For a long time, sickle cell disease patients have had few options. This should soon change, with several new drugs set to hit the market in the next few years, including gene therapies that could represent a cure.
Despite these new entrants an existing sickle cell player, Emmaus Life Sciences, which will soon go public via a reverse merger, thinks it will remain relevant. US sales of the group’s FDA-approved therapy Endari have started slowly, but Emmaus’s chief executive, Yutaka Niihara, tells Vantage that increasing awareness could be the key to turning things around.
This is despite question marks over Endari’s efficacy. These were underlined last month when European regulators recommended against approving the drug, which in this region is brand named Xyndari.
Endari’s active ingredient is the antioxidant L-glutamine. In sickle cell disease this is thought to reduce the stickiness of red blood cells, thereby improving blood flow to patients’ organs and reducing sickle cell crises, the painful episodes that are a hallmark of the disease.
However, it is unclear whether this is indeed the case. Endari’s phase III trial found a 25% reduction in the median frequency of sickle cell crises, which was initially non-significant with a p value of 0.063; a later analysis returned a p value of 0.05, which Emmaus hailed as a success.
This confusion did not seem to trouble the FDA, which gave Endari the nod for sickle cell disease in 2017.
But Europe’s CHMP recently ruled that the drug had not been proven to reduce sickle cell crises or hospitalisations. The organisation also raised concerns about a high number of drop-outs in the Xyndari versus placebo group, and that data on how the medicine worked in these patients were not available.
Apart from these efficacy questions, Endari's sales growth could be hampered by L-glutamine’s availability as a nutritional supplement. However, the company says the products are differentiated by the fact that the active ingredient used in Endari is pharmaceutical grade.
Despite all this, Mr Niihara is convinced that Endari will be able to hold its own if and when new sickle cell agents get approved.
Endari only brought in around $20m last year, but Mr Niihara points out that it was not launched until June 2018; Emmaus expects sales of $40-50m this year, he adds.
This should not trouble the incoming sickle cell therapies, which in terms of revenues are set to be headed up by Global Blood Therapeutics’ voxelotor and Bluebird Bio’s Zynteglo, according to EvaluatePharma sellside consensus. Voxeletor is closer to market, with Global Blood planning to file for US approval in the second half of this year after the FDA agreed to an accelerated pathway in December (Ash 2018 – Global Blood hammers home sickle cell advantage, 3 December 2018).
|The sickle cell landscape|
|Project||Company||Mechanism of action||Status||2024e sales ($m)*|
|Voxelotor||Global Blood Therapeutics||Sickle haemoglobin polymerisation inhibitor||Filing H2 2019||1,980|
|Zynteglo/Lentiglobin||Bluebird Bio||Haemoglobin beta gene therapy||Phase III to start end 2019||1,033|
|Crizanlizumab||Novartis||P-selectin antibody||Phase III||342|
|CTX001||Vertex/Crispr Therapeutics||Crispr-associated Cas9 gene therapy||Phase I/II||271|
|Rivipansel||Pfizer/Glycomimetics||Pan-selectin inhibitor||Phase III||136|
|*Sickle cell sales only. Source: EvaluatePharma.|
Meanwhile, Bluebird is set to start a phase III sickle cell study of Zynteglo – previously known as Lentiglobin – by the end of the year.
Speaking about Emmaus’s competitors Mr Niihara cites a scientific paper raising concerns about the safety of voxelotor’s mechanism, and questions Global Blood’s decision to focus on surrogate endpoints rather than hard outcomes. The accelerated approval filing will be based on haemoglobin improvements seen in part A of the Hope study, while the confirmatory trial will measure transcranial doppler flow velocity, an indicator of a patient’s risk of stroke.
For now, though, Emmaus has other things to worry about, including its entry onto the public markets. The group’s plan to reverse into Mynd Analytics took another step forward when it received regulatory clearance this week.
Emmaus chose this path rather than an IPO to minimise stock dilution, which Mr Niihara says was the most important consideration, although he concedes that there are pros and cons to each approach. “With a reverse merger we’re not going to have the reputable institutional investors that get involved in IPOs and we won’t be going out with a fanfare.”
Perhaps this lack of fanfare could be a problem if it really is publicity that Emmaus needs. The chief exec admits that Emmaus has been overshadowed by Global Blood and Bluebird, and as it stands this situation looks unlikely to change.