Halozyme CONSISTENT 1 trial testing Hylenex pretreatment in insulin pumpers shows non-inferiority on A1c, reductions in hypo – April 3, 2014

Halozyme just released positive topline data from the CONSISTENT 1 trial (ClinicalTrials.gov Identifier: NCT01848990) testing Hylenex pretreatment in 342 insulin pumpers vs. standard pump therapy (n=114). Management had previously guided for topline results in “1Q14,” and it was good to see the company hit the target on the very last possible day of the quarter. Overall, the trial met its non-inferiority endpoint: use of Hylenex pretreatment prior to insulin pump infusion set insertion was non-inferior (at an A1c margin of 0.4%) over a six-month period vs. standard insulin pump therapy. (Baseline and final A1c numbers were not provided; we look for more data to come at ADA 2014.)

The secondary endpoints offered some encouraging signs that Hylenex pretreatment can help reduce the occurrence of hypoglycemia. The rate of overall hypoglycemic events (<70 mg/dl) dropped by 12% with use of Hylenex (p=0.08), and hypoglycemia events <56 mg/dl (events we would usually characterize as severe hypoglycemia, or at least trending toward severe hypoglycemia) dropped by 23% (p=0.02). Nocturnal hypoglycemia events (<70 mg/dl) declined by 21% (p=0.02), and the rate of severe hypoglycemia events (requiring assistance from a third party) dropped by a notable 61% (p=0.08). The latter was the most exciting finding in our view (especially over just a six-month trial), though it’s hard to ascertain the true treatment effect without knowing the absolute number of events. A bit surprisingly, glycemic excursions after meals and glucose variability were not different between treatment groups versus the control group. However, these numbers were reported from blood glucose monitoring data, not the 90+ patients that were on CGM in the trial. We have little doubt that the continuous data will provide a much stronger case for the prandial benefits of Hylenex.

Given that Hylenex pretreatment speeds insulin absorption early in the infusion set life, and makes insulin absorption more consistent over three days (based on prior studies), A1c non-inferiority was not a surprise to see – still, it was good confirmation for the company as it moves forward, and the hypoglycemia data looks quite positive. Adverse events were similar across the treatment and control groups. The most common treatment related adverse event in those using Hylenex was mild infusion site discomfort (not quantified).

Halozyme intends to pursue an insulin-pump-specific label update for the already FDA approved Hylenex, which will include data from CONSISTENT 1 as part of the package. The company has initiated a dialogue with the FDA to understand what will be required and to clarify a path forward. Per remarks made in Halozyme’s 4Q13 call, these conversations are still in the early stages. While it’s not certain if the FDA will approve MannKind’s Afrezza (PDUFA date: April 15, 2014), the 13-1 positive vote for a type 1 diabetes indication from yesterday’s advisory committee was a positive regulatory sign for Halozyme.

• Broadly speaking, these results are in line with data we’ve seen on other ultra-rapid-acting insulins – MannKind’s Afrezza and Biodel’s BIOD-123. The pattern with all three compounds has been non-inferior declines in A1c in type 1 diabetes, though clear advantages on hypoglycemia. We assume the latter stems from a faster-on/faster-off profile, which reduces the long tail of insulin action and consequently the risk of late hypoglycemia. We continue to look forward to data on Novo Nordisk’s ultra-fast insulin aspart (NN1218), which is currently in four phase 3 trials. See our Novo Nordisk 4Q13 report for more information.

*Note that results are not directly comparable due to differences in trial design, data collection, reporting, etc.

• For the most part, we do not think the field expects dramatic A1c improvements with ultra-rapid-acting insulin – as Dr. Philip Raskin highlighted at CODHy Latin America, the pattern of A1c non-inferiority but advantages on hypoglycemia parallels what was seen in studies of analog insulins vs. NPH/human insulin. CGM is likely the best way to study ultra-rapid-acting insulin, as the postprandial advantages on hypoglycemia can be much better quantified through continuous data, now that much more accurate CGM is available.
• When studying ultra-rapid-acting insulin, we think it’s critical to get beyond A1c. The current diabetes research environment is perhaps overly concerned with this measure, though an insulin that does not show a statistically significant benefit on A1c could still have a massive impact on patient care: (i) less hypoglycemia; (ii) better postprandial glucose; (iii) less weight gain; (iv) higher quality of life (e.g., less need to pre-meal bolus); and (v) tighter control with an artificial pancreas. Using A1c alone misses the real nuance of these benefits, since less hypoglycemia would technically raise A1c and better postprandial control would lower A1c. For more on this topic, please see our diaTribe slides from the recent Open Public Hearing at the FDA Advisory Committee for MannKind’s Afrezza.
• As a reminder, Hylenex is already FDA approved to “increase the dispersion and absorption” of injected drugs, and the Agency did not request CONSISTENT 1 – rather, it was initiated based on Halozyme’s assessment of the needs of the patient population, detailed discussions with thought leaders in the space, and to “maximize peak sales.” It’s currently unclear how laborious the labeling discussions with the FDA will be, or if Halozyme will need to conduct additional studies. Still, it’s probably safe to say that the regulatory pathway will be much easier for the already approved Hylenex than for a novel insulin.
• Pricing of Hylenex for insulin pumpers is still a major question mark. The last time we heard about pricing was in the company’s 2012 Analyst Day, where management’s goal was to use copay programs to make it cost neutral to use Hylenex in insulin pumps. However, the cost was expected to be $52 per vial, and at one vial per infusion set change (120 site changes a year at minimum), at least $6,240 per year. This sounds very expensive relative to the efficacy shown thus far, and we are not certain if we originally misunderstood something about this. We look to hear much more as Halozyme advances the product to commercialization. Whatever the pricing, Hylenex for insulin pumpers will require at least some payer coverage, and perhaps a strong cost-effectiveness case could be made for reduction of severe hypoglycemia. The case for mild/moderate hypoglycemia reduction is less clear.
• Yesterday, Halozyme announced that Stephen Daly has been named Vice President, Hylenex Sales & Marketing. Mr. Daly will assume leadership of the current sales and marketing efforts for Hylenex in addition to leading the team working on Hylenex for use in insulin pumpers. Mr. Daly joined Halozyme in July 2013 as Executive Director, Endocrinology Marketing. Prior to Halozyme, Mr. Daly worked at Amylin for six years in marketing roles for products including Byetta and Symlin. The parallels from a commercial perspective to Symlin seem quite clear, and we expect Mr. Daly’s experience will be quite valuable on this front, especially given the ease of use and dosing challenges that have been major barriers to commercial uptake.

APPENDIX: CONSISTENT 1 STUDY DETAILS

• The CONSISTENT 1 trial (CONtinuous Subcutaneous Insulin infusion STudy ENrolling Type 1 Diabetes; ClinicalTrials.gov Identifier: NCT01848990) is evaluating the safety and efficacy of Hylenex recombinant and a new formulation of Hylenex under FDA review in a 24-month trial in 456 patients with type 1 diabetes. Patients were randomized 3:1 to either a treatment group or a control group. Patients in the two treatment groups are administered a Hylenex formulation consisting of 150 units of rHuPH20 once every three days through each new infusion cannula, immediately prior to initiation of insulin delivery (details below).
• The primary efficacy endpoint is comparison of change from baseline in A1c levels at six months using an industry standard non-inferiority margin of 0.4%. Secondary endpoints are hypoglycemia rates, hyperglycemia comparisons, glucose variability, and safety endpoints including adverse events, local tolerability, and immunogenicity. In accordance with the trial protocol pre-specified analysis of the endpoints, data from the two patient groups treated with Hylenex formulations (treatment groups) were pooled in comparison to patients using standard CSII with rapid acting analog insulin alone (control group). That data is discussed above.
• Patients have been provided with individualized instructions to optimize glucose control, including optimization of insulin dosing (both amount and timing) based on an intensive blood glucose monitoring program. The challenges of dosing were a big point of discussion at yesterday’s FDA Advisory Committee for MannKind’s Afrezza, and we look forward to learning more details about what instructions Halozyme provided patients with.
• Patients in the intervention groups are using a simple infusion set connector/syringe to administer Hylenex at each infusion set change. The administration solution works with patients’ existing infusion sets, meaning no special sets will be required. The process for a pumper using Hylenex will work as follows:
  • Insert a single new infusion site and disconnect the tubing that connects it to the pump (this works for traditional pumps but not the OmniPod);
  • Draw up Hylenex into provided syringe;
  • Connect syringe full of Hylenex to small length of provided tubing and purge the air out of the tubing;
  • Connect provided tubing/syringe with Hylenex to infusion site (just inserted from step one above);
  • Manually inject Hylenex through infusion site using syringe;
  • Disconnect Hylenex tubing/syringe from infusion site and discard; and
  • Connect infusion site (which just had Hylenex bolused through it) to the insulin pump tubing.
• It will be highly instructive to see the CGM data from CONSISTENT 1. A subset of trial participants will wear blinded CGM for a couple weeks at the end of each treatment phase, and seeing the time in zone data for these patients will be very instructive. Halozyme has not specified which blinded CGM is being used, though we assume it is the Dexcom G4 Platinum. We are eager to see much more use of CGM in drug trials, which should be much easier once more connected systems come to market (e.g., Dexcom’s Gen 5, Medtronic’s Connected Care). Additionally, if patients come into the study as regular CGM users, they will continue using their own CGM; this data will then be compiled and incorporated into the final analysis. As we understand it, about 25% of trial participants were on CGM at study entry, suggesting that Halozyme will gather CGM data on more than 90 patients. One issue that may arise is different accuracy with different CGM systems; we assume in the “regular” CGM users, there will be patients on Medtronic’s 530G with Enlite, Revel with the Guardian or Enlite, and the Dexcom G4 Platinum.

--by Adam Brown and Kelly Close