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Pepaxto's US Uptake to Stall in Multiple Myeloma Until FBA Provides Advice to Address Death Risk

Blood cancer oncologists are likely to hold back for now on using Oncopeptides’ (STO:ONCO) Pepaxto (melphalan flufenamide) in triple-class refractory multiple

myeloma patients, experts said. Oncologists will be waiting on the FDA to provide

further guidance on how to manage its increased death risk.

On 28 July, the FDA alerted oncologists that in the Phase III OCEAN trial (NCT03151811), Pepaxto led to an increased risk of death. Subsequently, the FDA encouraged them to review their patients’ progress with Pepaxto. All ongoing Pepaxto trials have also been suspended. A public meeting will be staged to discuss additional OCEAN findings and explore continued marketing of the treatment.

Until the FDA decides on how it should address Pepaxto’s OCEAN data, most US oncologists will likely be more reluctant to use the treatment, said OCEAN investigator Dr Fredrik Schjesvold, head, Oslo Myeloma Center, Norway. They will wait to hear from the FDA on any mitigation strategy to reduce risk before resuming use of Pepaxto, added Dr Thomas Martin, clinical professor of medicine, University of California San Francisco Medical Center.

Pepaxto garnered FDA accelerated approval in February 2021. And so, the treatment is

not so established in US oncologists’ practice for there to be a comfort level to keep using

Pepaxto, said OCEAN investigator Dr Ulf-Henrik Mellqvist, professor, Department of Hematology and Coagulation, Sahlgrenska University Hospital, Gothenburg, Sweden.

Upon accelerated approval, the therapy’s overall efficacy data drew some pause for

clinical benefit, which likely contributed to delayed uptake in the past five months, he

added. Pepaxto’s April net sales amounted to USD 3.3m, according to a 26 May media


The FDA advised oncologists to discuss the risks of continued Pepaxto administration

with patients in context of other treatments. In patients who are yet to take any therapies

in the triple-class refractory setting, there are two notable options available:

GlaxoSmithKline’s (LON:GSK) Blenrep (belantamab mafodotin) and Karyopharm

Therapeutics’ (NASDAQ:KPTI) Xpovio (selinexor), Martin said. However, both

treatments have respective side-effect issues, he noted, adding it might come down to

patient preference. Blenrep has a boxed warning on ocular toxicity; Xpovio has warnings

on thrombocytopenia, neutropenia, gastrointestinal toxicity, among others.

An Oncopeptides spokesperson said it does not have any concerns that the new FDA

warning would dramatically impact uptake in the US. Pepaxto’s patient population has an

unmet medical need with limited treatment options, he added. Perhaps Pepaxto can still

be used in patients who have early progression from Blenrep and Xpovio, Martin noted.

According to the FDA guidance, in the confirmatory trial OCEAN, in the overall survival

(OS) secondary endpoint, there were 117 deaths in the 246-patient Pepaxto arm (48%),

compared with 108 deaths in 249 patients (43%) in the Bristol Myers Squibb

(NYSE:BMY) Pomalyst (pomalidomide) active comparator arm. The median OS with

Pepaxto is 19.7 months, versus 25 months with Pomalyst. The spokesperson said it will

present OCEAN’s complete data at a scientific congress later this fall.

Subgroup analysis a possible way to find ideal Pepaxto patients

The next step to understand Pepaxto’s clinical value is to find patient subgroups who are

best suited for the therapy, experts said. OCEAN recruited all comers and finding

subpopulations may be paramount due to the trial comparing two therapies with different

mechanisms, Schjesvold noted. OCEAN investigated the peptide-conjugated alkylating

drug Pepaxto versus immunomodulatory imide drug Pomalyst. All patients are given

low-dose dexamethasone.

What treatment the patient has taken previously can help find Pepaxto’s ideal subgroup,

Schjesvold said. Triple-class refractory patients are ones resistant to all three classes of

standard myeloma therapies: proteasome inhibitors, immunomodulatory agents, and

monoclonal antibodies. Perhaps patients who have previously progressed from an

alkylating agent may not benefit from Pepaxto, Schjesvold noted. In OCEAN, there are

patients who have previously received an alkylating agent and some have not, he added.

Since the concerning discrepancy is related to Pepaxto’s OS data, results may have been

affected by what therapies OCEAN patients have taken after progressing from Pepaxto or

Pomalyst, Mellqvist said. For example, if a Pomalyst patient in OCEAN progressed

earlier than another patient on Pepaxto, the Pomalyst patient would have received

subsequent therapies sooner, he noted, adding this could bolster the Pomalyst patient’s

OS result.

It is also possible that these subsequent therapies would be more effective if the patients

have failed either Pomalyst or Pepaxto, further muddying OS data, Mellqvist added.

Nevertheless, data collection of OCEAN patients’ subsequent therapies is opportunity to

find subgroups that experience the most OS benefit, he said. However, subsequent

therapies can differ between countries, he noted.

"The next step to understand Pepaxto’s clinical value is to find patient subgroups who are best suited for the therapy"

The spokesperson said its analysis indicate there are patients that may benefit with

Pepaxto, as well as patients that should have Pomalyst. How these hypothesis-generating

data should be interpreted, and its clinical implications, are in an ongoing analysis, he

added. Patients best suited for Pomalyst may be hard to pinpoint in OCEAN because all

patients have progressed from an immunomodulatory imide drug, even if to various

degrees, Schjesvold noted.

Prophylactic antibiotics may be a valuable tool to extend survival

Another possible way to help increase Pepaxto’s OS data is to use prophylactic

antibiotics, Martin said. Triple-class refractory multiple myeloma patients are already

fragile, having gone through many prior lines of therapy on top of having low bone

marrow reserves, he explained. And Pepaxto can further negatively impact these reserves,

increasing risk of infection, he added. And so, preventive antibiotics might be able to


Apart from prophylactic antibiotics, another way is to increase these patients’ leukocyte

count, especially neutrophils, to be able to combat infections, Mellqvist added. Pepaxto’s

FDA label warns of thrombocytopenia, neutropenia, anemia and infections, among

others. Patients who end up with neutropenia become highly sensitive to infections, and

severe cases can be fatal, Martin explained.

But the spokesperson noted OCEAN did allow for antibiotics as prophylaxis and was

recommended in both arms. While prophylactic antibiotics might be helpful, Schjesvold

said that the number of infections in OCEAN between arms is not dramatically different.

Pomalyst had slightly more infection events than Pepaxto in OCEAN, according to a 26

May company presentation.

OCEAN efficacy data still worth digging into

While it was judicious for the FDA to pause ongoing Pepaxto trials on the back of new

OS data, there is still potential for the treatment to be used in its present setting where

there are currently limited options, experts said. In OCEAN’s primary endpoint,

progression-free survival (PFS), final analysis shows Pepaxto was superior to Pomalyst


In OCEAN, while the OS data might favor Pomalyst, the confidence interval of the

hazard ratio shows it may not be a definitive finding, Schjesvold added. The hazard ratio

for OS of Pepaxto versus Pomalyst was 1.104, with a 95% confidence interval range of

0.846 and 1.441.

"While it was judicious for the FDA to pause ongoing Pepaxto trials on the back of newm OS data, there is still potential for the treatment to be used in its present setting where there are currently limited options"

However, based on available data so far, it might be challenging for Pepaxto to

demonstrate dramatic superiority over Pomalyst in the OS endpoint, Schjesvold said.

Pomalyst is a high bar, in contrast to Pomalyst’s registrational trial which only compared

it to steroids, Mellqvist noted. Pomalyst was FDA approved in multiple myeloma in


Oncopeptides has a SEK 3.08bn (USD 358.1m) market cap.

September 6, 2021

Reynald Castaneda

Associate Editor, London

Reynald Castaneda, prior to moving to London, was a journalist for healthcare newspaper New Zealand Doctor, covering primary care health politics and medical research. He has a BSc in Biological Sciences from the University of Auckland and a postgraduate diploma in journalism from AUT University. Prior to venturing into journalism, Reynald worked as a laboratory technician for Massey University’s Institute of Molecular Biosciences.


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