Date: 2016-12-05
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 58th Annual Meeting of the American Society of Hematology (ASH)
Company: Alnylam Pharmaceuticals (USA - MA)
Product: ALN-CC5
Action
mechanism: RNAi. ALN-CC5 is an RNAi therapeutic targeting the C5 component of the complement pathway for the treatment of complement-mediated diseases. The complement system plays a central role in immunity as a protective mechanism for host defense, but its dysregulation results in life-threatening complications in a broad range of human diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic-uremic syndrome (aHUS), myasthenia gravis, neuromyelitis optica, amongst others. Complement component C5, which is predominantly expressed in liver cells, is a genetically and clinically validated target; loss of function human mutations are associated with an attenuated immune response against certain infections and intravenous anti-C5 monoclonal antibody therapy has demonstrated clinical activity and tolerability in a number of complement-mediated diseases. A subcutaneously administered RNAi therapeutic that silences C5 represents a novel approach to the treatment of complement-mediated diseases. ALN-CC5 utilizes Alnylam's ESC-GalNAc conjugate technology which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.
Disease: complement-mediated diseases, paroxysmal nocturnal hemoglobinuria (PNH)
Therapeutic area: Immunological diseases - Rare diseases
Country: UK
Trial
details: The Phase 1/2 trial of ALN-CC5 is being conducted in the UK in three parts. Parts A and B will be randomized (3:1, drug:placebo), double-blind, placebo-controlled, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 60 healthy adult volunteers. To mitigate against the risk of Neisseria meningitides, subjects received meningococcal vaccination and oral ciprofloxacin. Subjects in Part A are receiving a single subcutaneous administration of ALN-CC5 at fixed doses of 50, 200, 400, or 600 mg. Subjects in Part B are receiving multiple ascending doses of ALN-CC5, at a fixed dose level of 100 mg in the first cohort, administered once weekly for up to five weeks; bi-weekly and monthly dosing schedules may also be evaluated. The primary objective of these first two parts of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-CC5. Additional objectives include evaluation of clinical activity for ALN-CC5 as measured by knockdown of serum C5 and inhibition of serum complement activity, including measurements of complement alternative pathway (CAP) and complement classical pathway (CCP) activity by ELISA and serum hemolytic activity toward sheep erythrocytes. Part C will be an open-label, multi-dose study in up to eight patients with PNH, and will assess safety, tolerability, and clinical activity of ALN-CC5, administered as multiple subcutaneous doses for up to 13 weeks. This part of the study will include an exploratory evaluation of the effects of ALN-CC5 on levels of lactate dehydrogenase (LDH), a measure of endogenous red blood cell hemolysis. (NCT02352493)
Latest
news: * On December 5, 2016, Alnylam Pharmaceuticals presented new results from Part C of its Phase 1/2 clinical trial with ALN-CC5, a subcutaneously administered investigational RNAi therapeutic targeting complement component 5 (C5) for the treatment of complement-mediated diseases, in a poster presentation at the 58th Annual Meeting of the American Society of Hematology (ASH) . Part C evaluated the tolerability and clinical activity of ALN-CC5 in patients (N=6) with paroxysmal nocturnal hemoglobinuria (PNH). In an exploratory analysis, ALN-CC5 was evaluated in combination with eculizumab, an approved anti-C5 monoclonal antibody used for treatment of PNH. New results show that ALN-CC5-mediated knockdown of serum C5 has the potential to enable effective sparing of eculizumab in patients with PNH. These data further support development of ALN-CC5 to potentially reduce the dose level and frequency of eculizumab in patients with PNH, and to improve disease control in patients with an inadequate response to eculizumab. * On December 5, 2016, Alnylam Pharmaceuticals presented new results from Part C of its Phase 1/2 clinical trial with ALN-CC5, a subcutaneously administered investigational RNAi therapeutic targeting complement component 5 (C5) for the treatment of complement-mediated diseases, in a poster presentation at the 58th Annual Meeting of the American Society of Hematology (ASH) . Part C evaluated the tolerability and clinical activity of ALN-CC5 in patients (N=6) with paroxysmal nocturnal hemoglobinuria (PNH). In an exploratory analysis, ALN-CC5 was evaluated in combination with eculizumab, an approved anti-C5 monoclonal antibody used for treatment of PNH. New results show that ALN-CC5-mediated knockdown of serum C5 has the potential to enable effective sparing of eculizumab in patients with PNH. These data further support development of ALN-CC5 to potentially reduce the dose level and frequency of eculizumab in patients with PNH, and to improve disease control in patients with an inadequate response to eculizumab. * On December 17, 2015, Alnylam Pharmaceuticals announced that it initiated the final phase (Part C) of its Phase 1/2 clinical trial with ALN-CC5 for the treatment of complement-mediated diseases. Part C, which is being conducted in patients with paroxysmal nocturnal hemoglobinuria (PNH), will evaluate the safety and tolerability of multiple doses of ALN-CC5 as well as measures of its clinical activity, including knockdown of serum C5 levels, levels of residual C5, inhibition of serum hemolytic activity, and reduction of lactate dehydrogenase (LDH), a measure of red blood cell hemolysis. The company expects to report initial PNH patient data from this ongoing clinical study of ALN-CC5 in mid-2016 and initiate Phase 3 studies in 2017. * On December 6, 2015, Alnylam Pharmaceuticals announced interim results from its ongoing Phase 1/2 clinical study with ALN-CC5 for the treatment of complement mediated diseases. These new clinical data were presented at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 - 8 in Orlando, Florida . New results show that ALN-CC5 achieved up to 99 percent knockdown of serum C5 and up to 98 percent inhibition of serum hemolytic activity, an assay for complement activity. In addition, ALN-CC5 administration resulted in low levels of residual C5, which - based on comparisons from separate studies - were at or below the estimated levels of free C5 observed at therapeutic doses of eculizumab, an approved anti-C5 monoclonal antibody. The effects of ALN-CC5 were also found to be highly durable, with C5 knockdown and complement inhibition results supporting a once monthly and possibly a once quarterly subcutaneous dose regimen. Importantly, ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date. Consistent with previous guidance, the company remains on track to initiate dosing by year's end in Part C of the Phase 1/2 study, which is being conducted in patients with paroxysmal nocturnal hemoglobinuria (PNH), and expects to present initial results from this part of the study in mid-2016. * On June 12, 2015, Alnylam Pharmaceuticals announced initial positive results from its ongoing Phase 1/2 clinical trial with ALN-CC5, an investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. These new clinical data have been presented at the 20th Congress of the European Hematology Association (EHA) held June 11 – 14 in Vienna, Austria. Initial study results from 12 healthy volunteer subjects showed that single subcutaneous dose administration of ALN-CC5 resulted in potent, dose-dependent, durable, and statistically significant knockdown of serum C5 of up to 96%. In addition, single dose administration of ALN-CC5 achieved inhibition of serum complement activity of up to 92%, including an up to 61% inhibition of serum hemolytic activity. Further, ALN-CC5 has been found to be generally well tolerated to date. The company is continuing to dose healthy volunteer subjects in both the single ascending dose (SAD) and multiple ascending dose (MAD) stages of the study, and expects to present additional data from the trial in late 2015. Consistent with previous guidance, the company also plans to begin enrolling patients with paroxysmal nocturnal hemoglobinuria (PNH) into the trial by the end of 2015. Initial Phase 1/2 study results from 12 healthy volunteer subjects are being presented in an oral presentation at EHA and include all available data out to as long as 98 days from the 50, 200, and 400 mg SAD cohorts. Safety data are as of a data cut-off date of May 26, 2015, and clinical activity data are as of a data cut-off date of June 4, 2015. In the ongoing study, single doses of ALN-CC5 were found to be generally well tolerated, with no serious adverse events (including infections), study discontinuations, or significant clinical laboratory findings reported to date. The key additional objectives of the study were to evaluate the clinical activity of ALN-CC5 as measured toward C5 knockdown and effects on serum complement activity, including serum hemolytic activity. Single subcutaneous doses of ALN-CC5 resulted in potent, dose-dependent, statistically significant, and highly durable knockdown of serum C5 demonstrating human proof-of-concept. Specifically, a single ALN-CC5 dose resulted in an up to 96% knockdown of serum C5. A mean maximum knockdown of 94 +/- 2.0% (p less than 0.003 compared with placebo) was achieved in the 400 mg SAD cohort. Nadir C5 knockdown for all treated subjects was achieved between days 28 and 70 and effects were durable over a period of months. For example, an up to 94% knockdown of serum C5 was achieved at day 70 after a single dose of drug. The company believes that the durable and clamped nature of C5 knockdown could potentially support a once-monthly, fixed dose subcutaneous regimen. Finally, the level of C5 knockdown in humans after single dose administration was found to correlate closely (r2=0.83, p less than 0.0001) with corresponding single dose data in non-human primates. From these data, there appears to be an approximately three- to five-fold increased potency for ALN-CC5 in humans as compared with NHPs. In addition, single dose administration of ALN-CC5 was associated with potent, dose-dependent, and durable inhibitory effects toward complement activity. In particular, single dose ALN-CC5 administration resulted in an up to 87% inhibition of CAP activity (mean maximum 75 ± 7.2%), an up to 92% inhibition of CCP activity (mean maximum 82 ± 6.1%), and an up to 61% inhibition of serum hemolytic activity (mean maximum 43 ± 9.1%). These effects on complement activity were statistically significant (p less than 0.005 compared with placebo). In addition, the inhibitory effects of ALN-CC5 toward complement activity were found to be highly durable. For example, an up to 82% inhibition of CCP activity was observed at day 70 following a single dose administration. As seen in NHP studies with ALN-CC5 and consistent with all other Alnylam GalNAc-conjugate programs, further increases in inhibitory effects toward serum complement activity are expected with multi-dose administration. As reported at the American Society of Hematology meeting in December 2014, results in NHPs showed that a twice-monthly subcutaneous dose regimen of ALN-CC5 at 5 mg/kg achieved inhibition of serum hemolytic activity of over 80%. In contrast, additional NHP studies show that a single dose of ALN-CC5 at 5 mg/kg (comparable to the 400 mg fixed dose in the Phase 1/2 study) achieved a 49 ± 4.5% mean maximal inhibition of serum hemolytic activity. The company expects to present initial multi-dose data from the ongoing Phase 1/2 study in late 2015. * On February 2, 2015, Alnylam Pharmaceuticals announced that it has initiated a Phase 1/2 clinical trial with ALN-CC5, a subcutaneously administered investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. The Phase 1/2 trial will be conducted in normal human volunteers, and then in patients with paroxysmal nocturnal hemoglobinuria (PNH). The company expects to present initial clinical data from this trial in mid-2015 with additional data expected in late 2015. The Phase 1/2 trial of ALN-CC5 is being conducted in the U.K. , in three parts. Parts A and B will be randomized (3:1, drug:placebo), double-blind, placebo-controlled, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 60 healthy adult volunteers. Subjects will receive fixed subcutaneous doses of ALN-CC5, administered once weekly for up to five weeks; bi-weekly and monthly dosing schedules may also be evaluated. The primary objective of these first two parts of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-CC5. Secondary objectives include evaluation of clinical activity for ALN-CC5 as measured toward knockdown of serum C5 and inhibition of serum complement activity. Part C will be an open-label, multi-dose study in up to eight patients with PNH, and will assess safety, tolerability, and clinical activity of ALN-CC5, administered as multiple subcutaneous doses for up to 13 weeks, in PNH patients. This part of the study will include an exploratory evaluation of the effects of ALN-CC5 on levels of lactate dehydrogenase (LDH), a measure of red blood cell hemolysis. Alnylam recently presented pre-clinical data from its ALN-CC5 program at the American Society of Hematology (ASH) meeting in December 2014 . These data showed an up to 99.2% knockdown of serum C5 and up to 96.2% inhibition of serum hemolytic activity in non-human primates (NHPs) with bi-weekly or monthly subcutaneous dosing for over seven months. Based on human translational data for ESC-GalNAc conjugates, the company believes that this level of activity can be achieved in humans using a low-dose, low-volume monthly subcutaneous dosing regimen. Further, new pre-clinical results were reported for a C5 GalNAc-siRNA in a rat model of membranous nephropathy (MN). The results demonstrated that knockdown of liver-expressed C5 results in disease modifying effects, while local expression of C5 appears to play no significant role.
Clinical Activity Results: In the Phase 1/2 study, a total of 6 patients with PNH were enrolled in Part C of the trial, including patients who were eculizumab naive (N=3) and patients who were receiving background eculizumab therapy (N=3). ALN-CC5 was administered at weekly doses of 200 or 400 mg for 2 to 16 weeks and achieved C5 knockdown of up to 98 percent and residual serum C5 levels less than 1 microgram per milliliter (mcg/mL). Upon completion of ALN-CC5 dosing and in the setting of ongoing ALN-CC5 pharmacology, investigators elected to treat patients with 600 mg or 900 mg of eculizumab every 4 weeks, enabling an exploratory analysis of the potential of ALN-CC5 to reduce the dose and frequency of eculizumab. As of the data transfer date of October 13, 2016 , results showed that PNH patients who had previously been naive to eculizumab (N=3) achieved sustained control of disease hemolysis with normalization of lactate dehydrogenase (LDH) to less than or at approximately 1.5 times upper limit of normal (ULN) for up to 6 months while on a spared eculizumab regimen of 600 mg every 4 weeks. For patients who entered the study on background eculizumab (N=3), effective disease control with normalization of LDH to less than or at approximately 1.5 times ULN was achieved for up to 5 months while on a spared once-monthly regimen of 900 mg eculizumab. Using an assay for eculizumab plasma levels, both sparing regimens achieved stable eculizumab trough levels greater than 100 mcg/mL during the 5 to 6 month period. In aggregate, these results support the potential to achieve effective management of hemolysis in PNH during ALN-CC5 pharmacology with a spared eculizumab dosing regimen representing a 50 to 67 percent reduction in dose and a 2-fold extension of dose interval relative to the labeled eculizumab maintenance dose and regimen.
Safety Results: As previously reported, ALN-CC5 was generally well tolerated in patients with PNH after multiple doses for up to 16 weeks of dosing. During the course of spared eculizumab dosing, as of the data transfer date of October 13, 2016 , there were no serious adverse events (SAEs) or discontinuations due to adverse events (AEs) in the study, and the majority of reported AEs were mild or moderate in severity. One patient developed an episode of breakthrough hemolysis in the setting of an upper respiratory tract infection; this AE was moderate in severity and was considered unrelated to study drug by the investigator.
Alnylam Pharmaceuticals also announced that Sanofi Genzyme has decided not to exercise its opt-in right for the development of ALN-CC5 in territories outside of the United States , Canada and Western Europe , providing Alnylam with full global control of the program for further development and potential commercialization.
* On June 11, 2016, Alnylam Pharmaceuticals presented initial results from Part C of its ongoing Phase 1/2 clinical trial with ALN-CC5 - a subcutaneously administered investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases - in an oral talk at the 21st Congress of the European Hematology Association in Copenhagen, Denmark . Part C evaluated the tolerability and clinical activity of ALN-CC5 in six patients with paroxysmal nocturnal hemoglobinuria. In this study, ALN-CC5 was evaluated as a monotherapy or as an adjunct to eculizumab, an approved anti-C5 monoclonal antibody indicated for the treatment of PNH. Preliminary results demonstrate that ALN-CC5 achieved clamped knockdown of serum C5 and lowering of lactate dehydrogenase (LDH) - a biomarker of RBC hemolysis - in patients with PNH, and support further development of ALN-CC5 to potentially reduce the dose and frequency of eculizumab for PNH patients, and also to potentially improve disease control in patients with an inadequate response to eculizumab. As previously guided, the Company plans to initiate a Phase 2 trial by late 2016. A total of six patients with PNH were enrolled in Part C of the trial and completed dosing (N=3 eculizumab naïve, N=3 on background eculizumab). ALN-CC5 was administered at weekly doses of 200 or 400 mg for 2 to 16 weeks. Initial results below are based on data transferred up to June 6, 2016 .
In eculizumab naïve PNH patients (N=3), ALN-CC5 monotherapy achieved C5 knockdown and inhibition of complement activity, and was associated with 37-50 percent maximal reductions in LDH, but LDH levels remained above the goal of less than 1.5 times the upper limit of normal (ULN). ALN-CC5 administration resulted in mean maximum serum C5 knockdown greater than 98 percent and residual C5 levels less than 1 mcg/mL. ALN-CC5 also demonstrated robust inhibition of complement activity as measured in complement classical pathway (CCP C5b-9 ELISA) and sheep RBC (sRBC) hemolysis assays. In the latter assay, ALN-CC5 achieved a mean maximum inhibition of approximately 75 percent. These effects on C5 knockdown and complement activity were similar to those reported previously in healthy volunteers enrolled in Parts A and B of the ongoing Phase 1/2 study.
An exploratory data analysis was conducted to understand the potential for ALN-CC5 to reduce eculizumab dose and frequency. After ALN-CC5 dosing was completed, eculizumab naïve patients were initiated on eculizumab for the treatment of remaining hemolysis. In the setting of ongoing ALN-CC5-mediated knockdown of serum C5 of greater than 95 percent, investigators chose to administer a single eculizumab dose of 600 mg and monitor the patients' clinical responses. Upon administration of this single eculizumab infusion, all three patients achieved rapid lowering of LDH below 1.5 times the ULN which was sustained out to 4 weeks. These results provide preliminary exploratory evidence that inhibition of hepatic C5 synthesis by ALN-CC5 has the potential to reduce the dose and frequency of eculizumab. It is important to note that in eculizumab naïve patients, a single 600 mg eculizumab dose over 28 days represents 25 percent of the labeled induction dose (600 mg every week for the first 4 weeks) of eculizumab.
In the patients being treated with background eculizumab (N=3), ALN-CC5 also achieved robust C5 knockdown and inhibition of complement activity. In this group, one patient was enrolled who was experiencing breakthrough hemolysis and elevated LDH at baseline despite higher than labeled doses of eculizumab of 1200 mg every 2 weeks. In this inadequate response patient, ALN-CC5 administration resulted in rapid reduction of LDH to below 1.5 times the ULN and an over 1 g/dL increase in hemoglobin. Following ALN-CC5 administration, the investigator successfully reduced eculizumab to the labeled dose of 900 mg every 2 weeks. Finally, eculizumab plasma levels were measured to evaluate any effects of ALN-CC5 on eculizumab pharmacokinetics. Notably, ALN-CC5 knockdown of serum C5 resulted in an over 3-fold increase of pre-dose eculizumab trough levels. In summary, we believe that these preliminary results in eculizumab-treated patients suggest that ALN-CC5 can potentially improve disease control in inadequate responders and also potentially improve eculizumab pharmacokinetic properties.
ALN-CC5 was generally well tolerated in patients with PNH after multiple doses with the majority of adverse events (AEs) being mild or moderate in severity. There were no drug related serious AEs or discontinuations due to AEs in the study. One patient, who was also taking eculizumab, cyclosporine and anabolic steroids as concomitant medications, experienced a transient asymptomatic grade 3 elevation of liver transaminases that was deemed possibly related to study drug and dosing was interrupted. All other AEs reported were mild or moderate in severity. Mild and transient injection site reactions were reported in 3 of 6 patients. There were no clinically significant changes in vital signs, EKG, physical exams or clinical laboratory results.
"We believe that ALN-CC5 has the potential to transform the management of PNH, where clamped inhibition of hepatic C5 synthesis may provide the foundation for reduced frequency and doses of anti-C5 monoclonal antibody therapy. Preliminary data from a small number of PNH patients in our ongoing Phase 1/2 study suggest that ALN-CC5 has the potential to reduce the dose and frequency of eculizumab treatment, and also potentially improve disease control as seen in a patient with an inadequate response to eculizumab who was experiencing breakthrough hemolysis," said Akshay Vaishnaw , M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "Based on its durability of action, we believe that once-quarterly subcutaneous injections of ALN-CC5 have the potential to enable reduced doses and frequency of eculizumab, and we look forward to evaluating this further both in ongoing analyses of the PNH patients in the current Phase 1/2 study and in a new Phase 2 study, initially in inadequate responder patients, that we expect to start by year's end. In addition, we look forward to evaluating ALN-CC5 as monotherapy in other complement-mediated diseases, with studies that we expect to start in 2017."
Clinical data from the ongoing Phase 1/2 study were presented recently at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 - 8 in Orlando, Florida (see below) .
New data were presented in a poster at ASH, and include updated data (N=20) from the single ascending dose (SAD) cohorts, as well as initial data (N=12) from multiple ascending dose (MAD) cohorts. Safety data are as of a cutoff date of October 19 , 2015, and clinical activity data are as of a cutoff date of up to November 6, 2015 .
Preliminary Phase 1/2 Study Clinical Activity Results
In the SAD cohorts (N=20), ALN-CC5 achieved potent and dose-dependent knockdown of serum C5 of up to 99 percent, with a mean maximum knockdown of 98 ± 0.3 percent (p less than 0.01 compared with placebo) in the top dose cohort. After a single dose, nadir levels of residual C5 as low as 1.1 microgram/milliliter (mcg/mL) were achieved. This level of residual C5 in healthy volunteers is at or below the levels of free C5 estimated for eculizumab at therapeutic drug concentrations in an earlier published study in patients with atypical hemolytic uremic syndrome (aHUS)1. Maximal effects on C5 knockdown were achieved starting on day 20, and lasted for several months. For example, an up to 97.8 percent knockdown of serum C5 was still maintained at day 98 after just a single dose of drug in the top dose cohort. The company believes that the durable and clamped nature of C5 knockdown supports a once monthly and possibly a once quarterly, fixed dose subcutaneous regimen.
In addition, single dose administration of ALN-CC5 was associated with potent, dose-dependent, and durable inhibition of complement activity. In particular, a single ALN-CC5 dose resulted in an up to 95 percent inhibition of complement alternative pathway (CAP) activity, an up to 97 percent inhibition of complement classical pathway (CCP) activity, and an up to 79 percent inhibition of serum hemolytic activity (mean maximum 74 ± 4.2 percent). In addition, as with C5 knockdown, the inhibitory effects of ALN-CC5 toward complement activity were found to be highly durable, lasting for several months after just a single dose.
In MAD cohorts (N=12) receiving five weekly doses of ALN-CC5, an up to 99 percent knockdown of serum C5 was achieved with a mean maximum knockdown of 98 ± 0.2 percent (p less than 0.01 compared with placebo) in the top dose cohort. Following ALN-CC5 administration, nadir levels of residual C5 as low as 0.6 mcg/mL were observed. Regarding effects on complement activity, multiple doses of ALN-CC5 resulted in an up to 97 percent inhibition of CAP activity, an up to 97 percent inhibition of CCP activity, and an up to 98 percent inhibition of serum hemolytic activity (mean maximum 84 ± 7.6 percent). These effects on complement activity were statistically significant (p less than 0.05 compared with placebo). The level of CAP inhibition achieved in these healthy volunteers is comparable to results seen in people with homozygous C5 deficiency2,3, which highlights the highly robust knockdown of serum C5 levels achieved with ALN-CC5. Furthermore, multiple dose administration of ALN-CC5 achieved the 80 percent target level of serum hemolytic activity inhibition previously correlated with LDH reductions in PNH patients4. Finally, after the last dose of ALN-CC5, C5 knockdown and inhibition of complement activity were highly durable, with effects lasting several months. For example, after five weekly doses in the 200 mg cohort, an up to 98.3 percent knockdown of serum C5 was maintained at day 112.
Preliminary Phase 1/2 Safety Results
All safety results remain blinded as to treatment allocation. Single and multiple weekly subcutaneous doses of ALN-CC5 or placebo were generally well tolerated with no clinically significant, drug-related adverse events (AEs) reported to date. There were no serious adverse events (SAEs), study discontinuations, or clinically significant laboratory findings. In Part A of the study, a total of 29 AEs were observed, all of them mild or moderate in severity, of which 3 were deemed possibly related to ALN-CC5 or placebo. Two patients experienced mild, transient injection site reactions (ISRs). In Part B of the study, a total of 30 AEs were observed, all of them mild or moderate in severity, of which 12 AEs were deemed possibly related to ALN-CC5 or placebo. Four subjects experienced mild, transient ISRs.
