Polyphor’s lead programme is balixafortide, a CXCR4 antagonist. CXCR4 tends to have low or no expression in most healthy tissues (among healthy tissue it is most highly expressed in bone marrow and lymphoid tissues according to the Human Protein Atlas) but is highly expressed in a variety of tumour types and is correlated with poor outcomes (Exhibit 2) as it is associated with tumour immune evasion, angiogenesis and metastasis. Importantly, inhibiting CXCR4 has been shown in preclinical experiments to impair tumour migration, growth and angiogenesis. While CXCR4 inhibition does not appear to have much of a cytotoxic effect by itself, there does appear to be evidence of an enhanced cytotoxic/chemosensitisation effect per both clinical and preclinical data when combined with chemotherapy, hence the combination with eribulin in the Phase III programme.
Exhibit 2: CXCR4 expression is associated with shorter survival in cancer patients
|
|
Source: Zhao et al., CXCR4 over-expression and survival in cancer: a system review and meta-analysis.
Oncotarget. 2015 Mar 10;6(7):5022-40.
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While there are other CXCR4 inhibitors in the pipeline, balixafortide appears to be the only candidate for breast cancer. That is likely because there are so many potential targets for a CXCR4 inhibitor. For example, Mozobil (plerixafor) was approved in 2008 in combination with granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell mobilisation and is marketed by Sanofi. We should note that Polyphor previously had a programme to develop balixafortide for this indication but stopped development in 2015 when it was in Phase II. The company has stated that the compound demonstrated proof of mechanism and that it induced hematopoietic stem cell mobilisation but further development was not pursued for commercial reasons.
Exhibit 3: CXCR4 inhibitor pipeline
Molecule |
Company |
Lead indication |
Status |
Delivery |
Comments |
Plerixafor |
Sanofi |
Hematopoietic stem cell mobilisation |
Approved since 2008 |
Subcutaneous |
Mavorixafor |
X4 Pharma |
WHIM syndrome (a rare immunodeficiency disorder) |
Phase III |
Oral |
Also in Phase II for clear cell renal cell carcinoma and Phase I for severe congenital neutropenia and Waldenstrom macroglobulinemia |
Motixafortide |
BiolineRx |
Hematopoietic stem cell mobilisation for autologous transplantation |
Phase III |
Subcutaneous |
Also in Phase II for pancreatic cancer and acute myeloid leukemia (AML) |
Balixafortide |
Polyphor |
Metastatic breast cancer |
Phase III |
Intravenous |
A Phase II in earlier lines of breast cancer and in combination with other regimens is planned for Q420 |
Source: Edison Investment Research, Polyphor
The reasoning for choosing breast cancer is clear. In 13 studies covering 2,318 breast cancer patients (of which 31% were CXCR4 expressors), the hazard ratio was 1.8, indicating a significantly negative survival impact from being CXCR4 positive. In one study of 101 breast cancer patients, which compared the impact of high CXCR4 expression to other prognostic factors in breast cancer, it appeared to be the most important prognostic factor by far, more important than tumour size, hormone receptor status or the grade of the cancer (Exhibit 4).
Exhibit 4: Relative risk of high CXCR4 expression compared to other factors
Indicator |
Relative risk of cancer returning |
Relative risk of death |
High CXCR4 |
7 |
18.7 |
Size of the tumour |
2.9 |
2.93 |
Hormone receptor positivity |
0.3–0.33 |
0.19–0.21 |
Grade of cancer |
0.76 |
0.51 |
Source: Chu et al., Chemokine receptor CXCR4 overexpression predicts recurrence for hormone receptor-positive, node-negative breast cancer patients. Surgery. 2011 Feb;149(2):193-9. Note: A relative risk of 1 would equate to an average risk of recurrence or death for a breast cancer patient. Values over 1 are a higher risk of recurrence or death.
Breast cancer also remains a high unmet medical need, particularly in HER2-negative patients who tend to have lower rates of five-year survival than HER2-positive patients. In the United States alone there will be an estimated 276,480 new cases of breast cancer this year (with a total prevalence of 3.6 million) according to the National Cancer Institute, and there were 522,513 cases in Europe in 2018 according to the Global Cancer Observatory. A total of 68% of cases are ‘Luminal A’ (Exhibit 5), which means they are positive for hormone receptors on tumour cells (and that hormones such as oestrogen and progesterone may promote their growth) but have low levels of HER2.
Exhibit 5: Breast cancer subtypes and survival
Type |
Percent of breast cancer cases |
Five-year survival (localised) |
Five-year survival (regional) |
Five-year survival (distant) |
Hormone receptor positive/HER2 negative (‘Luminal A’) |
68% |
100.0% |
89.9% |
30.4% |
Hormone receptor negative/HER2 negative (‘Triple Negative’) |
10% |
91.2% |
65.0% |
11.5% |
Hormone receptor positive/HER2 positive (‘Luminal B’) |
10% |
98.7% |
89.5% |
43.5% |
Hormone receptor negative/HER2 positive (‘HER2-enriched’) |
4% |
96.1% |
81.7% |
36.8% |
Unknown |
8% |
95.7% |
77.1% |
15.3% |
Total |
100% |
98.9% |
85.7% |
28.1% |
Source: National Cancer Institute
Localised tumours are treated surgically, with or without radiotherapy. This is typically followed by adjuvant treatment including one or more anti-hormone therapies (also known as endocrine therapies), for instance aromatase inhibitors such as anastrozole and selective oestrogen receptor modulators such as tamoxifen. Adjuvant chemotherapy is not typically recommended for this population, due to the generally positive prognosis with hormone-based adjuvant therapy.
Non-resectable tumours or metastatic tumours of this class are typically treated initially with drugs such as Faslodex (fulvestrant, AstraZeneca), anastrozole, tamoxifen, or other drugs that interfere with HR signalling. A new class of drug that can be combined with hormone therapy are CDK4/6 inhibitors such as Ibrance (palbociclib, Pfizer) Kisqali (ribociclib, Novartis) and Verzenio (abemaciclib, Eli Lilly). Ibrance was the first drug of this class to be approved in 2015 and had sales of over $5bn in 2019, which speaks to the size of this market (Exhibit 6). These drugs have significant antiproliferative and antimetastatic activity and their increasing integration into the treatment algorithm is expected to replace or delay the use of other therapies for refractory disease.
Exhibit 6: Top 10 breast cancer drugs by 2019 sales
Drug |
Generic name |
Company |
Mechanism |
Indication |
2019 sales ($m) |
Year of approval |
Patent expiry |
Herceptin |
Trastuzumab |
Roche |
Epidermal growth factor receptor ErbB-2 (HER2) antibody |
First and second line therapy in HER2+ metastatic breast cancer patients. Also approved as an adjuvant therapy for breast cancer. Has an additional approval in gastric cancer. |
5,728 |
1998 |
2019 |
Ibrance |
Palbociclib |
Pfizer |
Cyclin-dependent kinase 4 (CDK4) inhibitor; Cyclin-dependent kinase 6 (CDK6) inhibitor |
HR+ HER2- metastatic breast cancer patients. |
4,961 |
2015 |
2028 |
Perjeta |
Pertuzumab |
Roche |
Epidermal growth factor receptor ErbB-2 (HER2) antibody |
HER2+ metastatic breast cancer patients. Also approved in adjuvant and neo-adjuvant breast cancer setting. |
3,544 |
2012 |
2025 |
Kadcyla |
Ado-trastuzumab emtansine |
Roche |
Tubulin polymerisation inhibitor; Epidermal growth factor receptor ErbB-2 (HER2) antibody |
HER2+ metastatic breast cancer patients after prior treatment with Herceptin and a Taxane. Also used in the adjuvant setting. |
1,402 |
2013 |
2025 |
Faslodex |
Fulvestrant |
AstraZeneca |
Oestrogen receptor antagonist |
HR+ HER2- advanced metastatic breast cancer patients. |
892 |
2002 |
2019 |
Afinitor |
Everolimus |
Novartis |
Mammalian target of rapamycin (mTOR) inhibitor |
Advanced HR+ HER2- breast cancer. Also approved in kidney, neuroendocrine tumours at various locations and tuberous sclerosis complex-related indications. |
831 |
2008 |
2020 |
Verzenio |
Abemaciclib |
Eli Lilly |
Cyclin-dependent kinase 4 (CDK4) inhibitor; Cyclin-dependent kinase 6 (CDK6) inhibitor |
Newly diagnosed HR+ HER2- metastatic breast cancer. |
580 |
2017 |
2029 |
Kisqali |
Ribociclib |
Novartis |
Cyclin-dependent kinase 4 (CDK4) inhibitor; Cyclin-dependent kinase 6 (CDK6) inhibitor |
HR+ HER2- advanced metastatic breast cancer patients. |
480 |
2017 |
2028 |
Abraxane |
Paclitaxel (albumin-bound) |
Bristol Myers |
Tubulin polymerisation inhibitor |
Advanced metastatic breast and pancreatic cancers as well as advanced non-small cell lung cancer. |
460 |
2005 |
2022 |
Halaven |
Eribulin mesylate |
Eisai |
Tubulin polymerisation inhibitor |
Metastatic breast cancer patients who have failed at least two chemotherapeutic regimens for metastatic disease. Also approved for liposarcoma. |
370 |
2010 |
2027 |
Source: Evaluate Pharma, FDA labels
Polyphor will be especially focused on Luminal A patients (although there will be some focus on triple negative patients as well) as they make up the bulk up of breast cancer patients but also have a low level of usage of novel agents once the patients progress past hormone therapy, with monotherapy chemotherapy remaining the standard once Luminal A patients reach that stage. Monotherapy chemotherapy is also the standard for these patients who are in a visceral crisis even if they have not previously been treated with hormone therapy. According to Global Data, this is not likely to change in the near future. They project the novel agent share in second to fifth line in 2023 being in the 4–9% range, with the rest being monotherapy chemotherapy. There is also not much of a standard chemotherapeutic regimen once patients have failed front line agents. In the eribulin Phase III Embrace registration trial of the drug in 762 heavily pretreated (87% had three or more prior lines of chemotherapy, 85% had prior hormone therapy, 83% had prior radiotherapy and 86% had surgery) locally recurrent or metastatic breast cancer patients, the comparator was a physician’s choice of therapy. In the control arm 25% of patients received vinorelbine, 19% gemcitabine, 18% capecitabine, 15% taxanes, 10% anthracyclines, 10% other chemotherapies and 4% hormone therapy.
The balixafortide Phase I data
Data we have so far have been positive, although early, and come from a Phase I dose-escalation study in combination with eribulin in 56 HER2-negative metastatic breast cancer patients (23% of which were triple negative). These patients were heavily pretreated with 78% having three or more prior chemotherapy regimens. In this trial there was a clear dose response with the high dose (the dose chosen in the Phase III FORTRESS study) achieving ORR, median PFS and median overall survival (OS) greater than was previously seen with eribulin alone. It is always tough to compare across trials, especially small Phase I trials versus Phase III results, but eribulin has not typically seen 38% response rates as a monotherapy (ORR has typically been around 13% as seen in its Phase III trial, see Exhibit 7) so this is likely indicative of an effect of balixafortide therapy.
Exhibit 7: Balixafortide Phase I comparison to eribulin Phase III
Group |
Sample size |
Balixafortide dose |
Eribulin dose |
ORR |
Median PFS (months) |
Median OS (months) |
Lower dose group |
15 |
0.5–2.0mg/kg |
1.1–1.4mg/m2 |
13% |
3.3 |
9.4 |
Mid dose group |
15 |
2.5–4.5mg/kg |
1.4mg/m2 |
33% |
3 |
11.2 |
High dose/expanded cohort) |
24 |
5.5mg/kg |
1.4mg/m2 |
38% |
6.2 |
18 |
Eribulin Phase III EMBRACE study |
762 (508 on rribulin) |
1.4mg/m2 |
13% |
3.6 |
13.1 |
Source: Polyphor, Pernas et al., Balixafortide plus eribulin in HER2-negative metastatic breast cancer: A Phase 1, single-arm, dose-escalation trial. The Lancet Oncology, 25 Apr 2018, 19(6):812-824. Cortes et al., Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A Phase 3 open-label randomised study. Lancet 2011; 377:914-23
Toxicity was very similar to the eribulin safety profile seen in the Phase III programme. In Phase I, only two patients discontinued due to treatment-related adverse events, one due to Grade 2 fatigue and another treatment-related to Grade 1 peripheral neuropathy. A total of 18% of patients required a reduction in eribulin dose but only 2% (one patient) required a reduction in balixafortide to manage infusion reactions at the first cycle (although the full dose was resumed in subsequent cycles). Two patients died during the trial due to adverse events although this is likely due to their advanced status as well as known eribulin toxicity. One patient enrolled in cohort one (the lowest dose for both balixafortide and eribulin), developed neutropenia (45% of patients in the eribulin Phase III developed Grade 3 or 4 neutropenia) and pneumonia and died of septic shock. They had multiple comorbidities on study entry and had received four lines of hormonal therapy, three lines of chemotherapy as well as radiation. The second patient was enrolled in the high dose/expanded cohort and had a history of asthma. They previously received three lines of hormonal therapy and three lines of chemotherapy as well as radiation. They died of pneumonia after having Grade 4 neutropenia.
Infusion reactions seem to be the biggest issue related specifically to balixafortide and the only one observed to have a dose response. In total, 46% of patients in the trial had a Grade 1–2 reaction and 2% (one patient) had a Grade 3 infusion reaction with reactions highest during the first cycle.
Polyphor is enrolling its pivotal FORTRESS study, which is a randomised global controlled trial studying balixafortide with eribulin versus eribulin alone, in 407 previously treated (320 third line and 87 second line) HER2-negative advanced breast cancer patients. Enrolment started in June 2019 and by early September 2020, 366 patients had been recruited, including all 87 second line patients, so a further 41 third line patients are needed for the trial to complete enrolment (expected at the end of September). The primary endpoint of the trial is PFS 12 months after the last patient is randomised. Those data are expected for Q421 and, if positive, would enable a standard NDA filing with the FDA as well as a filing with the EMA (although the EMA may also require some interim overall survival data for approval).
However, depending on the data, the company may be able to file for accelerated approval with the FDA (but not the EMA) on ORR data assessed in patients with measurable disease who are third line or later (estimated by the company to be 66–75% of the study population) based on discussions with the agency. These results should be available in Q221, six months after the last patient is randomised. Additionally, if the p-value of the balixafortide + eribulin arm versus eribulin is p≤0.001, the company plans to first apply for breakthrough therapy designation (BTD) with the FDA (the agency typically responds within just 60 days) prior to filing for accelerated approval. A BTD allows for more intense FDA involvement in the drug development process, an organisational commitment of senior managers and eligibility for both rolling and priority review.
Based on the characteristics of the pre-approval studies for drugs previously being granted accelerated approval from 2009 and 2013 (Exhibit 8), Polyphor would have a strong case if it is able to achieve the necessary ORR hurdle. The FORTRESS study is much larger than the median for those receiving accelerated approval, has an active comparator (63% of those receiving approval had no comparator at all) and has an appropriate endpoint. Also as recently as June 2020, lurbinectedin (Zepzelca) from PharmaMar/Jazz was approved on an accelerated basis by the FDA based on ORR from 105 small cell lung cancer patients in a single arm trial. In April 2020 Immunomedics (an acquisition by Gilead Sciences for $21bn was announced in September) received an accelerated approval for sacituzumab govitecan (Trodelvy) in third line or later triple-negative breast cancer based on a single arm trial with data from 108 patients (with a 33.3% ORR).
Exhibit 8: Characteristics of studies for drugs receiving accelerated approval
Characteristics |
Number or percentage |
Median enrolment |
132 |
Active comparator |
10% |
Placebo comparator |
20% |
No comparator |
63% |
Add-on comparator |
7% |
Primary endpoint - disease response surrogate (such as ORR) |
70% |
Primary endpoint - Progression free survival |
3% |
Other surrogate |
27% |
Characteristics |
Median enrolment |
Active comparator |
Placebo comparator |
No comparator |
Add-on comparator |
Primary endpoint - disease response surrogate (such as ORR) |
Primary endpoint - Progression free survival |
Other surrogate |
Number or percentage |
132 |
10% |
20% |
63% |
7% |
70% |
3% |
27% |
Source: Naci et al., Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration. JAMA. 2017;318(7):626-636.
With regards to timing of an accelerated approval, Polyphor believes an accelerated approval could occur in Q422 while the standard approval in the US/EU could happen in Q123.
Our estimates for balixafortide are based on the assumption that 60,000 patients in the US and another 90,000 patients in the EU5 will be eligible for therapy. This encompasses advanced/metastatic Luminal A patients who are third line or later in the US and second line or later in the EU5. We are not including triple-negative breast cancer patients in our estimates as it is both a smaller market (10% of breast cancer incidence versus 68% for Luminal A) and a more competitive one with a higher degree of novel therapies in use. These patients are included in the FORTRESS trial so we may decide to add them to our estimates but this will depend on the data as well as the commercial focus once balixafortide is on the market.
We estimate launch in 2023 and peak share to be 3% in the respective markets as the later line metastatic breast cancer market is relatively fragmented across different therapies, although this may change if the FORTRESS data are particularly strong. Our market share assumption also includes potential competition from Immunomedics, which is conducting a Phase III of sacituzumab govitecan in 400 third line or later Luminal A patients, with data likely in 2022/23. In 54 Luminal A patients in the sacituzumab govitecan Phase I/II study, the ORR was 31% with a PFS of 6.8 months, which is relatively similar to the data seen with balixafortide in the dose Polyphor is moving forward with in the FORTRESS study.
It is important to note this market share assumption does not include any future label expansions or use with other chemotherapies other than eribulin. We estimate a price of US$100,000 per treated patient in the United States, which we believe is reasonable for that market, especially as balixafortide will likely be considered a targeted therapy due to the CXCR4 mode of action. By way of reference, Kisqali, the CDK4/6 inhibitor for Luminal A patients, costs between $5,021 and $12,553 per month depending on the dose, according to Novartis, whereas sacituzumab govitecan for triple-negative breast cancer costs US$16,096 per 21-day cycle on average. In the EU, we assume a price of US$50,000 per patient. Taken together, we arrive at peak sales at CHF730m, which again focuses only on Luminal A patients and no label expansions.