On March 18, 2019 Array BioPharma Inc. (NASDAQ: ARRY) reported that the National Comprehensive Cancer Network (NCCN) has updated their Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer to include BRAFTOVI in combination with MEKTOVI and an anti-EGFR antibody as a Category 2a treatment for patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), after failure of one or two prior lines of therapy for metastatic disease (Press release, Array BioPharma, MAR 18, 2019, View Source [SID1234534454]). The BRAFV600E mutation is associated with a poor prognosis compared to patients with CRC who do not carry the BRAF mutation, and currently there are no FDA-approved therapies specifically for this high unmet need population. [1-5]

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"With no current FDA-approved therapies for BRAF CRC, this combination represents an important treatment option for this patient population," said Scott Kopetz, M.D., Ph.D., FACP, Associate Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "Historical published benchmarks in BRAFV600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy, are an overall response generally between 4% to 8%, a median progression-free survival of 2 to 3 months and median overall survival of 4 to 6 months. The NCCN recommendation underscores the potential for this triplet combination to benefit these patients in critical need."

The NCCN based their recommendation on data from the safety lead-in of the BEACON CRC trial evaluating the triplet combination of BRAFTOVI in combination with MEKTOVI and ERBITUX (cetuximab), in 29 patients with BRAFV600E-mutant mCRC. As presented at the ASCO (Free ASCO Whitepaper) 2019 Gastrointestinal Cancers Symposium (ASCO GI), confirmed overall response rate (ORR) and median progression-free survival (mPFS) results for patients treated with the triplet in the safety lead-in demonstrated 48% ORR (95% CI, 29.4–67.5) and 8 months mPFS (95% CI, 5.6-9.3). ORR by central assessment, 41% (95% CI 24%–61%), was consistent with local assessment. Mature median overall survival (OS) was 15.3 months (95% CI, 9.6–not reached) for patients with BRAF-mutant mCRC treated with the triplet.

"Patients with BRAFV600E-mutant mCRC are in great need of effective treatment options," said Ron Squarer, Chief Executive Officer. "Based on data from the safety lead-in portion of the BEACON CRC Phase 3 trial, the FDA granted Breakthrough Therapy Designation in August 2018 for BRAFTOVI, in combination with MEKTOVI and cetuximab for the treatment of patients with BRAFV600E-mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease. We look forward to the interim analysis of the randomized portion of the trial in the first half of this year."

As presented at ASCO (Free ASCO Whitepaper) GI, the triplet combination was generally well-tolerated with no unexpected toxicities. The most common grade 3 or 4 adverse events seen in at least 10% of patients were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate aminotransferase (10%) and urinary tract infections (10%). The rate of grade 3 or 4 skin toxicities was lower than generally observed with ERBITUX in mCRC.

About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. [6] In the U.S. alone, an estimated 140,250 patients were diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease each year. [7] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and represent a poor prognosis for these patients. [4,8-11] The V600 mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. [4-5] Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established observed historical published benchmarks in BRAFV600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy. These benchmarks include ORR of 4% to 8%, mPFS of 2 to 3 months and median OS of 4 to 6 months. [9-16] BRAFV600E-mutant mCRC is an area of high unmet need as there are currently no FDA-approved therapies specifically indicated for patients with BRAF-mutant mCRC, and these patients derive limited benefit from available chemotherapy regimens. [1-3] For more information about BRAFV600E-mutant mCRC visit www.brafmcrc.com.

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and ERBITUX in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAFV600E-mutant mCRC. Thirty patients were treated in the safety lead-in and received the triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and ERBITUX per label). Of the 30 patients, 29 had a BRAFV600 mutation. Microsatellite instability high, resulting from defective DNA mismatch repair, was detected in only 1 patient. As previously announced, the triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial. The randomized portion of the BEACON CRC trial is designed to assess the efficacy of BRAFTOVI in combination with ERBITUX with or without MEKTOVI compared to ERBITUX and irinotecan-based therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet combination, doublet combination (BRAFTOVI and ERBITUX) or the control arm (irinotecan-based therapy and ERBITUX). The study has been amended to include an interim analysis of endpoints including ORR. The primary overall survival endpoint is a comparison of the triplet combination to the control arm. Secondary endpoints address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include PFS, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial is being conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. The BEACON CRC trial is being conducted with support from Ono Pharmaceutical Co. Ltd., Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC is investigational and not approved by the FDA.

About BRAFTOVI + MEKTOVI
BRAFTOVI is an oral small molecule BRAF kinase inhibitor and MEKTOVI is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer and others. In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. In Europe, the combination is approved for adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation, as detected by a validated test. In Japan, the combination is approved for unresectable melanoma with a BRAF mutation.

Array has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and Canada. Array has granted Ono Pharmaceutical Co. Ltd., exclusive rights to commercialize both products in Japan and South Korea, Medison exclusive rights to commercialize both products in Israel and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Latin American and Asia (excluding Japan and South Korea).

BRAFTOVI + MEKTOVI have received regulatory approval in the United States, European Union, Australia and Japan. The Swiss Medicines Agency (Swissmedic) is currently reviewing the Marketing Authorization Applications for BRAFTOVI and MEKTOVI submitted by Pierre Fabre.

Indications and Usage
BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma.

BRAFTOVI + MEKTOVI Important Safety Information
The information below applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

Warnings and Precautions
New Primary Malignancies: Cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or V600K mutation prior to initiating BRAFTOVI.

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. Cardiomyopathy resolved in 87% of patients. Assess left ventricular ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. Safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal. Patients with cardiovascular risk factors should be monitored closely.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥ Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients. Assess for visual symptoms at each visit. Perform ophthalmological evaluation at regular intervals and for any visual disturbances, and to follow new or persistent ophthalmologic findings.

Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT) and 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. Monitor liver laboratory tests before and during treatment and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum creatine phosphokinase (CPK) occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated.

QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms.

Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.

Adverse Reactions
The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial): were fatigue, nausea, diarrhea, vomiting, abdominal pain, arthralgia, myopathy, hyperkeratosis, rash, headache, constipation, visual impairment, serous retinopathy.

In the COLUMBUS trial, the most common laboratory abnormalities (≥20%, all Grades): included increased creatinine, increased CPK, increased gamma glutamyl transferase, anemia, increased ALT, hyperglycemia, increased AST, and increased alkaline phosphatase.

Drug Interactions
Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided. Avoid co-administration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information. [17-18] You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Array at 1-844-Rx-Array (1-844-792-7729).

On March 18, 2019 Aclaris Therapeutics, Inc. (NASDAQ: ACRS), a physician-led biopharmaceutical company focused on dermatological and immuno-inflammatory diseases, reported financial results for the fourth quarter and full year 2018, and provided an update on its clinical development and commercial programs (Press release, Aclaris Therapeutics, MAR 18, 2019, View Source [SID1234534422]).

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In November 2018, Aclaris acquired the worldwide rights to RHOFADE (oxymetazoline hydrochloride) cream, 1% from Allergan Sales, LLC.
In December 2018, Aclaris began promoting RHOFADE, which is approved in the United States for the topical treatment of persistent facial erythema (redness) associated with rosacea in adults.
In February 2019, at the annual National Sales Meeting, Aclaris appointed Jeff Wayne as interim Head of Commercial and officially relaunched RHOFADE.
Today Aclaris is providing an update, including new photos, from AUATB-201 Topical, an open-label clinical trial in patients with eyebrow loss due to alopecia areata (AA), including patients with alopecia totalis or alopecia universalis.
"On the commercial side of the company, we made a change in leadership as we focus on the relaunch of RHOFADE in 2019. Our development stage pipeline continues to advance with multiple data read outs expected during the course of the year across both our JAK inhibitor and A-101 clinical programs. Finally, we look to move our first Confluence originated asset into the clinic in the second half of the year; a significant milestone given we acquired and integrated the team just 18 months ago. Given the anticipated data readouts, we expect 2019 to be a watershed year as we become a fully integrated biopharmaceutical company," said Dr. Neal Walker, President and Chief Executive Officer of Aclaris.

Clinical Pipeline Update:

A-101 45% Topical Solution:
Two pivotal Phase 3 trials, named THWART-1 and THWART-2, for the treatment of common warts are progressing as planned. THWART-2 has completed enrollment, and THWART-1 is expected to complete enrollment by the end of this month. These two trials will enroll a total of approximately 1,000 patients across both studies, and topline data are expected in the second half of 2019.
An open-label safety extension trial investigating A-101 45% Topical Solution for the treatment of common warts is also ongoing; if the results of these trials are positive, NDA submission is expected in the first half of 2020.
JAK Inhibitor Trials:
We have completed enrollment in all of the following JAK inhibitor trials:
AA-201 Topical – This ongoing Phase 2 randomized, double-blinded, parallel-group, vehicle-controlled trial is evaluating the safety, efficacy, and dose response of two concentrations of ATI-502, a topical JAK1/3 inhibitor, on the regrowth of hair in 129 patients with AA. Data are expected in the second quarter of 2019.
AGA-201 Topical – This ongoing Phase 2 open-label clinical trial is evaluating the safety and efficacy of ATI-502, a topical JAK1/3 inhibitor, on the regrowth of hair in 31 patients with androgenetic alopecia (AGA), also known as male/female pattern hair loss. 6-month data are expected in the second quarter of 2019 and 12-month data are expected in the second half of 2019.
VITI-201 Topical – This ongoing Phase 2 open-label clinical trial is evaluating the safety and efficacy of ATI-502, a topical JAK1/3 inhibitor, on the repigmentation of facial skin in 34 patients with vitiligo. 6-month interim data are expected in the second quarter of 2019 and 12-month data are expected in the second half of 2019.
AD-201 Topical – This ongoing Phase 2 open-label clinical trial is evaluating the safety and efficacy of ATI-502, a topical JAK1/3 inhibitor, in 22 adult patients with moderate-to-severe atopic dermatitis (AD). Data are expected in mid-2019.
AUAT-201 Oral – This ongoing randomized, double-blinded, parallel-group, placebo-controlled trial is evaluating the safety, efficacy, and dose response of three concentrations of ATI-501, an oral JAK 1/3 inhibitor, on the regrowth of hair in 87 patients with AA. Data are expected in the second half of 2019.
ATI-450 (MK-2 Inhibitor) – We expect to submit an Investigational New Drug (IND) application for rheumatoid arthritis to the FDA in mid-2019. If the IND is allowed by the FDA, we expect to initiate a Phase 1 and Phase 2 trial in the second half of 2019.
Recent Corporate Highlights:

Significant presence at 2019 Annual Academy of Dermatology (AAD) Annual Meeting to support the relaunch of RHOFADE. Aclaris also presented 6 posters, including 2 oral presentations regarding the clinical results of ESKATA for the treatment of raised seborrheic keratosis and A-101 45% topical solution for the treatment of common warts.
Aclaris received approval from the Swedish Medical Products Agency to market ESKATA (hydrogen peroxide) cutaneous solution, 685 mg, for the treatment in adults of seborrheic keratoses that are not pedunculated and have up to a maximum diameter of 15 mm each. Aclaris also has received approval to market the medicine in the United Kingdom, Iceland, and Belgium. Aclaris is seeking a commercial partner or partners to market the medicine as an aesthetic skin treatment in various European countries with the brand name ESKATA in Finland, Iceland, Netherlands, Norway, Portugal, Spain, Sweden, Czech Republic, and Belgium, and the brand name ESKERIELE in Austria, France, Germany, Ireland, Italy, and the United Kingdom.
Canadian partner Cipher Pharmaceuticals Inc. submitted a New Drug Submission for A-101 40% Topical Solution for the treatment of raised SKs, which was accepted for review by Health Canada in December 2018.
Commercial Update:

Jeff Wayne, Aclaris’ Vice President of Business Development, was recently appointed as interim Head of Commercial. Mr. Wayne brings over 30 years of pharmaceutical experience with the majority spent in dermatology. During his career, he has held positions of increasing responsibility in sales, marketing, and general management with Galderma, Intendis, Promius Pharma (where he built, launched, and led the commercial organization), Onset Dermatologics, and LEO Pharma. He launched METROGEL in both the United States and Canada and was responsible for the marketing of FINACEA in the United States; two medications prescribed for the treatment of rosacea. In his role as Vice President, Business Development, he managed the RHOFADE transaction from the beginning, providing a seamless transition of leadership.
Following our National Sales Meeting held mid-February, RHOFADE was officially relaunched, and featured prominently at the Aclaris booth and throughout the convention venue at the 2019 AAD Annual Meeting.
The Aclaris field sales team was realigned to optimize reach and call frequency on current and potential RHOFADE prescribers, as well as the top 10 ESKATA accounts in each territory.
Comparing the 4-week period ended March 8, 2019 to the immediately prior 4-week period, the IQVIA data showed an 8.4% increase in total prescriptions for RHOFADE.
Based on these early prescription trends, we believe the response to the RHOFADE message, which emphasizes the need to treat all rosacea patients with persistent facial erythema, appears positive.
Financial Highlights

Liquidity and Capital Resources

As of December 31, 2018, Aclaris had aggregate cash, cash equivalents and marketable securities of $168.0 million compared to $208.9 million as of December 31, 2017. The $30.9 million decrease during the year ended December 31, 2018 included:

Aggregate net proceeds of $100.2 million from the sale of common stock in a follow-on public offering of common stock in October 2018;
$67.1 million of cash used to acquire the global rights to RHOFADE;
$29.9 million of cash, net of issuance costs, borrowed under the loan agreement with Oxford Finance LLC;
$1.4 million in property and equipment purchases; and
Net loss of $132.7 million, offset by $9.4 million of net cash provided by working capital and $21.9 million of non-cash stock-based compensation expense, depreciation, and amortization.
Aclaris anticipates that its cash, cash equivalents and marketable securities as of December 31, 2018 will be sufficient to fund its operations into the fourth quarter of 2020, without giving effect to any potential new business development transactions or financing activities.

Fourth Quarter 2018 Financial Results

Net loss was $38.6 million for the fourth quarter of 2018, compared to $22.9 million for the fourth quarter of 2017.
Net revenues were $3.7 million for the quarter ended December 31, 2018, which consisted of $0.8 million of net ESKATA sales, $1.1 million of net RHOFADE sales (December only), $1.3 million of contract research revenues, and $0.5 million of other revenue. This compared to $1.0 million for the quarter ended December 31, 2017, all of which was contract research revenues. Cost of revenues was $3.5 million for the quarter ended December 31, 2018, compared to $0.8 million for the quarter ended December 31, 2017.
Total operating expenses for the fourth quarter of 2018 were $39.2 million, compared to $25.7 million for the fourth quarter of 2017.
Research and development expenses were $19.5 million for the fourth quarter of 2018, compared to $13.2 million for the fourth quarter of 2017. The increase of $6.3 million was mainly the result of the continued growth of Aclaris’ JAK inhibitor and common wart programs, as multiple Phase 2 trials of ATI-501 and ATI-502 and Phase 3 trials of A-101 45% were ongoing in the fourth quarter of 2018, as well as the increased headcount to support these programs.
Sales and marketing expenses were $13.0 million for the fourth quarter of 2018, compared to $6.6 million for the fourth quarter of 2017. The increase of $6.4 million was the result of increases in direct marketing and professional fees, as well as other commercial and personnel expenses incurred to support the continued commercialization of ESKATA following its launch in May 2018.
General and administrative expenses were $6.7 million for the fourth quarter of 2018, compared to $5.9 million for the fourth quarter of 2017. The increase was driven by headcount increases, and legal and business development costs related to the RHOFADE acquisition in the fourth quarter of 2018.
Full Year 2018 Financial Results

Net loss was $132.7 million for the year ended December 31, 2018, compared to $68.5 million for the year ended December 31, 2017.
Net revenues were $10.1 million for the year ended December 31, 2018, which consisted of $2.8 million of net ESKATA sales, $1.1 million of net RHOFADE sales (December only), $4.7 million of contract research revenues, and $1.5 million of other revenue. This compared to $1.7 million for the year ended December 31, 2017, all of which was contract research revenues. Cost of revenues was $6.9 million for the year ended December 31, 2018, compared to $1.2 million for the year ended December 31, 2017.
Total operating expenses were $138.7 million for the year ended December 31, 2018, compared to $72.9 million for the year ended December 31, 2017. Net cash used in operating activities was $100.8 million for the year ended December 31, 2018, compared to $54.7 million for the year ended December 31, 2017.
Research and development expenses were $63.0 million for the year ended December 31, 2018, compared to $39.8 million for the year ended December 31, 2017. The increase of $23.2 million was mainly the result of the continued growth of Aclaris’ JAK inhibitor and common wart programs, as multiple Phase 2 trials of ATI-501 and ATI-502 and Phase 3 trials of A-101 45% were conducted throughout 2018, as well as the increased headcount to support these programs. These increases were offset by a decrease in costs related to the development of ESKATA as Aclaris submitted the NDA for ESKATA in February 2017 following the completion of the clinical trials.
Sales and marketing expenses were $48.0 million for the year ended December 31, 2018, compared to $13.8 million for the year ended December 31, 2017. The increase of $34.2 million was the result of increases in direct marketing and professional fees, as well as other commercial expenses incurred to support the launch and commercialization of ESKATA in May 2018. Personnel expenses also increased as Aclaris completed the hiring of its field sales force early in 2018.
General and administrative expenses were $27.6 million for the year ended December 31, 2018, compared to $19.3 million for the year ended December 31, 2017. The increase of $8.3 million was the result of higher personnel expenses, due to increased headcount to support the commercial launch of ESKATA, as well as legal and business development costs related to the RHOFADE acquisition during 2018. General and administrative expenses for the year ended December 31, 2018 also included a $1.5 million ESKATA-related milestone payment, whereas the year ended December 31, 2017 included a $1.0 million ESKATA-related milestone payment.
As of December 31, 2018, Aclaris had 41.2 million shares of common stock outstanding.
2019 Financial Outlook

Aclaris expects 2019 GAAP research and development (R&D) expenses to be in the range of $61 to $64 million, including estimated stock-based compensation of $7 million. This expense guidance for R&D in 2019 contemplates the completion of Aclaris’ Phase 2 clinical trials in AA, open label trials in AGA, vitiligo and AD, and two pivotal Phase 3 trials in common warts, as well as the further advancement of Aclaris’ preclinical pipeline compounds, including ATI-450 and ATI-1777.
Aclaris expects 2019 GAAP sales and marketing (S&M) expenses to be in the range of $37 to $40 million, including estimated stock-based compensation of $4 million. This expense guidance for S&M in 2019 contemplates all salesforce costs and the selling and marketing initiatives to support our commercial brands.
Aclaris expects 2019 GAAP general and administrative (G&A) expenses to be in the range of $29 to $31 million, including estimated stock-based compensation of $10 million. This expense guidance for G&A in 2019 contemplates additional medical affairs, legal, and compliance activities to support our commercial brands.
Company to Host Conference Call

Management will conduct a conference call at 8:00 AM ET today to discuss Aclaris’ financial results and provide a general business update. The conference call will be webcast live over the Internet and can be accessed by logging on to the "Investors" page of the Aclaris Therapeutics website, www.aclaristx.com, prior to the event. A replay of the webcast will be archived on the Aclaris Therapeutics website for 30 days following the call.

To participate on the live call, please dial (844) 776-7782 (domestic) or (661) 378-9535 (international), and reference conference ID 9765869prior to the start of the call.

On March 18, 2019 Scholar Rock Holding Corporation (NASDAQ: SRRK), a clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, reported financial results for the full year ended December 31, 2018 and highlighted progress in 2018 and upcoming milestones for its pipeline programs (Press release, Scholar Rock, MAR 18, 2019, View Source [SID1234534501]).

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Key 2018 Accomplishments

Completed initial public offering and raised approximately $86 million in gross proceeds.
Entered into a strategic fibrosis-focused collaboration with Gilead Sciences, Inc. to discover and develop highly specific inhibitors of TGFβ activation ($80 million received upfront and eligible for up to an additional $1,450 million in potential milestone payments).
Transitioned to a clinical-stage company with the initiation of a Phase 1 clinical trial of SRK-015 in healthy volunteers.
Published preclinical data on the therapeutic benefit of inhibiting myostatin activation in mouse models of Spinal Muscular Atrophy (SMA) in peer-reviewed journal Human Molecular Genetics.
Received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) and Orphan Medicinal Product Designation from the European Commission (EC) for SRK-015 for the treatment of SMA.
Presented compelling preclinical data that demonstrate SRK-181-mIgG1 (murine version of SRK-181), a highly specific TGFβ1 inhibitor, can render resistant solid tumors vulnerable to PD1 blockade.
Progressed antibody platform for neuromuscular disorders, cancer immunotherapy, fibrosis, and anemias.
"2018 was a year of remarkable progress with our platform and for establishing a strong foundation as we transitioned to a public company," said Nagesh Mahanthappa, Ph.D, President and CEO of Scholar Rock. "We are focused on advancing our growing portfolio of product candidates, including SRK-015 for the treatment of SMA and SRK-181 to overcome primary resistance to checkpoint blockade therapy, as we continue to pursue our mission of developing innovative therapies to address significant unmet medical needs of patients."

R&D Highlights and Upcoming Milestones

SRK-015 Program:

Presented Interim Results from Phase 1 Clinical Trial of SRK-015 in Healthy Volunteers. In February 2019, Scholar Rock presented positive interim results from the Phase 1 clinical trial of SRK-015, a highly specific inhibitor of myostatin activation, which was observed to be well tolerated with no dose limiting toxicities identified up to the highest evaluated dose of 30 mg/kg. Pharmacodynamic data, measuring serum concentrations of latent myostatin, demonstrated robust and sustained target engagement, providing initial proof-of-mechanism for this unique therapeutic approach. Collectively, the favorable interim safety and tolerability, pharmacodynamic, and pharmacokinetic data supported the advancement of SRK-015 to a Phase 2 proof-of-concept clinical trial in patients with SMA.
Initiating Phase 2 Proof-of-Concept Trial for SRK-015 in SMA in First Quarter 2019. Scholar Rock is initiating a Phase 2 proof-of-concept trial to assess the safety and efficacy of SRK-015. The trial will consist of three non-overlapping cohorts, each evaluating a distinct subpopulation of patients with Type 2 and Type 3 SMA and all patients will receive SRK-015 dosed once every four weeks either as a monotherapy or in conjunction with an approved survival motor neuron (SMN) upregulator therapy. The primary efficacy endpoints will measure motor function through clinically meaningful outcome measures validated in SMA, such as the Hammersmith Functional Motor Scale Expanded (HFMSE) in non-ambulatory SMA and the Revised Hammersmith Scale (RHS) in ambulatory SMA, over a 12-month treatment period. Scholar Rock plans to provide additional details on the Phase 2 trial design at the time of initiating patient dosing in the second quarter of 2019. Interim safety and efficacy results for a subset of patients in each cohort with at least six months of treatment exposure are expected in the first half of 2020.
Plan to Identify Second Indication for SRK-015 in 2020. Scholar Rock continues to see multiple potential opportunities for which SRK-015 could offer clinical benefit and is assessing additional potential clinical settings in which the selective inhibition of the activation of myostatin may offer therapeutic benefit.
SRK-181 Program:

Nominated SRK-181 as Cancer Immunotherapy Product Candidate. In March 2019, Scholar Rock selected SRK-181, a highly specific inhibitor of TGFβ1 activation, as the first product candidate in its TGFβ1 cancer immunotherapy program based on the strength of preclinical data and human translational insights. SRK-181 is being developed for the treatment of tumors resistant to checkpoint blockade therapies (CBTs), such as anti-PD(L)1 antibodies. Scholar Rock plans to initiate a Phase 1 trial in patients with solid tumors in mid-2020.
Additional SRK-181-mIgG1 Preclinical Data to be Presented at Upcoming AACR (Free AACR Whitepaper) Annual Meeting. Scholar Rock will present additional preclinical data from multiple syngeneic mouse models of primary checkpoint resistance at the 2019 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held March 29-April 3, 2019. These studies demonstrate that co-administration of SRK-181-mIgG1 (murine version of SRK-181) with an anti-PD1 antibody permits effector T cell infiltration and expansion into the tumor microenvironment, resulting in tumor regression or control as well as significant survival benefit, while minimizing toxicities traditionally associated with pan-TGFβ inhibitors.
Full Year 2018 Financial Results

For the year ended December 31, 2018, net loss was $49.3 million or $3.15 per share compared to a net loss of $25.0 million or $15.30 per share for the year ended December 31, 2017.

Research and development expense was $36.3 million for the year ended December 31, 2018 compared to $19.9 million for the year ended December 31, 2017. The increase year-over-year in both periods reflect development and manufacturing costs associated with lead product candidate, SRK-015, research costs associated with preclinical studies, as well as increased personnel-related costs to support continued progress with the pipeline.
General and administrative expense was $14.4 million for the year ended December 31, 2018 compared to $5.1 million for the year ended December 31, 2017. The increase year-over-year was primarily attributable to increased headcount and higher professional and consulting fees associated with the IPO and collaboration with Gilead, as well as ongoing business activities and operations as a public company.
As of December 31, 2018, Scholar Rock had cash, cash equivalents, and marketable securities of $175.6 million, compared to $58.0 million as of December 31, 2017.

"We established a strong financial foundation in 2018 with contributions from our successful IPO and our strategic fibrosis collaboration with Gilead," said Rhonda Chicko, Chief Financial Officer of Scholar Rock. "As illustrated by the recent announcement of positive interim Phase 1 results for SRK-015 and the nomination of SRK-181 as the first product candidate in our cancer immunotherapy program, we continue to focus on our robust pipeline of highly specific growth factor modulators across a diverse range of therapeutic areas."

On March 18, 2019 IMV Inc. (IMV) (Nasdaq: IMV; TSX: IMV), a clinical stage immuno-oncology corporation, reported that Canadian bioresearch consortium CQDM has awarded a grant to a collaboration among IMV, Centre de recherche du CHU de Québec-Université Laval, and La Fondation du CHU de Québec (FCHUQc) (Press release, IMV, MAR 18, 2019, View Source [SID1234553817]).

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Under the leadership of Yves Fradet, M.D., professor of surgery and researcher in cancer immunotherapy, and his team, in collaboration with IMV’s team , this project will receive a grant of up to CAN$1.2M from CQDM and CAN$300,000 from the FCHUQc, to develop a novel dual target T cell therapy for an initial clinical application in bladder cancer.

The work will target immunogenic peptides identified by Dr Fradet’s team from the MAGE protein family member A9 (MAGE-A9). This protein is frequently expressed in various human cancers including bladder, lung, and kidney.1 These peptides will be combined with selected immunogenic peptides from the survivin protein composing the DPX-Survivac T cell drug candidate.

The researchers believe that MAGE-A9 and survivin peptides presented on the surface of cancer cells can be used to program T cells to destroy tumors and may represent ideal targets for anti-cancer T cell immunotherapies. The collaborators will combine these peptides with IMV’s proprietary DPX technology to develop a first-in-class dual target T cell therapy (DPX-SurMAGE).

"We believe that DPX is a truly disruptive technology that enables us to program T cells in vivo in a novel way, and we are grateful that CQDM and its funding partner the Quebec Ministry of Economy and Innovation, along with the FCHUQc, are willing to support this highly innovative program," said Stéphan Fiset, Vice President, Clinical Research at IMV. "Our goal remains to expand the range of patients able to benefit from T cell immunotherapies. This program provides an opportunity for us to collaborate with Dr. Fradet’s team and other experts in the bladder cancer field to advance a potential new candidate for the many patients whose current treatment options are limited."

DPX-SurMAGE will be initially evaluated in preclinical studies. Upon successful completion of these preclinical evaluations, researchers are aiming to test the candidate in two clinical studies in patients with:

Muscle invasive bladder cancer combined with an anti-PD-1 and intermittent low-dose cyclophosphamide (CPA) prior to cystectomy
Low-grade highly recurrent non muscle invasive bladder cancer combined with CPA prior to transurethral resection
"Bladder cancer remains a significant unmet medical need and we believe that a novel T cell therapy directed against two cancer targets that are expressed in the majority of bladder tumors may improve outcomes, particularly for those who are at higher risk of recurrence and progression," said Dr. Fradet. "We are pleased to be working under the support of CQDM and the FCHUQc with our partner IMV, and its novel clinical development approach, to advance the options in this cancer, which has already shown promising response to immunotherapy. This project contributes to position the Centre de recherche du CHU de Québec-Université Laval as a leader in medical innovation."

The project is expected to span a three-year period and will be supported by IMV, CQDM and FCHUQc. As part of the collaboration agreement, IMV holds an exclusive option to in-license intellectual property related to the program.

On March 18, 2019 Alpine Immune Sciences, Inc. (Nasdaq:ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer, autoimmune/inflammatory, and other diseases, reported financial results for the year ended December 31, 2018 (Press release, Alpine Immune Sciences, MAR 18, 2019, View Source [SID1234534423]).

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"This was a year of continued execution for Alpine as we transitioned from a preclinical company to a development stage company, dosing earlier this quarter the first subjects in our Phase I healthy volunteer study of ALPN-101, our lead therapeutic for the potential treatment of autoimmune and inflammatory diseases. In addition, we continue to advance our lead oncology program, ALPN-202, preparing it for the clinic with the goal of filing an IND or IND-equivalent late this year," said Mitchell H. Gold, M.D., Executive Chairman and Chief Executive Officer of Alpine. "With our recently completed private placement of $25.3 million led by Decheng Capital, we are well positioned to achieve key catalysts later this year in both of our programs."

Recent Corporate and Clinical Highlights

First Subjects Dosed in Phase I Healthy Volunteer Trial for Lead Autoimmune/Inflammatory Disease Program, ALPN-101: On February 11, 2019, we announced the successful initial dosing of our first-in-human Phase I study of ALPN-101, a first-in-class dual ICOS/CD28 antagonist. The study is designed to evaluate the safety and tolerability of single- and multiple-ascending intravenous and/or subcutaneous doses of ALPN-101 in healthy volunteers. In addition, pharmacokinetics, pharmacodynamics, and exploratory biomarkers are being evaluated to help determine ALPN-101’s potential for the treatment of autoimmune and inflammatory diseases.

Completion of $25.3 Million Private Placement: On January 15, 2019, we entered into a securities purchase agreement for the sale of units consisting of shares of common stock and warrants to purchase common stock in a private placement providing gross proceeds to us of approximately $25.3 million. The private placement was led by Decheng Capital with participation from existing investors OrbiMed Advisors, Frazier Healthcare Partners, Alpine BioVentures, and BVF Partners, L.P.

Strengthened Board of Directors and Scientific Advisory Board with Recent Key Appointments:

Upon closing of our $25.3 million private placement in January 2019, Min Cui, Ph.D., Founder and Managing Director of Decheng Capital, was appointed to our Board of Directors. Dr. Cui’s focus at Decheng is on partnerships with entrepreneurs and building early stage biotechnology companies, and he currently holds Board positions at several companies. He has co-founded two companies, Pacific Pharmaceuticals and Hucon Biopharmaceuticals, where he led the research and development of key inflammatory and oncology therapies.
In addition, we appointed Vijay Kuchroo, DVM, Ph.D., Rafi Ahmed, Ph.D., James Welsh, M.D., Anne Davidson, M.B.B.S., and John Thompson, M.D. to our Scientific Advisory Board. They join a team of distinguished translational and clinical scientists in inflammatory and autoimmune diseases and cancers, including Scientific Advisory Board Chair Andrew Scharenberg, M.D., Manish Butte, M.D., Ph.D., and Paul Tumeh, M.D.
Key Preclinical Data Presentations at Medical Meetings: We showcased preclinical data for our lead programs, ALPN-101 and ALPN-202, at the following recent medical meetings:

ALPN-202 preclinical data presented at SITC (Free SITC Whitepaper): In November 2018, we presented preclinical data of our lead oncology program, ALPN-202, a PD-L1/CTLA-4 dual antagonist with PD-L1 dependent CD28 costimulation, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 33rd Annual Meeting in Washington, D.C. Data presented demonstrated the superiority of ALPN-202 over PD-L1 inhibition in a preclinical tumor model.
ALPN-101 GvHD preclinical data highlighted in oral presentation and posters at ASH (Free ASH Whitepaper) 2018: In December 2018, we presented positive results from multiple preclinical studies of our lead autoimmune/inflammatory program, ALPN-101, via poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s (ASH) (Free ASH Whitepaper) 60th Annual Meeting & Exposition in San Diego, CA. In addition, in an oral presentation, researchers from the lab of Indiana University School of Medicine’s Sophie Paczesny, M.D., Ph.D., one of our collaborators, found ALPN-101 significantly improved survival in preclinical models of acute graft versus host disease (GvHD) and highlighted the novel role of ICOS ligand in GvHD.
ALPN-101 GvHD preclinical data presented at 2019 TCT Meetings: In February 2019, we presented preclinical data for ALPN-101 GvHD at the 2019 Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR (TCT Meetings) in Houston, TX. Data presented demonstrated potent and dose-dependent suppression of GvHD in a human/NSG xenograft model, with activity superior to CD28 or ICOS single pathway antagonists.
Full Year 2018 Financial Results

As of December 31, 2018, we had cash, cash equivalents, and short-term investments totaling $52.3 million. Net cash used in operating activities for the year ended December 31, 2018 was $28.4 million compared to $16.6 million for the year ended December 31, 2017. We recorded a net loss of $36.5 million and $7.8 million for the years ended December 31, 2018 and 2017, respectively.

Collaboration revenue for the year ended December 31, 2018 was $705,000 compared to $1.7 million for the year ended December 31, 2017. The increase was primarily attributable to the timing of revenue recognized under our collaboration agreement with Kite Pharma, Inc., a Gilead (Nasdaq: GILD) company. As previously announced, under the terms of this research collaboration and license agreement, we received upfront payments of $5.5 million, which were initially recorded as deferred revenue and expensed over the period of the research term. The research term of the agreement with Kite was extended in October 2018.

Research and development expenses for the year ended December 31, 2018 were $29.0 million compared to $10.6 million for the year ended December 31, 2017. The increase was primarily attributable to an increase in direct research, contract manufacturing, and process development activities to support ALPN-101 and ALPN-202, plus increases in research personnel related to expanding research and discovery programs and associated overhead and facility costs.

General and administrative expenses for the year ended December 31, 2018 were $8.4 million compared to $6.1 million for the year ended December 31, 2017. The increase was primarily attributable to professional and legal fees and operating as a public company, in addition to personnel-related expenses and the costs associated with expanding the company’s operations as we accelerate preclinical activity.

Cash Guidance

We expect to have sufficient cash to fund operations into 2021, including the clinical advancement of our lead autoimmune/inflammatory program, ALPN-101, and our lead oncology program, ALPN-202.

About ALPN-101

ALPN-101 is a novel Fc fusion protein of a human inducible T cell costimulator ligand (ICOSL) variant immunoglobulin domain (vIgD), and a first-in-class therapeutic simultaneously inhibiting the CD28 and ICOS inflammation pathways. CD28 and ICOS are closely related costimulatory molecules with partially overlapping roles in T cell activation likely connected to multiple autoimmune and inflammatory diseases. In preclinical models of graft versus host disease, inflammatory arthritis, and multiple sclerosis, ALPN-101 demonstrates efficacy superior to blockade of the CD28 or ICOS pathways alone.

ALPN-101 was engineered using our vIgD platform, which uses directed evolution to transform native IgSF proteins into multifunctional protein therapeutics. ALPN-101 is currently enrolling a Phase I healthy volunteer trial.