether the FDA wants to see FIX levels measured by chromogenic assay or an alternative test, the third investigator said. Until it is known what kind of results the FDA is looking for, approval remains questionable, she explained.

While the first investigator said the drug would suit a broad adult population, Cuker, Boggio and the third investigator said young adults have expressed greater enthusiasm about gene therapy due to their active lifestyle and strong desire for a complete cure. A potential caveat to uptake in this population is excessive alcohol consumption, the third investigator added.

Gene therapies require patients to cease alcohol consumption for some time post-treatment because the viral vector is delivered through the liver, the second investigator explained. As young adults are more likely to drink alcohol, physicians may be cautious when prescribing the treatment due to doubts over whether patients would follow instructions, the third investigator explained.

Amortized scheme structure will depend on duration of response

Despite the high costs associated with gene therapies, the price-benefit profile could tip in favour of strong uptake, Cuker said. The current standard of care for patients with severe haemophilia B is prophylaxis with factor infusions or Roche’s Hemlibra (emicizumab-kxwh), which costs approximately $500,000 per year for an adult male patient. If this therapy costs $1.5m, the price will be covered in just three years of treatment, Cuker explained.

However, a gene therapy of this kind would likely be priced between $2m and 5m, said Joel Hay, PhD, professor of pharmaceutical and health economics, USC School of Pharmacy, Los Angeles, California, and Jonathan Greuber, PhD, Ford professor of economics, Massachusetts Institute of Technology, Cambridge. This price could edge towards the higher end of the scale prior to rebates and discounts if the drug proves truly curative in terms of demonstrating sustained FIX levels, they explained.

The treatment would be reimbursed through an amortized scheme, Hay and Greuber said. If the treatment is not fully curative and FIX levels drop after a certain number of years, the amortized scheme would be value-based, according to Hay. In this situation, annual payments would be given at regular instalments as long as FIX levels were sustained, Hay added.

by Ayisha Sharma in London

Ayisha Sharma is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.

Cell & Gene Therapy Coverage on Clinical Trials Arena supported by Cytiva.

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