Local breast drug delivery
Atossa’s strategy is to develop locally administered pharmaceuticals for treating breast (fibroglandular) hyperplasia and early-stage breast cancer. The lead product candidate is AfTG, which is slated to start Phase II studies in mid-2016 and is initially intended as a treatment for breast hyperplasia in high-risk patients. Atossa is also planning a Phase II trial using its proprietary IDMCs to deliver fulvestrant, an approved metastatic breast cancer drug marketed by AstraZeneca, to treat ductal carcinoma in-situ (DCIS), and potentially other breast cancers. Before engaging in these areas, Atossa developed medical devices relating to breast health, including breast aspirators, and operated a laboratory that performed cytology testing and pharmacogenomics tests. These businesses generated revenue but were not consistently profitable.
AfTG licensed for breast hyperplasia, option for other cancers
In May 2015, Atossa acquired the worldwide exclusive rights from Besins Healthcare (the developer of AndroGel, a topical testosterone gel) to develop and commercialize AfTG, a proprietary transdermal afimoxifene gel formulation, for the treatment and prevention of breast hyperplasia, a precancerous condition. Atossa would be obligated to pay Besins a royalty of 8% to 9% of net sales for the first 15 years of commercialization. Atossa also has non-exclusive AfTG rights for breast cancer and other breast diseases (such as DCIS). To obtain exclusive rights, Atossa must pay $5m for each new indication, plus a $20m milestone upon starting Phase III studies for each indication.
Afimoxifene (4-hydroxytamoxifen) is an active metabolite of tamoxifen. Orally dosed tamoxifen is metabolized in the liver by a cytochrome P450 isoform into active metabolites including afimoxifene. These molecules work as ER antagonists, thus blocking circulating estrogen for binding to this receptor and inhibiting the transcription or expression of estrogen-responsive genes. Afimoxifene has 30-100 times more affinity for ER than tamoxifen itself. The rationale for AftG development is to provide the local ER antagonistic therapeutic activity associated with tamoxifen, while reducing the risks of systemic effects associated with oral tamoxifen.
Hyperplasia and breast cancer implications
Most breast cancers are preceded by hyperplasia (increase in the number of cells) in breast lobules (the parts of the breast that produce milk) or ducts (pipes of the breast that drain milk out to the nipple). Hyperplasia is usually discovered by mammography or after a biopsy to evaluate a suspicious area identified on a mammogram or during a clinical breast exam.
In usual hyperplasia, the pattern of cells is very close to normal. Atypical hyperplasia (AH), also called hyperplasia with atypia, refers to cases where cells are more distorted or abnormal looking. Patients with AH have a 3.5 to 5 times higher lifetime breast cancer risk (vs those without hyperplasia). AH is generally treated with surgery to remove the abnormal cells and to make sure no in situ or invasive cancer is present in the area. AH is found in about 10% of the one million breast biopsies with benign findings performed a year in the US.
Tamoxifen helps prevent breast cancers but side-effect profile limits use
Following surgical treatment for AH or non-invasive breast cancer (such as DCIS), additional treatment with a SERM drug, such as tamoxifen or raloxifene (Evista), is often recommended. A large-scale randomized study (IBIS-I), where over 7,000 women (aged 35-70 with elevated breast cancer risk) were randomized to five years of tamoxifen vs placebo, found that tamoxifen reduced breast cancer incidence in high-risk women by 30-50% over five years of treatment, for ER-positive cancer and DCIS. Approximately 75-80% of breast cancers are ER positive (ie they grow in response to estrogen). IBIS-I found that after a median follow-up of 16 years, tamoxifen-treated patients had a 7.0% risk of developing breast cancer, versus 9.8% in the placebo group. The reduction in ER-positive invasive breast cancer was maintained for at least 11 years after cessation of tamoxifen.
Despite evidence of reduced ER-positive breast cancer risk, SERM use has been limited to under 1% of AH patients. The low uptake is believed to be attributable to patients’ fear of adverse effects (AE) of SERM drugs,, which include increased risks of thromoboemoblic events (including blood clots, stroke), menopausal symptoms, and endometrial cancer. Chemoprevention use (the use of drugs to reduce cancer risk) remains low even though raloxifene, a newer oral SERM approved by the FDA in 2007, has a more advantageous AE profile vs tamoxifen. , Some research suggests that women may be reluctant to add new risks to their health when oral SERM drugs tamoxifen will not eliminate their risk of breast cancer completely.
The rationale behind AfTG would be to attempt to generate the local efficacy of SERM drugs at desired target sites (eg estrogen receptors in the breast) while limiting systemic distribution to lower risks of associated AEs. The well-developed internal lymphatic circulation of the breast could provide a mechanism of preferentially targeted local drug delivery to the region.
Aromatase inhibitors reduce risk, but only on postmenopausal women
An alternative preventative option for postmenopausal women would be aromatase inhibitors (AIs), such as exemestane (Aromasin), anastrozole (Arimidex) and letrozole (Femara). The enzyme aromatase normally converts androgen into small amounts of estrogen, and its inhibition decreases estrogen production, reducing the amount of hormone available to stimulate the growth of ER-positive cancer cells. A disadvantage of AIs is that they do not block estrogen production from ovaries, so they can generally only be effective in post-menopausal women. Some studies suggest that AIs are more effective than tamoxifen/SERMs in preventing cancer in postmenopausal women. AIs tend to cause fewer pro-thrombotic side effects than SERMs, but are more likely to cause cardiac problems or bone loss and osteoporosis than tamoxifen.
Exhibit 2: Hormonal treatments used in ER-positive breast cancers
Class |
Description |
Example |
Notes |
Selective estrogen receptor modulators (SERMs) |
Have a combination of estrogen agonist or antagonist activities depending on targeted tissue site; have antagonist properties at breast and agonist at bone |
Tamoxifen, Raloxifene |
Oral tamoxifen is indicated for reduction of the incidence of breast cancer in women at high risk for breast cancer, and raloxifene is approved for risk reduction in post-menopausal women |
Aromatase inhibitors |
Block the conversion of androgens to estrogen, leading to reduced estrogen levels in postmenopausal women |
Letrozole, Anastrozole (non-steroidal, with reversible aromatase binding), Exemestane (steroidal, permanent aromatase binding) |
Only effective in post-menopausal women, but can be more efficacious (eg 10-year survival) than oral SERMs in this population |
Pure antagonist |
Block estrogen activity in all tissues, and may also degrade ERs |
Fulvestrant |
Approved by the FDA for hormone treatment in postmenopausal women with ER-positive breast cancer that has failed previous hormone therapies |
Source: Edison Investment Research, Dowsett M, Forbes JF, Bradley R, et al. Lancet. 2015 Oct 3;386(10001):1341-52
Clinical data suggestive of AfTG local penetration
A Besins-sponsored study recruited 27 patients (including both premenopausal and postmenopausal) with DCIS (which is normally treated with surgery) and randomly assigned them to take oral tamoxifen and placebo gel, or oral placebo and AfTG (also transdermally applied to the breast) once daily in the weeks (at least six weeks) leading to surgical removal/treatment of a breast with DCIS; 26 patients completed the study (n=12 in the AfTG arm; n=14 in oral tamoxifen).
Exhibit 3: Phase II data of afimoxifene gel vs oral tamoxifen on clinical markers
|
Oral-T (20mg/day) |
AfTG (4mg/day) |
P-value between arms |
|
Mean +/- SD |
Mean +/- SD |
|
Ki-67 labelling Index (%) in DCIS breast lesion |
|
|
|
Baseline |
8.3 +/- 5.2 |
6.7 +/- 5.6 |
|
Post-treatment |
3.2 +/- 2.3 |
3.2 +/- 2.6 |
|
Mean changes from baseline |
-5.1 +/- 5.5 |
-3.4 +/- 5.0 |
0.99 |
P-value vs baseline |
0.008 |
0.03 |
|
|
|
|
|
Systemic (plasma) parameters |
|
|
|
|
|
|
|
Plasma (Z) 4-OHT (afimoxifene) post-treatment (ng/mL) |
1.1 +/- 0.7 |
0.2 +/- 0.2 |
0.0003 |
|
|
|
|
IGF-1 (ng/mL) |
|
|
|
Baseline |
59.0 +/- 11.4 |
63.7 +/- 8.6 |
|
Post-treatment |
50.3 +/- 9.7 |
58.5 +/- 6.6 |
|
Changes from baseline |
-8.7 +/- 8.3 |
-5.2 +/- 9.5 |
0.35 |
P-value vs baseline |
0.003 |
0.35 |
|
|
|
|
|
SHBG (ng/mL) |
|
|
|
Baseline |
98.4 +/- 45.0 |
89.4 +/- 70.2 |
|
Post-treatment |
143.9 +/- 69.0 |
99.7 +/- 76.0 |
|
Changes from baseline |
45.5 +/- 40.2 |
10.3 +/- 74.4 |
0.20 |
P-value vs baseline |
0.002 |
0.67 |
|
|
|
|
|
von Willebrand factor (%) |
|
|
|
Baseline |
167.4 +/- 89.2 |
179.9 +/- 68.3 |
|
Post-treatment |
218.6 +/- 134.6 |
177.3 +/- 65.3 |
|
Changes from baseline |
51.2 +/- 71.0 |
-2.6 +/- 52.3 |
0.06 |
P-value vs baseline |
0.020 |
0.88 |
|
|
|
|
|
Factor VIII (%) |
|
|
|
Baseline |
157.1 +/- 47.5 |
158.4 +/- 23.4 |
|
Post-treatment |
168.7 +/- 51.6 |
167.1 +/- 24.5 |
|
Changes from baseline |
11.6 +/- 17.3 |
8.7 +/- 18.5 |
0.70 |
P-value vs baseline |
0.030 |
0.17 |
|
Source: Lee O, Page K, Ivancic D, et al. Clin Cancer Res. 2014 July 15; 20(14): 3672–3682. Note: For all measures other than Ki-67, Oral-T arm had N=13 and AfTG arm had N=10; for Ki-67 in DCIS, N = 9 for each arm; SD = standard deviation.
The study aimed to show whether AfTG can provide comparable effectiveness as oral tamoxifen in reducing Ki-67, a protein marker for cellular proliferation whose density level correlates with cancer growth and progression. Ki-67 has prognostic significance in several tumour models including breast cancer. A Ki-67 reduction from AfTG therapy comparable to oral tamoxifen, may lead to similar reductions in breast cancer risk. The study also aimed to evaluate AfTG on a number of systemic endocrine plasma markers and coagulation proteins known to be affected by oral tamoxifen, to determine whether topical therapy could reduce the potential for systemic effects.
The data showed that both oral tamoxifen (20mg/day) and AfTG (4mg/day) had statistically significant reductions in Ki-67 (61% and 52%, respectively). Although the reduction in the oral tamoxifen arm was higher, the difference between both arms was not significant. However, the small sample size limited the statistical power of the comparisons and separations between both arms in most of the measures.
Systemic measures clearly showed less absorption in the AftG arm. Breast adipose tissue concentrations of (Z) 4-OHT (afimoxifene) were equivalent in the oral and AfTG groups (over 5ng/mg tissue in both arms), but plasma concentrations of this active ingredient in the gel group were c 20% of those in the oral arm. In endocrine parameters, there were significant increases in IGF-1 (p=0.003) and decreases in SHBG in the oral tamoxifen group (which have also been shown in other studies), but changes in the AfTG arms were not significant. Post-treatment levels of factor VIII and von Willebrand factor (both proteins associated with blood clotting) were significantly increased post-therapy in the tamoxifen but not the AfTG group. Thus, AfTG could avoid the changes in the clotting cascade that contribute to the pro-thrombotic effects of oral SERMS.
The study was limited in that it did not reach the target accrual of 112 patients (presumably due to recruitment challenges). The authors concluded that AfTG and oral tamoxifen had equivalent anti-proliferative effects (based on Ki-67 measures), but that systemic effects on endocrine and coagulation parameters were reduced given AfTG’s transdermal delivery. This study’s recruitment challenges could be indicative of the possible difficulties in engaging women to undertake prophylactic treatments to prevent breast cancer. AfTG was previously studied in 15 other Phase I and Phase II studies conducted in a variety of indications with over 365 patients.
Commercial opportunity for AfTG in hyperplasia and DCIS
Mammary DCIS accounts for 20% of new breast cancers, with 57,000 newly diagnosed patients in the US in 2011. Although 10-year DCIS-specific survival rates are 96-98%, the risk for the development of subsequent invasive breast cancer is up to 30% following local DCIS treatment. For AH, Hartmann et al reported a cumulative incidence of breast cancer of 30% within 25 years following diagnosis. This rate was calculated from a 698-patient cohort of women with AH, who were followed for a mean of 12.5 years, and of these 143 developed cancer (81% developed invasive disease, 19% developed DCIS). These rates justify a role for preventative therapy. There may be a commercial opportunity for AfTG if it can show comparable efficacy benefits to oral SERMs while demonstrating a clear safety advantage through a significantly lower AE profile.
NCI may provide funding for AfTG in DCIS study
The National Cancer Institute (NCI) approved a Letter of Intent submitted by a university-affiliated US cancer research center, to study AfTG in patients with DCIS. Proposed study design details have not been made public. If the clinical protocol is approved, the majority of this Phase II study’s costs could be funded by NCI, although our model assumes that Atossa will fund these costs. As Atossa only has non-exclusive rights in DCIS, it would need to pay additional funds to Besins to obtain exclusive DCIS rights (which we assume would be necessary for a viable commercial path). Atossa plans to finalize the next AfTG study indication and protocol in H116, with the goal of enrolling a first patient in mid-2016. We assume the study will track drug pharmacokinetics (PK) and measure relevant breast cancer markers such as Ki-67, and systemic thromboembolic markers.
Atossa had previously developed or acquired proprietary medical devices directed towards breast cancer and health diagnosis, including an IDMC. Its second therapeutic strategy involves using its IDMC to deliver therapeutics for breast cancer and/or pre-cancerous conditions, with lower systemic exposure vs established therapies or delivery approaches. The IDMCs are designed to irrigate each of the five to seven breast ducts and can also collect the lavage fluid, which can then be analysed by a laboratory for biomarkers. The IDMCs are now being developed to deliver drugs to the breast region. Dr. Susan Love and collaborators conducted a Phase I study in China on the feasibility of intraductal chemotherapy drug administration into multiple ducts within one breast in patients awaiting mastectomy for invasive breast cancer treatment. Carboplatin or pegylated liposomal doxorubicin (PLD), was administered into five to eight ducts, and results showed that both drugs were absorbed into the bloodstream. The investigators concluded the study was supportive of the safety and feasibility of intraductal therapy.
While this targeted delivery approach could potentially apply to many pharmaceuticals, Atossa’s initial therapeutic approach is with fulvestrant (marketed as Faslodex by AstraZeneca, and FDA approved for ER-positive metastatic breast cancer). Atossa is planning a Phase II (n=30) clinical trial at Columbia University using its proprietary IDMCs to deliver fulvestrant as a pre-operative therapy in patients with DCIS or invasive breast cancer, who are scheduled for mastectomy (full breast removal). Fulvestrant is a complete ER antagonist (with no agonist effects), which also accelerates the proteasomal degradation of the ER. Fulvestrant administration is generally intramuscular (IM) via a monthly injection of two shots (into the buttocks).
In the open-label PK study, six patients will receive IM fulvestrant, and 24 will receive IDMC administration. Subjects will undergo serial blood draws to determine fulvestrant blood concentration levels. Through this study and follow-on studies, Atossa aims to show that its proprietary IDMCs can provide more targeted treatment with fewer side effects than IM administration. Study results are expected in H217. Atossa indicates that one of its internal analyses suggests that the drug levels in breast tissue might be over 20,000 times more concentrated with IDMC versus systemic administration.
505(b)2 pathway could lead to more rapid development trajectory
Atossa believes the IDMC-fulvestrant program may qualify for designation under the 505(b)(2) application status. This is in contrast to the conventional FDA 505(b)1 application approach, typically employed for most new molecular entities (NMEs), or the premarket approval (PMA) process often employed for invasive medical devices. Under 505(b)(2), Atossa may be able to rely on much of the existing safety, efficacy, and preclinical data already established on fulvestrant, including what was submitted under the drug’s original NDA. Since fulvestrant is generally used systemically (IM dosage) and the safety profile is well understood, depending on the outcome of its discussions with FDA, Atossa may only be required to complete Phase I pharmacokinetic equivalency studies (and potentially only a relatively small Phase III study), to gain regulatory approval, if the 505(b)2 pathway is accepted (as we forecast in our model). If the FDA instead requires the PMA process, more comprehensive, costly and lengthy dose-ranging and pivotal studies may be required.