On February 27, 2019 Orion Corporation and Bayer reported the completion of the rolling submission of a New Drug Application (NDA) for darolutamide to the U.S. Food and Drug Administration (FDA) (Press release, Bayer, FEB 27, 2019, View Source [SID1234533747]).

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The submission, which was initiated in December 2018, is based on data from the Phase III ARAMIS trial in men with non-metastatic castration-resistant prostate cancer (nmCRPC) showing a statistically significant improvement in metastasis-free survival (MFS) for darolutamide plus androgen deprivation therapy (ADT). Darolutamide plus ADT has shown a favorable safety profile compared to placebo plus ADT.1 These data were recently presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium (ASCO GU) in San Francisco and published simultaneously in The New England Journal of Medicine.

"Darolutamide is highly effective in the patient population with non-metastatic castration-resistant prostate cancer, and it has a side-effect profile that parallels that of placebo. Patients who received Darolutamide had substantially longer MFS in the ARAMIS trial, and there was also a strong trend for improved overall survival. These results are truly exciting. We are looking forward to taking the next steps in bringing Darolutamide to men with nmCRPC and their treating physicians", said Christer Nordstedt, MD, PhD, Senior Vice President, Research and Development, Orion Corporation.

Bayer has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for darolutamide in men with nmCRPC. Bayer is also in discussions with other health authorities regarding a submission of darolutamide. The compound is being developed jointly by Orion Corporation and Bayer.

About ARAMIS

The ARAMIS trial is a randomized, Phase III, multi-center, double-blind, placebo-controlled trial evaluating the safety and efficacy of oral darolutamide in patients with nmCRPC who are currently being treated with ADT and are at high risk for developing metastatic disease. 1,509 patients were randomized in a 2:1 ratio to receive 600 mg of darolutamide twice a day or placebo along with ADT.

About darolutamide

Darolutamide is a non-steroidal androgen receptor antagonist with a distinct chemical structure that binds to the receptor with high affinity and exhibits strong antagonistic activity, thereby inhibiting the receptor function and the growth of prostate cancer cells. In preclinical studies, darolutamide demonstrated lower blood-brain barrier penetration compared to other currently available AR antagonists. This may also explain the overall low incidence of central nervous system (CNS)-related adverse events seen in the ARAMIS Phase III study.

In addition to the Phase III trial ARAMIS in men with nmCRPC, darolutamide is also being investigated in a Phase III study in metastatic hormone-sensitive prostate cancer (ARASENS). Information about these trials can be found at www.clinicaltrials.gov.

Darolutamide is not approved by the U.S. FDA, the European Medicines Agency or any other health authority.

About castration-resistant prostate cancer (CRPC)

Prostate cancer is the second most commonly diagnosed malignancy in men worldwide.2 In 2018, an estimated 1.2 million men were diagnosed with prostate cancer, and about 358,000 died from the disease worldwide.2 Prostate cancer is the fifth leading cause of death from cancer in men.2 Prostate cancer results from the abnormal proliferation of cells within the prostate gland, which is part of a man’s reproductive system.3 It mainly affects men over the age of 50, and the risk increases with age.4 Treatment options range from surgery to radiation treatment to therapy using hormone-receptor antagonists, i.e., substances that stop the formation of testosterone or prevent its effect at the target location.5 However, in nearly all cases, the cancer eventually becomes resistant to conventional hormone therapy.6

CRPC is an advanced form of the disease where the cancer keeps progressing even when the amount of testosterone is reduced to very low levels in the body. The field of treatment options for castration-resistant patients is evolving rapidly, but until recently, there have been no effective treatment options for CRPC patients who have rising prostate-specific antigen (PSA) levels while on ADT and no detectable metastases. In men with progressive nmCRPC, a short PSA doubling time has been consistently associated with reduced time to first metastasis and death.7

on February 27, 2019 Horizon Pharma plc (Nasdaq: HZNP) reported its fourth-quarter and full-year 2018 financial results and provided its full-year 2019 net sales and adjusted EBITDA guidance (Press release, Horizon Pharma, FEB 27, 2019, View Source [SID1234533746]).

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"2018 was a year of exceptional progress – in addition to generating total company net sales growth of 14 percent, we executed on our strategic objectives – advancing our pipeline and driving net sales growth of KRYSTEXXA, which increased 65 percent," said Timothy P. Walbert, chairman, president and chief executive officer, Horizon Pharma plc. "We enrolled the Phase 3 trial of our biologic candidate teprotumumab well ahead of schedule and are now expecting top-line data by the end of the first quarter.

"We are building on the momentum we established in 2018 and expect continued strong commercial execution across our operating segments," continued Walbert. "We plan to submit our biologics license application for teprotumumab in mid-2019 if the clinical data is positive and expect to initiate two important clinical trials for KRYSTEXXA, with the MIRROR trial initiating in the second quarter and a new study in kidney transplant patients with uncontrolled gout beginning in the second half of 2019."

Fourth-Quarter and Recent Company Highlights

Accelerated Teprotumumab Phase 3 Top-Line Data Read-Out Timeline: The Company announced in January that it expects top-line data results for its pivotal teprotumumab Phase 3 confirmatory trial, OPTIC (Treatment of Graves’ Orbitopathy (Thyroid Eye Disease) to Reduce Proptosis with Teprotumumab Infusions in a Randomized, Placebo-Controlled, Clinical Study), by the end of first quarter of 2019. This is accelerated from the initial second quarter of 2019 timeline, and the Company is tracking to a mid-2019 biologics license application (BLA) submission.

Teprotumumab is a fully human monoclonal antibody insulin-like growth factor-1 receptor (IGF-1R) inhibitor in Phase 3 development for the treatment of thyroid eye disease (TED), in which the muscles and fatty tissue behind the eye expand and become inflamed, which can lead to proptosis (eye bulging) and diplopia (double vision) as well as quality-of-life issues.
Phase 2 Teprotumumab Data Presented at American Thyroid Association (ATA)and American Academy of Ophthalmology (AAO) Meetings: Additional data for the pivotal Phase 2 teprotumumab trial presented at ATA and AAO demonstrated durability of the Phase 2 trial 48 weeks following the end of the treatment period (Week 24) and nearly a year off therapy. At Week 24, 71.4 percent (30 of 42) of patients responded with reductions of ≥2mm in proptosis and 61.9 percent of patients (26 of 42) responded with improvement of at least one grade in diplopia, both of which are considered a clinically meaningful change. At Week 72, 48 weeks following the study completion and nearly a year off therapy, 53.3 percent of the Week 24 proptosis responders maintained the reductions and 69.2 percent of patients with diplopia improvement maintained the benefit. These results demonstrate that teprotumumab has the potential to be the first and only disease-modifying therapy for thyroid eye disease.
New KRYSTEXXA Study in Kidney Transplant Patients with Uncontrolled Gout: The Company is announcing today that it plans to initiate a clinical trial in the second half of 2019 evaluating the effect of KRYSTEXXA, the Company’s medicine for uncontrolled gout, on serum uric acid levels in kidney transplant patients with uncontrolled gout (uncontrolled gout is chronic gout that is refractory to conventional therapies). Kidney transplant patients have more than a tenfold increase in the prevalence of gout when compared to the general population, and literature suggests that high serum uric acid levels are associated with organ rejection. Managing uncontrolled gout is one of the most common and significant unmet needs of kidney transplant patients.
New KRYSTEXXA Immunomodulation Data Presented at American College of Rheumatology/ Association of Rheumatology Health Professionals (ACR) Meeting: At the October 2018 ACR meeting, external investigators shared results from a case series of nine sequential patients with uncontrolled gout, evaluating the administration of KRYSTEXXA with the immunomodulator methotrexate to improve the durability of KRYSTEXXA response. The study stated that of the nine patients followed out to five months, all nine were responders as defined by >80 percent of serum uric acid levels being maintained at goal <6.0 mg/dL during the observation period.
Expanded Indication for RAVICTI: The Company received U.S. Food and Drug Administration (FDA) approval in December to expand the age range for chronic management of urea cycle disorders to birth and older from the previous age range of two months of age and older.
Recent Business Development Initiatives: On Dec. 28, 2018, the Company sold the rights to RAVICTI and AMMONAPS outside of North America and Japan to Medical Need Europe AB for $35 million. In addition, effective Jan. 1, 2019, the RAYOS and LODOTRA license and supply agreements were amended, including the transfer of LODOTRA to Vectura Group plc, the current third-party supplier. Beginning in 2019, the Company will no longer recognize revenue from RAVICTI and AMMONAPS sales outside of North America and Japan, or from sales of LODOTRA. AMMONAPS is known as BUPHENYL and LODOTRA is known as RAYOS in the United States.
Research and Development Programs

Orphan Candidate and Program:

Teprotumumab: The pivotal Phase 3 confirmatory study, OPTIC, is evaluating teprotumumab for the treatment of TED, which has no FDA-approved treatments. OPTIC completed enrollment September of 2018, ahead of the year-end target, and top-line results are expected by the end of first-quarter 2019. OPTIC-X, a 48-week extension study in which participants may receive up to eight additional infusions of teprotumumab, continues to enroll patients. The objective of OPTIC-X is to evaluate the potential for retreatment as well as longer duration of treatment with teprotumumab.
Rheumatology Pipeline Candidates and Programs:

KRYSTEXXA Study in Kidney Transplant Patients: The Company plans to initiate a clinical trial in the second half of 2019 evaluating the effect of KRYSTEXXA on serum uric acid levels in kidney transplant patients with uncontrolled gout. Kidney transplant patients have more than a tenfold increase in the prevalence of gout when compared to the general population, and literature suggests that high serum uric acid levels are associated with organ rejection. Managing uncontrolled gout is one of the most common and significant unmet needs of kidney transplant patients.
KRYSTEXXA Immunomodulation Study: The Company is evaluating the use of methotrexate to enhance the response rate to KRYSTEXXA through its MIRROR (Methotrexate to Increase Response Rates in Patients with UncontrolledGOut Receiving KRYSTEXXA) open-label study. Methotrexate, the immunomodulator most commonly used by rheumatologists, has been shown to reduce anti-drug antibodies when combined with other biologics. The Company is adapting MIRROR’s trial design to support the potential for registration, with enrollment expected to begin in the second quarter of 2019.
Next-generation Biologic Programs for Uncontrolled Gout: The Company is pursuing two development programs for next-generation biologics for uncontrolled gout, HZN-003 and PASylated uricase technology, to support and sustain the Company’s market leadership in uncontrolled gout. The programs are exploring the use of optimized uricase technology coupled with optimized PEGylation or PASylation technology, to improve the molecule’s half-life, with the potential for subcutaneous dosing.
Augmented Rheumatology Pipeline with HemoShear Collaboration: The Company is collaborating with HemoShear Therapeutics, LLC, a privately held biotechnology company, to discover and develop novel therapeutics for gout.
Fourth-Quarter Financial Results

Note:For additional detail and reconciliation of non-GAAP financial measures to the most directly comparable GAAP financial measures, please refer to the tables at the end of this release.

Net Sales: Fourth-quarter 2018 net sales were $355.5 million, an increase of 30 percent, driven by continued strong growth of the Company’s orphan and rheumatology segment.
Gross Profit: Under U.S. GAAP, the fourth-quarter 2018 gross profit ratio was 69.2 percent compared to 47.8 percent in the fourth quarter of 2017. The non-GAAP gross profit ratio in the fourth quarter of 2018 was 89.1 percent compared to 89.3 percent in the fourth quarter of 2017.
Operating Expenses: Research and development (R&D) expenses were 5.5 percent of net sales and selling, general and administrative (SG&A) expenses were 49.1 percent of net sales. Non-GAAP R&D expenses were 5.3 percent of net sales and non-GAAP SG&A expenses were 41.4 percent of net sales.
Income Tax Rate: In the fourth quarter of 2018, the income tax benefit rate on a GAAP basis was 114.9 percent and the income tax expense rate on a non-GAAP basis was 8.2 percent.
Net Income: On a GAAP basis in the fourth quarter of 2018, net income was $87.6 million. Fourth-quarter 2018 non-GAAP net income was $116.8 million.
Adjusted EBITDA: Fourth-quarter 2018 adjusted EBITDA was $151.1 million.
Earnings (Loss) per Share: On a GAAP basis in the fourth quarter of 2018, diluted earnings per share were $0.50 versus a diluted loss per share of $0.23 in the fourth quarter of 2017. Non-GAAP diluted earnings per share in the fourth quarter of 2018 and 2017 were $0.67 and $0.29, respectively. Weighted average shares outstanding used for calculating GAAP and non-GAAP diluted earnings per share in the fourth quarter of 2018 were 174.2 million.
Fourth-Quarter Segment Results

Management uses net sales and segment operating income to evaluate the performance of the Company’s two segments. While segment operating income contains certain adjustments to the directly comparable GAAP figures in the Company’s consolidated financial results, it is considered to be prepared in accordance with GAAP for purposes of presenting the Company’s segment operating results.

(1)On Jun. 23, 2017, Horizon Pharma completed the divestiture of a European subsidiary that owned the marketing rights to PROCYSBI and QUINSAIR in Europe, the Middle East and Africa (EMEA) to Chiesi Farmaceutici S.p.A. Horizon Pharma retains marketing rights for the two medicines in the United States, Canada, Latin America and Asia. Horizon Pharma’s 2017 net sales of PROCYSBI and QUINSAIR in EMEA were $9.5 million.

Fourth-quarter 2018 net sales of the orphan and rheumatology segment were $237.6 million, an increase of 33 percent over the prior year’s quarter, driven by continued strong KRYSTEXXA growth as well as growth of RAVICTI, PROCYSBI and RAYOS. Fourth-quarter 2018 orphan and rheumatology segment operating income was $84.8 million, an increase of 39 percent.
For the full-year 2018, KRYSTEXXA net sales of $258.9 million represented a 65 percent year-over-year increase, in line with the Company’s expectation.
On Dec. 28, 2018, the Company sold the rights to RAVICTI and AMMONAPS (AMMONAPS is known as BUPHENYL and LODOTRA is known as RAYOS in the United States) outside of North America and Japan to Medical Need Europe AB for $35.0 million. In addition, effective Jan. 1, 2019, the RAYOS and LODOTRA license and supply agreements were amended, including the transfer of LODOTRA to Vectura Group plc, the current third-party supplier. Beginning in 2019, the Company will no longer recognize revenue from RAVICTI and AMMONAPS sales outside of North America and Japan, or from sales of LODOTRA.

Fourth-quarter 2018 net sales of the primary care segment were $117.9 million and operating income was $66.2 million.
Cash Flow Statement and Balance Sheet Highlights

On a GAAP basis in the fourth quarter of 2018, operating cash flow was $108.7 million. Non-GAAP operating cash flow was $115.1 million.
The Company had cash and cash equivalents of $958.7 million as of Dec. 31, 2018.
As of Dec. 31, 2018, the total principal amount of debt outstanding was $1.993 billion, which consisted of $818 million in senior secured term loans due 2024; $300 million senior notes due 2024; $475 million senior notes due 2023 and $400 million exchangeable senior notes due 2022. As of Dec. 31, 2018, net debt was $1.034 billion and our net-debt-to-last-12-months adjusted EBITDA leverage ratio was 2.3 times.
2019 Guidance

The Company expects full‐year 2019 net sales to range between $1.23 billion and $1.25 billion and full‐year 2019 adjusted EBITDA is expected to range between $440 million and $455 million, reflecting investment in preparation for the potential U.S. launch of teprotumumab and continued R&D pipeline programs to drive long-term growth.

Webcast

At 8 a.m. EST / 1 p.m. IST today, the Company will host a live webcast to review its financial and operating results and provide a general business update. The live webcast and a replay may be accessed at View Source Please connect to the Company’s website at least 15 minutes prior to the live webcast to ensure adequate time for any software download that may be needed to access the webcast. A replay of the webcast will be available approximately two hours after the live webcast.

On February 27, 2019 Idera Pharmaceuticals, Inc. (NASDAQ: IDRA) reported completion of enrollment into the ongoing phase 2 expansion of the ILLUMINATE-204 trial investigating tilsotolimod, Idera’s intratumorally-delivered toll-like receptor 9 (TLR9) agonist, in combination with ipilimumab (Yervoy*) in patients with unresectable or metastatic melanoma following failure of PD-1 inhibitor treatment (Press release, Idera Pharmaceuticals, FEB 27, 2019, View Source [SID1234533745]).

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52 patients have been dosed in the trial which included two separate patient groups. The company completed the targeted enrollment of 40 patients in the primary enrollment population, constituting patients who are naïve to prior ipilimumab treatment in the metastatic setting. This patient population mirrors the enrollment for the ILLUMINATE-301 phase 3 pivotal trial. The secondary exploratory enrollment population targeted up to 20 patients who had prior ipilimumab treatment in the metastatic setting.

The ILLUMINATE-204 trial is a multi-center trial being conducted at 10 sites throughout the United States.

The company is currently enrolling ILLUMINATE-301, a global, multi-center, randomized Phase 3 trial that compares effectiveness and safety between two treatment groups: tilsotolimod combined with ipilimumab versus ipilimumab given alone. This trial is being conducted at up to 100 centers with a target enrollment of 308 patients. Enrollment remains on track and is expected to be completed in the 4th quarter of 2019.

The company also recently received notice from the U.S. Food and Drug Administration that the company can proceed to implement the ILLUMINATE-206 clinical trial under a new Investigational New Drug (IND) Application. The ILLUMINATE-206 trial will test the safety and effectiveness of tilsotolimod in combination with ipilimumab and nivolumab in treating patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) and Microsatellite Stable Colorectal Cancer (MSS-CRC). The ILLUMINATE-206 trial is expected to initiate in the second quarter of 2019.

"We made tremendous progress with the clinical development of tilsotolimod in the second half of 2018, and enrollment in the phase 3 study in patients with melanoma progressing on PD-1 therapy is tracking to complete by the end of 2019." stated Joanna Horobin, M.B. Ch.B, Idera’s Chief Medical Officer. "Oncologists are enthusiastic to extend the use of tilsotolimod to potentially improve the outcome of immuno-therapy for other patient populations, such as head and neck cancer, and in microsatellite stable CRC where so far immunotherapy outcomes have not been optimal."

As a reminder, the company provided an interim data update from the ILLUMINATE-204 trial in December 2018.

Summary of ILLUMINATE-204 Key Findings from the December 2018 Update:

37 patients dosed with 8 mg of tilsotolimod in combination with ipilimumab were evaluated for the December 2018 update;
All 37 patients were evaluable for safety;
The combination regimen continues to be generally well tolerated. 9/37 subjects (24.3%) had immune-related toxicities indicating that tilsotolimod + ipilimumab does not appear to add immune-related toxicity versus ipilimumab alone;
Injection-related toxicities were grade 1-2 transient fever and flu-like symptoms lasting <48 hours;
34 patients were evaluable for efficacy;
Responses, including 3 Complete Responses (CR), were observed in 11 of the 34 evaluable patients (32.4%);
Duration of response ranges from > 1 month to > 30 months, with 36% of responses ongoing at the time of the report;
Per RECIST v1.1, the Overall Response Rate (ORR) is 29.4%; one patient with an unconfirmed Partial Response (uPR) at the end of treatment assessment progressed due to a new lesion at the 3-month follow-up disease assessment;
Overall, 26 patients out of 34 evaluable for efficacy (76.5%) experienced disease control (CR, PR, or Stable Disease [SD]);
Analysis of spider plots show tumor shrinkage in both injected and uninjected lesions, indicating an abscopal effect;
Responding subjects include one patient with mucosal melanoma and one patient with acral melanoma, two forms of melanoma that are particularly difficult to treat; and
Importantly, 2 of 5 patients with prior ipilimumab experience achieved responses, further demonstrating a signal that tilsotolimod has the potential to help overcome prior ipilimumab resistance.
Additionally:

A RECIST v1.1 PR of > 2.5 years is ongoing in 1 patient treated with tilsotolimod 4 mg in combination with ipilimumab; and
A RECIST v1.1 CR of > 1 year is ongoing in 1 patient treated with tilsotolimod 16 mg in combination with pembrolizumab.
About Tilsotolimod (IMO-2125)
Tilsotolimod is a TLR 9 agonist that received Fast Track Designation from the US Food and Drug Administration (FDA) in 2017 for the treatment of anti-PD-1 refractory melanoma, in combination with ipilimumab as well as orphan drug designation from the FDA for the treatment of melanoma Stages IIb to IV. It signals the immune system to create and activate cancer-fighting cells (T-cells) to target solid tumors. Currently approved immuno-oncology treatments, specifically check-point inhibitors, work for some but not all, as many patients’ immune response is missing or weak and thus they do not benefit from the checkpoint therapy. Intratumoral injections with tilsotolimod are designed to selectively enable the tumor-specific T-cells to recognize and attack cancers that remained elusive and unrecognized by the immune system exposed to checkpoint inhibitors alone, while limiting toxicity or impact on healthy cells in the body.

About ILLUMINATE-301
The ILLUMINATE-301 study (2125-MEL-301) is for patients who have metastatic melanoma for whom treatment with an anti-PD-1 drug like Keytruda (pembrolizumab) or Opdivo (nivolumab) has failed. ILLUMINATE-301 is a global, multi-center, randomized Phase 3 study that compares the effectiveness and safety between two treatment groups: IMO-2125 combined with ipilimumab (Yervoy) versus ipilimumab given alone.

For additional details about ILLUMINATE-301, please go to clinicaltrials.gov and search for study identifier NCT03445533.

About ILLUMINATE-204
The ILLUMINATE-204 study (2125-204) is for patients who have metastatic melanoma for whom treatment with an anti-PD-1 drug like Keytruda** (pembrolizumab) or Opdivo* (nivolumab) has failed. ILLUMINATE-204 is a multi-center, two-arm Phase 1/2 study that tests the safety and effectiveness of tilsotolimod in combination with either ipilimumab (Yervoy) or pembrolizumab (Keytruda) for the treatment of patients with anti-PD-1 refractory metastatic melanoma.

For additional details about ILLUMINATE-204, please go to clinicaltrials.gov and search for study identifier NCT02644967.

About ILLUMINATE-206
The ILLUMINATE-206 study (2125-206) is a Phase 2 multi-center, multi-cohort study of intratumoral tilsotolimod in combination with nivolumab and ipilimumab in patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) who are either immunotherapy naïve and immunotherapy refractory and immunotherapy naïve patients with Microsatellite Stable Colorectal Cancer (MSS-CRC). The trial is expected to open for enrollment in the second quarter of 2019.

About Metastatic Melanoma
Although melanoma is a rare form of skin cancer, it comprises over 75% of skin cancer deaths. The American Cancer Society estimates that there were approximately 76,000 new invasive melanoma cases and 10,000 deaths from the disease in the USA in 2016. Additionally, according to the World Health Organization, about 132,000 new cases of melanoma are diagnosed around the world every year.

On February 27, 2019 Starpharma (ASX: SPL, OTCQX: SPHRY) reported its interim report and financial results for the half-year ended 31 December 2018 (Press release, Starpharma, FEB 27, 2019, View Source [SID1234533744]).

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Financial Summary

Reported loss of $7.3M (Dec 2017: $6.2M); and
Cash position at 31 December 2018 of $44.4M (June 2018: $51.3M), which excludes the expected $4.0M FY18 R&D tax incentive to be received.
VivaGel

VivaGel BV was licensed to ITF Pharma, Inc., for the US for milestones of up to US$101M in addition to escalating, double-digit royalties;
Starpharma and its partners, Mundipharma and Aspen, undertook extensive preparations for the upcoming launches of VivaGel BV in multiple regions scheduled for the first half of 2019. Extensive marketing activities such as packaging design, sales staff training, promotional material development, and launch meetings occurred in parallel with supply chain activities. Manufactured product has been delivered to Aspen subsequent to half-year end, and manufacturing of product for Europe is well-advanced;
US FDA completed its review of the VivaGel BV NDA and advised it requires confirmatory clinical data prior to approval. In preparation for a meeting with the FDA to discuss the data required, Starpharma has been working closely with expert FDA consultants and is currently awaiting confirmation of the meeting date;
VivaGel condom received final regulatory approval in Japan and Starpharma’s partner, Okamoto, commenced launch activities; and
Positive independent market research was conducted in the US for SPL7013 ophthalmic drops for viral conjunctivitis and a patent was granted for the product.
DEP Drug Delivery

Recruitment activities progressed well for two DEP clinical trials – for DEP docetaxel (phase 2) and DEP cabazitaxel (phase 1 / 2), with new sites opened to support recruitment. Efficacy signals have been observed in a number of patients and both products continue to exhibit a notable lack of bone marrow toxicity and other common side effects including hair-loss, anaphylaxis and oedema;
Final preclinical work for the DEP irinotecan phase 1 / 2 trial was completed, study product was manufactured, and other trial preparations, including CRO/site selection, are well advanced ahead of the planned trial commencement later in FY19;
AstraZeneca’s first patent application on DEP Bcl2/xL inhibitor conjugates was published and included compelling efficacy data on DEP Bcl2/xL inhibitor conjugates, both alone and in combination with market-leading anti-cancer treatments, in various human leukemia models;
DEP irinotecan showed impressive efficacy and safety benefits over standard irinotecan in combination with 5-FU in a human pancreatic cancer model;
DEP docetaxel & DEP cabazitaxel outperformed both gemcitabine & Abraxane in a human pancreatic cancer model; and
A range of DEP radiopharmaceutical and other DEP candidates have been made and are currently undergoing testing in a variety of models.
Starpharma concluded the half-year in a strong financial position with a cash balance of $44.4 million, which does not include the $4.0M FY18 R&D tax incentive expected to be received after 31 December 2018. The net loss after tax for the half-year of $7.3 million (Dec 2017: $6.2 million) reflects investment across the VivaGel and DEP portfolio, including DEP docetaxel, DEP cabazitaxel, and DEP irinotecan. Expenditure includes an increased investment in commercialisation, regulatory and operating costs associated with the US VivaGel BV licence and the preparation for product launch in a number of territories.

Starpharma’s CEO, Dr Jackie Fairley, commented: "We achieved several important milestones in the VivaGel portfolio during the half-year, including signing a US licence for VivaGel BV with ITF Pharma, Inc. We were clearly surprised and disappointed by the FDA’s request for confirmatory data and we are working with expert FDA consultants to expedite this process. In non-US territories, launch activities are in the final stages as we approach the launch of VivaGel BV in Australia and Europe (1HCY19). We also continue to work closely with our partner, Mundipharma, on further registrations to support launches in several other regions."

Commenting on the DEP drug delivery portfolio, Dr Fairley said: "We’re pleased to see efficacy signals once again in both our DEP clinical trials as well as a notable lack of bone marrow toxicity and other common side effects. An abundance of positive data from the DEP platform, both preclinical and clinical, continues to build amid partnered program discussions with a number of multinational and US pharmaceutical companies. Our first partnered program with AstraZeneca for AZD0466 is expected to commence clinical trials this year and preparations at AstraZeneca for this activity continue with priority. This partnered program is just one example of the value that can be generated from our unique DEP platform."

Dr Fairley concluded: "We expect to announce a number of key milestones throughout 2019, in addition to the launch of VivaGel BV in Australia and Europe, and regulatory progress across a range of markets, including the US; launch of the VivaGel condom in Japan; regulatory approval of the VivaGel condom in other regions; and progress across internal and partnered DEP programs including commencement of the DEP irinotecan and AZD0466 clinical trials."

On February 27, 2019 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases, reported presentations highlighting next-generation CAR T platform and mesothelin-targeted CAR T clinical safety and efficacy results from Memorial Sloan Kettering Cancer Center (MSK) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Atara Biotherapeutics, FEB 27, 2019, View Source [SID1234533742]). The event will be held March 29 to April 3 in Atlanta, Georgia.

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"Atara has established a leading next-generation CAR T portfolio," said Dietmar Berger, M.D., Ph.D., Global Head of Research and Development of Atara Biotherapeutics. "Encouraging pre-clinical results at AACR (Free AACR Whitepaper) show the potential of our EBV-specific T cell platform to generate off-the-shelf, allogeneic CAR T immunotherapies. We also look forward to our MSK collaborators’ clinical results of a mesothelin-targeted autologous CAR T for patients with advanced malignant pleural disease."

Mesothelin is a solid tumor-associated antigen that is expressed at high levels on the surface of cells in aggressive solid tumors including mesothelioma, triple-negative breast cancer, ovarian cancer, pancreatic cancer and non-small cell lung cancer. Initial results from an ongoing MSK investigator-sponsored Phase 1 study (NCT02414269) of a mesothelin-targeted CAR T immunotherapy for patients with malignant pleural cancers were presented at the 2018 American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) Annual Meeting and support activity and safety in patients with advanced mesothelioma1,2. This ongoing Phase 1 dose-escalation study continues to accrue patients and the initial results at ASGCT (Free ASGCT Whitepaper) 2018 showed enhanced response rates when patients were subsequently treated with pembrolizumab, a PD-1 checkpoint inhibitor. MSK is also investigating mesothelin-targeted CAR T cells for patients with advanced breast and lung cancer (NCT02792114).

In January 2019, Atara announced an exclusive license and collaboration agreement with MSK to develop a next-generation, mesothelin-targeted CAR T using novel 1XX CAR signaling domain and PD-1 dominant negative receptor (DNR) checkpoint inhibition technologies for patients with mesothelin-associated solid tumors.

Abstract 2310: Functional demonstration of CD19 chimeric antigen receptor (CAR) engineered Epstein-Barr virus (EBV) specific T cells: An off-the-shelf, allogeneic CAR T-cell immunotherapy platform
Session Category: Immunology
Session Title: Adoptive Cell Therapy 2
Poster Presentation Date and Time: Monday, April 1, 2019 from 1:00 pm – 5:00 pm EDT
Location: Georgia World Congress Center, Exhibit Hall B
Authors: Blake T. Aftab, Rhine R. Shen, Christina D. Pham, Michelle Wu, Daniel J. Munson
Affiliations: Atara Biotherapeutics
Summary: Atara engineered EBV-specific T cells to express second-generation CD19 CARs, utilizing CD28 or 4-1BB co-stimulatory domains, resulting in high expression of both CD19 CAR and EBV T cell receptor (TCR). The chimeric EBV.CD19.CAR T cells exert potent and specific cytotoxicity against CD19-positive cells but have limited activity against CD19-negative cells. These findings establish feasibility for engineering EBV-specific T cells by leveraging next-generation CAR technologies, and support further development as an off-the-shelf, allogeneic CAR T immunotherapy platform.

Title: A Phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy
Session: Advances in Novel Immunotherapeutics
Clinical Trials Minisymposium Date and Time:Sunday, March 31, 2019 from 3:00 pm – 5:00 pm EDT
Location:Room A411 – Georgia World CC
Authors:Prasad S. Adusumilli, Marjorie Zauderer, Valerie Rusch, Roisin O’Cearbhaill, Amy Zhu, Daniel Ngai, Erin McGee, Navin Chintala, John Messinger, Alain Vincent, Elizabeth Halton, Claudia Diamonte, John Pineda, Shanu Modi, Steve Solomon, David R Jones, Renier Brentjens, Isabelle Riviere, Michel Sadelain
Affiliations:Memorial Sloan Kettering Cancer Center

References
1Adusumilli PS, et al. A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CART cells: safety and efficacy – a preliminary report. Abstract 342; 2018 ASGCT (Free ASGCT Whitepaper) Annual Meeting; Chicago, IL; May 16-19, 2018.
2Adusumilli PS, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med. 2014 Nov 5;6(261):261ra151. doi: 10.1126/scitranslmed.3010162.