November 18, 2016
The Medicines Company (MDCO) — Inclisiran — ORION Interim Look Confirms Best-In-Class Profile With True Blockbuster Potential
MDCO presented the details of the ORION-1 Phase II trial interim results of 501 patients given MDCO-PCSK-9si at a Late-Breaker Session at the AHA.
I. Impressive Efficacy On Par With MAbs. The depth, durability and consistency of response with Inclisarin appear to offer the best profile and widest therapeutic index of the PCSK9 class.
1. 3-Month 51% Reduction in LDL With One Injection — The pre-planned analysis was a look at the reduction of LDL levels at 90 days plus safety and tolerability. On an apples-to-apples comparison compared to the existing PCSK9-blockers on the market, MDCO-PCSK9si – now called Inclisiran – on a single injection – reduced LDL-C by a nadir mean of 51% out to 90 days. This is on par with both AMGN’s Repatha (57% QW2, 53% QW4) and REGN/SNY’s Praluent (-47%-53% QW2). The major difference is simple: Inclisiran achieved this reduction — on top of statins — with ONE INJECTION compared with SIX for the others. From what we understand, the consensus was looking for anything in the 50%+ range for efficacy to competitive and that was achieved with strong statistical significance (p<0.0001) at all doses in the trial.
2. 6-Month 57% Reduction With Two Injections — With a second injection given at 3 months, patients treated with Inclisiran subsequently experienced a 57% reduction in LDL for patients on the 300 mg dose. Hence, the second dose gave an extra LDL reduction boost that makes it on par with Repatha in comparable studies. The nadir of the single injection patients reached 60% at day 60, and at 180 day (6 months) the reduction was approximately 45%. On the second dose, the nadir touched 59% and settled at 57%. Most cardiologists surveyed believe that the 45% would be an acceptable level at 180-days but other might want the extra 10-15% with the second dose. When exploring dosage options down the road, based upon this data patients may get a single dose to start and another “booster” dose at 90 days. Then afterwards need only a bi-annual shot every six months.
II. Durable & Consistent LDL Reduction Out To Six Months, Correlates With >30% Reduction In Outcomes
1. At The 300 mg Dose, Inclisiran Resulted In A 65 mg/dL Mean Absolute Reduction With 2 Injections At 180 Days — As the go-forward Phase III dose, not only is the absolute reduction very impressive, the consistency is something that creates further differentiation. The median reduction is 64 mg/dL. In comparison, the Repatha trials achieved a strong 73 mg/dL absolute decrease in LDL, however the median decrease in LDL mg/dL was 48 mg/dL, suggesting a wide variability of response. With a fixed dose of the MAbs, and the variability of baseline PCSK9 plasma levels, compared to the ability to turn off LDL production via the synthesis inhibitor, it makes sense that the MDCO/ALNY drug would lead to a more consistent response across all patients regardless of baseline PCSK9 levels. 65 mg/dL mean AND 64 mg/dL median reductions appear to be more consistent and perhaps reliable efficacy than Repatha at this stage. The bar chart from ORION below shows this beautifully.
2. 2-3 or 12-24 & A Lot Less Drug — When administering Inclisiran, patients will need only 2 or 3 injections per year. From what we can tell by the Phase I data published earlier this week in the New England Journal of Medicine and now the Phase II data from ORION, the first year may be 3 shots, and then 2 annually after that. In addition, the lower overall dose (300 mg 2 or 3 times per year or 600-900mg total volume vs. 140 mg 24x per year or 3,360 mg) will expose patients to a significantly lower amount of drug over time. While the mechanisms of action regarding the long-term safety of the “si†versus the “MAbs†will be determined over time, we now have safety data for repeated dosing of Inclisiran and the side effect profile looks rather benign.
III. Safety — At Least As Safe As MAbs — The attention to safety of the MDCO compound has been magnified ever since partner ALNY terminated Phase III trials of its lead compound in October. MDCO has since reviewed the 501 patients in the ORION trial, declaring its clean safety profile. The details released this morning wholly concur with its assessment.
1. Injection Site Reactions Same Or Less — The rate of roughly 3-4% of ISRs in the ORION trial is on par with published results of Repatha (4%) and Praluent (5-6%). We understand that, since the ALNY issues, MDCO included one of the most thoughtful definitions and stringent assessments of “injection site reaction†that has been used by investigators in these studies. (We are unsure of the definition of ISR used by the others.)
Most important, all ISRs observed after >4 hours in the 300 mg dose group were resolved by the next injection and we understand skin adverse events after the second injection in those who got one, we are also infrequent. This is reassuring in the light of the recently abandoned PFE PCSK-9 antibody. As a result, we believe that this aspect of safety — whether standalone or compared with the drugs in the class — continue to display inclisiran’s clean and possibly cleaner profile.
2. Liver and Muscles Are Clean, Too. The table below shows that the incidence of elevated liver enzymes above the upper limit of normal were minimal, with only one patient out of 370 with an ALT>3x ULN (the same patient is in the table counted twice with an AST > 3 ULN). Importantly, this patient was given an increase in statin dose just before entering the study, The investigator indicated the event was statin related, and furthermore, the enzymes went back to normal once the statin was discontinued. Moreover, even including this patient, the overall incidence was between 1-2%, well in line with the MAbs (see table above) and lower (0-1%) excluding that one patient.
As for the myalgia rate of 5-7%, it is similar to those reported rates with both placebo (5%) and Repatha (6%) and consistent with the incidence of the study population of patients taking high-dose statins.
3. Well Tolerated and No Increase Over Placebo or Dose Dependency of TEAEs —The most common side effects seen in the study were quite mild (see table below). Treatment emergent adverse events >2% included myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhea and dizziness. Again, the overall rate of TEAEs was the same as placebo (54% each) and are not unexpected in a moderate-to-high cardiovascular risk group (including elderly, obese and diabetic patients). Importantly, there were no dose-related TEAEs among the four groups, either. There was one death in the entire 501 person trial —an elderly male with a long history of heart disease who had a massive MI about 100 days after receiving his first dose of inclisiran. Investigators confirmed that his death was not considered related to study drug.
Conclusion: ORION Results — Maximizing The Life Saving Value of Inclisiran
The >60mg/dL durable and consistent reduction in LDL seen in the 300 mg dose group of inclisiran can be correlated with a >30% reduction in cardiovascular outcomes using contemporary estimates. Based up on the longer-term data of the PCSK-9 antibodies, both of which are expected to report Phase III CVOT data by 2017 (AMGN in Q1:17 and REGN/SNY may have a positive look this month), in our view, the ORION data will make inclisiran the standard of care in this approaching blockbuster class. One cannot forget the value proposition of this compound — it can be priced at ~1/3 the list price of the antibodies and still generate pharmaceutical margins. Insurers will appreciate it, too, especially compared with the MAbs. Taking a ‘cholesterol shot’ maybe twice a year in the doctors office only adds to drug’s appeal.
With these pristine and highly competitive results, the Company will be deciding quickly its path going forward. They already know the dose and a Phase III study design is likely to happen fast. They have enough cash (>$600 million at the end of 3Q and other assets to gain sizable non-dilutive funds reported) to go it alone, but may look overseas for funding/infrastructure help. After ORION, in our view, potential partners will be clamoring to get some piece, if not all, of this asset. There is no doubt the takeover potential of MDCO will rise, too, especially in the current post-Trump win biotech rally that is on fire primarily due to the expectation of the repatriation of overseas cash for acquisitions. Now that the data are out – clearly confirming inclisiran’s best-in-class profile, to us, this makes MDCO a must-own biotech stock.
MDCO is a BUY under 50 with a TARGET PRICE of 75.