Upcoming events – Jazz and Macrogenics look to phase III readouts

Jazz wants to expand its sleep portfolio, while Macrogenics hopes trial data will support its first new drug application.

Welcome to your weekly digest of approaching regulatory and clinical readouts. While Jazz Pharmaceuticals awaits a US FDA decision on solriamfetol for sleep apnoea and narcolepsy, another big catalyst is approaching for its sleep portfolio – phase III data from JZP-258.

Launching JZP-258 will be an important moment in the Jazz product life cycle. A low-sodium oral solution version of Xyrem, JZP-258 is expected to start picking up sales around the time Xyrem faces generic competition.

JZP-258 is a mixture of oxybate salts, and its lead indication is identical to that of Xyrem, namely cataplexy and excessive daytime sleepiness in narcolepsy. The phase III trial compares the new formulation with placebo in 130 patients. The design calls for all enrolees to take JZP-258 for 12 weeks, after which they will be randomised to either continue on the active drug or be withdrawn with a placebo substitute for 21 weeks.

The two arms will be compared based on the number of cataplexy attacks per week, and as a secondary endpoint, change on the Epworth sleepiness scale. Presumably, for JZP-258 to appeal to physicians and payers it will need to look at least as good as Xyrem, although the two agents are not being compared directly.

In Xyrem’s randomised withdrawal trial, patients on active drug did not see an increased number of cataplexy attacks over baseline numbers during the withdrawal stage, while those taking placebo experienced a median of 21 more episodes in two weeks.

On the Epworth sleepiness scale, patients taking 6mg of Xyrem saw a median reduction of two points and those taking 9mg a reduction of five points, compared with 0.5 points for patients taking placebo.

From a commercial standpoint, the advantage of the low sodium formulation could be limited. After speaking with a payer representative in early 2017, Leerink analyst Jason Gerberry noted that most of the narcolepsy patients in that payer’s plans already exceed dietary limitations on sodium intake. Therefore, reducing daily sodium intake by up to 1.6g may not have much benefit except in the case of patients with dietary restrictions, which represents about one-third of narcolepsy patients.

Jazz is also testing JZP-258 in idiopathic hypersomnia, which could help differentiate it from Xyrem.

Replacing Xyrem: the Jazz sales forecast
    WW  sales ($m)
Product Therapeutic Subcategory 2018e 2020e 2022e 2024e
Xyrem Other CNS drugs 1,392 1,557 1,462 961
Solriamfetol Psychostimulants - 138 338 489
Vyxeos Other cytostatics 103 203 313 404
JZP-258 Other CNS drugs - 29 198 297
Defitelio Cerebral & peripheral vasotherapeutics 154 209 247 279
Erwinaze Other cytostatics 171 193 221 242
FazaClo Anti-psychotics 6 5 4 4
Total   1,826 2,335 2,783 2,675
Source: EvaluatePharma.

JZP-258 is expected to achieve sales of $297m in 2024, according to EvaluatePharma’s consensus of sellside analysts. This will help offset some of the losses from Xyrem’s patent expiry in 2023. Sales of Xyrem are forecast to peak at $1.6bn in 2020 and shrink to $961m by 2024.

Trial ID 
JZP-258 in narcolepsy with cataplexy NCT03030599
JZP-258 in idiopathic hypersomnia  NCT03533114

Large margetuximab

Macrogenics drew unwanted attention a month ago when it was forced to announce that trials of its bispecific antibody, MGD009, had been halted on safety concerns. Its main driver of growth, margetuximab, remains intact, though, and the Maryland-based company is due to report data from its phase III Sophia trial in second-line or later HER2-positive metastatic breast cancer, in which margetuximab is pitted in combination with chemotherapy against Herceptin and chemotherapy in 530 patients.

This week, Macrogenics executives told analysts that the trial had accrued enough progression-free survival events to proceed to final analysis, so readout could be imminent. The company believes the drug might work best as a third- or fourth-line option, where no consensus treatment exists – Herceptin is sometimes used – and median progression-free survival is 3.3 months. This stage of breast cancer represents 18,800 patients annually.

In initiating coverage on Macrogenics in May 2018, Evercore ISI analysts wrote that they believe Sophia has a low probability of success because the dose being used here did not generate a response in earlier trials. Moreover, going up against Herceptin presents a major challenge – a chemo combo trial managed to yield 8.2-month progression-free survival in this setting.

Margetuximab is expected to achieve sales of $440m in 2024. A successful readout would likely bring big companies to the table to discuss potential partnerships or acquisitions. With a market capitalisation of $603m and 10 projects in the clinic, Macrogenics could represent a relatively low-risk bet for any biopharma group looking to beef up its pipeline.

Trial ID
Margetuximab + chemo vs Herceptin + chemo in HER2+ metastatic breast cancer progressing after anti-HER2 therapies NCT02492711

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