Dyax's Management Presents at DX-2930 Phase 1a Data Review Conference (Transcript)

Feb.26.14 | About: Dyax Corp. (DYAX)

Dyax Corp. (NASDAQ:DYAX)

DX-2930 Phase 1a Data Review Conference Call

February 25, 2014 5:00 PM ET

Executives

Jennifer Robinson – Associate Director-Investor Relations

Burt A. Adelman – Executive Vice President and Chief Medical Officer

Young Chung – Senior Director of Medical Research

Chris TenHoor – Senior Vice President of Preclinical Development and Pharmacology

Analysts

Joseph P. Schwartz – Leerink Partners LLC

Phil Nadeau – Cowen and Company

Biren Amin – Jefferies & Co.

Chris Marai – Wedbush Securities

Serge Belanger – Needham & Company

Operator

Good afternoon, and welcome, ladies and gentlemen, to Dyax Corp's DX-2930 Phase 1a Data Review conference call and webcast. At this time, I would like to inform you that this conference is being recorded and that all participants are in a listen-only mode. At the request of the Company, we will open up the call for a brief question-and-answer period at the end of the presentation.

Before turning the call over to Dr. Burt Adelman, Executive Vice President of Research and Development, and Chief Medical Officer of Dyax, the Company will now read their forward-looking statements.

Jennifer Robinson

This afternoon Dyax issued a press release concerning results from a Phase 1a clinical trial for DX-2930. Dyax would like to remind everyone that these statements made today reflect current expectations, estimates and projections about its products, programs, collaborations, strategies and financial performance, and are forward-looking statements.

These statements, including those relating to Dyax's clinical stage product candidate DX-2930 are subject to risks and uncertainties that could cause actual events and results to differ materially. Important information concerning these risks and uncertainties is contained in Dyax's press release today and described or referred to in its most recent Form 10-K and other periodic reports filed with the SEC, and are also available on the company's website at www.dyax.com.

I will now turn the call over to Dr. Burt Adelman, Executive Vice President of Research and Development, and Chief Medical Officer of Dyax. Sir?

Burt A. Adelman

Thank you, Jen. Good afternoon, and welcome to Dyax's presentation of the results of our Phase 1a study DX-2930. As Jen mentioned I am Burt Adelman, Dyax’s Executive Vice President of Research and Development, and Chief Medical Officer. I am joined on this call by Dr. Young Chung [ph], Senior Director of Medical Research, and Dr. Chris TenHoor, our Senior Vice President of Preclinical Development and Pharmacology.

As many of you are aware, Dyax issued a press release today announcing positive results from the first in-human clinical study of our investigational product, DX-2930. We are pleased to report that our Phase 1a study met all objectives of assessing safety, tolerability and pharmacokinetics of DX-2930. During this conference call, we will walk you through the trial results in detail over the next 35 minutes. And then be glad to answer questions.

I know that many of you have a thorough understanding of heredity angioedema and the rationale underlying the development of DX-2930. However, in the event that we have some folks on the phone who are new to this topic, I will begin with a general introduction to HAE, its pathobiology and current treatment. Hereditary angioedema is a rare disorder characterized by repeated episodes of swelling and pain that can affect the extremities, genital area, face, pharynx and bowels.

Attack frequency can vary dramatically and unpredictably among patients. Affected individuals may suffer numerous attacks per year. Patients presenting with laryngeal edema and airway obstruction are at great risk for significant morbidity and even death if appropriate therapy is not given urgently. All HAE patients face the very real risk that their next attack will involve the pharynx and compromise breathing.

HAE results from a deficiency of the protein C1 inhibitor. C1 inhibitor is a member of the serpin protease inhibitor family. Serpin protease modulate critical enzyme pathways in the body. In the case of HAE, C1 inhibitor deficiency affects control of the contact activation pathway. Once activated, these pathways are hard to stop because they self- accelerate by autoactivation and intrinsic feedback loops. C1 inhibitor is made in the liver and secreted into the blood.

In normal individuals the plasma concentration of C1 inhibitor is about 0.25 milligrams per mill, and the plasma half-life is approximately 56 hours. In 85% of HAE patients level C1 inhibitor is less than normal. In the remainder of patients, a nonfunctioning protein is produced. HAE is inherited as an autosomal dominant disorder. The United States HAE Association reports that there are 65,000 affected patients in the U.S. HAE is recognized throughout the world and physicians who are expert in the diagnosis and treatment of HAE can be found in many countries.

Much of the pathobiology of HAE is understood. Attacks of swelling and pain are initiated by uncontrolled activation of the contact system resulting in persistent generation of a vasoactive peptide bradykinin, by plasma kallikrein acting on its substrate high molecular weight kininogen. Bradykinin then binds to the B2 receptor on endothelial cells causing vasodilation and painful vascular leak. Bradykinin has a half-life in blood of only seconds.

However, during a HAE attack, because of the absence of C1 inhibitor, the enzyme plasma kallikrein continuously generates bradykinin allowing an HAE attack to progress for hours or even days. Eventually, kinin pathway activation abates and the attack resolves. Current management strategies for HAE include acute treatment of individual attacks and chronic treatment to attempt to prevent attacks. Because preventive therapies are not consistently effective, many patients find they must supplement chronic therapy with additional acute treatments.

Drug development and discovery are often evolutionary and influenced by knowledge learned from direct experience in a disease area. After introducing ecallantide, we soon realized that HAE patients choosing prophylactic therapy would benefit from access to a yet more convenient and effective drug than their current options. Our discovery and development program for DX-2930 is intended to determine if it can meet this need. We believe that the therapeutic profile of an effective prophylactic agent should include the following key attributes. The drug must impact a target understood to be critical to the disease process. In the case of DX-2930, we believe that plasma kallikrein is a valid target in HAE.

Plasma kallikrein is targeted by both C1 inhibitor and ecallantide. As shown in this x-ray crystal structure, DX-2930 binds to the active site on plasma kallikrein occupying the same approximate space as ecallantide. The drug must be safe during chronic use. To begin to ensure safe use in chronically treated patients, the drug candidate must have high affinity and specificity for its target. Our data indicate that DX-2930 binds and inhibits plasma kallikrein with high affinity and great specificity. Unlike small molecule drugs, monoclonal antibodies as a class have reduced risk of off-target effects. Of course, extensive preclinical and clinical testing is required to adequately define the risk profile of DX-2930. We are just at the beginning of this effort.

The drug must have a long half-life and a predictable pharmacokinetic profile. To prevent attacks of an unpredictable recurrent disease such as HAE, drug levels in the blood must consistently stay within the therapeutic range. As we will discuss in a few minutes, data to date indicate that DX-2930 has a very long half-life, exceeding two weeks in normal individuals. Drugs with long half lives enable infrequent and less precise dosing schedules to achieve stable, steady state blood levels. Drugs with very short half lives must be dosed frequently, and the dosing schedule is often very critical.

Think of drugs such as Tysabri and Humira that are dosed just once or twice a month to achieve effective disease control. On the other hand, think of how difficult it would be to manage diabetes with only a short-acting insulin formulation. And, finally, any drug that a patient must take for a long period of time should be easy to self-administer. Data to date indicates that DX-2930 can be formulated at a high concentration that should enable infrequent self-administration by subcutaneous injection. Injection volumes of 1to 1.5 milliliter appear likely.

At Dyax, we are undertaking a methodical development path for DX-2930. Each step of our program is intended to both confirm previous findings and expand our understanding of DX-2930. Emerging clinical results build on and extend data we have already developed through completed and ongoing preclinical toxicology and pharmacology studies.

The purpose of this Phase 1a study was to establish for the first time in normal individuals critical pharmacokinetic parameters and to identify any early safety signals associated with DX-2930 exposure. This was a single dose study enabled by our 28-day toxicology studies. Following completion of our long-term toxicology studies and the soon to be initiated multidose Phase 1b study in HAE patients, we will be prepared to start a proof-of-concept Phase 2 study.

In some disease states, surrogate markers can be measured that allow us to predict the effect of a drug on disease progression. For example, the measurement of hemoglobin A1 c can be used to assess the ability of a drug to regulate sugar metabolism in diabetic patients. Currently, no such marker exists to assist in the development of drugs to treat HAE. Consequently, the only way to prove that a new drug candidate will prevent HAE attacks is to conduct well controlled clinical trials in HAE patients.

Certainly, in HAE, Phase 1 is not the new Phase 3. That said, we have developed a set of assays that allow us to characterize the pharmacodynamic effect of DX-2930 in plasma following systemic administration. We believe these assays will help us refine DX-2930 dosing when applied to HAE patients. We have explored the use of these assays in the Phase 1a study and will share the results with you. I believe you will all agree that they provide useful, supportive data.

Now, let me turn the presentation over to Young and Chris, who will take you through the Phase 1a data.

Young Chung

Thank you, Burt. As typical of a first-in-human study, the primary goal of the Phase 1a trial was to evaluate the safety and tolerability of a single administration of DX-2930 across a range of doses. An important secondary objective was to characterize the pharmacokinetic parameters of this investigational product. And, as Burt had mentioned, we also utilized our biomarker assays to explore the pharmacodynamic profile of DX-2930.

This trial was a single ascending dose study in healthy subjects and was randomized, double-blind, and placebo-controlled. The study was conducted in a single center with extensive experience in first-in-human trials, including those in monoclonal antibodies and other biologics. There were four dosing cohorts ranging from 0.1 to 3 milligram per kilogram, the total of 32 subjects overall. Each cohort was comprised of 6 subjects treated with active drug and 2 subjects treated with placebo, with each subject to undergo 16 weeks of follow-up.

As a summary overview of the safety results from the study. DX-2930 appears to be well tolerated, and there was no evidence of any dose-limiting toxicity associated with single administrations up to the highest tested dose of 3 milligrams per kilogram. Based on the data, there is no evidence at this time of any clinically significant safety signals related to DX-2930. Here is a more detailed outline of the safety data.

There was no meaningful imbalance between the pool of all subjects treated with DX-2930 as compared to the pool of all subjects treated with placebo. Following dosing, adverse events were reported in 66.7% of all DX-2930-treated subject as compared to 75% of placebo-treated subjects. There were no deaths, serious adverse events, or any subject discontinuations due to an adverse event.

The relatedness of adverse events following dosing was assessed by a blinded investigator. Adverse events assessed as treatment-related in this blinded fashion were reported in 25% of all DX-2930-treated subjects as compared to 50% of placebo-treated subject. There was no clinically significant imbalance between the DX-2930 and placebo groups for any particular adverse event. The most commonly reported adverse event after dosing was headache, which occurred at an equal rate of 25% in both the DX-2930 and placebo groups.

None of the headaches were severe and all resolved. There were only two subjects with a severe adverse event following dosing that was reported as treatment related by the blinded investigator. In both instances, the adverse event with an elevation of creatine phosphokinase noted upon laboratory testing, with one occurrence in a subject treated at 0.1 milligram per kilogram of DX-2930 and another in a placebo-treated subject. This corresponds to a rate of 4.2% of all DX-2930 treated subjects and 12.5% of all placebo-treated subjects.

Notably, neither CPK elevation was associated with any adverse event or finding that would indicate clinical importance such as myalgia or muscle weakness. Finally, there we’re no injection site reactions reported in any subject. Clinical laboratory tests were diligently reviewed and there was no meaningful imbalance identified between placebo and DX-2930 for any clinically significant lab findings including prothrombin time.

One subject had findings of an upper respiratory infection determined to be mild and unrelated to treatment by the investigator. Otherwise, no subject had any clinically significant abnormalities on physical examination or vital signs. In addition, there were no clinically significant abnormalities in electrocardiogram results in any subjects. Anti-drug antibody testing was conducted and based on currently available analyses there has been no evidence to date of any seroconversion.

To summarize the safety results from study, DX-2930 appeared to be well tolerated without any evidence of dose-limiting toxicity following single doses up to 3 milligrams per kilogram. There is no evidence at this time of any clinically significant safety signals related to DX-2930.

Now, I will turn the presentation over to Chris, who will take you through the pharmacokinetic data for the study.

Christopher TenHoor

Thanks, Young. Throughout the preclinical development of DX-2930, we knew we had a molecule with excellent pharmacokinetic properties. When evaluated in preclinical studies following single dose administration, the elimination half life was almost two weeks. Pharmacokinetic modeling of preclinical data suggested that we would have an antibody with a prolonged half life in humans as well. For that reason, we designed a Phase 1a study in healthy subjects to include an extensive 112-day post-dose sampling period.

The next Slide, the concentration time plots for each cohort are displayed on a log scale. The arrow bars are standard deviations. The profiles demonstrate a linear dose-dependent exposure. The parallel elimination phases across dose groups are consistent with a well behaved antibody with dose independent kinetics in that all doses behave in a uniform manner.

The next Slide shows the pharmacokinetic parameter estimates for each dose cohort. As illustrated on the previous slide the mean Cmax and AUClast values exhibit a strict linear dose dependency consistent with a well behaved antibody. As Burt mentioned in his introductory comments, drugs with long half lives enable infrequent and less precise dosing schedules to achieve stable, steady state blood levels. DX-2930 demonstrated a consistent extended half-life of almost three weeks across dose groups.

As we touched on earlier, an optimal therapeutic candidate for prophylaxis of HAE should have a long half-life and a predictable pharmacokinetic profile to enable infrequent dosing and a logical technical dosing rationale. Due to the consistent pharmacokinetic profile of DX-2930, we will be able to determine a dosing regimen that may enable us to provide significant therapeutic benefit to patients with HAE.

My last Slide, illustrates the predicted plasma concentrations that would be achieved following repeat dosing of the 3 milligram per kilogram dose of DX-2930. The initial concentration profile is consistent with the profile observed upon single dose administration in healthy subjects. While we have not yet conducted the clinical studies in HAE patients to determine the actual therapeutic level of DX-2930 needed to suppress HAE attacks, this simulation provides some insight into potential dosing regimens.

As Burt also mentioned previously, chronically administered drugs must also have a good safety profile. The Cmax of approximately 25 micrograms per milliliter as shown in this simulation still provides a 15-fold safety margin when compared to maximum plasma concentrations achieved in the preclinical studies.

I will now turn it back over to Young.

Young Chung

Thank you, Chris. In considering the PK profile of DX-2930, you may be wondering how these data might be relevant to our hypothesized product profile and dosing strategy in preventing HAE attacks. It is helpful at this point to consider the principles of prophylaxis for diseases in general.

For prophylaxis, the critical requirement for effectiveness is that the relevant drug target be inhibited at a level above the minimum required amount on a continual basis. It is vital that gaps in inhibition coverage be minimized or avoided altogether. Any time the level of innovation drop below the minimum required level.

The individual is biologically vulnerable for activation of the pathologic process and thereby placed at risk clinically for the disease event. But successfully achieving a state of prophylaxis is not always straightforward. Anticoagulation with warfarin to prevent thromboembolic events is a classic illustration.

Continually maintaining a threshold level of anticoagulation is critical to protect against serious events such as stroke. However, the use of warfarin is complicated by inter – and intra-individual variability in the pharmacologic response, the possibility that individuals might not take the drug on a precisely regular basis, as well as other considerations.

Consequently, dosing of this oral small molecule agent carefully titrated a company’s by intensive monitoring of the INR in order to avoid levels of anticoagulation moving outside of the therapeutic window.

Now, in considering HAE, there is no logical or scientific reason why this disease would be exempt from widely established principles of prophylaxis. In HAE, plasma kallikrein represents a validated drug target that is critical to the pathogenesis of angioedema attack. Successfully preventing HAE attacks then we will require that plasma kallikrein inhibition continually maintain above the minimum therapeutic level.

Again it is important that gaps in coverage over time be minimized to avoid periods of vulnerability. This need is further emphasized by the phenomenon of a positive feedback list that is hypothesized to play an important role in HAE attacks. Upon initiation of this cascade, activation of plasma kallikrein leads to Factor XII activation that in turn drives more plasma kallikrein generation.

So the natural question to ask, then, is what level of plasma kallikrein addition is necessary to prevent HAE attacks. In other words what is that minimum level of activity that a prophylactic agent must continually maintain to prevent attacks. Although it is not known for certain there are two important piece of data that help define this target level. First the Kaufman study evaluated plasma kallikrein levels generated during an HAE attack by measuring levels of plasma kallikrein alpha 2 macroglobulin complexes. This study yielded estimates at a range 30 to 110 nanomolar of plasma kallikrein is generated during HAE attacks.

Notably this estimate indicates only a subtraction to the total 500 nanomolar free kallikrein in the plasma is converted into plasma kallikrein during HAE attacks. This suggest that only partial inhibition of all potentially available plasma kallikrein in plasma is necessary in treating HAE. Independently data from the ecallantide clinical development program provides a more precise estimate of what amount of plasma kallikrein needs to be inhibited by DX-2930 to prevent HAE attacks.

Ecallantide is a short acting plasma kallikrein inhibitor that is approved for treatment of acute HAE attacks in the United States, following dosing the average peak drug levels of ecallantide in the plasma or Cmax is 80 nanomolar, as ecallantide appears to have approximately one to one binding with plasma kallikrein in this concentration range.

This observation suggest that the amount of plasma kallikrein generate during an HAE attack is no higher than 80 nanomolar I continually inhibiting this amount of plasma kallikrein in the plasma with the prophylactic agent then we can hypothesize the HAE attacks maybe prevented from even occurring.

Now let us turn our attention back to DX-2930. We compared the inhibition of plasma kallikrein by DX-2930 with ecallantide in an in vitro assay and that system human plasma is exposed to an agent that initiates the contact system and converts free kallikrein to active plasma kallikrein.

You may notice that 80 nanomolar of ecallantide which of course is the peak drug concentration in the plasma following dosing in patients here as only partial inhibition of plasma kallikrein, this further reinforces the prior observation by Kaufman and colleagues that HAE attacks associated with only a subtraction of the plasma kallikrein that could potentially be generated from available free kallikrein.

Importantly around this concentration range of 80 nanomolar, these assay results showed that DX-2930 has potency comparable to ecallantide. In considering all these data and observations together one can now assemble the picture of what plasma drug levels at

DX-2930 are necessary to prevent HAE attacks given that 80 nanomolar appears to be the plasma kallikrein level relevant for HAE attacks and given the comparable potency of DX-2930 with ecallantide and inhibiting plasma kallikrein at this concentration range, we hypothesized that maintaining DX-2930 continually above plasma drug concentration of 80 nanomolar would prevent HAE attacks.

Although 80 nanomoloar is our target, it is possible that lower or higher drug levels of DX-2930 maybe necessary, however the 80 nanomolar target for DX-2930 plasma drug levels appears to be revised based upon currently available data and understanding of disease biology.

So let us now consider that PK parameters at DX-2930 following a single dose and healthy subjects. Following a single three milligram per kilogram dose plasma drug concentrations exceeding the target level of 80 nanomolar were obtained. Drug levels either around or greater than 80 nanomolar were maintained or approximately 10 days now remember that this was just the drug levels achieved following only a single administration of the drug.

Drug levels will continue to accumulate upon repeated administration of the drug until steady state is reached. It is therefore noteworthy that even following only a single dose of DX-2930 drug levels exceeding the target of 80 nanomolar were attained and maintained for a long period of time. PK modeling can be performed to guess what might happen upon chronic dosing. This figure represents a hypothetical scenario in which DX-2930 is dosed at 3 milligrams per kilogram every 28 days in healthy subjects. Results of this modeling suggests that after the steady state has been obtained, repeat administrations will continually maintain drug concentrations around or above the targeted 80 nanomolar level.

It should be noted that this model is purely hypothetical and also does not predict what might happen in HAE patients. The PK profile of DX-2930 in HAE patients is currently unknown and might be different than in healthy subjects. Nonetheless, PK data from the Phase 1a study support the feasibility of a dosing strategy to attain plasma drug concentration above the targeted 80 nanomolar level and to then continually maintain them.

Furthermore, contingent upon future safety and toxicology data not identifying any safety concerns, it appears possible to aim for higher drug levels beyond 80 nanomolar if necessary to attain sufficient plasma kallikrein inhibition relevant to prophylactic. To further characterize DX-2930, exploratory biomarker assays were performed ex vivo on subject plasma samples to evaluate the pharmacodynamic profile of the molecule. Two independent assays were conducted - plasma kallikrein activity assay using an artificial fluorogenic substrate and a Western blot assay measuring the cleavage of kininogen, the native substrate of plasma kallikrein from which bradykinin is generated.

These assays are semi-quantitative at best, if not qualitative, and data points should therefore be interpreted relative to other data points within that experiment and not compared across the assays or to other assay systems, is also important to highlight that these assay results in no way can be used to predict the efficacy of DX-2930 in HAE patients.

These assays are conducted in normal subject plasma with normal levels of C1 inhibitor and these subjects, of course, do not develop HAE attacks. Ultimately, only adequate and well controlled clinical studies can determine the efficacy of DX-2930, or of any drug, for that matter. Instead, the goal of these biomarker assessments was to confirm that DX-2930 and plasma from dose subjects does indeed have inhibitory activity against plasma kallikrein. Equally important, we wish to assess if the pharmacodynamic results corroborated the observed PK profile.

These results are from the plasma kallikrein assay that uses the fluorogenic substrates. Plasma from treated subjects was activated ex vivo to induce the contact system pathway and there by stimulates plasma kallikrein generation and activity. Here, for the sake of simplicity and illustration purposes, data from the one and three milligram per kilogram groups are displayed. Plasma kallikrein inhibition was clearly evident particularly in the one and three milligram per kilogram dose groups. No appreciable inhibition was observed in the 0.1 milligram per kilogram or placebo group.

The observed inhibition with both dose and time-dependent and confirms the inhibitory activity of DX-2930. Here we can see that the pharmacokinetic data corroborates the PK profile that was a third. The overall time course of pharmacodynamic activity aligns with that observed from the PK results. In the second experimental assay system Western blots were used to set the cleavage of kininogen by plasma kallikrein up on ex vivo activation of plasma.

In addition of plasma kallikrein can be observed as attenuation in the amount of cleaved kininogen species displayed here at percent two chain high molecular weight kininogen. Although qualitative in nature, the advantage of this system is that it evaluates activity of plasma kallikrein upon its native substrates from which data of bradykinin is formed. In the placebo group there was no meaningful difference in cleavage levels in plasma obtained prior to dosing and that obtained at day five after dosing.

In contrast, notable inhibition of kininogen cleavage was observed in activated plasma obtained from three milligram per kilogram treated subjects at day five following dosing in comparison to cleavage levels from free dose plasma. There was a suggestion of cleavage inhibition in the 1 milligram per kilogram group, but it was not statistically significant. Kininogen cleavage was also assessed in plasma obtained at day 28 following dosing.

The inhibition of plasma kallikrein observed in plasma from the 3 milligram per kilogram group at day five following dosing was still evident at day 28 following dosing. This finding suggests durable drug exposure and effect in a manner consistent with results from the first assay system. Taken together data from these two exploratory biomarker systems provide evidence for an important pharmacodynamic effect of DX-2930 in human. The observed drug effect appears to persist for several weeks in the highest dose group.

Since the prevention HAE tests were acquired sustained suppression of plasma kallikrein activity. These biomarker data highlight the promise of DX-2930 as a potential long-term prophylactic agent. Further biomarker data in the Phase 1b study in HAE patients will contribute to the characterization of DX-2930 and can inform the design of the Phase 2 study to assess the safety and efficacy of DX-2930 for long-term prophylactic of HAE. In summary DX-2930 appears to be well tolerated and healthy subjects following a single dose of DX-2930 after the highest dose test of three milligram per kilogram.

The observed PK profile suggests the feasibility of a dosing strategy to attain and then continually sustain the target plasma levels. Dose proportional drug exposure was observed in this study. Maximal plasma concentrations exceeding the 80 nanomolar target level were attained even after only a single dose when steady state has not yet been reached.

The drug has a long half-life in healthy subjects following a single dose of approximately 17 to 20 days. It is therefore reasonable to hypothesize that a chronic dosing regimen can be developed to maintain drug levels continually above that 80 nanomolar target level. Pharmacodynamic data from two independent ex vivo biomarker assays corroborates the PK profile.

The data in healthy subject plasma that demonstrate dose and time-dependent inhibition of plasma kallikrein and suggests sustained bioactivity of several weeks following a single dose. Finally, the administration burden associated with the drug appears to be low. DX-2930 is administered subcutaneously and low injection volumes are anticipated. No injection site reactions were observed in healthy subjects following a single dose.

The PK data supports potential for a long half-life that may enable infrequent drug administration in HAE patients. With that, I will now turn the presentation back to Burt for closing remarks.

Burt A. Adelman

Thank you, Young and Chris. Before we open the phone line for questions, let me make a few concluding remarks and tell you about our going forward plans. We are very excited about the results that we've shared with you today of this first in-human study. Let’s go back to the list of key attributes of an effective drug for the treatment of a serious, lifelong, unpredictable disorder such as HAE and see how DX-2930 is stacking up.

First, is plasma kallikrein relevant to prophylactic treatment of HAE? We believe the answer is yes. HAE attacks result from aberrant activation of the contact activation system and plasma kallikrein is the central enzyme in that pathway. Further supportive evidence comes from the clinical efficacy above ecallantide and human C1 inhibitor replacement therapy, but a definitive answer requires a Phase 2 proof-of-concept study.

Second, well DX-2930 be safe during chronic use. We have engineered DX-2930 to bind the plasma kallikrein with high affinity and to be highly specific for its target. This will limit the possibility of off-target toxic effects. Preclinical testing has demonstrated that DX-2930 is well tolerated at high doses and over extended periods of time, and today you have been told that DX-2930 appears to be well tolerated in normal subjects given single doses.

Obviously, only extensive clinical testing can provide a final and definitive answer to this question. Third, does DX-2930 have a PK profile that will enable persistent exposure at that necessary therapeutic plasma level? Data presented to you today clearly demonstrate that DX-2930 has a long half-life, approximately 20 days and behaves predictably across a range of doses. This long half-life will allow infrequent dosing and facilitate maintenance of a stable therapeutic blood level. So, we think the answer to this question is likely to be yes, treatment of patients with HAE will provide a definitive answer.

Fourth, will DX-2930 be available on dosage form convenient for patient self-administration? To date we have been able to formulate DX-2930 at 100 milligrams per milliliter. Higher concentrations are being evaluated in ongoing stability studies. We believe DX-2930 will be formulated so it can be self-administered by infrequent 1 to 1.5 milligrams injection. So we believe that DX-2930 is making great progress against this list of key attributes. Our next trial will be a Phase 1b blinded multicenter repeat dose and dose escalation study exploring DX-2930 in patients with HAE. We plan to accrue patients into three fixed dose groups. Each group will have approximately four DX-2930 and two placebo-treated patients.

The primary purpose of this study will be to gain safety and PK date in the target patient population. We will also use our biomarker assays to access the possible impact of DX-2930 on basal plasma kallikrein activity. We hope to start accrual of this trial midyear. Thanks for your attention. I’ll now open the line for some questions.

Question-and-Answer Session

Operator

(Operator Instructions) And your first question comes from the line of Joseph Schwartz with Leerink Partners. Please proceed.

Burt A. Adelman

Hi, Joe.

Joseph P. Schwartz – Leerink Partners LLC

Hi, there. Congratulations on these exciting results. I was wondering if you could talk a little bit about the doses that you contemplate testing going forward. It looks like you could continue to go higher in dose based on the tolerability and maybe keep more patients above that 80 nanograms per milliliter level. And then can you talk a little bit more about that level? Because if that’s the level to actually curtail an attack with Kalbitor, why wouldn't it be reasonable to think that maybe a less aggressive level might be required in order to prophylax?

Burt A. Adelman

Right. So, those are all excellent questions. Just a minor point, it's 80 nanomolar, not 80 nanogram. The – so, yes, if I remember all these questions going backwards and then Young will answer all the ones that I've forgotten, I'm sure. Absolutely right. The therapeutic dose could be much lower than the 80 nanomolar. Going forward, we – as we were thinking about the dosing strategy in this Phase 1a study, we tried to say let's put a stake in the ground at a guess of what might, you know, defensible by data, might be a therapeutic dose. And then we said to Chris TenHoor, because he had all of this excellent preclinical data.

To do model a range of doses for this Phase 1a study that would give us at least a theoretical chance of seeing if we could get up to that dose. So, in essence that’s how we came up the dosing strategy for the Phase 1a study. And I would completely agree with you, a range of doses higher or lower may yet be effective in patients who actually have HAE, because if all you really need to do is prevent acceleration of the feedback loop, then you might not actually need as much drug to prevent attack as you do to treat an acute attack.

Joseph Schwartz – Leerink Partners

That's very helpful. It's a fascinating science. It sounds like you're doing great work. I was just curious if, what doses are you thinking about for the Phase 1b?

Young Chung

Sure, absolutely. This is Young. So, we are moving forward, switching to a fixed dose for each subject. So, the three doses that we're looking at for the dosing cohorts are 30 milligrams, 100 milligrams and 300 milligrams. Now, with that said, there is some flexibility built into the study that we're planning, so we could always modify as needed, but going forward as of now, that's the current plan.

Joseph Schwartz – Leerink Partners

Right. So, it sounds like you are kind of bracketing based on just quick arithmetic, the doses that you've tested here and you might be going up a little bit on a milligram per kilogram basis?

Young Chung

Yeah, but we are very interested, it is a new experiment, and HAE patients have probably – well, they do have evidence of ongoing plasma kallikrein activation. So, it's possible that the pharmacokinetic profile of the drug would be different in that setting, because the basic behavior of the drug is so predictable. Whenever we learn there, we will be able to take forward into understanding what to do in actual proof of concept studies.

Joseph Schwartz – Leerink Partners

Okay, great. I'll get back in the queue. Congratulations.

Young Chung

Thanks.

Operator

And your next question comes from the line of Phil Nadeau with Cowen and Company. Please proceed.

Phil Nadeau – Cowen and Company

Good afternoon and thanks for taking my question. First one on the safety profile and side effects, I realize that there was no difference in the incidence of headaches or creatine phosphokinase elevations, but was there any difference in timing or the ones for patients on drug, like [Indiscernible] injection, whereas, the others were not possible?

Burt A. Adelman

Yes, very good question. So we would love to – as a clinical presentation of the various adverse events and try to see if there was a signal, was it clinically significant, and we didn't see any apparent signal that would indicate clinical significance. And like we talked about earlier for the headache, for example, the good thing was also that all the headaches, none of them severe, they all resolved, and regards to the CPK elevation, it was just an isolated lab finding. We didn't see – for both instances we didn't see any associated other adverse events or findings that might suggest there is something going on clinically, such as myalgia or muscle weakness.

Phil Nadeau – Cowen and Company

Okay, great. And then, second, follow-up to Joe's question on the dosing again. Do you think that there would be any benefit to doing a loading dose? It does seem like maybe with the first injection, patients wouldn't have full coverage for that first month?

Burt A. Adelman

Sure. And, of course, we use 28 days as just one example of a dosing schedule. You are absolutely right. We could dose – we could either use a loading dose or we could dose more frequently for the first month, to get people up to steady state. So there are multiple possible ways to get to a steady state pretty quickly. And we will think about all of those with respect to patient convenience and what will work best.

Phil Nadeau – Cowen and Company

Okay, great. And then one last question for me, are there any barriers to going above a 300 milligram fixed dose? So anything like, you don't have the preclinical data or the volume will be too big, so it wouldn't be a 1 to 1.5 milliliter injection. Are you capped at 300 milligrams or could you go to 450, 500 milligrams if you needed to?

Burt A. Adelman

Well, I think that – so [indiscernible] 400 milligrams in ML, I mean antibodies are big proteins and they tend to get a little sick when you get up to concentrations like that. So I don’t know where we'll top out in terms of the useful concentration in formulation. But certainly we believe we will get above 100 milligrams per mill. So I’m sure we’ll have some options in concentration and dosage.

Phil Nadeau – Cowen and Company

Okay, great. Thanks for taking my questions.

Operator

And your next question comes from the line of Biren Amin with Jefferies. Please proceed.

Biren Amin – Jefferies & Co.

Yes, thanks for taking my questions and congrats on the data. Burt, I guess on the Phase 1b trial that you're about to start, will patients be given two doses of 2930?

Burt A. Adelman

Yes, I will hand that over to Young.

Young Chung

Yes, so it will be repeat doses it gives each subject will receive the same dose. So, in other words, if they get in the 30 milligram group they’ll get 30 milligrams again separated by some interval time. We're thinking maybe two weeks at this stage, and then we'll set safety, tolerability, PK and biomarker in those subjects.

Biren Amin – Jefferies & Co.

So, you're going to give it every two weeks, or you're going to separate the second dose by two weeks?

Burt A. Adelman

Its is just two dose study we are just in the midst of finishing our long-term pre-clinical studies that will enable essentially continuous exposure. So we are just sort of its one step it time we had 28 day data we think the 28 data will support single or double dosing and then will have complete analysis of our long-term dosing and will be able – will be offset for the Phase 2 study sometime next year that will have obviously extended exposure.

Biren Amin – Jefferies & Co.

Okay and maybe if I could ask on cross-trial comparisons. You're probably going to get this question, and given what we saw with the BioCryst Phase 1 data, and if I look at your 3 milligram per kilogram inhibition of plasma kallikrein, how would that compare to the BioCryst data?

Burt A. Adelman

I think that as Young clearly indicated, we don't even know exactly how they ran their assay. You can set these assays up also to ways I think its do very problematic trying to compare once that a data to another. I think what’s more important is that we’ve tried to create an internal standard that you can use the gage the likelihood of clinically relevant activity of the drug by telling you that one that ecallantide therapeutic concentration is likely to be 80 nanomolar because that’s the Cmax following a administration.

And then showing you that the activity of ecallantide and 2930 is essentially equally molar in the same assay system and then being able to say okay if the two drugs work approximately have the same affinity at the same inhibitory activity at the same concentration, we can then tell you how are we doing with DX-2930 against a standard define by non-active drug. So I think that, that’s the best answer to that question is that we have presented a internally consistent and benchmarked analysis of activity of 2930.

Biren Amin – Jefferies & Co.

Great, thanks for taking my questions.

Operator

And your next question comes from the line of Chris Marai with Wedbush. Please proceed.

Chris Marai – Wedbush Securities

Great. Thanks, guys, for taking my questions. I don't know if I missed it, but with respect to the long-term GLP talk studies, are those going to be ready by the time want to get start on the Phase 1b? And then additionally, given your biomarker assays and the great data we've seen here today, I was wondering if you've made any other progress on other indications, particularly in autoimmune disorders or macular edema? Thanks.

Burt A. Adelman

Yes, hey Chris those are all great question. So the long-term talk studies will be done shortly. We don’t believe that necessary to support two time dosing in the Phase 1b study anyway, but everything will certainly all be ramped to what us move forward on time to start Phase 2. And we are indeed working hard with that western block biomarker assay to look at evidence for plasma kallikrein activation across a spectrum autoimmune diseases and we hope to be able to and share some of those results with you all in the next couple of months.

Chris Marai – Wedbush Securities

Great. And one final…

Burt A. Adelman

Yes, sure.

Chris Marai – Wedbush Securities

With respect to your Phase 1b, when do you expect results to read out from that?

Young Chung

So I mean obviously depended upon how that study approves and whatnot, but we'll see how it goes. But maybe beginning of next year actually but we will see how it goes and I think part of it is what ultimately we end up with in terms of Phase 1b design how the dose escalation part goes, there is a lot of unknown variables at this time but we could think about that maybe beginning of next year we may have some results here.

Burt A. Adelman

I mean we’re pressing hard, we’ve got a lot of very excited investigators both in United States and abroad, we’ve got a lot of great support from the clinical community for the development of this product, Young has had a number of investigator meetings, we have reviewed the Phase 1b protocol with investigators, so I think there is great excitement to part of the development team for 2930, so we’re really enthusiastic that things are going to move very quickly.

Chris Marai – Wedbush Securities

Great thanks congratulations on the data.

Burt A. Adelman

Thanks again.

Operator

(Operator Instructions) And your next question comes from the line of Serge Belanger with Needham & Company. Please proceed.

Serge Belanger – Needham & Company

Good evening, and congratulations again. I have a few more questions on the Phase 1b plans. I just wanted to know what kind of HAE patients you will be recruiting for the study? Are these high frequency type patients or just regular HAE patients? And then you also mentioned it was a multicenter study. Are you going to be recruiting in the U.S. only, or both U.S. and Europe?

Burt A. Adelman

Yes it’s a great question so and to regards to your first question it will be a broad HAE patient population because this is a safety study first in HAE patients, so we will be evaluating safety and tolerability, PK so we thought at that point it makes sense patient population. In terms of the tax frequency et cetera with regards to being multicenter yes you are right, we will be U.S. as well as the overseas Europe et cetera.

Young Chung

Let me just add you know Serge we believe that every patient who has who is at risk of having an HAE attack whether they one or five year or 20 year remains at risk of having a laryngeal attack, so our general outlook is that all patients with the disease should be eligible for inclusion in clinical trials and hopefully assuming that the drug words should be eligible for treatment if that is choice.

Serge Belanger – Needham & Company

Okay. And you mentioned using the biomarker study again. This is going to be the proxy for reduction in frequency of attacks?

Burt A. Adelman

While we are certainly interested there is a literature already out there that says even in HAE patients when they are not having an attack there is evidence that two chain high molecular weight kininogen is deductible by Western blot at levels that exceeds those normal individuals and they when they having attack it goes up quite high, so we are interested to see whether one or two of the doses that we use might suppress that [indiscernible] of two chain high- molecular kininogen.

Serge Belanger – Needham & Company

Okay last one.

Burt A. Adelman

Sure.

Serge Belanger – Needham & Company

Did you have any interactions with the FDA in designing the Phase 1b?

Burt A. Adelman

Not specifically, I mean when we had our pre IND meeting we talked to them about Phase 1, Phase 2 and they helped us understand what would be necessary to transition from a single dose study in normal individuals into a multidose long-term study in HAE patients.

Serge Belanger – Needham & Company

Okay.

Unidentified Company Representative

This is part of the solution to there too, the issues that they described to us.

Unidentified Company Representative

I don’t think there are anymore questions. So operator if there are any more questions in the queue.

Operator

At this time, we have no further questions.

Burt A. Adelman

Okay then we will thank you all for joining us and I am sure we will talk to some of you view in the near future.

Operator

Ladies and gentlemen that concludes today’s conference. Thank you for your participation. You now disconnect and have a great day.

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