PharmaMar — Zepsyre misses in Ovarian, SCLC still promising

PharmaMar recently announced that the 443-patient CORAIL study in platinum-resistant ovarian cancer missed the primary endpoint and Zepsyre showed no PFS benefit over Topotecan and PLD, which are the standard of care. Details are scarce as the company expects to present the full results at a scientific conference. However, the company acknowledged that PFS for Zepsyre, Topotecan and PLD were the same (indicating that the drug does have single agent activity, just not enough to show a benefit over the standard of care). This is a bit disappointing following the data from a previous Phase II trial comparing Zepsyre to Topotecan, in which the drug showed a statistically significant PFS benefit in platinum-resistant cancer patients (5.7 months versus 1.7 months, p=0.005) in the randomised-controlled stage of the trial.

So what happened? There were some important changes in the design of the Phase III trial compared to the Phase II, which may have affected the results. First, the comparator arm is different as patients could receive either Topotecan or PLD rather than just Topotecan. Initially, the Phase II trial was supposed to have PLD as a comparator but, due to a worldwide shortage at the time, it was switched to Topotecan. Additionally, in the Phase III, patients who received Topotecan only received the standard, five-day regimen rather than the weekly regimen. In the Phase II, patients could receive both and 21 of the 29 Topotecan patients were on the weekly regimen. In a previous trial comparing the two Topotecan regimens in platinum-resistant ovarian cancer patients, there were trends favouring the five-day regimen in both response rate (15% vs 4%) and PFS (4.3 months vs 3.0 months), although neither difference was significant.1

Another key change is that the company amended the Zepsyre dosing regimen. It was a flat dose of 7mg given every three weeks in the Phase II, but was based on body surface area in the Phase III. At a dose of 3.2mg/m2 and an average body surface area of around 1.7 for women with ovarian cancer,2 the average dose would be approximately 5.4mg, somewhat lower than the 7mg dose used in the Phase II. The main reason for the change was the high level of neutropenia found in the Phase II (85% grade 3/4, 64% grade 4), especially in those with low body surface area. Changes to the control arm likely benefited its performance, while changing the Zepsyre dosing regimen likely negatively affected its efficacy.

Despite the negative trial result in platinum-resistant ovarian cancer, we continue to be optimistic about the drug’s potential in other cancers, especially SCLC. PharmaMar recently presented promising updated data on Zepsyre in SCLC patients at ESMO in Madrid. The new data include Cohort B, which had a body surface area-based dose of Zepsyre (2mg/m2) in combination with 40mg/m2 of doxorubicin (DOX), as well as a single agent arm with Zepsyre at a 3.2mg/m2 body surface area-based dose. In both the new arms, the response rate is much higher than the response rate typically seen with Topotecan (13-24%3). Importantly, in Cohort B, which has the same dose as that being used in the Phase III trial, PFS was 5.3 months, which is higher than the 3-4 months typically seen with Topotecan. The PFS in Cohort B, which featured body surface area-based dosing, was also higher than the PFS seen in Cohort A, which featured fixed dosing for patients.

In August 2016, PharmaMar initiated the ATLANTIS trial, which is a multicentre, open-label, randomised Phase III trial in 600 patients with relapsed (second-line) SCLC following platinum-containing therapy. The primary endpoint is progression free survival (PFS) comparing patients treated with the combination of Zepsyre and doxorubicin to the control arm where patients are treated with either Topotecan or the CAV regimen, a combination of cyclophosphamide, adriamycin (the brand name for doxorubicin) and vincristine. Data from the ATLANTIS trial are expected in 2019.

Other than SCLC, Zepsyre has had promising data in endometrial cancer (EC), which were recently presented at the ASCO meeting held in Chicago on 2-6 June 2017. The ASCO data included four cohorts of endometrial cancer patients from three separate studies, who were treated with Zepsyre as a single agent or in combination with chemotherapy drugs.

In Cohort B (which used the regimen that will be used in the upcoming Phase III trial: Zepsyre at 2mg/m2, doxorubicin at 40mg/m2) of the Zepsyre plus doxorubicin Phase Ib trial, there was 44% response rate (8/18) and acceptable toxicity. Only three of the 18 subjects experienced disease progression, so the disease control rate (DCR) was a high 83%.

In Cohort A where patients received a fixed dose of 3-5mg Zepsyre in combination with 50mg/m2 of doxorubicin every three weeks, there was a 28% ORR (4/14), including two patients who had a complete response rate. However, there was also a high incidence of myelosuppression, including febrile neutropenia in 40% of subjects (3/14). In other cohorts, the toxicity was more tolerable, with only 16% of subjects experiencing febrile neutropenia in Cohort B and 3.6% in the Zepsyre-only arm. Patients in the Zepsyre/doxorubicin trials had been treated with up to two lines of prior chemotherapy for advanced disease (median one prior line).

The 44% response rate seen in Cohort B of the Zepsyre/doxorubicin combination trial is a very encouraging outcome for a study in which all of the subjects were undergoing second-line chemo treatment where EC is largely a chemo-resistant disease.4 Also, the platinum-free interval (PFI) in these patients was just 4.3 months, an interval associated with a low rate of response (the average response rate for those with a PFI of less than six months is 25% compared to 65% for patients with a PFI of greater than 24 months5). The 13% single agent response rate was also promising as typical single agent chemotherapy response rates for patients who received platinum therapy previously range from 4-13.5%.6 The 7.7- to 7.8-month PFS seen in the Zepsyre/doxorubicin combination trial was also encouraging as PFS is typically closer to 3.2 months in similar patients.7

PharmaMar plans to initiate a Phase III study of Zepsyre in EC. While the design has not been finalised, it is expected to have 500 patients who will either receive 2.0mg/m2 of Zepsyre plus 40mg/m2 of doxorubicin or 60mg/m2 of doxorubicin with a primary endpoint of overall survival. The trial is expected to begin in H118.

The company is also planning a registrational trial in 116 BRCA2 mutated, HR-positive, HER2-negative metastatic breast cancer patients, which will be a single arm study in which patients would receive 3.5mg/m2 of Zepsyre. That protocol is currently being finalised.

We are decreasing our valuation from €1.84bn or €8.28/share to €1.35bn or €6.06/share as we have removed Zepsyre in ovarian cancer from our model. We have also delayed our expected EU launch timeline for Aplidin to 2021 from 2018 and reduced the probability of success to 30% from 90% due to a negative CHMP recommendation in Europe, which the company is appealing (a final decision is expected in the June/July time frame) as well as uncertainty regarding the future of the product. Otherwise, we are keeping our valuation the same. We have also updated our financial estimates by removing Aplidin sales from 2018. We will make a more complete update of financials and the valuation following the Q417 results report.