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December 19, 2013 at 5:36 pm #21718
From Seeking Alpha (investor website):
Merck Vs. Bristol In PD-1 Cancer Drug Race
Dec 18 2013, 18:48 | 7 commentsby: Peter Geschek | about: MRK, BMY, includes: RHHBY Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article. (More…)
In November Merck (MRK) reported additional data about its lambrolizumab (previously known as MK-3475) trial, an experimental anti-PD-1 immunotherapy, conducted in 135 patients with advanced melanoma.
The results from Merck’s trial were almost identical to the results from the Bristol-Myers’ (BMY) trial which tested a combination of Yervoy and its experimental drug, nivolumab.
The objective response rate in the Merck trial across all doses was 38 percent, as evaluated by a blinded central review committee. Objective response rate includes all the patients who had either a complete or partial response.
In Bristol-Myers Squibb’ presentation at ASCO in May, its drug nivolumab, in combination with Yervoy, achieved an objective response rate of 40 percent among the 53 patients treated.
Merck’s lambrolizumab trial has also showed an estimated overall survival rate of 81 percent at one year across all dosing groups. This is the first time overall survival data have been reported from the Phase 1b clinical trial which is still ongoing.
Merck’s clinical trials
Merck is running a huge network of clinical trials to expand its immunotherapy effort.
Lambrolizumab has eight clinical trials running with a total enrollment of 3,000 patients across a broad range of cancer types, including bladder, colorectal, gastric, head and neck, melanoma, non-small cell lung, triple negative breast and hematological malignancies. Additional trials are also planned.
The expansion of the lambrolizumab clinical development program is based on preliminary evidence from Merck’s foundational Phase 1b trial which included 1,000 patients with late-stage metastatic carcinoma.
Lambrolizumab was intravenously applied at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients who had received prior treatment with Yervoy as well as those who had not.
The confirmed response rate as evaluated by an independent radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST) was 38 percent.
The highest confirmed response rate was observed in the group that received 10 mg per kilogram every 2 weeks.
Responses were durable in the majority of patients during a median follow-up of 11 months. 81 percent of the patients who had a response were still receiving treatment at the time of the analysis cut-off date in March 2013.
The overall median progression-free survival among the 135 patients was longer than 7 months.
The bottom line is that in patients with advanced melanoma, including those who had disease progression while receiving Yervoy, treatment with lambrolizumab resulted in a high rate of sustained tumor regression.
Bristol-Myers isn’t wasting any time extending the range of its own drug, nivolumab.
It has 6 late-stage studies underway, with FDA designated fast-track status in place for melanoma, lung cancer and kidney cancer. If the data continues to support the early results, Bristol-Myers will have a major new therapy in its portfolio.
The blockbuster Yervoy disables an immune system brake called CTLA-4, but it shrinks tumors in only about 10 percent of patients. Even though the effect in that small percentage of patients can be long-lasting and highly effective, that still leaves an urgent need for new drugs for patients with advanced melanoma.
Roche (OTCQX:RHHBY) targets PD-L1, which the company believes may be a safer approach. Early data from a small study showed that investigators could use the maximum dose safely, making this a strong candidate in mid-stage studies.
Roche’s compound is known as MPDL3280A, developed by its Genentech subsidiary. Overall, tumors in 29 patients, or 21 percent, responded to the drug in an early trial.
In the future it may be possible to test tumors for the presence of PD-L1, and use the drugs mainly for those patients, where it is expected to work more effectively.
Roche is also in a hurry, it recently rushed the drug into Phase 3.
Bristol’s nivolumab, and Merck’s lambrolizumab are antibodies that bind to PD-1, while Roche’s drug binds to PD-L1. It is not clear yet which approach is better.
The key is the interaction between the PD-1 (programmed death) protein and PD-L1 (programmed death ligand) protein that allows cancer cells to escape and multiply.
By giving a patient the correct antibody protein to block either the PD-1 or PD-L1 from interacting, the immune system will destroy the cancer cells.
For decades scientists have been trying to understand why the body’s immune system doesn’t see cancer cells as the enemy and attack them.
Recent discoveries found that tumors create a sort of cloak of invisibility from the immune system. The new class of drugs lifts the cloaking device and allows the immune system to attack.
“You’re setting up a fair fight” with the disease, said Nils Lonberg, a senior vice president at Bristol-Myers, in an interview. “The immune system is just as adaptable as the cancer.”
It is not clear yet how many types of tumors the drugs will work for. All the companies are targeting melanoma because there is evidence that it is sometimes controlled spontaneously by the immune system. The companies also have data for lung and kidney cancer. Roche’s study showed some effect in colorectal and head and neck cancer as well.
Some immunotherapy agents hold particular promise in being paired with drugs that specifically target genetic mutations driving the tumors. Since immunotherapy agents are treating the immune system, and not the cancer itself, this sort of approach should work against different kinds of cancer.
Even companies that don’t have any PD-1 or PD-L1 drugs in their pipeline, like Pfizer, are interested studying them in combination with their own targeted cancer drugs.
For PD-1 and PD-L1, the most important interaction is at the tumor site as opposed to the broader impact across the immune system, which is what Yervoy does by targeting CTLA-4.
In the third quarter Merck’s pharmaceutical sales declined 4 percent to $9.5 billion.
Sales of Singulair, Maxalt, Temodar and Cozaar declined following loss of market exclusivity. The losses were partially offset by growth in Remicade, Gardasil vaccine, Simponi and Isentress.
Singulair, a once-daily oral medicine for the chronic treatment of asthma and the relief of symptoms of allergic rhinitis, declined 53 percent in sales to $280 million in the third quarter. The patents for Singulair expired in the U.S. in 2012 and in major European markets in early 2013. A rapid fall in sales followed the patent expiry.
Combined sales of Remicade and Simponi, treatments for inflammatory diseases, increased 22 percent to $700 million in the third quarter.
Global sales of the combined diabetes franchise of Januvia and Janumet decreased 1 percent to $1.4 billion.
Sales of Zetia and Vytorin (a combination of Zetia and Zocor), medicines for lowering LDL cholesterol, decreased 1 percent to $1.1 billion in the third quarter. The decrease reflects lower sales of Vytorin, partially offset by growth of Zetia in the U.S.
Merck’s sales of Gardasil, a vaccine to help prevent diseases caused by four types of human papillomavirus, were $665 million, an increase of 15 percent for the quarter. The increase was driven by continued strong uptake of its use in males in the U.S., and higher public sector sales of $60 million.
The company’s gross margin declined to 62.8 percent in the third quarter of 2013 from 64.0 percent for the third quarter of 2012, reflecting primarily the impact of patent expiries.
Merck has lowered its non-GAAP earnings forecast to a range of $3.48 – $3.52 per share.
The company has increased its quarterly dividend to $0.44, up $0.01 from $0.43 per share paid last quarter. Payment will be made on January 8, 2014, to stockholders of record on December 16, 2013.
Over the past few years Merck has gained a reputation of having a hugely expensive research program coupled with a growing roster of setbacks in the clinic.
There is an air of urgency and excitement around lambrolizumab, which is demonstrated by the sheer size of the clinical trials, unprecedented for the company. Merck badly needs a winner from its pipeline and lambrolizumab has a clear promise to become one.December 20, 2013 at 12:37 pm #63252Catherine PooleKeymaster
My opinion is neither is moving fast enough. The author is incorrect in his numbers, Merck’s PD1 was updated in November as having a 41% response rate up from 38%. The beauty of these drugs is the lack of side effects, but there is the 60% who don’t respond and again we will look to combinations to raise these numbers overall. Thanks for posting Mat, realizing of course that the profit incentive moves these drugs as a motivator overall.December 20, 2013 at 2:19 pm #63253 My takeaway from the article is that I’m now more hopeful for FDA approval in 2014. I think our community is fortunate that there is competition here. Some additional takeaways from other recent articles (not posted):
1. MRK formed an internal cross-discliplinary team in October to expedite FDA approval. Would’ve been nice for them not to wait 6 mos. after they received their “breakthrough” designation, but at least it is in place now. This sort of news also puts pressure on BMS.
2. MRK is partnering with GSK for a trial combining PD-1 with a GSK drug (not Tafinlar or Mekinist) for a clinical trial for another type of cancer. This is a huge risk prior to FDA approval. Further evidence in my mind that MRK thinks approval is forthcoming in the near term.December 20, 2013 at 3:16 pm #63254LesliParticipant
Thanks to you both for this information. 2 questions:
1) Can we predict the roadmap and timeline of such approval(s), when competition is a factor?
2) Much like some insurance companies have done for the GSK combo, and have agreed to cover both drugs in anticipation of FDA approval that they be combined, what are the chances they might do the same for Yervoy and a PD-1 drug?
Thanks in advance, LeslieDecember 20, 2013 at 5:45 pm #63255
Lesli, I don’t know the answers to your questions, but I’ll speculate that for business reasons, BMS will go for approval for Nivo to be used in combination with ipi. Why orphan your existing blockbuster (ipi)?December 20, 2013 at 9:25 pm #63256Catherine PooleKeymaster Mat is probably correct, it may also speed it along for approval, putting it in tandem with a previously approved drug. But I certainly can’t make a guess to how long this will take. I think Merck might win the race only because they had an amazing number of trials running and accruing due to the cross-over. But I just want one of them to get there fast and would love to see expanded use too!January 1, 2014 at 7:57 am #63257lak1Participant MERK UK told me that they only have supply of the drug for existing trials( didnt expect so many survivors so needed more than anticipated- cant get more supply on market till 2016 I have no idea whether this is true its just why they told me they were closing new admissions to trials world wide.
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