Achillion Reports Positive Data from Phase 2 Study of Danicopan (ACH-4471) in Combination with Eculizumab in PNH Patients who Have an Inadequate Response to Eculizumab Monotherapy at the 61st American Society of Hematology Meeting
– 2.4 g/dL mean increase in hemoglobin at 24 weeks –
– Reduction in blood transfusions from 34 to 1; and improvements in markers of hemolysis –
- Completed End of Phase 2 Meeting; Phase 3 Trial Initiation in early 2020 -
The primary endpoint of the trial was an increase in hemoglobin from baseline. A mean increase of 2.4 g/dL at 24 weeks of treatment was achieved in this proof-of-concept trial. Danicopan, in combination with eculizumab, resulted in a significant reduction in blood transfusions with 10 patients receiving 34 transfusions (58 units) in the 6 months prior to screening to 1 patient receiving 1 transfusion (2 units) during the 24-week trial.
|Phase 2 Open-label Study of Danicopan in Patients with PNH who Have an Inadequate Response to Eculizumab Monotherapy|
|Total bilirubin (xULN)||2.17||1.35|
|Direct bilirubin (xULN)||1.6||1.2|
|PNH red cell clone size (%)||54||84*|
|C3 fragment deposition on PNH RBCs (%)||30||18|
|Transfusions N = 10**||24 Weeks Prior||24 Week Trial|
|Number of transfusions||34||1|
|Units of blood||58||2|
|Quality of Life|
|FACIT-Fatigue (Max Score 52)***||34||45|
|* N=7; for four patients, samples were out of stability range.|
|** N=10; Patient A excluded from transfusion results due to religious objection to receiving transfusions; baseline Hgb = 5 g/dL.|
|***Scores based on the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT) Fatigue Scale V4. Score range 0-52. A score of less than 30 indicates severe fatigue.|
“C5 inhibition, the current standard of care, is an effective treatment approach for patients with PNH. While this treatment approach shows control of intravascular hemolysis and improved overall survival, many patients remain anemic and some may continue to be transfusion dependent due to persistent extravascular hemolysis,” stated Dr. Austin Kulaskeraraj MBBS, MD, MRCP, FRCPath, lead author of this Phase 2 poster presentation at ASH and consultant hematologist at
In addition to improvements in hemoglobin and transfusions, there were also meaningful improvements in markers of hemolysis including bilirubin, reticulocytes, and PNH red blood clone size (%). “The increase in PNH specific red blood cell clone size, and reduction of reticulocytes, is likely due to the prevention of C3-mediated extravascular hemolysis, a result of targeting upstream in the Alternative Pathway, while retaining the control of MAC-mediated intravascular hemolysis,” said Dr.
In this clinical trial, danicopan was generally well tolerated. All treatment emergent adverse events were considered mild to moderate in severity except for Grade 3 severe adverse events that occurred in two patients. Both patients had resolution of their events, remained on danicopan, and completed the study.
The Company was granted Breakthrough Therapy designation by
The poster presentation detailing the Phase 2 top-line results is being presented today,
Poster Presentation: “A Phase 2 Open-Label Study of Danicopan (ACH-0144471) in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Who Have an Inadequate Response to Eculizumab Monotherapy”
Abstract Number: 3514
Session Name: 101. Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron: Poster III
Location: Hall B
Danicopan (ACH-4471) Phase 2 Add-on Trial with Eculizumab
Danicopan was evaluated as an add-on with eculizumab, an intravenous C5 inhibitor that is currently approved as monotherapy for PNH. This is a Phase 2, open-label, multiple dose trial in adult patients on stable eculizumab treatment with blood transfusion dependent anemia, defined as receiving at least one transfusion in the 12 weeks prior to the study and a hemoglobin level below 10 g/dL. In addition to their usual dose of eculizumab, patients were administered danicopan orally three times a day at a dose determined by patient clinical response. The primary outcome of the trial is the change in hemoglobin at 24 weeks compared to baseline. Secondary outcomes include the number of blood transfusions required, impact on selected clinical parameters, and safety. Patients completing the study were eligible to enroll in a long-term extension study continuing on danicopan and their C5 background therapy of eculizumab or ravulizumab.
About Paroxysmal Nocturnal Hemoglobinuria
PNH is a rare, acquired blood disease caused by a somatic mutation resulting in the absence of key receptors, CD55 and CD59, on the surface of red blood cells (RBCs). The complement system recognizes these unprotected RBCs as foreign and destroys them in the circulatory system (intravascular hemolysis [IVH]) and in the liver or spleen (extravascular hemolysis [EVH]). The current standard of care for PNH targets IVH by inhibiting C5 complement protein (C5), leaving some patients with persistent EVH from early phases of complement activation (alternative pathway [AP] activity) which C5 inhibition cannot address. This may leave patients with partial control of their PNH symptoms. Up to seventy-five percent of PNH patients treated with C5 inhibitors remain anemic during treatment, with up to one-third of those patients reporting the need for blood transfusions within the last year. Factor D is the critical, rate-limiting protein within the AP. By targeting Factor D, proximal AP inhibition may disable both downstream terminal complement activation (IVH) and upstream C3 fragment opsonization (EVH). Achillion is developing a potentially more complete approach to PNH with factor D inhibition to selectively block alternative pathway activity and protect against both destructive processes of RBCs in PNH with convenient oral therapies.
More information is available at http://www.achillion.com/patients-and-clinicians/.
About the Achillion Complement Factor D Portfolio
Achillion has leveraged its internal discovery capabilities and a novel complement-related platform to develop oral small molecule drug candidates that are inhibitors of complement factor D. Factor D is an essential serine protease involved in the AP of the complement system, a part of the innate immune system. Achillion's complement platform is focused on seeking to advance oral small molecules that inhibit the AP and can potentially be used in the treatment of immune-related diseases in which complement AP plays a critical role. Potential indications currently being evaluated for these compounds include PNH, C3 glomerulopathy (C3G), and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN).
More information is available at http://www.achillion.com.
Cautionary Note Regarding Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other important factors that could cause actual results to differ materially from those indicated by such forward-looking statements. Achillion may use words such as “expect,” “anticipate,” “project,” “target,” “intend,” “plan,” “aim,” “believe,” “seek,” “estimate,” “can,” “could,” “focus,” “will,” “look forward,” “continue,” “goal,” “strategy,” “objective,” “may,” “potential,” and similar expressions to identify such forward-looking statements. These forward-looking statements include statements about: the potential benefits of FDA’s Breakthrough Designation and EMA’s PRIME designation for danicopan; the potential benefits of factor D inhibition as a treatment for complement-mediated diseases, including danicopan (ACH-4471) for PNH; Achillion’s expectations regarding the advancement of, and timeline for reporting results from, clinical trials of its product candidates (including danicopan and ACH-5228); Achillion’s expectations regarding the timing of regulatory interactions and filings; and other statements concerning Achillion’s strategic goals, efforts, plans, and prospects. Among the important factors that could cause actual results to differ materially from those indicated by such forward-looking statements are risks relating to, among other things, Achillion’s ability to: continue to meet the clinical development program criteria for Breakthrough Designation and PRIME designation; accelerate the development timeline for danicopan utilizing benefits available through the Breakthrough Designation and PRIME designation; demonstrate in any current and future clinical trials the requisite safety, efficacy and combinability of its product candidates, including danicopan and ACH-5228; advance the preclinical and clinical development of its complement factor D inhibitors under the timelines it projects in current and future preclinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of that trial or whether results of early clinical trials or preclinical studies will be indicative of the results of later clinical trials; enroll patients in its clinical trials on its projected timelines; obtain and maintain patent protection for its product candidates and the freedom to operate under third party intellectual property; obtain and maintain necessary regulatory approvals, and the granting of orphan designation does not alter the standard regulatory requirements and process for obtaining such approval; establish commercial manufacturing arrangements; identify, enter into and maintain collaboration and other commercial agreements with third-parties; compete successfully in the markets in which it seeks to develop and commercialize its product candidates and future products; manage expenses; manage litigation; raise the substantial additional capital needed to achieve its business objectives; and successfully execute on its business strategies. These and other risks are described in the reports filed by Achillion with the
In addition, any forward-looking statement in this press release represents Achillion's views only as of the date of this press release and should not be relied upon as representing its views as of any subsequent date. Achillion disclaims any duty to update any forward-looking statement, except as required by applicable law.
Senior VP, Corporate Communications
Source: Achillion Pharmaceuticals, Inc.