Oncopeptides AB remains on track for an NDA filing in the second quarter for its peptide-drug conjugate, melflufen, in relapsed refractory multiple myeloma (RRMM). The Stockholm-based firm reported Thursday, March 26, that the drug attained an overall response rate (ORR) of 30% – as assessed by the independent review committee (IRC) – in the intent-to-treat (ITT) analysis of the pivotal open-label phase II Horizon study (n=157).

According to the IRC assessment, it attained an ORR of 26% in a subgroup of patients who were refractory to three drug classes (n=119) and an ORR of 27% in patients with extramedullary (metastatic) disease (n=57). “They are notoriously hard to treat,” Oncopeptides CEO Jakob Lindberg told an analyst call audience.

Jakob Lindberg, CEO, Oncopeptides

The IRC numbers, unusually, are more favorable to the study than those computed by the study investigators, who put the ORR at 29% in the ITT analysis, 26% in triple-refractory patients and 24% in the extramedullary disease subgroup. “This just speaks to the integrity of the dataset and the robustness of our internal analysis,” Lindberg said. Survival data have not been disclosed at this point – the company plans to publish the complete dataset in a peer-reviewed journal.

The drug comprises a peptide carrier linked to melphalan, an alkylating agent long used in myeloma treatment. The lipophilic complex is taken up efficiently by all cells. Myeloma cells highly express peptidase enzymes, which break down the molecule, leading to the entrapment of the hydrophobic cytotoxic drug within the cell. Induction of apoptosis occurs in about two hours.

Oncopeptides is planning an FDA submission late in the second quarter. With an accelerated approval, the drug could reach the market early next year. The firm was lucky in its timing. The study was fully recruited by September 2019 and Jan. 14 was the cut-off date for the data analysis. The database is now locked, and the filing is in the company’s hands. The main risk factor for the submission process is the impact of the coronavirus pandemic on the company’s own staff. “If COVID-19 hits us hard, as an organization, that could cause delays,” Lindberg said.

The pandemic has delayed plans for rolling out an early access program. The company still plans to undertake one, but the timing is not clear at this point. “I think I need to say ‘pass’ on that question,” Lindberg said in reply to a question on the issue. “We obviously had a very solid plan, and now a lot of things are changing on the ground.” The unmet need is “dire,” he added, given the lack of options for highly refractory patients. “We just haven’t done the full impact assessment on how fast we can roll out or not roll out this program under these conditions,” he said.

The pandemic’s impact on its phase III Ocean study in 450 patients refractory to Revlimid (lenalidomide) is a little unclear at this point. It is nearly fully enrolled in any case – 423 of a planned 450 patients are recruited. However, recruitment of the remaining patients is highly variable. “Two weeks ago, we saw a fairly big drop in recruitment, and then last week, we saw a big uptick in recruitment in all countries, especially in Italy and Spain,” Lindberg said.

The head-to-head study is comparing melflufen plus dexamethasone with Pomalyst (Imnovid; pomalidomide, Bristol Myers Squibb Co.) plus dexamethasone, the current standard of care in this setting. Paradoxically, the present crisis may strengthen the case for using melflufen, given the current challenges attached to using the other main alternative, the anti-CD38 antibody Darzalex (daratumumab, Johnson & Johnson).

“Intravenous daratumumab under the current conditions is actually a nightmare to give, given the administration schedule, and it’s almost out of the question for these patients, because of the numerous amount of [hospital] visits you need to do on a monthly basis,” Lindberg said. “It’s a fantastic drug, but the admin schedule really poses challenges under pandemic conditions.”

Top-line data from the Ocean study are expected in the third quarter, which would form the basis of an application for approval in patients refractory to one or two agents. Oncopeptides’ regulatory strategy is based on a stepwise movement from the most heavily refractory and the extramedullary patients toward refractory patients on a single agent and eventually refractory patients undergoing combination therapy. The latter represents the largest market opportunity, as patients in that setting remain on drug longer than those in the other settings.

But the immediate priority is to complete the first filing on time, particularly as Newton, Mass.-based Karyopharm Therapeutics Inc. is shooting for a line extension for its exportin 1 inhibitor, Xpovio (selinexor), in patients who have tried one to three therapies. It is already approved for treating RRMM patients who have tried at least four therapies. The sNDA is based on the recent read-out from the Boston study, in which patients on a combination of Xpovio, Velcade (bortezomib, Takeda Pharmaceutical Co. Ltd.) and low-dose dexamethasone (SVD) had a 47% improvement in progression-free survival as compared with those on the VD regimen.

The pandemic has disrupted other plans for clinical trials at Oncopeptides. The Anchor study, which is testing melflufen plus dexamethasone with either bortezomib or daratumumab, has been paused. Recruitment onto the Bridge study, which is assessing melflufen plus dexamethasone in renally impaired patients, has been paused. So, too, has recruitment onto a study of melflufen plus dexamethasone in a phase II study in immunoglobulin light chain amyloidosis. Initiation of the phase III Lighthouse study, which pits melflufen plus dexamethasone plus daratumumab against dexamethasone plus daratumumab, has been put on hold for now.

Shares in Oncopeptides (Stockholm:ONCO) closed March 26 at SEK120.70 ($12.16), a gain of 37% on the previous close.

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