On February 3, 2020 BioNTech SE (Nasdaq: BNTX, "BioNTech" or "the Company") reported, that it has filed a registration statement on Form F-1 with the United States Securities and Exchange Commission (the "SEC") to offer 6,000,000 American Depositary Shares ("ADSs") representing its ordinary shares (Press release, BioNTech, FEB 3, 2020, View Source [SID1234553769]). In addition, BioNTech intends to grant the underwriters a 30-day option to purchase up to an additional 900,000 of ADSs in connection with the offering. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering. BioNTech is a clinical-stage biopharmaceutical company focused on patient-specific immunotherapies for the treatment of cancer and other serious diseases.

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J.P. Morgan, BofA Securities, Berenberg and SVB Leerink are acting as lead joint book-running managers for the offering.

The proposed offering will be made only by means of a prospectus. Copies of the preliminary prospectus relating to the offering may be obtained, when available, for free by visiting EDGAR on the SEC’s website at www.sec.gov. Alternatively, copies of the preliminary prospectus, when available, may be obtained from J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, New York 11717, or by telephone at +1 (866) 803-9204, or by e-mail at [email protected]; BofA Securities, Inc., NC1-004-03-43; 200 North College Street, 3rd Floor, Charlotte, North Carolina 28255-0001, Attention: Prospectus Department, or by e-mail at [email protected]; Berenberg Capital Markets LLC, Attention: Investment Banking, 1251 Avenue of the Americas, 53rd Floor, New York, New York 10020, or by telephone at +1 (646) 949-9000, or by e-mail at [email protected]; or SVB Leerink LLC, Attention: Syndicate Department, One Federal Street, 37th Floor, Boston, Massachusetts 02110, or by telephone at +1 (800) 808-7525, ext. 6132, or by e-mail at [email protected].

A registration statement relating to these securities has been filed with the SEC but has not yet become effective. These securities may not be sold nor may offers to buy be accepted prior to the time the registration statement becomes effective. This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or other jurisdiction.

On February 3, 2020 Alector, Inc. (Nasdaq: ALEC), a clinical-stage biotechnology company pioneering immuno-neurology, reported the closing of its previously announced underwritten public offering of 9,602,500 shares of its common stock at the public offering price of $25.00 per share (Press release, Alector, FEB 3, 2020, View Source [SID1234553766]). This includes 1,252,500 shares sold pursuant to the underwriters’ full exercise of their option to purchase additional shares. Alector received total gross proceeds of approximately $240.0 million, before deducting the underwriting discounts and commissions and other offering expenses.

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Morgan Stanley, Goldman Sachs & Co. LLC, BofA Securities, and Cowen acted as joint book-running managers for the offering.

Registration statements relating to the securities were filed with, and declared effective by, the Securities and Exchange Commission (the "SEC"). Copies of the registration statements can be accessed through the SEC’s website at www.sec.gov. This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

The offering was made only by means of a prospectus. Copies of the final prospectus relating to the offering may be obtained from:

Morgan Stanley & Co. LLC, Attention: Prospectus Department, 180 Varick Street, 2nd Floor, New York, New York 10014 or by email at [email protected];
Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, New York 10282, or by email at [email protected];
BofA Securities, NC1-004-03-43, 200 North College Street, 3rd Floor, Charlotte, NC 28255-0001, Attn: Prospectus Department, or by email [email protected]; or
Cowen and Company, LLC c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY, 11717, Attn: Prospectus Department, by email at [email protected] or by telephone at (833) 297-2926.

On February 3, 2020 United Therapeutics Corporation (Nasdaq: UTHR) reported topline results from the phase 2/3 DISTINCT clinical study evaluating Unituxin (dinutuximab) Injection added to irinotecan compared to irinotecan or topotecan alone in patients with relapsed or refractory small cell lung cancer (SCLC) (Press release, United Therapeutics, FEB 3, 2020, View Source [SID1234553764]). The DISTINCT trial did not meet its primary efficacy objective of extending the overall survival with Unituxin and irinotecan versus using irinotecan alone. The safety profile of dinutuximab in DISTINCT was consistent with prior studies and the current Unituxin product label.

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Full data from the DISTINCT study will be made available through scientific disclosure at upcoming conferences and in peer-reviewed publications.

"We thank the principal investigators, patients and their families for participating in the DISTINCT study" said Gil Golden, M.D., Ph.D., Chief Medical Officer of United Therapeutics. "We’re clearly disappointed with the DISTINCT results but we’ll continue to seek out underappreciated avenues in our core therapeutic areas addressing rare diseases in oncology and pulmonary hypertension. In addition, we look forward to announcing the results of our INCREASE study by the end of the first quarter or shortly thereafter."

United Therapeutics is also pursuing a label expansion for Unituxin in combination with irinotecan and temozolomide for the treatment of pediatric patients with relapsed or refractory neuroblastoma, based on results from the ANBL1221 study conducted by the Children’s Oncology Group. United Therapeutics plans to meet with the FDA to discuss the proposed label expansion in the first half of 2020 and file a supplemental BLA shortly thereafter.

About DISTINCT

DISTINCT was a phase 2/3, two-part, open-label, randomized, international, multi-center study of dinutuximab and irinotecan versus irinotecan for second line treatment of patients with relapsed or refractory small cell lung cancer. The phase 2 portion of the study of 12 patients was completed in October 2017. Global enrollment in the phase 3 portion of the study was completed in October 2018 with a total of 471 patients. Patients were randomized 2:2:1 into three arms: irinotecan (190 patients); irinotecan and dinutuximab (187 patients); or topotecan (94 patients). This event-driven study was conducted in 198 centers from 22 countries in North America, Europe, and Asia-Pacific, with 312 observed deaths in the dinutuximab plus irinotecan and irinotecan alone groups as of the data extract used for analysis. The primary objective of this study was to compare overall survival (OS) in patients treated with dinutuximab and irinotecan versus patients treated with irinotecan alone as a second-line treatment for relapsed or refractory small cell lung cancer (SCLCThe secondary objectives of the study were:

·To compare progression-free survival (PFS), objective response rate (ORR) (complete response [CR] + partial response [PR]), and clinical benefit rate (CR + PR + stable disease [SD]) in patients treated with dinutuximab and irinotecan to patients treated with irinotecan alone.
·To compare the safety of patients treated with dinutuximab and irinotecan to patients treated with irinotecan alone.
·To evaluate the pharmacokinetics (PK) of patients treated with dinutuximab.
·To compare OS, PFS, ORR, and clinical benefit rate (CBR) in patients treated with dinutuximab and irinotecan to patients treated with topotecan alone.

The exploratory objective of the study was to assess the relationship between selected biomarkers and survival of patients treated with dinutuximab.

About Unituxin

Indication

Unituxin is a GD2-binding monoclonal antibody indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy.

Important Safety Information for Unituxin

CONTRAINDICATIONS

Unituxin is contraindicated in patients with a history of anaphylaxis to dinutuximab.

WARNINGS AND PRECAUTIONS

BOXED WARNING

Serious Infusion Reactions

·Serious and potentially life-threatening infusion reactions (facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension) occurred in 26% of patients treated with Unituxin.

·Administer required prehydration and premedication including antihistamines prior to each Unituxin infusion.

·Monitor patients closely for signs and symptoms of an infusion reaction during and for at least four hours following completion of each Unituxin infusion.

·Immediately interrupt Unituxin for severe infusion reactions and permanently discontinue Unituxin for anaphylaxis.

Neurotoxicity

·Unituxin causes serious neurologic adverse reactions including severe neuropathic pain and peripheral neuropathy.

·Severe neuropathic pain occurs in the majority of patients.

·Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion.

·In clinical studies of patients with high-risk neuroblastoma, severe (Grade 3) peripheral sensory neuropathy ranged from 2% to 9%.

·In clinical studies of Unituxin and related GD2-binding antibodies, severe motor neuropathy has occurred. Resolution of motor neuropathy did not occur in all cases.

·Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, and moderate to severe peripheral motor neuropathy.

Serious Infusion Reactions

·Serious infusion reactions requiring urgent intervention including blood pressure support, bronchodilator therapy, corticosteroids, infusion rate reduction, infusion interruption, or permanent discontinuation of Unituxin included facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension. Infusion reactions generally occurred during or within 24 hours of completing the Unituxin infusion. Due to overlapping signs and symptoms, it was not possible to distinguish between infusion reactions and hypersensitivity reactions in some cases.

·Severe (Grade 3 or 4) infusion reactions occurred in 35 (26%) patients in the Unituxin/13-cis-retinoic acid (RA) group compared to 1 (1%) patient receiving RA alone. Severe urticaria occurred in 17 (13%) patients in the Unituxin/RA group but did not occur in the RA group. Serious adverse reactions consistent with anaphylaxis and resulting in permanent discontinuation of Unituxin occurred in 2 (1%) patients in the Unituxin/RA group. Additionally, 1 (0.1%) patient had multiple cardiac arrests and died within 24 hours after having received Unituxin in Study 2.

Neurotoxicity

·Pain: 114 (85%) patients treated in the Unituxin/RA group experienced pain despite pretreatment with analgesics including morphine sulfate infusion. Severe (Grade 3) pain occurred in 68 (51%) patients in the Unituxin/RA group compared to 5 (5%) patients in the RA group. For severe pain, decrease the Unituxin infusion rate to 0.875 mg/m2/hour. Discontinue Unituxin if pain is not adequately controlled despite infusion rate reduction and institution of maximum supportive measures.

·Peripheral Neuropathy: Severe (Grade 3) peripheral sensory neuropathy occurred in 2 (1%) patients and severe peripheral motor neuropathy occurred in 2 (1%) patients in the Unituxin/RA group. Permanently discontinue Unituxin in patients with peripheral motor neuropathy of Grade 2 or greater severity, Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, or Grade 4 sensory neuropathy.

·Neurological Disorders of the Eye:

·Neurological disorders of the eye experienced by two or more patients treated with Unituxin included blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema. In Study 1, 3 (2%) patients in the Unituxin/RA group experienced blurred vision, compared to no patients in the RA group. Diplopia, mydriasis, and unequal pupillary size occurred in 1 patient each in the Unituxin/RA group, compared to no patients in the RA group. The duration of eye disorders occurring in Study 1 was not documented. In Study 3, eye disorders occurred in 16 (15%) patients, and in 3 (3%) patients resolution of the eye disorder was not documented. Among the cases with documented resolution, the median duration of eye disorders was 4 days (range: 0, 221 days).

·Interrupt Unituxin in patients experiencing dilated pupil with sluggish light reflex or other visual disturbances that do not cause visual loss.

·Upon resolution and if continued treatment with Unituxin is warranted, decrease the Unituxin dose by 50%.

·Permanently discontinue Unituxin in patients who experience loss of vision and in patients with recurrent eye disorder following dose reduction.

·Prolonged Urinary Retention: Urinary retention that persists for weeks to months following discontinuation of opioids has occurred in patients treated with Unituxin. Permanently discontinue Unituxin in patients with prolonged urinary retention that does not resolve with discontinuation of opioids.

·Transverse Myelitis: Transverse myelitis has occurred in patients treated with Unituxin. Promptly evaluate any patient with signs or symptoms such as weakness, paresthesia, sensory loss, or incontinence. Permanently discontinue Unituxin in patients who develop transverse myelitis.

·Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has occurred in patients treated with Unituxin. Institute appropriate medical treatment and permanently discontinue Unituxin in patients with signs and symptoms of RPLS (e.g., severe headache, hypertension, visual changes, lethargy, or seizures).

Capillary Leak Syndrome

·Severe (Grade 3 to 5) capillary leak syndrome occurred in 31 (23%) patients in the Unituxin/RA group and in no patients treated with RA alone.

·Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin and institute supportive management in patients with symptomatic or severe capillary leak syndrome.

Hypotension

·Severe (Grade 3 or 4) hypotension occurred in 22 (16%) patients in the Unituxin/RA group compared to no patients in the RA group.

·Prior to each Unituxin infusion, administer required intravenous hydration.

·Closely monitor blood pressure during Unituxin treatment.

·Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin and institute supportive management in patients with symptomatic hypotension.

Infection

·Severe (Grade 3 or 4) bacteremia requiring intravenous antibiotics or other urgent intervention occurred in 17 (13%) patients in the Unituxin/RA group compared to 5 (5%) patients treated with RA alone. Sepsis occurred in 24 (18%) of patients in the Unituxin/RA group and in 10 (9%) patients in the RA group.

·Monitor patients closely for signs and symptoms of systemic infection and temporarily discontinue Unituxin in patients who develop systemic infection until resolution of the infection.

Bone Marrow Suppression

·Severe (Grade 3 or 4) thrombocytopenia (39% vs. 25%), anemia (34% vs. 16%), neutropenia (34% vs. 13%), and febrile neutropenia (4% vs. 0 patients) occurred more commonly in patients in the Unituxin/RA group compared to patients treated with RA alone.

·Monitor peripheral blood counts closely during Unituxin therapy.

Electrolyte Abnormalities

·Electrolyte abnormalities occurring in at least 25% of patients who received Unituxin/RA in Study 1 included hyponatremia, hypokalemia, and hypocalcemia. Severe (Grade 3 or 4) hypokalemia and hyponatremia occurred in 37% and 23% of patients in the Unituxin/RA group, respectively, compared to 2% and 4% of patients in the RA group.

·Monitor serum electrolytes daily during therapy with Unituxin.

Atypical Hemolytic Uremic Syndrome

·Hemolytic uremic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension occurred in two patients following receipt of the first cycle of Unituxin.

·Permanently discontinue Unituxin and institute supportive management.

Embryo-Fetal Toxicity

·Unituxin may cause fetal harm.

·Advise pregnant women of the potential risk to a fetus.

·Advise females of reproductive potential to use effective contraception during treatment, and for two months after the last dose of Unituxin.

ADVERSE REACTIONS

The most common serious adverse reactions (≥ 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome.

The most common adverse drug reactions (≥ 25%) in Unituxin/RA compared with RA alone are pain (85% vs. 16%), pyrexia (72% vs. 27%), thrombocytopenia (66% vs. 43%), lymphopenia (62% vs. 36%), infusion reactions (60% vs. 9%), hypotension (60% vs. 3%), hyponatremia (58% vs. 12%), increased alanine aminotransferase (56% vs. 31%), anemia (51% vs. 22%), vomiting (46% vs. 19%), diarrhea (43% vs. 15%), hypokalemia (43% vs. 4%), capillary leak syndrome (40% vs. 1%), neutropenia (39% vs. 16%), urticaria (37% vs. 3%), hypoalbuminemia (33% vs. 3%), increased aspartate aminotransferase (28% vs. 7%), and hypocalcemia (27% vs. 0%). In post-approval use of Unituxin, the adverse reactions of prolonged urinary retention, transverse myelitis, and reversible posterior leukoencephalopathy syndrome were observed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

On February 3, 2020 OncoSec Medical Incorporated ("OncoSec") (Nasdaq: ONCS), a company developing late-stage intratumoral cancer immunotherapies, reported data from a feasibility study of its visceral lesion applicator (VLA) electroporation device that were presented at the Annual Meeting of the Society of Interventional Oncology (SIO) in New Orleans (Press release, OncoSec Medical, FEB 3, 2020, View Source [SID1234553763]). The study, which was awarded "Best Technology Scientific Abstract" at SIO, showed investigators were able to successfully and safely reach target organs located deep inside the body and deploy the device’s applicator tip in a large animal model.

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In the study, titled, "Novel Electroporation Device Platform Supports Controlled Delivery of Potent Immunotherapy Directly to Target Organs," healthy animal subjects were placed under general anesthesia while investigators safely and successfully accessed and deployed the VLA in the lungs with a flexible, catheter-based applicator using a bronchoscope and a steerable catheter, and liver using ultrasound-guided laparoscopy with a rigid-trocar-based applicator. Electroporation was performed in the liver using the APOLLO generator with no adverse effects recorded during or after electroporation. Additionally, initial data from the APOLLO generator’s built-in feedback system embedded within the platform detected and recorded trends in impedance values between different tissue types, as well as between the presence and absence of DNA. The APOLLO generator was also able to indicate when the applicator tip was not effectively placed within the tissue. These data highlight the safety mechanisms as well as the future possibility of differentiating between healthy tissue and a local tumor.

"These early feasibility trials are an important confirmation of our VLA platform and help to pave the way toward, initially, safety data to include in an investigational device exemption (IDE) application and eventually a Phase 1 safety trial in human subjects," said Daniel J. O’Connor, President and CEO of OncoSec. "It is an important step toward the development of our platform as a complete and dynamic treatment system that will allow us to continue to treat cancer in internal organs utilizing the electroporation of TAVO (plasmid-based interleukin-12) to eliminate cancer cells."

On February 3, 2020 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting highly resistant tumors, reported that its open label, single arm US Phase 1 trial met its primary objective of demonstrating the safety of Liposomal Annamycin ("Annamycin") in treating relapsed or refractory acute myeloid leukemia ("AML") (Press release, Moleculin, FEB 3, 2020, View Source [SID1234553762]). The Company also announced an update on interim enrollment, safety and efficacy data in its parallel Phase 1 trial in Europe, which continues with dose escalation, thus far without safety concerns.

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Safety of Annamycin in AML Patients
The US Phase 1 trial met its primary endpoint, demonstrating the safety of Annamycin in treating AML when delivered to patients at or below the lifetime maximum anthracycline dose established by the FDA. The primary safety signal was the absence of cardiotoxicity (potential damage to the heart), a serious and often treatment-limiting issue prevalent with currently approved anthracyclines. This was determined by echocardiograms, as well as cardiac health biomarkers, principally blood troponin levels, which are considered an indicator of potential long-term heart damage. The data showed no cardiotoxicity in any of the 6 patients evaluated in the US Phase 1 trial. Additionally, there were no unexpected serious adverse events and no dose limiting toxicities at any dose tested.
Preliminary Evidence of Effectiveness
Although the primary objective of the Phase 1 trial was to evaluate safety, the study also gathered data to support a preliminary assessment of the product’s potential efficacy. Among other things, the study recorded complete response (CR), partial response (PR), event-free survival, overall survival (Kaplan-Meier), and time to and duration of remission/response. Based on these criteria, efficacy was seen in 2 of the US patients, even though the drug was dosed at what was expected to be sub-therapeutic levels. The evidence of efficacy consisted of 1 patient who achieved a "morphologically leukemia-free state," which the protocol defined as a CR with incomplete recovery of platelets or neutrophils (CRi), and another patient who had a substantial remission of leukemia cutis (a somewhat rare leukemia symptom), from diffuse to 3 small lesions.

Moleculin Chairman and CEO Walter Klemp commented, "To see this kind of activity this early is very encouraging, especially since Phase 1 trials are primarily designed to demonstrate safety, not efficacy, and the dosing was therefore at a level we expected to be sub-therapeutic, based on previous data. We also are pleased because Annamycin is being studied as a single agent, not in combination with any other drugs. We believe this is potentially significant, because our clinical advisors believe the vast majority of relapsed or refractory AML patients do not respond to single agents. Although this is very early data from a small sample size, we are especially encouraged because the dosing was well below our anticipated recommended Phase 2 dose. We look forward to the potential validation of these results in further study and believe that, if the level of activity experienced in the US trial can be demonstrated in a larger patient population, we may be well-positioned to seek accelerated approval from the FDA. FDA has already granted Fast Track designation, which recognizes that Annamycin shows the potential to address unmet medical needs, which can include providing efficacy comparable to available therapies while avoiding toxicity associated with the existing treatment."
European Phase 1 Trial
The Company is conducting a very similar Phase 1 trial in Europe, but with dose escalation beyond what FDA permitted in the US. To date, 11 patients have been dosed in Europe, and the study has shown similar safety outcomes, including no cardiotoxicity in any patient. To date, only one adverse event related to Annamycin has been reported in the European trial; a patient experienced grade 2 mucositis that resolved to grade 1 within 2 days.
The European patients have been dosed at levels ranging from 120 mg/m2 to 210 mg/m2, with 2 patients now having been enrolled in the fourth cohort in Europe receiving a single dose of 210 mg/m2. Between the US and European studies, 14 AML patients have been evaluated after receiving Annamycin at or above 120 mg/m2. When they entered the study, 9 of the 14 patients were considered relapsed and 5 were considered refractory. Although reduction in bone and circulating blasts has been seen in both relapsed and refractory AML patients, each of the 5 patients where efficacy endpoints were met was a relapsed patient. The efficacy-related data for those patients (which includes the 2 US patients mentioned above) include:

One patient had a CRi, which the protocol defined as a complete response with incomplete recovery of white blood cells and/or platelets;

Two patients had PRs (partial responses, meaning that bone marrow blasts were reduced 50% and to below 25%);

One patient had a substantial remission of their somewhat rare leukemic symptom known as leukemia cutis; and

One patient was bridged to bone marrow transplant (BT) based on a sufficient reduction in bone marrow blasts.

We refer to Annamycin as a "next generation anthracycline," because it is designed to provide enhanced therapeutic benefits when compared with traditional anthracyclines (like doxorubicin) while reducing the potential for unwanted cardiotoxicity, or damage to the heart. This design intent has previously been validated with preclinical toxicology studies in animal models (as required by FDA) demonstrating Annamycin has little to no cardiotoxicity when compared with doxorubicin. Of the 17 patients treated and fully evaluated thus far in both trials, including those treated below 120 mg/m2, none has shown any evidence of cardiotoxicity. This includes 9 patients in Poland who were treated at levels above the US maximum allowable lifetime cumulative anthracycline dose level (550 mg/m2), a limitation not imposed on our trial in Europe. If confirmed in further studies, this lack of toxicity could be an important differentiator between Annamycin and the currently approved anthracyclines, for which cardiotoxicity is a well-known treatment limitation.
For example, a recent review published in Cardiovascular Drugs and Therapy (View Source) reported that 65% of patients who received the equivalent of 550 mg/m2 of doxorubicin (a current standard of care anthracycline) exhibited sub-clinical cardiotoxicity, defined as a reduction in left ventricular ejection fraction >10% points to a value <50%. In the 5 patients mentioned above who were treated in our European trial above 550 mg/m2, no evidence of cardiotoxicity was detected. The same published review also suggested that a better long-term indicator of cardiotoxicity may be the measurement of an increase in a biomarker called troponin. When measured as an early biomarker of cancer therapy-related cardiotoxicity, troponin rise occurs consistently in 21% – 40% of patients after treatment with current standard of care anthracycline chemotherapy and, per the published review, such an increase in troponin is associated with an increased risk of heart disease later in life. Of the 17 patients treated thus far in both of our Annamycin clinical trials, none has shown an increase in troponin levels.
Study Design
The Company is studying Annamycin in both the US and Europe in open label, single arm clinical trials to assess the safety and efficacy of Annamycin for the treatment of adults with relapsed or refractory acute myeloid leukemia. The US and European trials have the same study design, consisting of a Phase 1 intended to establish a "Recommended Phase 2 Dose" (RP2D), to which the studies will then proceed. The Phase 1 studies provide for escalating doses in cohorts of 3 patients each, with each successive cohort receiving the next higher dose level until "dose limiting toxicities" prevent further increases. Cohorts 1, 2 and 3 in Europe received a dose of 120, 150 and 180 mg/m2, respectively, and the results have permitted moving to Cohort 4 with dosing at 210 mg/m2, in which 2 of the 3 patients have been enrolled and treated. Cohort 1 in the US started at 100 mg/m2, and the results supported moving to Cohort 2 at 120 mg/m2 which has now been fully recruited, treated, and evaluated. Beyond this dose level patients would receive greater than the lifetime maximum anthracycline dose of 550 mg/m2 allowed by the FDA. Once the Company establishes an RP2D, the intent is to advance to a Phase 2 arm planned to assess the safety and efficacy of Annamycin in 21 additional patients.
The data reported here is preliminary as collected by independent CRO site monitors per standard practice and is subject to subsequent quality assurance review.
We have been and intend to continue reporting top-line results by cohort in each trial, with each announcement also including an update on the other trial. Top-line results will include reporting of any drug-related adverse events (AEs) and assessment of cardiotoxicity, including ECHO or MUGA scans measuring change in ejection fraction and measuring blood troponin level, which is considered a biomarker for potential long-term cardiovascular impairment. Top-line results will also include the number of partial responses (PRs), complete responses (CRs) and patients deemed capable of progressing to a potentially curative bone marrow transplant, which we term "bridge to transplant" (BTs), each of which is essentially a function of the magnitude of reduction in a patient’s bone marrow blasts. For purposes of these clinical trials, a CR means that the patient’s bone marrow blasts reduced to 5% or less (with CRi meaning a CR where there was incomplete recovery of white blood cell and/or platelet counts), a PR means the patient’s bone marrow blasts reduced by 50% and resulted in a blast count of 25% or less, and a BT means patients are deemed capable of progressing to a potentially curative bone marrow transplant.

The US trial also differs from the European trial in that the FDA would like to review safety data relating to cardiotoxicity from patients treated prior to advancing beyond 120 mg/m2, as exceeding this dose level would require the patient to exceed the established lifetime maximum exposure to anthracyclines (presuming all anthracyclines are cardiotoxic). The Company believes that the additional patient safety data gained from the European trial may also assist in the FDA’s review of Annamycin’s cardiac safety.