Go or no go? August FDA decisions for Axsome, Sanofi and Merck

Axsome and Sanofi face FDA verdicts in depression and Pompe disease respectively, while a Keytruda combo ups the ante in kidney cancer.

As we head into the last month of summer one of the biggest regulatory events left for the year approaches: the FDA decision on Axsome’s major depressive disorder project AXS-05. Elsewhere, Sanofi’s next-gen Pompe disease therapy avalglucosidase alfa could struggle commercially against the company’s own approved therapy. 

In oncology, Keytruda and Lenvima have impressed in front-line kidney cancer and hope to edge out the competition. And, while a definite Pdufa date for Fibrogen/Astrazeneca’s ill-fated roxadustat has not been disclosed, this could come next month.  

Roxadustat, a HIF-PH inhibitor, is as a treatment for anaemia associated with chronic kidney disease in patients on and pre-dialysis. Cardiac safety issues have plagued it, and a highly negative adcom in July means that US approval is unlikely (Panel puts Fibrogen project to an almost certain death, July 16, 2021).  

Axsome’s first

Axsome could gain its first approved product next month. AXS-05 is filed for use in major depressive disorder, where it could become the first rapid-acting agent to market, ahead of Sage/Biogen’s zuranolone.

Axsome’s phase 3 Gemini study showed that AXS-05 significantly improved patients' depressive symptoms versus placebo at six weeks, as well as hitting several secondary endpoints (Axsome rides the bull case, December 17, 2019). 

long-term safety study called Comet showed no new toxicity signals, and discontinuations were low at 8.4%. Remission from depression after treatment with AXS-05 was achieved by 52.5% of patients at week six, and this was sustained or increased with long-term treatment, with 68.7% and 69.0% of patients respectively in remission at six and 12 months

While an approval looks likely, AXS-05 could have trouble commanding a premium price given that it comprises two generically available medicines: buproprion, the active ingredient in Glaxosmithkline’s depression blockbuster Wellbutrin, and the cough medicine dextromethorphan.  

Sanofi’s incumbent 

Sanofi will be hoping that its next generation enzyme replacement therapy (ERT) avalglucosidase alfa can get FDA backing in Pompe disease next month. The decision had been due in May but was postponed for three months for undisclosed reasons.

If approved, avalglucosidase could struggle commercially; Sanofi’s own first-generation ERT Myozyme, also called Lumizyme, is expected to remain market leader. 

Although Sanofi had hoped that avalglucosidase alfa would be more potent than the older drug, the pivotal Comet study, in late-onset disease, only managed to demonstrate non-inferiority to Myozyme/Lumizyme on the primary endpoint of forced vital capacity.

A phase 2 study called mini-Comet, in infantile-onset disease, is also part of the filing.

Myozyme/Lumizyme has been approved for over 10 years, and sales are forecast to reach $1.2bn by 2026, according to Evaluate Pharma sellside consensus. Avalglucosidase comes in second place, with $372m by 2026.  

Amicus’s AT-GAA was once seen as a real competitive threat to Sanofi’s Pompe franchise, but also failed to beat Myozyme in its pivotal Propel study (Amicus fail dents Pompe pipeline, February 12, 2021). Despite the setback a rolling BLA submission for AT-GAA is ongoing. 

Gene therapy approaches could offer longer-term options for patients, but assets from Bayer and Astellas are still in early development. This leaves Sanofi with the Pompe market sewn up for now.

Edging out the competition 

Meanwhile, a combination of Merck & Co’s Keytruda and Eisai’s tyrosine kinase inhibitor Lenvima is up for a supplemental Pdufa towards the end of the month in front-line kidney cancer.

The Clear/Keynote-581 study showed a spectacular 61% reduction in risk of progression or death versus Sutent, Pfizer’s first-line standard of care. However, the TKI was, as expected, associated with high levels of toxicity, with serious treatment-related adverse events seen in 72-73% of patients in two Lenvima cohorts, versus 59% for Sutent. 

The Merck/Eisai therapy could join a four-way battle in first-line disease, and looks to have the edge over competition that includes Opdivo plus Cabometyx. That combo, from Bristol Myers Squibb and Exelixis, was approved in January on the basis of the Checkmate-9ER study (Esmo 2020 puts Opdivo and Cabometyx back in the game, September 19, 2020).

The other threatened therapies include Pfizer’s Bavencio plus Inlyta, which looks distinctly inferior to the Merck/Eisai therapy, while Merck’s own Keytruda plus Inlyta also underperforms the Lenvima combination (Asco-GU – Clear blue water between Keytruda and kidney cancer rivals, February 13, 2021). 

The tables below list first-time and supplementary US approvals due next month, with consensus forecasts from Evaluate Pharma.

Notable first-time US approval decisions due in August
Project Company PDUFA date Indication(s) 2026e sales by indication ($m) Note
Evrenzo (roxadustat) Fibrogen/Astrazeneca/
Est Aug Anaemia in patients with chronic kidney disease on/not on dialysis 2,558* Negative adcom in July (Panel puts Fibrogen project to an almost certain death)
TicoVac Pfizer Aug Tick-borne encephalitis 217 Vaccine, already on the market in Europe
Topiramate oral solution Eton Aug 6 Tonic-clonic seizures, partial-onset seizures, and as preventative treatment of migraine - Topiramate is the active ingredient in Topamax and Trokendi XR
Vicineum Sesen Bio Aug 18 High risk BCG-unresponsive non-muscle invasive bladder cancer - Anti-epithelial cell adhesion molecule MAb-pseudomonas exotoxin protein conjugate
Avalglucosidase alfa  Sanofi Aug 18 Pompe disease 372 See text
AXS-05 Axsome Aug 22 Major depressive disorder 893** See text
Korsuva injection Cara/Vifor Aug 23 Pruritus in haemodialysis patients - Oral version is also in development, though it failed a mid-stage study in atopic dermatitis (Cara fails to convince, but pushes on anyway)
Epsolay Sol-Gel Est Q3 Papulopustular rosacea - Delayed in April, no new date disclosed
*Forecasts before July adcom, **SBI not split out by depression type. Source: Evaluate Pharma & company releases. 


Supplementary and other notable approval decisions in August
Product Company Indication (clinical trial) Date
Xywav Jazz Adult patients with idiopathic hypersomnia (NCT03533114) Aug 12
Keytruda + Lenvima Merck/Eisai 1L advanced renal cell carcinoma (Clear/Keynote-581/Study 307) Aug 25/26
Source: Evaluate Pharma & company releases.

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